AU2013204899A1

AU2013204899A1 - Purine derivatives useful as hsp90 inhibitors

Info

Publication number: AU2013204899A1
Application number: AU2013204899A
Authority: AU
Inventors: Gabriela Chiosis; Weilin Sun; Tony Taldone
Original assignee: Sloan Kettering Institute for Cancer Research
Current assignee: Memorial Sloan Kettering Cancer Center
Priority date: 2009-10-07
Filing date: 2013-04-12
Publication date: 2013-05-16
Anticipated expiration: 2030-10-07
Also published as: AU2013204882B2; AU2013204109B2; AU2013204891B2; AU2013204899B2; AU2013204882A1; AU2013204891A1; AU2013204109A1

Abstract

The present application provides substituted purine derivatives and related compounds of the formulae shown. These compounds are useful as inhibitors of HSP90, and hence in the treatment of related diseases. NH2 X NH2 X2 X4 e Xc XC R Xb R Xb-Xd - -Y x~Z 2 XN, 5 R OR1 Z1-Z3, Xa-Xc X2, X4, Y and R are as defined in the specification.

Description

P/00/001 Regulation 3.2 AUSTRALIA Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Invention title: PURINE DERIVATIVES USEFUL AS HSP90 INHIBITORS The following statement is a full description of this invention, including the best method of performing it known to us: la PURINE DERIVATIVES USEFUL AS HSP90 INHIBITORS Statement of Related Cases This application is a divisional of Australian patent application no. 2010303343, the entire disclosure of which is incorporated herein by reference. Background of the Invention This application relates to compounds that inhibit heat shock protein 90 (Hsp90). The Hsp90 family of proteins has four recognized members in mammalian cells: Hsp90 a and P, Grp94 and Trap-1. Hsp90 a and P exist in the cytosol and the nucleus in association with a number of other proteins. Hsp90 in its various forms is the most abundant cellular chaperone, and has been shown in experimental systems to be required for ATP- dependent refolding of denatured or "unfolded" proteins. It has therefore been proposed to function as part of the cellular defense against stress. When cells are exposed to heat or other environmental stresses, the aggregation of unfolded proteins is prevented by pathways that catalyze their refolding or degradation. This process depends on the association of the unfolded protein in an ordered fashion with multiple chaperones (Hsp 60, 90 and 70 and p23), forming a "refoldosome" and ultimately the ATP-dependent release of the chaperones from the refolded protein. Hsp90 may also play a role in maintaining the stability and function of mutated proteins. It seems to be required for expression of mutated p53 and v-src to a much greater extent than for their wild-type counterparts. It has been suggested that this occurs as a result of Hsp90-mediated suppression of the phenotypes of mutations that lead to protein unfolding. Hsp90 is also necessary to the conformational maturation of several key proteins involved in the growth response of the cell to extracellular factors. These include the steroid receptors as well as certain transmembrane kinases (i.e., Raf serine kinase, v-src and Her2). The mechanism whereby Hsp90 affects these proteins is not fully understood, but appears to be similar to its role in protein refolding. In the case of the progesterone receptor, it has been shown that binding and release of Hsp90 from the receptor occurs in a cyclic fashion in concert with release of other chaperones and immunophilins and is required for high affinity WO 2011/044394 PCT/US2010/051872 2 binding of the steroid to the receptor. Thus, Hsp90 could function as a physiologic regulator of signaling pathways, even in the absence of stress. Hsp90 has been shown to be overexpressed in multiple tumor types and as a function of oncogenic transformation. Whether it plays a necessary role in maintaining transformation is unknown, but it could have at least three functions in this regard. Cancer cells grow in an environment of hypoxia, low pH and low nutrient concentration. They also rapidly adapt to or are selected to become resistant to radiation and cytotoxic chemotherapeutic agents. Thus, the general role of Hsp90 in maintaining the stability of proteins under stress may be necessary for cell viability under these conditions. Secondly, cancer cells harbor mutated oncogenic proteins. Some of these are gain-of-function mutations which are necessary for the transformed phenotype. Hsp9O may be required for maintaining the folded, functionally active conformation of these proteins. Thirdly, activation of signaling pathways mediated by steroid receptors, Raf and other Hsp 9 0 targets is necessary for the growth and survival of many tumors which thus probably also require functional Hsp90. Hsp90 has been recognized as a viable target for therapeutic agents. Hsp90 family members possess a unique pocket in their N-terminal region that is specific to and conserved among all Hsp90s from bacteria to mammals, but which is not present in other molecular chaperones. The endogenous ligand for this pocket is not known, but it binds ATP and ADP with low affinity and has weak ATPase activity. The ansamycin antibiotics geldanamycin (GM) and herbimycin (HA) have been shown to bind to this conserved pocket, and this binding affinity has been shown for all members of the Hsp90 family. International Patent Publication No. W098/51702 discloses the use of ansamycin antibiotics coupled to a targeting moiety to provide targeted delivery of the ansamycin leading to the degradation of proteins in and death of the targeted cells. International Patent Publication No. WOOO/61578 relates to bifunctional molecules having two moieties which interact with the chaperone protein Hsp90, including in particular homo- and heterodimers of ansamycin antibiotics. These bifunctional molecules act to promote degradation and/or inhibition of HER-family tyrosine kinases and are effective for treatment of cancers which overexpress Her-kinases. Exemplary small molecule therapeutics that bind to the same binding pocket of Hsp90 as ATP and the ansamycin antibiotics are disclosed in PCT Publication Nos. W002/36075, W02006/084030, W009/042646 and W009/065035, and US Patent WO 2011/044394 PCT/US2010/051872 3 Publications 2005/0113339, 2005/0004026, 2005/0049263, 2005/0256183, 2005/0119292, 2005/0113340, 2005/0107343, 2008/0096903, 2008/0234297, 2008/0234314 and 2008/0253965, all of which are incorporated herein by reference. Many of these compounds are based on a scaffold of the type disclosed by Chiosis et al in PCT Publication No. W002/36075, with variations in substituents. In some cases, the compositions can be described by one of the following two general formulas:

NH

2 NH 2 Z- - z)'a Z -c -Xa ;A Z2 N \/ Z2 t X yX cY XXc R Xb (lA) or R Xb-Xd (1B) wherein Z1, Z2, Z3 are selected from C and N in which numerous options are disclosed for each variable substituent, resulting in an astronomical number of combinations and permutations. In other cases, the compositions can be described by a structural formula in which Xa, Xb, Xc and Xd are not connected to one another but are simply substituents on the benzene ring. These structures have the general formula:

NH

2 x2 Xd N x 4 z 2 R Xc Xb (IC) wherein Zl, Z2, Z3 are selected from C and N. While these compounds are generally active as inhibitors of Hsp90, the level of activity is extremely variable with measured values for

EC

50 and IC 50 being reported in both micromolar and nanomolar ranges.

WO 2011/044394 PCT/US2010/051872 4 Summary of the Invention The present application provides compounds useful in the inhibition of Hsp90, and hence in the treatment of disease. Brief Description of the Figures Fig. I shows examples of unsubstituted aryl groups, including some heterocyclic aryl groups. Fig. 2 shows examples of unsubstituted heterocyclic groups. Fig. 3 shows average tumor volume in mice treated with compound 1B-1 -HC or with vehicle. Detailed Descintion of the Invention The present invention provides compounds within the scope of Formula IA, 1B or IC with particular combinations of substituents that are effective to inhibit Hsp90. Inhibitors of Hsp90 are recognized as effective in treatments of cancer, and also can be used in the treatment of neurodegenerative diseases as described in PCT Patent Publication W02008/005397. WO 2007/14360 discloses the use of Hsp90 inhibitors in treatment of neurofibromatosis Thus, the compounds of the invention can be used in therapeutic methods in the same manner as used other known Hsp90 inhibitors, by administering a therapeutically effective amount of a compound of the invention to an individual, including a human, in need of treatment for cancer, neurodegenerative disease or other condition for which Hsp90 inhibition is relevant. As used in this application, the term "treatment" refers to delaying the onset of symptoms, reducing the severity or delaying the symptomatic progression of cancer, neurodegenerative disease or other condition in the individual. A cure of the disease is not required to fall within the scope of treatment. Further, it will be appreciated that the specific results of these treatment goals will vary from individual to individual, and that some individuals may obtain greater or lesser benefits than the statistical average for a representative population. Thus, treatment refers to administration of composition to an individual in need, with the expectation that they will obtain a therapeutic benefit.

WO 2011/044394 PCT/US2010/051872 5 The term "administering" refers to the act of introducing into the individual the therapeutic compound. In general, any route of administration can be used. Thus, administration by oral, intrathecal, intravenous, intramuscular or parenteral injection is appropriate depending on the nature of the condition to be treated. Administration may also be done to the brain by inhalation because there is a compartment at the upper side of the nose that connects with the brain without having the BBB capillaries. Compounds that cross the blood brain barrier are preferred for this mode of administration, although this characteristic is not strictly required. The term "therapeutically effective amount" encompasses both the amount of the compound administered and the schedule of administration that on a statistical basis obtains the result of preventing, reducing the severity or delaying the progression of the disease in the individual. As will be appreciated, preferred amounts will vary from compound to compound in order to balance toxicity/tolerance with therapeutic efficacy and the mode of administration. Determination of maximum tolerated dose and of the treatment regime in terms of number and frequency of dosing is a routine part of early clinical evaluation of a compound. In all of the compounds of the present invention, the compound may be as depicted, or as a pharmaceutically acceptable salt or ester thereof. In naming options for X 2 , X 4 and R, the name refers to the type of group that is directly attached to the central structure, which group may include additional functionality. Thus, "alky' group refers to a linear, cyclic or branched saturated hydrocarbon, for example a hydrocarbon having from 1 to 10 carbon atoms, in which the atom directly attached to the central structure is a carbon atom. Such an alkyl group may include substituents other than hydrogen, for example an oxygen-containing group including without limitation hydroxyl and alkoxy; a halogen group; a nitrogen-containing group including without limitation amino, amido and alkylamino; an aryl group; a sulfur-containing group including without limitation thioalkyl; and/or a non-aromatic cyclic group including heterocycles and carbocycles. Carbon atoms in these substituents may increase the total number of carbon atoms in the alkyl group to above 10 without departing from the invention. All references to alkyl groups in the specification and claims hereof encompass both substituted and unsubstituted alkyl groups unless the context is clearly to the contrary.

WO 2011/044394 PCT/US2010/051872 6 "Alkenyl" group refers to a linear, cyclic or branched hydrocarbon, for example a hydrocarbon having from I to 10 carbon atoms, and at least one double bond, in which the atom directly attached to the central structure is a carbon atom. The alkenyl group may include any of the substituents mentioned above for an alkyl group. All references to alkenyl groups in the specification and claims hereof encompass both substituted and unsubstituted alkenyl groups unless the context is clearly to the contrary. "Alkynyt' group refers to a linear, cyclic or branched hydrocarbon, for example a hydrocarbon having from 1 to 10 carbon atoms, and at least one triple bond, in which the atom directly attached to the central structure is a carbon atom. The alkynyl group may include any of the substituents mentioned above for an alkyl group. All references to alkynyl groups in the specification and claims hereof encompass both substituted and unsubstituted alkynyl groups unless the context is clearly to the contrary. "Aryl" group refers to any group derived from a simple aromatic ring. Aryl group includes heteroaryl.(See Fig. 1) Aryl groups may be substituted or unsubstituted. When X2,

X

4 and R is identified as an aryl group, an atom of the aryl ring is bound directly to an atom of the central structure. An aryloxy substituent is an aryl group connected to the central structure through an oxygen atom. The aryl group may include any of the substituents mentioned above for an alkyl group, and in addition an aryl group may include an alkyl, alkenyl or alkynyl group. All references to aryl groups in the specification and claims hereof encompass both substituted and unsubstituted aryl groups unless the context is clearly to the contrary. "Amino" group refers to any group which consists of a nitrogen attached by single bonds to carbon or hydrogen atoms. In certain instances, the nitrogen of the amino group is directly bound to the central structure. In other instances, an amino group may be a subtituent on or within a group, with the nitrogen of the amino group being attached to the central structure through one or more intervening atoms. Examples of amino groups include NH12, alkylamino, alkenylamino groups and N-containing non-aromatic heterocyclic moiety (i.e., cyclic amines). Amino groups may be substituted or unsubstituted. All references to amino groups in the specification and claims hereof encompass substituted and unsubstituted amino groups unless the context is clearly to the contrary. "Halogen " group refers to fluorine, chlorine, bromine or iodine.

WO 2011/044394 PCT/US2010/051872 7 "Heterocyclic" group refers to a moiety containing at least one atom of carbon, and at least one atom of an element other than carbon, such as sulfur, oxygen or nitrogen within a ring structure. These heterocyclic groups may be either aromatic rings or saturated and unsaturated non-aromatic rings. Some examples are given in Fig. 2. Heterocylic groups may be substituted or unsubstituted. All references to heterocyclic groups in the specification and claims encompass substituted and unsubstituted heterocyclic groups unless the context is clearly to the contrary. In the compounds of the invention, all of the atoms have sufficient hydrogen or non hydrogen substituents to satisfy valence, or the compound includes a pharmaceutically acceptable counterion, for example in the case of a quaternary amine. In the structures set forth below examples are provided in which all of Zl, Z2 and Z3 are nitrogen. These examples are intended as exemplary, and are not intended to exclude options in which one or more of Zl, Z2 and Z3 is carbon. In particular, corresponding compositions in which Z2 or Z3 is carbon are considered to be within the scope of this disclosure. A. Structures of formula 1A in which Xa or Xb is 0 In accordance with a first embodiment of the invention, the compounds have general formula 1A, in which one of Xa or Xb is 0, and Xc and the other of Xa and Xb is CH 2 Thus, the compounds of this embodiment may be represented by the general formula

NH

2 NNN \/ Xa XI> R (2) wherein: one of Xa and Xb is 0 and the other is -CH2-; Y is -CH 2 - or -S-,

X

4 is hydrogen or halogen; and WO 2011/044394 PCT/US2010/051872 8

X

2 and R are in combinations as discussed below. A-. In some embodiments of the invention, X 2 is halogen. In these embodiments, R is suitably a primary aminoalkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl, with the proviso that R is not a piperidino moiety. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropy amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino)-propyl, 3 (cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2 (methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl, and 3-(lH-imidazoyl) propyl. Specific examples of compounds in accordance with this embodiment of the invention are listed in Tables 1A and lB (Compounds 1A-1 to 1A-4, IA-6, IA-I1, 1A-18 to 1A-28, 1A-30, 1A-31, IA-49, 1B-1 to 1B-5, 1B-18, IB-23 to 1B-25, IB-29 to 1B-32, 1B-34,1B-35, 1B-37, 1B-49, 1B-52 1B-56 and1B-57). As shown, in preferred embodiments of formula (2), X 4 is H, chlorine or fluorine. In a particular preferred embodiment of formula (2), Y is S, X 4 is H, X 2 is I. In a particular preferred embodiment of formula (2), Y is CH2, X 4 is Cl, X2 is I. In a particular preferred embodiment of formula (2), Y is CH 2 , X4 is F, X2 is I. In a particular preferred embodiment of formula (2), Y is S, X 4 is F, X 2 is I. Tests were mun on compounds in accordance with the first embodiment of the invention, and the EC50 for Hsp90 binding in JNPL3 brain cell lysate and SKBr3 cell lysate was assessed. The results are summarized in Table 2A. While all of the compounds had desirable low EC 50 values, both compounds tested in which Xb is 0 were superior to the related compound in which Xa is 0. In addition, compound 1B-1 was superior to an otherwise identical compound in which both Xa and Xb are 0 (PU-HZ150 disclosed in US WO 2011/044394 PCT/US2010/051872 9 12/307,063) which has an EC 50 of 12-14.4 nM and compound 1B-2 was superior to an otherwise identical molecule in which both Xa and Xb are 0 (PU-H71 disclosed in US 11/814,506) which has an EC5 0 of 30.8-54 nM in the same experimental system. Animal Studies. Four- to 6-week-old nu/nu athymic female mice were obtained from Taconic Farms. Experiments were carried out under an Institutional Animal Care and Use Committee approved protocol, and institutional guidelines for the proper and humane use of animals in research were followed. Before administration, a solution of I B-1-HCI was formulated in PBS (pH 7.4). All mice received Augmentin (amoxicillin/clavulanate potassium; SmithKline Beecham) in their drinking water while on therapy. Mice were killed by CO 2 euthanasia. Mice bearing MDA-MB-468 tumors (n=5) reaching a volume of 100-150 mm 3 were treated i.p. (i.p.) using 1B-1-HCl at 50 mg/kg 3 x week or vehicle. Tumor volume was determined by measurement with Vernier calipers, and tumor volume was calculated as the product of its length x width 2 xO.4. Tumor volume was expressed on indicated days as the median tumor volume ± SD indicated for groups of mice. The average tumor volumes are summarized in Fig. 3. As shown, in the 35 days of the experiment the average tumor volume in the control mice increased by about a factor of 3X, while the tumor size in the mice treated with 1B-1-HC1 decreased. Table 2B shows measured values for EC 50 in JNPL3 brain cell lysates for compounds 1B-3, 1B-4 and 1B-25 in accordance with this embodiment of the invention which incorporates a fluorine as X4 and in which Y is -CH 2 -. Desirably low values of ECso were observed. In addition, Table 2B shows measured values for EC 50 in JNPL3 brain cell lysates for compound 1B-24 in accordance with this embodiment of the invention which incorporates a hydrogen as X 4 and in which Y is S. Desirably low values of ECso were observed. A-II. In some embodiments of the invention, X 2 is an aryl group. In these embodiments, R may be any of the groups disclosed as a substituent at the 9-position nitrogen in this application, or in the various patents and patent applications cited herein. Table 8 provides a summary of the R groups from these patents and applications.

WO 2011/044394 PCT/US2010/051872 10 In some embodiments within this group, R includes a heteroatom, such as nitrogen, oxygen or sulfur. In some embodiments, the heteroatom is nitrogen. In some of these embodiments, R is a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2 (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl, and 3-(1 H-imidazoyl) propyl. In embodiments of formula (2) within this group, R has the formula: site of 9N-attachnrent xNR, N, R1 where R, is selected from COH, COMe, COEt, COnPr, COiPr, SO 2 Me, CH 2 OX where X can be H or oxygen, nitrogen, sulphur or halogen containing alkyl of linear, branched or cyclic nature. In embodiments of the invention within this group, R has the formula site of 9N-attachment H H i

X-(CH

2

-N-(CH

2 )- N-S- NH 2 0 0 X-(CH2)-O-S-NH 2 0 where m-- 2-S andn=- 1-6.

WO 2011/044394 PCT/US2010/051872 11 In embodiments within this group, R has the formula site of 9N-attachurnt H 0 X-(CH29-N-(CH2)w HN-OH where m= 2-3 and n= 1-6. In specific embodiments, X 2 is an aromatic heterocycle. In specific embodiments, X 2 is a furan, thiophene, pyrazole, imidazole, pyrrole, oxazole or thiazole. In specific embodiments, X2 is a firan, thiophene, pyrazole, imidazole, oxazole or thiazole. In particular embodiments of formula (2), Y is S, X4 is H, X 2 is 2-, 3-furan or 5 methyl-2-furanyl. In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X 2 is 2-, 3- furan or 5 methyl-2-furanyl. In particular embodiments of formula (2), Y is CH 2 , X 4 is F, X 2 is 2-, 3-firan or 5 methyl-2-furanyl. In particular embodiments of formula (2), Y is S, X 4 is F, X 2 is 2-, 3-furan or 5 methyl-2-furanyl. In particular embodiments of formula (2), Y is 5, X 4 is H, X 2 is 2- or 3-thiophene. In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X 2 is 2- or 3- thiophene. In particular embodiments of formula (2), Y is CH 2 , X 4 is F, X 2 is 2- or 3-thiophene. In particular embodiments of formula (2), Y is S, X 4 is F, X 2 is 2- or 3-thiophene. In particular embodiments of formula (2), Y is S, X4 is H, X 2 is 2- or 3-pyrazole. In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X 2 is 2- or 3- pyrazole. In particular embodiments of formula (2), Y is CH 2 , X 4 is F, X 2 is 2- or 3-pyrazole. In particular embodiments of formula (2), Y is S, X 4 is F, X 2 is 2- or 3-pyrazole. In particular embodiments of formula (2), Y is S, X 4 is H, X 2 is 2-thiazolyl, 5-methyl 2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl.

WO 2011/044394 PCT/US2010/051872 12 In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X 2 is 2-thiazolyl, 5 methyl-2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl.. In particular embodiments of formula (2), Y is CH 2 , X 4 is F, X 2 2-thiazolyl, 5-methyl 2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is S, X 4 is F, X 2 is 2-thiazolyl, 5-methyl 2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is S, X 4 is H, X2 is 2-thiazolyl, 5-methyl 2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X 2 is 2-thiazolyl, 5 methyl-2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is CH 2 , X4 is F, X 2 is 2-thiazolyl, 5 methyl-2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is S, X4 is F, X 2 is 2-thiazolyl, 5-methyl 2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In these particular embodiments, R may be any one of the types of groups described above. Specific examples of compounds in accordance with this embodiment of the invention are listed in Tables 1A and lB (Compounds IA-5, lA-7, IA-12, 1A-13, lA-15 to lA-17, IA 36, 1A-37, IA-42, IA-45 to 1A-48, IA-50 to IA-52, IB-6, IB-8, I B-12, IB-14, lB-15, 1B 17, IB-26, lB-27, IB-33, 1B-42 to 1B-44, 1B-46, lB-50, 1B-51, 1B-53 to 1B-55). As shown, in preferred embodiments of formula (2) in which X 2 is an aryl group, X4 is H, chlorine or fluorine. Table 2C shows measured values for EC 50 in JNPL3 brain cell lysates for compounds 1 B-26 and 1 B-27 in accordance with this embodiment of the invention which incorporates a hydrogen as X4 and in which Y is S. Desirably low values of EC5o were observed. A-I. In some embodiments of the invention, X2 is an alkynyl group. In these embodiments, R may be any of the groups disclosed as a substituent at the 9-position nitrogen in this application, or in the various patents and patent applications cited herein. See Table 8. In some embodiments within this group, R includes a heteroatom, such as nitrogen, oxygen or sulfur.

WO 2011/044394 PCT/US2010/051872 13 In some embodiments, the heteroatom is nitrogen. In some of these embodiments, R is a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl . Specific R groups include without limitation 2-(methyl, t butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2 (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2 -(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl, and 3-(1IH-imidazoyl) propyl. In embodiments of formula (2) within this group, R has the formula: site of 9N-attachnent N'R1NR where R 1 is selected from COH, COMe, COEt, COnPr, COiPr, SO 2 Me, CH 2 OX where X can be H or oxygen, nitrogen, sulphur or halogen containing alkyl of linear, branched or cyclic nature. In embodiments of the invention within this group, R has the formula site of 9N-attachment H H 1 X-(CH2)r,-N-(CH2)n-N-S- NH2 0 0

X-(CH

2 )n-O-S-NH 2 0 where m= 2-3 and n= 1-6. In embodiments within this group, R has the formula WO 2011/044394 PCT/US2010/051872 14 site of 9N-attachnent H 0 X-(CH2-N-(CH2)n HN-OH where m= 2-3 and n= 1-6. In specific embodiments, X 2 is acetylene. In particular embodiments of formula (2), Y is S, X4 is H, X 2 is acetylene. In particular embodiments of formula (2), Y is CH 2 , X4 is Cl, X2 is acetylene. In particular embodiments of formula (2), Y is CH 2 , X4 is F, X 2 is acetylene. In particular embodiments of formula (2), Y is S, X4 is F, X 2 is acetylene. In these particular embodiments, R may be any one of the types of groups described above. Specific examples of compounds in accordance with this embodiment of the invention are listed in Tables IA and lB (Compounds 1A-8, IA-14, IA-29, 1A-32 to 1A-35, lB-10, 1B-13, 1B-16, 1B-19, IB-28, 1B-36, 1B-38 to 1B-41, 1B-45 1B-47 and 1B-58). As shown, in preferred embodiments of formula (2) in which X2 is an alkynyl group, X4 is H, chlorine or fluorine. Table 2D shows a measured value for EC 50 in JNPL3 brain cell lysates for compound 1B-28 in accordance with this embodiment of the invention which incorporates a hydrogen as X4 and in which Y is S. A desirably low value of EC 50 was observed. A-fIV. In some embodiments of the invention, X2 is a cyano group. In these embodiments, R is suitably a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl , and with the proviso that R is not a piperidino moiety. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, WO 2011/044394 PCT/US2010/051872 15 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl, and 3-(lH-imidazoyl) propyl. In a particular preferred embodiment of formula (2), Y is S, X 4 is H, X 2 is CN. In a particular preferred embodiment of formula (2), Y is CH 2 , X4 is Cl, X 2 is CN. In a particular preferred embodiment of formula (2), Y is CH 2 , X4 is F, X 2 is CN. In a particular preferred embodiment of formula (2), Y is S, X 4 is F, X 2 is CN. Specific examples of compounds in accordance with this embodiment of the invention are listed in Table IA and 1B (Compounds 1A-9, 1B-11 and 1B-20). A-V. In some embodiments of the invention, X 2 is an amino group. In these embodiments, R may be any of the groups disclosed as a substituent at the 9-position nitrogen in this application, or in the various patents and patent applications cited herein. See Table 8. In some embodiments within this group, R includes a heteroatom, such as nitrogen, oxygen or sulfur. In some embodiments, the heteroatom is nitrogen. In some of these embodiments, R is a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl . Specific R groups include without limitation 2-(methyl, t butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2 (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl, and 3-(1H-imidazoyl) propyl. In embodiments of formula (2) within this group, R has the formula: WO 2011/044394 PCT/US2010/051872 16 site of 9N-atachnrent R1 where R 1 is selected from COH, COMe, COEt, COnPr, COiPr, SO 2 Me, CH 2 OX where X can be H or oxygen, nitrogen, sulphur or halogen containing alkyl of linear, branched or cyclic nature. In embodiments of the invention within this group, R has the formula site of 9N-attachrent H H 0 X--(CH2)m -N-(CH2)n-N-S-NH2 00 X-(CH2)n-O-S-NH2 0 where m= 2-3 and n= 1-6. In embodiments within this group, R has the formula site of 9N-attachrment H 0 X-(CH2)m-N-(CH2)n H O HN-OH. where m= 2-3 and n= 1-6. In a particular preferred embodiment of formula (2), Y is S, X 4 is H, X2 is dimethylamino In a particular preferred embodiment of formula (2), Y is CH 2 , X 4 is Cl, X 2 is dimethylamino In a particular preferred embodiment of formula (2), Y is CH 2 , X 4 is F, X2 is dimethylamnno. In a particular preferred embodiment of formula (2), Y is S, X 4 is F, X 2 is dimethylamino.

WO 2011/044394 PCT/US2010/051872 17 In a particular preferred embodiment of formula (2), Y is S, X 4 is H, X 2 is aziridino. In a particular preferred embodiment of formula (2), Y is CH 2 , X 4 is Cl, X 2 is a3iridino. In a particular preferred embodiment of formula (2), Y is CH 2 , X 4 is F, X 2 is aziridino. In a particular preferred embodiment of formula (2), Y is S, X 4 is F, X 2 is aziridino. Specific examples of compounds in accordance with this embodiment of the invention are listed in Tables IA and lB (Compounds lA-10, 1A-38 to 1A-41, 1A-43, IA-44, 1B-7, 1B-21 and 1B-48). A-VI. In some embodiments of the invention, X 2 is a cycloalkyl or a cycloalkenyl. In these embodiments, R may be any of the groups disclosed as a substituent at the 9-position nitrogen in this application, or in the various patents and patent applications cited herein. See Table 8. In some embodiments within this group, R includes a heteroatom, such as nitrogen, oxygen or sulfur. In some embodiments, the heteroatom is nitrogen, In some of these embodiments, R is a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2 (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl, and 3-(1H-imidazoyl) propyl. In embodiments of formula (2) within this group, R has the formula: WO 2011/044394 PCT/US2010/051872 18 site of 9N-aftachment x, x N R1 where R, is selected from COH, COMe, COEt, COnPr, COiPr, SO 2 Me, CH 2 OX where X can be H or oxygen, nitrogen, sulphur or halogen containing alkyl of linear, branched or cyclic nature. In embodiments of the invention within this group, R has the formula site of 9N-attachment H H 0 X-(CH2z-N-(CH 2

)-N-S-NH

2 0 0 X-(CH2)n-O-S-NH 2 0 where n= 2-3 and n= 1-6. In embodiments within this group, R has the formula site of 9N-attachnent H 0 X-(CH29-rN-(CH2)n HN-OH where m= 2-3 and n= 1-6. In specific embodiments, X 2 is a cycloalkyl with one ring. In specific embodiments, X 2 is a cyclopropane, a cyclobutane or a cyclopentane. In particular embodiments of formula (2), Y is S, X4 is H, X 2 is cyclopentyl. In particular embodiments of formula (2), Y is CH 2 , X 4 is F, X 2 is cyclopentyl. In particular embodiments of formula (2), Y is CH2, X 4 is Cl, X 2 is cyclopentyl. In particular embodiments of formula (2), Y is S, X 4 is F, X 2 is cyclopentyl. In these particular embodiments, R may be any one of the types of groups described above.

WO 2011/044394 PCT/US2010/051872 19 Specific examples of compounds in accordance with this embodiment of the invention are listed in Table lB (Compounds 1B-9, and 1 B-22) although the embodiment is not limited to the option in which Xb is 0, and includes compounds in which Xa is 0. B. Structures of formula 1A in which Xa or Xb is S In accordance with a second embodiment of the invention, the compounds have general formula IA, in which one of Xa or Xb is S, and Xc and the other of Xa and Xb is CH, Thus, the compounds of this embodiment may be represented by the general formula

NH

2 NN N \Xa Xb R (2) wherein: one of Xa and Xb is S and the other is -CH 2 -; Y is -CH 2 - or -S-, X4 is hydrogen or halogen; and X2 and R are as discussed below. In these embodiments, R may be any of the groups disclosed as a substituent at the 9-position nitrogen in this application, or in the various patents and patent applications cited herein. See Table 8. In some embodiments within this group, R includes a heteroatom, such as nitrogen, oxygen or sulfur. In some embodiments, the heteroatom is nitrogen. In some of these embodiments, R is a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a WO 2011/044394 PCT/US2010/051872 20 nonaromatic heterocycle-alkyl. In some of these embodiments, R is a primary, secondary or tertiary alkyl-amino-alkyl, alkyl-aryl, or an alkyl-nonaromatic heterocycle. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl,. 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2 (hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3 (hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2-(cyclopropylmethyl amino) ethyl, 2 (methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl, and 3-(IH-imidazoyl) propyl. In embodiments of formula (2) within this group, R has the formula: site of 9N-attachment X " 'N , R 1 N, ,R 1 where R, is selected from COH, COMe, COEt, COnPr, COi~r, SO 2 Me, CH2OX where X can be H or oxygen, nitrogen, sulphur or halogen containing alkyl of linear, branched or cyclic nature. In embodiments of the invention within this group, R has the formula site of 9N-attachment 0 -H H " x-(CH-N-(CHnN-SNH 2 0

X-(CH

2 )n-0-S-NH 2 0 where m 2-3 and n= 1-6. In embodiments within this group, R has the formula WO 2011/044394 PCT/US2010/051872 21 site of 9N-attachnent H0 X-(CF O-N(CH2)n HN-OH where m= 2-3 and n= 1-6. In embodiments of formula (2) in which Xa or Xb is S, X 2 may be any group shown to be attached to the same position as X 2 in any of the compounds disclosed herein or in the various patents and patent applications cited above. Specifically, X 2 may be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, saturated or unsaturated heterocycle, aryl, halogen, aryloxy, alkoxy, halogenated alkoxy, alkenyloxy, hydroxyalkyl, amino, alkylamino, dialkylamino, acylamino, carbaryl, amido, dialkylamido, alkylamido, alkylsulfonamido, sulfonamido, tribalocarbon, -thioalkyl, S0 2 -alkyl, -COO-alkyl,- COalkyl, OH, NO 2 , CN or alkyl-CN, or part of a ring formed by R; In particular embodiments of the invention, X 2 is halogen, and R is an (alkylamino) alkyl or (dialkylamino) alkyl. In particular embodiments, X 2 is halogen and R is 2-(methyl, t-butyl- amino) ethyl, 2 (methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2 (ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2 (isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino) propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl, or 3-(hydroxyethyl, isopropyl amino) propyl. In some embodiments of the invention, X 2 is an aryl group. In particular embodiments, X 2 is aryl and R is 2-(methyl, t-butyl- amino) ethyl, 2 (methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2 (ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2 (isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino) propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl, or 3-(hydroxyethyl, isopropyl amino) propyl.

WO 2011/044394 PCT/US2010/051872 22 In some embodiments of the invention, X 2 is a heteroaryl group. In some embodiments, X 2 is a heteroaryl group and R is 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl, or 3-(hydroxyethyl, isopropyl amino) propyl. In particular embodiments, X 2 is 2- or 3-furan and R is 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl, or 3-(hydroxyethyl, isopropyl amino) propyl. In particular embodiments, X 2 is 2- or 3-thiophene and R is 2-(methyl, t-butyl amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl, or 3-(hydroxyethyl, isopropyl amino) propyl. In particular embodiments, X 2 is 3-pyrazolyl and R is 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, WO 2011/044394 PCT/US2010/051872 23 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl, or 3-(hydroxyethyl, isopropyl amino) propyl. In some embodiments of the invention, X 2 is an alkynyl group. In some embodiments of the invention, X2 is an alkynyl group, and R is 2-(methyl, t butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2 (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl, or 3-(hydroxyethyl, isopropyl amino) propyl. In particular embodiments of the invention, X 2 is acetylene, and R is 2-(methyl, t butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2 (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl, or 3-(hydroxyethyl, isopropyl amino) propyl. In some embodiments of the invention, X 2 is CN. In particular embodiments of the invention, X 2 is CN, and R is 2-(methyl, t-butyl amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylainno)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl, or 3-(hydroxyethyl, isopropyl amino) propyl. In some embodiments of the invention, X 2 is an amine. In some embodiments of the invention, X 2 is an amine, and R is 2-(methyl, t-butyl amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl- WO 2011/044394 PCTUS2010/051872 24 amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3- (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl, or 3-(hydroxyethyl, isopropyl amino) propyl. In particular embodiments of the invention, X 2 is dimethyl amine, azetidino or aziridino, and R is 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3 (neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3 (isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2 (hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N morpholino) propyl, or 3-(hydroxyethyl, isopropyl amino) propyl. Specific examples of compounds in accordance with this embodiment ofthe invention are listed in Tables IC and ID. C. Structures of formula 1A in which Xa. Xb and Xc are all carbon In accordance with a third embodiment of the invention, the compounds have general formula 1A; in which Xa, Xb and Xc are all carbon, connected by two single or one single bond and one double bond, and wherein Y is -CH 2 - or -S-;

X

4 is hydrogen or halogen; and

X

2 and R are in combinations as discussed below. C-1. In some embodiments of the invention in which Xa, Xb and Xc are all carbon,

X

2 is halogen. In some embodiments within this group, R includes a heteroatom, such as nitrogen, oxygen or sulfur with the proviso that R does not include a piperidino moiety.

WO 2011/044394 PCT/US2010/051872 25 In some embodiments, R is suitably an optionally substituted primary alkyl-amino, an optionally substituted secondary or tertiary alkyl-amino-alkyl, alkyl-aryl, or an alkyl nonaromatic heterocycle, with the proviso that R is not a piperidino moiety. In soffie embodiments, the heteroatom is nitrogen. In some of these embodiments, R is a primary, secondary or tertiary alkyl-amino-alkyl, alkyl-aryl, or an alkyl-nonaromatic heterocycle, with the proviso that R does not include a piperidino moiety. Specific R groups include without limitation 2 -(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2 (hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3 (hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2-(cyclopropylmethyl amino) ethyl, 2 (methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl, and 3-(1H-imidazoyl) propyl. In embodiments of the invention within this group, R has the formula site of 9N-attachment H H90

X-(CH

2 )mN-(CH 2 )n-N--NH 2 *0 0

X-(CH

2

),-O-S-NH

2 0 where m= 2-3 and n= 1-6. In embodiments within this group, R has the formula site of 9N-attachnent H 0 X-(CFXn-N-(CH 2 )n

HN-OH

WO 2011/044394 PCT/US2010/051872 26 where m= 2-3 and n= 1-6. Specific examples of compounds in accordance with this embodiment of the invention are listed in Tables 1E (Compounds 1E-1 to 1E-4, 1E-6, 1E-18, IE-21, 1E-23 to lE-26, 1E 35, 1E-38, lE-39, IE-42 to IE-48, IE-68 to IE-76). As shown, in preferred embodiments of formula (2), X 4 is H, chlorine or fluorine. In a particular preferred embodiment of formula (2), Y is S, X 4 is H, X 2 is I. In a particular preferred embodiment of formula (2), Y is CH 2 , X 4 is Cl, X 2 is I. In a particular preferred embodiment of formula (2), Y is CH 2 , X 4 is F, X 2 is I. In a particular preferred embodiment of formula (2), Y is S, X 4 is F, X 2 is I. Table 2E shows measured values for EC 50 in JNPL3 brain and SKBr3 cell lysates for compounds IE-2, IE21 and lE-23 in accordance with this embodiment of the invention which incorporates a hydrogen as X 4 and in which Y is S. Desirably low values of EC5o were observed. C-H. In some embodiments of the invention, X 2 is an aryl group. In these embodiments, R may be any of the groups disclosed as a substituent at the 9-position nitrogen in this application, or in the various patents and patent applications cited herein. See Table 8. In some embodiments within this group, R includes a heteroatom, such as nitrogen, oxygen or sulfur. In some embodiments, the heteroatom is nitrogen. In some of these embodiments, R is a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2 (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylnethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2- WO 2011/044394 PCT/US2010/051872 27 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl, and 3-(IH-imidazoyl) propyl. In embodiments of formula (2) within this group, R has the formula: site of 9N-attachmntt XN N,, R1 where R, is selected from COH, COMe, COEt, COnPr, COizr, SO 2 Me, CH20X where X can be H or oxygen, nitrogen, sulphur or halogen containing alkyl of linear, branched or cyclic nature. In embodiments of the invention within this group, R has the formula site of 9N-attachment H H 0 X-(CH2)mrN-(CH2)n-N-S-NH 2 0 0 X-(CH2)n-O-S-NH 2 0 where m= 2-3 and n= 1-6. In embodiments within this group, R has the formula site of 9N-attachrnt H X-(CHy-N-(CH2)n HN-OH where m= 2-3 and n= 1-6. In specific embodiments, X 2 is an aromatic heterocycle. In specific embodiments, X 2 is a furan, thiophene, pyrazole, imidazole, pyrrole, oxazole and thiazole. In specific embodiments of the X 2 is a furan, thiophene, pyrazole, oxazole and thiazole or imidazole.

WO 2011/044394 PCT/US2010/051872 28 In specific embodiments, X 2 is an aromatic heterocycle. In specific embodiments, X 2 is a furan, thiophene, pyrazole, imidazole, pyrrole, oxazole or thiazole. In specific embodiments, X 2 is a furn, thiophene, pyrazole, imidazole, oxazole or thiazole. In particular embodiments of formula (2), Y is S, X 4 is H, X 2 is 2-, 3-firan or 5 methyl-2-fluranyl. In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X 2 is 2-, 3- furan or 5 methyl-2-flranyl. In particular embodiments of formula (2), Y is CH 2 , X 4 is F, X 2 is 2-, 3-furan or 5 methyl-2-furanyl. In particular embodiments of formula (2), Y is S, X 4 is F, X 2 is 2-, 3-furan or 5 methyl-2-fLranyl. In particular embodiments of formula (2), Y is S, X 4 is H, X 2 is 2- or 3-thiophene. In particular embodiments of formula (2), Y is CH 2 , X4 is Cl, X 2 is 2- or 3- thiophene. In particular embodiments of formula (2), Y is CH 2 , X4 is F, X2 is 2- or 3-thiophene. In particular embodiments of formula (2), Y is S, X4 is F, X 2 is 2- or 3-thiophene. In particular embodiments of formula (2), Y is S, X4 is H, X2 is 2- or 3-pyrazole. In particular embodiments of formula (2), Y is CH 2 , X4 is Cl, X 2 is 2- or 3- pyrazole. In particular embodiments of formula (2), Y is CH 2 , X 4 is F, X 2 is 2- or 3-pyrazole. In particular embodiments of formula (2), Y is S, X4 is F, X2 is 2- or 3-pyrazole. In particular embodiments of formula (2), Y is S, X4 is H, X2 is 2-thiazolyl, 5-methyl 2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is CH 2 , X4 is Cl, X2 is 2-thiazolyl, 5 methyl-2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is CH 2 , X4 is F, X2 2-thiazolyl, 5-methyl 2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is S, X4 is F, X2 is 2-thiazolyl, 5-methyl 2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is S, X4 is H, X2 is 2-thiazolyl, 5-methyl 2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl.

WO 2011/044394 PCT/US2010/051872 29 In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X 2 is 2-thiazolyl, 5 methyl-2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is CH 2 , X 4 is F, X 2 is 2-thiazoly1, 5 methyl-2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is S, X 4 is F, X 2 is 2-thiazolyl, 5-methyl 2-thiazolyl, .2-oxazolyl or 5-methyl-2-oxazolyl. In these particular embodiments, R may be any one of the types of groups described above. Specific examples of compounds in accordance with this embodiment of the invention are listed in Tables iE (Compounds 1E-5, lE-7, IE-I1 to lE-13, IE-15 to lE-17, lE-27, iE 29 to lE-33, 1E-36, lE-37, 1E-41, IE-59 to lE-76, lE-84 and lE-85). As shown, in preferred embodiments of formula (2) in which X 2 is an aryl group, X 4 is H, chlorine or fluorine. C-IH. In some embodiments of the invention, X 2 is an alkynyl group. In these embodiments, R may be as described above in Section CII, In specific embodiments, X 2 is acetylene. In particular embodiments of formula (2), Y is S, X 4 is H, X 2 is acetylene. In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X 2 is acetylene. In particular embodiments of formula (2), Y is CH 2 , X 4 is F, X 2 is acetylene. In particular embodiments of formula (2), Y is S, X 4 is F, X 2 is acetylene. In these particular embodiments, R may be any one of the types of groups described above. Specific examples of compounds in accordance with this embodiment of the invention are listed in Tables 1E (Compounds 1E-8, 1E-14, 1E-19. 1E-20, 1E-22, 1E-40, IE-49 to 1E 58 and 1E-77 to 1E-82). As shown, in preferred embodiments of formula (2) in which X 2 is an alkynyl group, X 4 is H, chlorine or fluorine. Table 2F shows a measured value for EC 50 in JNPL3 brain cell lysates for compound 1E-22 in accordance with this embodiment of the invention which incorporates a hydrogen as X4 and in which Y is S. A desirably low value of EC 50 was observed.

WO 2011/044394 PCT/US2010/051872 30 C-IV. In some embodiments of the invention, X 2 is a cyano group. In these embodiments, R may be as described above in Section C-II, with the proviso that R does not include a piperidino moiety. In a particular preferred embodiment of formula (2), Y is S, X 4 is H, X 2 is CN. In a particular preferred embodiment of formula (2), Y is CH 2 , X 4 is Cl, X 2 is CN. In a particular preferred embodiment of formula (2), Y is CH 2 , X 4 is F, X 2 is CN. In a particular preferred embodiment of formula (2), Y is S, X 4 is F, X 2 is CN. In these particular embodiments, R may be any one of the types of groups described above. A specific example of a compound in accordance with this embodiment of the invention is listed in Table lE (Compound IE-9). C-V. In some embodiments of the invention, X 2 is an amino group. In these particular embodiments, R may be any one of the types of groups described in Section C-IL. In a particular preferred embodiment of formula (2), Y is S, X 4 is H, X 2 is azetidino. In a particular preferred embodiment of formula (2), Y is CH2, X 4 is Cl, X 2 is azetidino. In a particular preferred embodiment of formula (2), Y is CH 2 , X4 is F, X 2 is azetidino. In a particular preferred embodiment of formula (2), Y is S, X4 is F, X2 is azetidino. Specific examples of compounds in accordance with this embodiment of the invention are listed in Table 1E (Compound 1E-10, 1E-28 and IE-34). C-VI. In some embodiments of the invention, X 2 is a cycloalkyl or a cycloalkenyl. In these particular embodiments, R may be any one of the types of groups described in Section C-II. In specific embodiments, X 2 is a cycloalkyl with one ring. in specific embodiments, X 2 is a cyclopropane, cyclobutane or cyclopentane. In particular embodiments of formula (2), Y is S, X 4 is H, X 2 is cyclopentyl. In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X2 is cyclopentyl. In particular embodiments of formula (2), Y is CH2, X 4 is F, X 2 is cyclopentyl. In particular embodiments of formula (2), Y is S, X4 is F, X 2 is cyclopentyl.

WO 2011/044394 PCT/US2010/051872 31 In these particular embodiments, R may be any one of the types of groups described above. D. Structures of formula 1A in which Xa or Xb is N In accordance with a fourth embodiment of the invention, the compounds have general formula 1A, in which one of Xa or Xb is N, and Xc and the other of Xa and Xb are

CH

2 . The N may be unsubstituted (i.e. NH) or substituted, for example with methyl, ethyl, acetyl. Thus, the compounds of this embodiment may be represented by the general formula

NH

2 X2 N N X(KN X, N Xa Xb R (2) wherein: one of Xa and Xb is N bonded to H or a substituent, and the other is -CH 2 -; Y is -CH 2 - or -S-,

X

4 is hydrogen or halogen; and

X

2 and R are as discussed below. In these embodiments, R may be any of the groups disclosed as a substituent at the 9 position nitrogen herein or in the various patents and applications cited above. See Table 8. In some embodiments, R includes a nitrogen heteroatom. In fTrther embodiments, R is any of the options discussed above in Section B.

X

2 may be any group shown to be attached to the same position in any of the compounds disclosed in the various patents and patent applications cited above, or as described above in Section B. In particular embodiments of the invention, X 2 is halogen, and R is an amino alkyl, an alkylaminoalkyl, dialkylaminoalkyl, or trialkylammonioalkyl group, in which each alkyl portion may be linear, cyclic or branched, or an alkyl heterocycle, where the alkyl may be WO 2011/044394 PCT/US2010/051872 32 L4 bound to a nitrogen in the heterocyclic group. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3 (ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3 (allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2-(cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, and 3-(lH-imidazoyl) propyl. In some embodiments of the invention, X 2 is an aryl group. In particular embodiments, X2 is aryl and R is 2-(methyl, t-butyl- amino) ethyl, 2 (methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2 (ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2 (isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino) propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl or 3-(hydroxyethyl, isopropyl amino) propyl. In some embodiments of the invention, X 2 is a heteroaryl group. In some embodiments, X 2 is a heteroaryl group and R is 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl or 3-(hydroxyethyl, isopropyl amino) propyl. In particular embodiments, X 2 is 2- or 3-fiaran and R is 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2 -(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) WO 2011/044394 PCI/US2010/51872 33 L4 propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl or 3-(hydroxyethyl, isopropyl amino) propyl. In particular embodiments, X 2 is 2- or 3-thiophene and R is 2-(methyl, t-butyl amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl or 3-(hydroxyethyl, isopropyl amino) propyl. In particular embodiments, X 2 is 3-pyrazolyl and R is 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl, or 3-(hydroxyethyl, isopropyl amino) propyl. In some embodiments of the invention, X 2 is an alkynyl group. In some embodiments of the invention, X 2 is an alkynyl group, and R is 2-(methyl, t butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2 (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl or 3-(hydroxyethyl, isopropyl amino) propyl.

WO 2011/044394 PCT/US2010/051872 34 In particular embodiments of the invention, X 2 is acetylene, and R is 2-(methyl, t butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2 (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino) propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl or 3-(hydroxyethyl, isopropyl amino) propyl. In some embodiments of the invention, X 2 is CN. In particular embodiments of the invention, X 2 is CN, and R is 2-(methyl, t-butyl amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl or 3-(hydroxyethyl, isopropyl amino) propyl. In some embodiments of the invention, X 2 is an amine. In some embodiments of the invention, X 2 is an amine, and R is 2-(methyl, t-butyl amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino) propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl or 3-(hydroxyethyl, isopropyl amino) propyl. In particular embodiments of the invention, X 2 is dimethyl amine or aziridino, and R is 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-ainno) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3- WO 2011/044394 PCI/US2010/51872 35 (ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl or 3 (hydroxyethyl, isopropyl amino) propyl. Specific examples of compounds in accordance with this embodiment of the invention are listed in Tables IF and 1G. - E Structures of formula 1A in which Xa or Xb is carbonyl or thiocarbonyl In accordance with a fifth embodiment of the invention, the compounds have general formula IA, in which one of Xa or Xb is carbonyl (C=O) or thiocarbonyl (C=S), and Xc and the other of Xa and Xb is CH2. Thus, the compounds of this embodiment maybe represented by the general formula

NH

2 :_ CN N fY \/Xa N N -Xb R (2) wherein: one of Xa and Xb is C=O or C=S, and the other is -CH 2 -; Y is -CHi- or -S-,

X

4 is hydrogen or halogen; and

X

2 and R are as discussed below. In these embodiments, R may be any of the groups disclosed as a substituent at the 9-position nitrogen in this application, or in the various patents and patent applications cited herein (See Table 8), with the proviso that when X 2 is halogen or CN, R does not include a piperidino moiety. In some embodiments within this group, R includes a heteroatom, such as nitrogen, oxygen or sulfur. In some embodiments, the heteroatom is nitrogen. In these embodiments, R is suitably a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-aryl, or a WO 2011/044394 PCT/US2010/051872 36 nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2 (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino) propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl, and 3-(lH-imidazoyl) propyl. In embodiments of formula (2) within this group when X 2 is thiocarbonyl, R may have the formula: site of 9N-altachment xN N, R1 where R 1 is selected from COH, COMe, COEt, COnPr, COiPr, SO2Me, CH20X where X can be H or oxygen, nitrogen, sulphur or halogen containing alkyl of linear, branched or cyclic nature. In embodiments of the invention within this group, R has the formula site of 9N-attachment H H 0 X-(CH)m-N-(CH 2 )-N-- NH 2 0 0

X-(CH

2 )n-O-S-NH 2 0 where m= 2-3 and n= 1-6. In embodiments within this group, R has the formula WO 2011/044394 PCI/US2010/51872 37 site of 9N-attachnent H 0 X-(CF )r-N-(CH2)4 HN-OH where m= 2-3 and n= 1-6.

X

2 may be any substituent shown to be attached at the same position in any of the compounds disclosed in the various patents and patent applications cited above, or as described above in Section B. In particular embodiments of the invention, X 2 is halogen, and R is suitably a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(1H-imidazoyl) propyl. In some embodiments of the invention, X 2 is an aryl group. In particular embodiments, X 2 is aryl and R is suitably a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino)-propyl, 3 (cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2- WO 2011/044394 PCT/US2010/051872 38 (methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(IH-imidazoyl) propyl. In some embodiments of the invention, X 2 is a heteroaryl group. In some embodiments, X 2 is a heteroaryl group and R is suitably a primary amino alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle alkyl. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2 (methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2 (ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2 (isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino) propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(lH-imidazoyl) propyl. In particular embodiments, X 2 is 2- or 3-fian and R is suitably a primary amino alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle alkyl. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2 (methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2 (ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2 (isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino) propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(lH-imidazoyl) propyl.

WO 2011/044394 PCT/US2010/051872 39 In particular embodiments, X 2 is 2- or 3-thiophene and R is suitably a primary amino alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle alkyl. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2 (methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2 (ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2 (isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino) propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(1 H-imidazoyl) propyl. In particular embodiments, X 2 is 3-pyrazolyl and R is suitably a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino)-propyl, 3 (cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2 (methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylnethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(IH-imidazoyl) propyl. In some embodiments of the invention, X2 is an alkynyl group. In some embodiments of the invention, X 2 is an alkynyl group, and R is suitably a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2- WO 2011/044394 PCT/US2010/051872 40) (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3 -(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, and 3-(1H-imidazoyl) propyl. In particular embodiments of the invention, X 2 is acetylene, and R is suitably a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2 (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, and 3-(lH-imidazoyl) propyl. In some embodiments of the invention, X 2 is CN. In particular embodiments of the invention, X 2 is CN, and R is suitably a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl, with the proviso that R does not include a piperidino moiety. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl WO 2011/044394 PCT/US2010/051872 41 amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3 (hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2-(cyclopropylmethyl amino) ethyl, 2 (methyl, isobutyl amino) ethyl, and 3-(lH-imidazoyl) propyl. In some embodiments of the invention, X 2 is an amine. In some embodiments of the invention, X 2 is an amine, and R is suitably a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, and 3-(IH-imidazoyl) propyl. In particular embodiments of the invention, X 2 is dimethyl amine or aziridino, and R is suitably a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2 (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2- WO 2011/044394 PCT/US2010/051872 42 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, and 3-(lH-imidazoyl) propyl. Specific examples of compounds in accordance with this embodiment of the invention are listed in Tables 1IH and 11. F. Structures of formula 1A in which Xa, Xb and Xe include at least one non carbon atom and -Xa-Xc-Xb- includes a double bond In accordance with a sixth embodiment of the invention, the compounds have general formula 1A, with Xa, Xc, Xb and the bonds between them selected from a combination in the following table: Xa Bond Xc bond Xb C double C single 0 C double C single N C double C single S o single C double C N single C double C S single C double C N double C single 0 N double C single S N single C double N o single C double N S single C double N N double N single 0 WO 2011/044394 PCT/US2010/051872 43 4 N double N single S N double N single C 0 single N double N N single N double N S single N double N rC single N double N Y is -CH 2 - or -S-,

X

4 is hydrogen or halogen; and

X

2 and R are as discussed below. In these embodiments, R may be any of the groups disclosed as a substituent at the 9 position nitrogen herein or in the various patents and applications cited above. In some embodiments, R includes a nitrogen heteroatom. In further embodiments, R is any of the options discussed above in Section B.

X

2 may be any group shown to be attached at the same position in any of the compounds disclosed in the various patents and patent applications cited above, or as described above in B. In particular embodiments of the invention, X 2 is halogen, and R is an aminoalkyl (alkylamino) alkyl or (dialkylamino) alkyl. In particular embodiments, X 2 is halogen and R is suitably a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl, . Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino)-propyl, 3 (cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2- WO 2011/044394 PCT/US2010/051872 44 (methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylnethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(IH-imidazoyl) propyl. In some embodiments of the invention, X 2 is an aryl group. In particular embodiments, X 2 is aryl and R is suitably an amino alkyl, a secondary or tertiary alkyl-amino-alkyl, a trialkylammonicalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl, . Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylnethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(lH-imidazoyl) propyl. In some embodiments of the invention, X 2 is a heteroaryl group. In some embodiments, X 2 is a heteroaryl group and R is suitably an amino alkyl, a secondary or tertiary alkyl-amino-alkyl, a trialkylammonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2 (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2- WO 2011/044394 PCT/US2010/051872 45 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(1H-imidazoyl) propyl. In particular embodiments, X 2 is 2- or 3-furan and R is suitably an amino alkyl, a secondary or tertiary alkyl-amino-alkyl, a trialkylammonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3 (hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2-(cyclopropylmethyl amino) ethyl, 2 (methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(1H-imidazoyl) propyl. In particular embodiments, X2 is 2- or 3-thiophene and R is suitably an amino alkyl, a secondary or tertiary alkyl-amino-alkyl, a trialkylammonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2 (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylanino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylnethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(1 H-imidazoyl) propyl. In some embodiments of the invention, X 2 is an alkynyl group, and R is suitably an amino alkyl, a secondary or tertiary alkyl-amino-alkyl, a trialkylammonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation WO 2011/044394 PCT/US2010/051872 46 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3 (ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3 (allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2-(cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino)propyl and 3-(lH-imidazoyl)propyl. In particular embodiments of the invention, X 2 is acetylene, and R is suitably an amino alkyl, a secondary or tertiary alkyl-amino-alkyl, &trialkylammonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3 (ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3 (allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2-(cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(1H-imidazoyl) propyl. In some embodiments of the invention, X 2 is CN. In particular embodiments of the invention, X 2 is CN, and R is suitably an amino alkyl, a secondary or tertiary alkyl-amino-alkyl, a trialkylammonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2 (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3- WO 2011/044394 PCT/US2010/051872 47 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(lH-imidazoyl) propyl. In some embodiments of the invention, X 2 is an amine. In some embodiments of the invention, X 2 is an amine, and R is suitably an amino alkyl, a secondary or tertiary alkyl-amino-alkyl, a trialkylammonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2 (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(lIH-imidazoyl) propyl. In particular embodiments of the invention, X 2 is dimethyl amine or aziridino, and R is suitably an amino alkyl, a secondary or tertiary alkyl-amino-alkyl, a trialkylammonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-ainno) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3 (allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, WO 2011/044394 PCT/US2010/051872 48 cyclohexyl amino) propyl, 2-(cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(1H-imidazoyl) propyl. Specific examples of compounds in accordance with this embodiment of the invention are listed in Tables 3A-3F. G. Structures of formula 1A in which Xa and Xb are both 0 In accordance with a seventh embodiment of the invention, the compounds have general formula A, in which Xa and Xb are 0 and Xc is CH 2 . Thus, the compounds of this embodiment may be represented by the general formula

NH

2 X2 NN \/ Xa X4 N N - -Xb R (2) wherein: in which Xa and Xb are 0, Y is -CH 2 - or -S-, X4 is hydrogen or halogen; and

X

2 and R are in combinations as discussed below. G-I. In some embodiments of the invention, X 2 is an aryl group. In these embodiments, R may be any of the groups disclosed as a substituent at the. 9-position nitrogen in this application, or in the various patents and patent applications cited herein. See Table 8. In some embodiments within this group, R includes a heteroatom, such as nitrogen, oxygen or sulfur. In some embodiments, the heteroatom is nitrogen. In some of these embodiments, R is suitably a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t- WO 2011/044394 PCT/US2010/051872 49 butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2 (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl, and 3-(lH-imidazoyl) propyl. In embodiments of formula (2) within this group, R has the formula: site of 9N-attachment N.N X N 'R N , 'R 1 where RI is selected from COH, COMe, COEt, COnPr, COiPr, SO 2 Me, CH 2 OX where X can be H or oxygen, nitrogen, sulphur or halogen containing alkyl of linear, branched or cyclic nature. In embodiments of the invention within this group, R has the formula site of 9N-attachment H H 0

X-(CH

2 )mN-(CH 2 )n-N- -NH 2 0 0 X-(CH2)n-O-S-NH 2 0 where m= 2-3 and n= 1-6. In embodiments within this group, R has the formula site of 9N-attachment H 0 X-(CH2 r-N-(CH2)n

-HN-OH

WO 2011/044394 PCT/US2010/051872 50 where m= 2-3 and n= 1-6. In specific embodiments, X 2 is a heterocycle. In specific embodiments, X 2 is phenyl, furan, thiophene, pyrazole, imidazole, thiazole, oxazole or pyrrole. In specific embodiments of the X2 is phenyl, furan, methylfuran, thiophene, pyrazole, thiazole, oxazole or imidazole. In particular embodiments of formula (2), Y is S, X4 is H, X2 is 2-, 3-furan or 5 methyl-2-furanyl. In particular embodiments of formula (2), Y is CH 2 , X4 is Cl, X 2 is 2-, 3- furan or 5 methyl-2-furanyl. In particular embodiments of formula (2), Y is CH 2 , X4 is F, X 2 is 2-, 3-furan or 5 methyl-2-furanyl. In particular embodiments of formula (2), Y is S, X4 is F, X2 is 2-, 3-fiuran or 5 methyl-2-furanyl. In particular embodiments of formula (2), Y is S, X4 is H, X 2 is 2- or 3-thiophene. In particular embodiments of formula (2), Y is CH 2 , X4 is Cl, X 2 is 2- or 3- thiophene. In particular embodiments of formula (2), Y is CH 2 , X4 is F, X2 is 2- or 3-thiophene. In particular embodiments of formula (2), Y is S, X4 is F, X2 is 2- or 3-thiophene. In particular embodiments of formula (2), Y is S, X4 is H, X 2 is 2- or 3-pyrazole. In particular embodiments of formula (2), Y is CH2, X4 is Cl, X2 is 2- or 3- pyrazole. In particular embodiments of formula (2), Y is CH 2 , X4 is F, X 2 is 2- or 3-pyrazole. In particular embodiments of formula (2), Y is S, X4 is F, X 2 is 2- or 3-pyrazole. In particular embodiments of formula (2), Y is S, X4 is H, X 2 is 2-thiazolyl, 5-methyl 2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is CH 2 , X4 is Cl, X 2 is 2-thiazolyl, 5 methyl-2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is CH 2 , X4 is F, X2 is 2-thiazolyl, 5 methyl-2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is S, X 4 is F, X2 is 2-thiazolyl, 5-methyl 2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl.

WO 2011/044394 PCT/US2010/051872 51 L4 In particular embodiments of formula (2), Y is S, X 4 is H, X 2 is optionally substituted phenyl. In particular embodiments of fonnula (2), Y is CH 2 , X 4 is Cl, X 2 is optionally substituted phenyl. In particular embodiments of formula (2), Y is CH 2 , X 4 is F, X 2 is optionally substituted phenyl. In particular embodiments of formula (2), Y is S, X4 is F, X 2 is optionally substituted phenyl. In particular embodiments of formula (2), Y is S, X 4 is H, X 2 is optionally substituted pyridine. In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X 2 is optionally substituted pyridine. In particular embodiments of formula (2), Y is CH 2 , X 4 is F, X 2 is optionally substituted pyridine. In particular embodiments of formula (2), Y is S, X 4 is F, X 2 is optionally substituted pyridine, In particular embodiments of formula (2), Y is S, X 4 is H, X 2 is optionally substituted isooxazole. In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X 2 is optionally substituted isooxazole. In particular embodiments of formula (2), Y is CH 2 , X 4 is F, X 2 is optionally substituted isooxazole. In particular embodiments of formula (2), Y is S, X 4 is F, X 2 is optionally substituted isooxazole. In particular embodiments of formula (2), Y is S, X 4 is H, X 2 is optionally substituted imidazole. In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X 2 is optionally substituted imidazole. In particular embodiments of formula (2), Y is CH 2 , X 4 is F, X 2 is optionally substituted imidazole.

WO 2011/044394 PCT/US2010/051872 52 In particular embodiments of formula (2), Y is S, X4 is F, X 2 is optionally substituted imidazole. In these particular embodiments, R may be any one of the types of groups described above. Specific examples of compounds in accordance with this embodiment of the invention are listed in Tables 4A, 4C, 4D, 4F, 4G and 4H. As shown, in preferred embodiments of formula (2) in which X2 is an aryl group, X 4 is H, chlorine or fluorine. Table 2G shows measured values for EC50 in JNPL3 brain cell lysates and in SKBr3 cell lysate for compounds 4A-1 to 4A-8, 4C1 to 4C-11, 4C14, 4C-16, 4C-38 to 4C-41, 4D-1 to 4D-3, 4D-16, 4D-17, 4F-1, 4G-i to 4G-7, 4G-9, 4H-1 to 41-7 in accordance with this embodiment of the invention which incorporates a hydrogen as X 4 and in which Y is S or a fluorine as X 4 and in which Y is -CH 2 -. Desirably low values of EC 50 were observed for several examples. G-H1. In some embodiments of the invention, X 2 is an alkynyl group. In these embodiments, R may be any of the groups disclosed as a substituent at the 9-position nitrogen in this application, or in the various patents and patent applications cited herein. See Table 8. In some embodiments, when X 2 is alkynyl, R includes a nitrogen heteroatom. In a further embodiment, when X 2 is alkenyl, R is suitably an amino alkyl, a secondary or tertiary alkyl-amino-alkyl, a trialkylammonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2 (methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2 (ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2 (isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino) propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2- WO 2011/044394 PCT/US2010/051872 53 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(1H-imidazoyl) propyl. In embodiments of formula (2) when X 2 is alkynyl, R has the formula: site of 9N-attachurnt FR1 where R 1 is selected from COH, COMe, COEt, COnPr, COitr, SO 2 Me, CH2OX where X can be H or oxygen, nitrogen, sulphur or halogen containing alkyl of linear, branched or cyclic nature. In embodiments of the invention when X 2 is alkynyl, R has the formula site of 9N-attachment H H 0 X-(CH2)m-N-(CH2)n-N-S-NH2 0 00

X-(CH

2 )gO-S-NH 2 0 where m= 2-3 and n= 1-6. In embodiments when X 2 is alkynyl, R has the formula site of 9N-attachnrnt H 0 X-(ClHgy,-N-(CH-2)n HN-OH where m- 2-3 and n= 1-6. In specific embodiments, X 2 is acetylene. In particular embodiments of formula (2), Y is S, X 4 is H, X 2 is acetylene. In particular embodiments of formula (2), Y is CH 2 , X4 is Cl, X 2 is acetylene. In particular embodiments of formula (2), Y is CH 2 , X4 is F, .X 2 is acetylene. In particular embodiments of formula (2), Y is S, X 4 is F, X2 is acetylene.

WO 2011/044394 PCT/US2010/051872 54 In these particular embodiments, R may be any one of the types of groups described above. Specific examples of compounds in accordance with this embodiment of the invention are listed in Tables 4B. As shown, in preferred embodiments of formula (2) in which X 2 is an alkynyl group, X 4 is H, chlorine or fluorine. Table 2H shows measured values for EC5o in JNPL3 brain cell lysates and in SKBr3 cell lysate for compounds 4B-1 to 4B-4, 4B13 and 4B-14 in accordance with this embodiment of the invention which incorporates a hydrogen as X 4 and in which Y is S, or a fluorine as X4 and in which Y is -CHr 2 -. Desirably low values of EC 5 o were observed. G-IR. In some embodiments of the invention, X 2 is a cyano or cyanoalkyl group. In these embodiments, R is suitably an amino alkyl, a secondary or tertiary alkyl-amino-alkyl, a trialkylammonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino) propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3 (hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2-(cyclopropylmethyl amino) ethyl, 2 (methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(1H-imidazoyl) propyl. In a particular preferred embodiment of formula (2), Y is S, X4 is H, X 2 is CN. In a particular preferred embodiment of formula (2), Y is CH 2 , X4 is Cl, X2 is CN. In a particular preferred embodiment of formula (2), Y is CH 2 , X4 is F, X2 is CN. In a particular preferred embodiment of formula (2), Y is S, X4 is F, X2 is CN.

WO 2011/044394 PCT/US2010/051872 55 In other embodiments in which X 2 is cyano or cyanoalkyl group, R is site of 9N-attachment H H 0

X-(CH

2 )-N-(C)nN-NH 2 0 0 X-(CH2)n-O-S-NH 2 0 where m= 2-3 and n= 1-6, or site of 9N-attachrent H 0 x-(CH~y-N-(CH2)n HN-OH where m= 2-3 and n= 1-6. A specific example of a compound in accordance with this embodiment of the invention is listed in Table 4E. Table 21 shows measured values for EC 50 in JNPL3 brain cell lysates and in SKBr3 cell lysate for compounds (4E-1 to 4E-4) in accordance with this embodiment of the invention which incorporates a hydrogen as X 4 and in which Y is S or a fluorine as X 4 and in which Y is -CH 2 -. Desirably low values of EC 50 were observed for several examples. G-IV. In some embodiments of the invention, X 2 is a cycloalkyl (saturated carbocyclic) or cycloalkenyl. In these embodiments, R maybe any of the groups disclosed as a substituent at the 9-position nitrogen in this application, or in the various patents and patent applications cited herein. (See Table 8) In some embodiments within this group, R includes a nitrogen heteroatom. In a further embodiment within this group, R is suitably an amino alkyl, a secondary or tertiary alkyl-amino-alkyl, a trialkylammonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3- WO 2011/044394 PCT/US2010/051872 56 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylnethyl amino) ethyl; 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(lH-imidazoyl) propyl. In embodiments of formula (2) within this group, R has the formula: sie of 9N-attachment NR1 where R, is selected from COH, COMe, COEt, COnPr, COiPr, SO 2 Me, CH 2 OX where X can be H or oxygen, nitrogen, sulphur or halogen containing alkyl of linear, branched or cyclic nature. In embodiments of the invention within this group, R has the formula site of 9N-attachment H H 9

X-(CH

2 )m-N-(CH 2 )n-N-S-NH 2 0 0

X-(CH

2 )n-O-S-NH 2 0 where m= 2-3 and n= 1-6. In embodiments when X 2 is aryl, R has the formula site of 9N-attachuent H 0 X-(CFt),-N-(CH2)n HN-OH where m= 2-3 and n= 1-6. In specific embodiments, X 2 is a cycloalkyl with one ring.

WO 2011/044394 PCT/US2010/051872 57 In specific embodiments, X 2 is a cyclopropane, cyclobutane or cyclopentane. In particular embodiments of formula (2), Y is S, X4 is H, X 2 is cyclopentyl. In particular embodiments of formula (2), Y is CH 2 , X 4 is F, X 2 is cyclopentyl. In particular embodiments of formula (2), Y is S, X 4 is F, X 2 is cyclopentyl. In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X 2 is cyclopentyl. In these particular embodiments, R may be any one of the types of groups described above. Specific examples of compounds of this type are shown in Table 41. Table 2J shows measured values for EC 50 in JNPL3 brain cell lysates and in SKBr3 cell lysate for compound 41-12 in accordance with this embodiment of the invention which incorporates a hydrogen as X4 and in which Y is S. Desirably low values of EC 50 were observed for several examples. Table 2G shows results for EC 50 measured in SKBr3 breast cancer cells and JNPL3 brain cell lysates for compounds listed in Table 4A. As shown, compounds of this type are generally more active with respect to brain cancer cells. As shown, the greatest activity was observed for compound 4A-1, in which there is no substituent on the X 2 phenyl group, and the least activity is seen for compounds 4A-3 and 4A-4 in which electron withdrawing CF 3 substituents are at the meta positions. An embodiment of the invention therefore has the structure (2) shown above, in which Y is S, X 4 is hydrogen, X 2 is phenyl, optionally substituted at the para position, and R includes a nitrogen heteroatom, and therefore is an alkylamino, an (alkylamino) alkyl or (dialkylamino) alkyl. Preferred R groups of this type are as listed above. Examples of compounds within this seventh embodiment of the invention, in which

X

2 is alkynyl are shown in Table 4B. Table 2H shows results for EC 5 o for Hsp90 binding in JNPL3 brain cell lysates. As shown, all of the compounds tested were active, however, those with an acetylene substituent, such as 4B-1, 4B-4, 4B-13 and 4B-14, were most active. Examples of compounds within this seventh embodiment of the invention, in which

X

2 is an aryl group containing an oxygen atom are shown in Table 4C. Specific suitable substituent groups are 2-furanyl, 3-furanyl and 5-methyl-2-furanyl. Table 2G shows results for EC 50 for Hsp90 binding in SKBr3 breast cancer cells and JNPL3 brain cell lysates for some of the compounds shown in Table 4C. All of the WO 2011/044394 PCT/US2010/051872 58 compounds show good activity in both experimental systems. In Table 4C, compound 4-Cl I has X 2 = isoxazole, whereas 4C-l 1, 4C-38 and 4C-39 have X 2 = oxazolyl, including both a nitrogen and an oxygen. Compounds with X 2 = 2-oxazolyl (4C-38 and 4C-39) were more active than those with X2 = iso-oxazolyl (4C-1 1). Examples of compounds within this seventh embodiment of the invention, in which

X

2 is.an aryl group containing a sulfur atom in the aryl ring are shown in Table 4D. Table 2G shows results for ECso for Hsp90 binding in SKBr3 breast cancer cells and JNPL3 brain cell lystates for some of the compounds shown in Table 4D. All of the compounds show good activity in both experimental systems. In Table 4D, compounds 4D-16 and 4D-17 have X 2 = 2-thiazolyl, including both a nitrogen and an oxygen. Examples of compounds within this seventh embodiment of the invention, in which

X

2 is -CN or cyanoalkyl are shown in Table 4E. Table 21 shows results for EC 50 for Hsp90 binding in JNPL3 brain cell lystates for the two -CN compounds shown in Table 4E. Both of the compounds show good activity in both experimental systems. An example of a compound within this seventh embodiment of the invention, in which X 2 is a 6-meinbered aryl ring containing a nitrogen atom in the aryl ring, with the proviso that there is not also an oxygen in the ring, is shown in Table 2 (labeled as 4F-1). In Compound 4F-1, X 2 is 4-pyridinyl. X 2 could also be 2-pyridinyl, 3-pyridinyl, or pyrazinyl, 4 pyrimidinyl, 5- pyrimidinyl, 3-pyridazinyl or 4-pyridazinyl.

EC

50 for Hsp90 binding in SKBr3 breast cancer cells and JNPL3 brain cells were determined for compound 4F-1 to be 9,620 nM and 4,120 nM, respectively. Examples of compounds within this seventh embodiment of the invention, in which

X

2 is a 5-membered aryl rings containing 2 nitrogens in the ring are shown in Table 4G. The specific X 2 groups shown are 3-, 4- and 5-pyrazolyl. Other examples of X 2 groups in this category are 4- or 5-imidazolyl.

EC

5 o for Hsp90 binding in SKBr3 breast cancer cells and JNPL3 brain cell lysates were determined for some of the compounds listed in Table 4G. The results are summarized in Table 2K. Particularly good results were observed for compounds 40-3, 4G-6 and 40-9 in which the substituent is a 3-pyrazolyl.

WO 2011/044394 PCT/US2010/051872 59 Examples of compounds within this seventh embodiment of the invention, in which X, is a pyrrolyl group are shown in Table 4H. The specific X 2 groups shown are 2 or 3 pyrrolyl. EC5 0 for Hsp90 binding in SKBr3 breast cancer cells and JNPL3 brain cell lysates were determined for some of the compounds listed in Table 4H. The results are summarized in Table 2L. H. Structures of formula 1B in which Xa and Xb are 0 In accordance with an eighth embodiment of the invention, the compounds have general formula IB, in which both Xa and Xb are 0, and Xc and Xd are CH 2 . Thus, compounds of this embodiment are represented by the formula: 0 0

NH

2 AN X4'N N R (3) wherein Y is -CH 2 -, -0- or -S-; X4 is hydrogen or halogen; and X2 and R are as discussed below. H-L In some embodiments of compounds in accordance with formula (3), X 2 is halogen. In these embodiments, R is suitably an amino-alkyl, a secondary or tertiary alkyl anino-alkyl, a trialkylammonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl, with the proviso that R does not include a piperidino moiety.

WO 2011/044394 PCT/US2010/051872 60 Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2 (methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2 (ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2 (isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino) propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2 -(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(1H-imidazoyl) propyl. In specific embodiments of the invention, X2 is 1. In particular embodiments of the invention X 2 is I, Y is S and X 4 is H. Specific examples of compounds within this group are shown in Table 5A. Examples of compounds within this group, in which X 2 is a halogen, are shown in Table 5A (5A-1 to 5A-19). Table 2M shows EC 50 values for binding of Hsp90 in JNPL3 brain cells for some of the compounds of Table 5A. All show values of less than 100 nM. H-I. In some embodiments of compounds in accordance with formula (3), X 2 is aryl. In these embodiments, R maybe any of the groups disclosed as a substituent at the 9 position nitrogen in this application, or in the various patents and patent applications cited herein. See Table 8. In some embodiments, when X 2 is aryl, R includes a nitrogen heteroatom. In these embodiments, R is suitably an amino-alkyl, a secondary or tertiary alkyl-amino alkyl, a trialkylammonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-ainino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino) propyl, 3 (cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopmpyl amino) propyl, 3-(ethyl, isopropyl amino) WO 2011/044394 PCT/US2010/051872 61 propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2 (methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(1H--imidazoyl)propyl. In embodiments of formula (2) when X 2 is aryl, R has the formula: site of 9N-altachtnrnt sX e tN R1 R1 where R] is selected from COH, COMe, COEt, COnPr, COiPr, SO 2 Me, CH2OX where X can be H or oxygen, nitrogen, sulphur or halogen containing alkyl of linear, branched or cyclic nature. In embodiments of the invention when X 2 is aryl, R has the formula site of 9N-attachment H H 0

X-(CH

2 )m-N-(CH 2 )n-N-S-NH 2 0 0

X-(CH

2 )n-O-S-NH 2 0 where m= 2-3 and n= 1-6. In embodiments when X 2 is aryl, R has the formula site of 9N-attachnrent H 0 X-(CH2)m-N-(CH2)n HN-OH where m= 2-3 and n= 1-6. In specific embodiments, X 2 is an aromatic heterocycle. In specific embodiments, X 2 is a firan, thiophene, pyrazole, imidazole, pyrrole, oxazole or thiazole.

WO 2011/044394 PCT/US2010/051872 62 In specific embodiments, X 2 is a furan, thiophene, pyrazole, imidazole, oxazole or thiazole. In particular embodiments of formula (2), Y is S, X4 is H, X 2 is 2-, 3-fian or 5 methyl-2-furanyl. In particular embodiments of formula (2), Y is CH2, X4 is Cl, X 2 is 2-, 3- furan or 5 methyl-2-furanyl. In particular embodiments of formula (2), Y is CH 2 , X4 is F, X 2 is 2-, 3-furan or 5 methyl-2-firanyl. In particular embodiments of formula (2), Y is S, X4 is F, X 2 is 2-, 3-furan or 5 methyl-2-furanyl. In particular embodiments of formula (2), Y is S, X4 is H, X 2 is 2- or 3-thiophene. In particular embodiments of formula (2), Y is CH 2 , X4 is Cl, X 2 is 2- or 3- thiophene. In particular embodiments of formula (2), Y is CH 2 , X4 is F, X 2 is 2- or 3-thiophene. In particular embodiments of formula (2), Y is S, X4 is F, X 2 is 2- or 3-thiophene. In particular embodiments of formula (2), Y is S, X4 is H, X 2 is 2- or 3-pyrazole. In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X 2 is 2- or 3- pyrazole. In particular embodiments of formula (2), Y is CH 2 , X4 is F, X 2 is 2- or 3-pyrazole. In particular embodiments of formula (2), Y is S, X4 is F, X 2 is 2- or 3-pyrazole. In particular embodiments of formula (2), Y is S, X4 is H, X 2 is 2-thiazolyl, 5-methyl 2-tbiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is CH 2 , X4 is Cl, X 2 is 2-thiazolyl, 5 methyl-2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is CH 2 , X4 is F, X 2 is 2-thiazolyl, 5 methyl-2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is S, X4 is F, X 2 is 2-tbiazolyl, 5-methyl 2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is S, X4 is H, X 2 is 2-thiazolyl, 5-methyl 2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula.(2), Y is CH 2 , X4 is Cl, X 2 is 2-thiazolyl, 5 methyl-2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl.

WO 2011/044394 PCT/US2010/051872 63 In particular embodiments of formula (2), Y is CH 2 , X4 is F, X 2 is 2-thiazolyl, 5 methyl-2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is S, X4 is F, X 2 is 2-thiazolyl, 5-methyl 2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In these particular embodiments, R may be any one of the types of groups described above. Examples of compounds in which X 2 is an aryl group containing an oxygen atom in the aryl ring, are shown in Table 5B. Table 2N shows measured values for ECs 0 in JNPL3 brain cell lysates for compounds 5B-1, 5B-7, 5B-33 and 5B-34 in accordance with this embodiment of the invention which incorporates a fluorine as X4 and in which Y is -CH 2 - or a hydrogen as X4 and in which Y is S. Desirably low values of EC 50 were observed. Examples of compounds in which X2 is an aryl group containing a sulfur atom in the aryl ring are shown in Table 5C. Examples of compounds in which X2 is a 5-membered aryl rings containing 2 nitrogens in the ring are shown in Table 5D. Table 20 shows measured values for EC5o in JNPL3 brain cell lysates for compounds 5D-2 and 5D-4 in accordance with this embodiment of the invention which incorporates a fluorine as X4 and in which Y is -CH 2 - or a hydrogen as X4 and in which Y is S. Desirably low values of ECso were observed. An embodiment of the invention has the structure shown in formula (3), in which Y is

-CH

2 -or S, X4 is hydrogen of fluorine, X2 is X2 is a pyrazolyl, particularly a 3-pyrazolyl, or an imidazolyl. Preferred R groups of this type are as listed above. H-H. In some embodiments of the invention, X2 is an alkynyl group. In these embodiments, R may be as described above in Section H-Il. In specific embodiments, X 2 is acetylene. In particular embodiments of formula (2), Y is S, X4 is H, X 2 is acetylene. In particular embodiments of formula (2), Y is CH 2 , X4 is Cl, X 2 is acetylene. In particular embodiments of formula (2), Y is CH 2 , X4 is F, X2 is acetylene. In particular embodiments of formula (2), Y is S, X4 is F, X2 is acetylene.

WO 2011/044394 PCT/US2010/051872 64 In these particular embodiments, R may be any one of the types of groups described above. Specific examples of compounds in accordance with this embodiment of the invention are listed in Tables 5E. As shown, in preferred embodiments of formula (2) in which X 2 is an alkynyl group, X 4 is H, chlorine or fluorine. H-IV. In some embodiments of the invention, X2 is a cyano group. In these embodiments, R is suitably an amino alkyl, a secondary or tertiary alkyl-amino-alkyl, a trialkylammonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl, with the proviso that R does not contain a piperidino moiety. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino) propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3 (allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2-(cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(lH-imidazoyl) propyl. In a particular preferred embodiment of formula (2), Y is S, X 4 is H, X 2 is CN. In a particular preferred embodiment of formula (2), Y is CH 2 , X4 is Cl, X 2 is CN. In a particular preferred embodiment of formula (2), Y is CH 2 , X 4 is F, X 2 is CN. In a particular preferred embodiment of formula (2), Y is S, X4 is F, X 2 is CN. In other embodiments in which X2 is cyano or cyanoalkyl group, R is site of 9N-attachmnet H H 0

X-(CH

2

)-N-(CH

2 )n-N- -NH 2 I I 0 0 11

X-(CH

2 )n-O-S-NH 2 O1 0 WO 2011/044394 PCT/US2010/051872 65 where m= 2-3 and n= 1-6, or site of 9N-atlachnrnt H0 X-(CH2m-N--(CH2)n4 HN-OH where m= 2-3 and n= 1-6. Specific examples of compounds in accordance with this embodiment of the invention are listed in Table 5F. H-V. In some embodiments of the invention, X 2 is an amino group. In these particular embodiments, R may be any of the R groups described in Section H-II. In a particular preferred embodiment of formula (2), Y is S, X 4 is H, X 2 is azetidino. In a particular preferred embodiment of formula (2), Y is CH 2 , X 4 is Cl, X 2 is azetidino. In a particular preferred embodiment of formula (2), Y is CH 2 , X 4 is F, X 2 is azetidino In a particular preferred embodiments of formula (2), Y is S, X 4 is F, X 2 is azetidino. A specific examples of a compounds in accordance with this embodiment of the invention is listed in Table 5G H-VI. In some embodiments of the invention, X 2 is a cycloalkyl or cycloalkenyl. In these particular embodiments, R may be any of the R groups described in Section H-II. In specific embodiments, X 2 is a cycloalkyl with one ring. In specific embodiments, X 2 is a cyclopropane, cyclobutane or cyclopentane. In particular embodiments of formula (2), Y is S, X 4 is H, X 2 is cyclopentyl. In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X 2 is cyclopentyl. In particular embodiments of formula (2), Y is CH 2 , X 4 is F, X 2 is cyclopentyl. In particular embodiments of formula (2), Y is S, X 4 is F, X 2 is cyclopentyl. A specific examples of a compounds in accordance with this embodiment of the invention is listed in Table SH WO 2011/044394 PCT/US2010/051872 66 I. Structures of formula 1B in which Xa and/or Xb is a heteroatom. but not both 0 In accordance with a ninth embodiment of the invention, the compounds have general formula 1B, in which one or both of Xa or Xb is a heteroatom such as 0, N or S, with the proviso that both of Xa and Xb are not 0 (see Section H). Specific examples of compounds within this group are shown in Table 6A. I-I. In some embodiments of compounds in accordance with formula (3), X 2 is halogen. In these embodiments, R is suitably an amino-alkyl, a secondary or tertiary alkyl amino-alkyl, a trialkylammonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl, with the proviso that R is not a piperidino moiety. . Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2 (methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2 (ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2 (isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino) propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(IH-imidazoyl) propyl. In specific embodiments of the invention, X 2 is I. In particular embodiments of the invention X 2 is I, Y is S and X4 is H. I-II. In some embodiments of compounds in accordance with formula (3), X 2 is aryl. In these embodiments, R may be any of the groups disclosed as a substituent at the 9-position nitrogen herein or in the various patents and applications cited above. See Table 8. In some embodiments, when X 2 is aryl, R includes a nitrogen heteroatom.

WO 2011/044394 PCT/US2010/051872 67 In these embodiments, R is suitably an amino alkyl, a secondary or tertiary alkyl amino-alkyl, a trialkylammonioalkyl group, aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino) propyl, 3 (cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2 (methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(IH-imidazoyl) propyl. In embodiments of formula (2) when X 2 is aryl, R has the formula: site of 9N-attachment xN R 1 xN R 1 where R, is selected from COH, COMe, COEt, COnPr, COiPr, SO 2 Me, CH 2 OX where X can be H or oxygen, nitrogen, sulphur or halogen containing alkyl of linear, branched or cyclic nature. In embodiments of the invention when X2 is aryl, R has the formula site of 9N-attachment H H 0

X-(CH

2 )-N-(CH2)n-N-S-NH 2 0 0

X-(CH

2 )n-O--NH 2 0 where m= 2-3 and n= 1-6. In embodiments when X 2 is aryl, R has the formula WO 2011/044394 PCT/US2010/051872 68 site of 9N-attachment H 0 X-(CF -N--(CH2)n HN-OH where m= 2-3 and n= 1-6. In specific embodiments, X 2 is an aromatic heterocycle. In specific embodiments, X 2 is a fian, thiophene, pyrazole, imidazole, pyrrole, oxazole or thiazole. In specific embodiments, X 2 is a fian, thiophene, pyrazole, imidazole, oxazole or thiazole. In particular embodiments of formula (2), Y is S, X4 is H, X2 is 2-, 3-furan or 5 methyl-2-furanyl. In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X 2 is 2-, 3- furan or 5 methyl-2-furanyl. In particular embodiments of formula (2), Y is CH 2 , X4 is F, X 2 is 2-, 3-furan or 5 methyl-2-fLranyl. In particular embodiments of formula (2), Y is S, X 4 is F, X 2 is 2-, 3-furan or 5 methyl-2-furanyl. In particular embodiments of formula (2), Y is S, X4 is H, X 2 is 2- or 3-thiophene. In particular embodiments of formula (2), Y is CH 2 , X4 is Cl, X 2 is 2- or 3- thiophene. In particular embodiments of formula (2), Y is CH2, X4 is F, X 2 is 2- or 3-thiophene. In particular embodiments of formula (2), Y is S, X4 is F, X 2 is 2- or 3-thiophene. In particular embodiments of formula (2), Y is S, X4 is H, X 2 is 2- or 3-pyrazole. In particular embodiments of formula (2), Y is CH 2 , X4 is Cl, X 2 is 2- or 3- pyrazole. In particular embodiments of formula (2), Y is CH 2 , X4 is F, X 2 is 2- or 3-pyrazole. In particular embodiments of formula (2), Y is S, X4 is F, X2 is 2- or 3-pyrazole. In particular embodiments of formula (2), Y is S, X4 is H, X 2 is 2-thiazolyl, 5-methyl 2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is CH 2 , X4 is Cl, X 2 is 2-thiazolyl, 5 methyl-2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl.

WO 2011/044394 PCT/US2010/051872 69 In particular embodiments of formula (2), Y is CH 2 , X 4 is F, X 2 is 2-thiazolyl, 5 methyl-2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is S, X4 is F, X 2 is 2-thiazolyl, 5-methyl 2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is S, X 4 is H, X2 is 2-thiazolyl, 5-methyl 2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X 2 is 2-thiazolyl, 5 methyl-2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is CH2, X 4 is F, X 2 is 2-thiazolyl, 5 methyl-2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is S, X 4 is F, X 2 is 2-thiazolyl, 5-methyl 2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In these particular embodiments, R maybe any one of the types of groups described above. I-IL. In some embodiments of the invention, X 2 is an alkynyl group. In these embodiments, R may be as described above in Section I-IL. In specific embodiments, X 2 is acetylene. In particular embodiments of formula (2), Y is S, X 4 is H, X 2 is acetylene. In particular embodiments of formula (2), Y is CH 2 , X4 is Cl, X 2 is acetylene. In particular embodiments of formula (2), Y is CH 2 , X4 is F, X 2 is acetylene. In particular embodiments of formula (2), Y is S, X4 is F, X2 is acetylene. In these particular embodiments, R may be any one of the types of groups described above. I-IV. In some embodiments of the invention, X 2 is a cyano group. In these embodiments, R is suitably an amino alkyl, a secondary or tertiary alkyl-amino-alkyl, a trialkylammonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl, with the proviso that R does not include a piperidino moiety. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-anino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl WO 2011/044394 PCT/US2010/051872 70 amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino) propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3 (allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2-(cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(IH-imidazoyl) propyl. In a particular preferred embodiment of formula (2), Y is S, X4 is H, X 2 is CN. In a particular preferred embodiment of formula (2), Y is CH 2 , X 4 is Cl, X 2 is CN. In a particular preferred embodiment of formula (2), Y is CH 2 , X 4 is F, X 2 is CN. In a particular preferred embodiment of formula (2), Y is S, X 4 is F, X 2 is CN. In other embodiments in which X 2 is cyano or cyanoalkyl group, R is site of 9N-attaclent H H 0 X-(CH2),-N-(CH2)n-N-S-NH2 0 0

X-(CH

2 )n-O-S-NH 2 0 where m= 2-3 and n= 1-6, or site of 9N-attachnent H X-(CH2)m-N-(CH2)n4 HNOH where m= 2-3 and n= 1-6. I-V. In some embodiments of the invention, X 2 is an amino group. In these particular embodiments, R may be any of the R groups described in Section I-II. In a particular preferred embodiment of formula (2), Y is S, X4 is H, X2 is aziridino. In a particular preferred embodiment of formula (2), Y is CH 2 , X4 is Cl, X2 is aziridino WO 2011/044394 PCT/US2010/051872 71 In a particular preferred embodiment of formula (2), Y is CH 2 , X 4 is F, X 2 is aziridino. In a particular preferred embodiment of formula (2), Y is S, X 4 is F, X 2 is aziridino. J. Structures of formula 1B in which Xa. Xc. Xd and Xb are all carbon In accordance with a tenth embodiment of the invention, the compounds have general formula I B, in which Xa, Xc, Xd and Xb are all carbon connected by single or double bonds. In these embodiments, R may be any of the groups disclosed as a substituent at the 9-position nitrogen herein or in the various patents and applications cited above. (See Table 8) In some embodiments, when X 2 is aryl, R includes a nitrogen heteroatom. In these embodiments, R is suitably an aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or trialkylamnnonioalkyl group, in which each alkyl portion may be linear, cyclic or branched, or an alkyl heterocycle, where the alkyl may be bonded to a nitrogen in the heterocyclic group. Specific R groups include without limitation 2-(methyl, t-butyl amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino) propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(1H-imidazoyl) propyl. In embodiments of formula (2) when X 2 is aryl, R has the formula: site of 9N-attachment NR1 NR1 where R, is selected from COH, COMe, COEt, COnPr, COiPr, SO 2 Me, CH 2 OX where X can be H or oxygen, nitrogen, sulphur or halogen containing alkyl of linear, branched or cyclic nature.

WO 2011/044394 PCT/US2010/051872 72 In embodiments of the invention when X 2 is aryl, R has the formula site of 9N-attachmert H H X-(CH2)m -N-(CH2)n-NS -NH2 00

X-(CH

2 )n-O-S-NH 2 0 where m=- 2-3 and n- 1-6. In embodiments when X 2 is aryl, R has the formula site of 9N-attachrent H 0 X-(CH

-N-(CH

2 )n HWOH where m= 2-3 and n= 1-6. Specific examples of compounds within this embodiment of the invention are shown in Table 6B. Table 2P shows measured values for EC 50 in JNPL3 brain cell lysates for compounds 6B-25 in accordance with this embodiment of the invention which incorporates a hydrogen as X4 and in which Y is S. Desirably low values of EC 50 were observed. K. Structures of formula 1C In some embodiments of the present invention having the general formula 1C, the compounds of the invention can be represented by the general formula: WO 2011/044394 PCT/US2010/051872 73

NH

2 XN N, R OR, (4) m which RI is alkyl, for example methyl or ethyl, Y is S or CH 2 ,

X

4 is H or halogen,

X

2 is saturated or unsaturated non-aromatic carbocycle or heterocycle, aryl, alkylamino, dialkylamino, alkynyl or part of a ring formed by R; and R is hydrogen, alkyl, alkenyl, or alkynyl, linear, branched or cyclic, optionally including heteroatoms such as N, S or 0, optionally connected to the 2'-position to form an 8 to 10 member ring. In some embodiments, R is suitably an alkylaminoalkyl, dialkylaminoalkyl, or trialkylammonioalkyl group, in which each alkyl portion may be linear, cyclic or branched, or an alkyl heterocycle, where the alkyl may be bonded to a nitrogen in the heterocyclic group. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino) propyl, 3 (cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2 (methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(1 H-imidazoyl) propyl. In embodiments of formula (3), R has the formula: WO 2011/044394 PCT/US2010/051872 74 site of 9N-attachment X""'-"ON R1 ,,R where R, is selected from COH, COMe, COEt, COnPr, COiPr, SO 2 Me, CH 2 OX where X can be H or oxygen, nitrogen, sulphur or halogen containing alkyl of linear, branched or cyclic nature. In embodiments of formula (3), R has the formula site of 9N-attachnert H H 0

X-(CH

2 )m-N-(CH 2 )n-N-SN 2 0 0

X-(CH

2 )n-O-S-NH 2 0 where m= 2-3 and n= 1-6. In embodiments of formula (3) R has the formula site of 9N-attachernt H 0 X-(CH Xrn-N-(CH12)n HN-OH where m= 2-3 and n= 1-6. In some embodiments, X 2 is alkynyl, such as acetylene. Examples of such structures are shown in Table 7A In some embodiments, X 2 is cyano or cyanomethyl. Examples of such structures are shown in Table 7B. In some embodiments, X 2 is a heterocycle, including without limitation aziridine, azetidine, oxetane, thietane, tetrahydrofuran, tetrahydropyrrole, tetrahydrothiophane, imidazolidine, oxazolidine, thiazolidine, azirine, oxirine, pyrroline, pyrrole, dihydrofuran, furan, dihydrothiophene, thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1,2,4-tuiazole, dithiazole, tetrazole, pyridine, pyran, thiine, diazine, thiazine, dioxin, triazine, tetrazine. Examples of such structures are shown in Tables 7C-7F.

WO 2011/044394 PCT/US2010/051872 75 Table 2Q shows measured values for EC5 0 in JNPL3 brain and SKBr3 cell lysates for compounds (7A-20, 7C-13, 7D-3 and 7E-6) in accordance with this embodiment of the invention which incorporates a hydrogen as X 4 and in which Y is S. Desirably low values of EC5o were observed, although X 2 = -OCH 3 was observed to be less active than X2 = -0-CHz 0- in every shown instance: 4C-5 vs 7C-13 (6.5 nM vs 84nM), 4D-3 vs 7D-3 (18.5nM vs 24OnM) and 4G-9 vs 7E-6 (5.5nM vs 32nM). L. Structures in which X, is alkvnvl In accordance with a further aspect of the present invention, compounds are provided in accordance with any of formulas (1A), (1B) or (iC) in which X 2 is alkynyl. In these compounds, Y is CH 2 , S, 0, C=O, C=S, N or any other linking group disclosed in a compound with the same scaffold structure herein or in the patents and patent applications cited above;

X

4 is H or halogen or any other group disclosed at this position in a compound with the same scaffold structure herein or in the patents and patent applications cited above; Xa, Xb, Xc and Xd are any group(s) disclosed at this position herein or in the patents and patent applications cited above; and R is any R group disclosed at this position of the same scaffold structure herein or in the patents and patent applications cited above. (See Table 8) In some embodiments, Zi, Z2, and Z3 are all nitrogen. In some embodiments, Zi and Z3 are nitrogen and Z2 is carbon. In some embodiments, Z3 is carbon. M. Structures in which X 2 is Furan, Thiophene. Pyrazole. Oxazole or Thiazole In accordance with a further aspect of the present invention, compounds are provided in accordance with any of formulas (lA), (IB) or (IC) in which X 2 is a furan, thiophene, 3 pyrazole, oxazole or thiazole. In these compounds, Y is CH 2 , S, 0, C=O, C=S, N or any other linking group disclosed in a compound with the same scaffold structure herein or in the patents and patent applications cited above; WO 2011/044394 PCT/US2010/051872 76

X

4 is H or halogen or any other group disclosed at this position in a compound with the same scaffold structure herein or in the patents and patent applications cited above; Xa, Xb, Xc and Xd we any group(s) disclosed at this position herein or in the patents and patent applications cited above; and R is any R group disclosed at this position of the same scaffold structure herein or in the patents and patent applications cited above. In some embodiments, Z1, Z2, and Z3 are all nitrogen. In some embodiments, Zi and Z3 are nitrogen and Z2 is carbon. In some embodiments, Z3 is carbon. Synthetic Methods Compounds in accordance with formulas (lA) and (iB) can be made through the application of the following methodologies.

NH

2

NH

2 x >-SH a,b N NN N 5 or 6 member ring

NH

2 X, NH 2 X2 c,d N NN 'N N DN' N ,'D~ (>) n=1,2 (() n=1.2

NR

1

R

2

NR

1

R

2 (a) Cul, neocuproine, NaOt-Bu, DMF, 110 *C; (b) NIS, acetonitrile, RT; (c) Cs 2

CO

3 , 1,2-dibromoethane or 1,3 dibromopropane; (d) HNR1R 2 , DMF, rt (e) X 2 M, Pd (cat.), DMF, 50-100 0 C. Scheme 1.

WO 2011/044394 PCT/US2010/051872 77

NH

2

NH

2 H O O C H N H 2 a, b FN + HN N NF N N 5 or 6 member ring

NH

2 NH 2 X2 c,d ,e F N f F N F IN ( n=1,2 ( n=1,2

NR

1

R

2

NR

1

R

2 (a) triphenyl phosphite, pyridine, microwave; (b) HF-pyridine, NaNC 2 ; (c) NIS, acetonitrile, rt; (d) Cs 2 CO, 1,2-dibromoethane or 1,3-dibromopropane; (e) HNR 1

R

2 , DMF, rt; (f) X 2 M, Pd (cat.), DMF, 50-100 C. Scheme 2. General Methods: 'H and "C NMR spectra were recorded on a Bruker 500 MHz instrument. Chemical shifts are reported in 8 values in ppm downfield from TMS as the internal standard. 'H data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q= quartet, br = broad, m = multiplet), coupling constant (Hz), integration. "C chemical shifts are reported in S values in ppm downfield from TMS as the internal standard. High resolution mass spectra were recorded on a Waters LCT Premier system. Low resolution mass spectra were obtained on a Waters Acquity Ultra Performance LC with electrospray ionization and SQ detector. High-performance liquid chromatography analyses were performed on a Waters Autopurification system with PDA, MicroMass ZQ, and ELSD detector, and a reversed phase column (Waters X-Bridge C18, 4.6 x 150 mm, 5 pm) using a gradient of; method A (a) H 2 0 + 0.1% TFA and (b) CH 3 CN + 0.1% TFA, 5 to 95% b over 10 minutes at 1.2 mL/min; method B (a) H20 + 0.1% TFA and (b) CH 3 CN + 0.1% TFA, 20 to 90% b over 16 minutes at 1.0 mL/min. Column chroniatography was performed using 230400 mesh silica gel (EMD). Specific compounds were synthesized as follows; WO 2011/044394 PCT/US2010/051872 78

NH

2

NH

2 X2 N -N N S N NH NH PU-H71 Reagents and conditions: (a) RB(OH) 2 , PdCl 2 (PPh 3

)

2 , NaHCO 3 , H20, DMF, 90*C. Scheme 3. Suzuki coupling of PU-H71. 9-(3-(isopropylanino)propyl)-8-(6-phenylbenzo[d][1,3]dioxol-5-ylthio)-9H-purin-6 amine [DZ2-3881. Phenylboronic acid (10.7 mg, 0.0876 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (0.5 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2

C

2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated undernitrogen at 90 0 C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2

CI

2 :MeOH-NH 3 (7N), 10:1) to give 19.8 mg (73%) of DZ2-388. 'H NMR (500 MHz, MeOH-d) 6 8.14 (s, 1H), 7.28-7.34 (m, 3H), 7.17-7.21 (m, 2H), 7.12 (s, 1 H), 6.90 (s, 1 H), 6.09 (s, 2H), 4.03 (t, J= 6.4 Hz, 2H), 3.27 (septet, J= 6.6 Hz, 1H), 2.72 (t, J= 6.6 Hz, 2H), 2.13 (m, 2H), 1.40 (d, J= 6.5 Hz, 6H); 13 C NMR (125 MHz, MeOH-d4) 8 156.0, 153.4, 152.1, 151.1, 150.3, 149.4, 142.3, 141.8, 130.4, 129.1, 128.7, 120.3, 119.8, 115.7, 112.2, 103.8, 52.2, 43.2, 41.1, 27.6, 19.3; HRMS (ESI) m/z [M+H]* calcd. for C 2 4H27N 6

O

2 S, 463.1916; found 463.1905; HPLC: method A R, = 6.50, method B R, = 7.40. 8-(6-(4-tert-butylphenyl)benzo[d] [1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H purin-6-amine [DZ2-3901. 4-tert-Butylphenylboronic acid (15.6 mg, 0.0876 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (0.5 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This WO 2011/044394 PCT/US2010/051872 79 was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H 2 0 (0.1 mL) and Pd(PPh 3

)

2

C

2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 3 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2

CI

2 :EtOAc:MeOH-NH 3 (7N), 4:5:2:1) to give 25.0 mg (83%) of DZ2-390. 'H NMR (500 MHz, MeOH-d) 8 8.11 (s, lH), 7.27 (d, J= 8.4 Hz, 2H), 7.14 (s, I H), 7.12 (d, J 8.4 Hz, 2H), 6.86 (s, IH), 6.06 (s, 2H), 3.93 (t, J= 6.9 Hz, 2H), 2.92 (septet, J= 6.5 Hz, IH), 2.61 (t, J= 7.3 Hz, 2H), 1.86 (m, 2H), 1.28 (s, 9H), 1.12 (d, J= 6.5 Hz, 6H); "C NMR (125 MHz, MeOH-d4) 8 155.9, 153.3, 151.9, 151.8, 150.9, 150.2, 149.2, 141.9, 138.8, 130.0, 125.9, 120.4, 120.3, 115.4, 112.3, 103.6, 50.6,44.0,41.8,35.4, 31.8, 29.3, 21.1; HRMS (ESI) m/z [M+H]* calcd. for C 2 8H 35

N

6

O

2 S, 519.2542; found 519.2545; HPLC: method A Rt = 7.43, method B R, = 9.45. 8-(6-(3,5-bis(trifluoromethyl)phenyl)benzo[d] [1,3Jdioxol-5-ylthio)-9-(3 (isopropylamino)propyl)-9H-purin-6-amine [DZ2-3911. 3,5 Bis(trifluoromethyl)phenylboronic acid (22.6 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (0.5 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2

C

2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 3 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2 C1 2 :EtOAc:MeOH-NH3 (7N), 4:5:2:1) to give 24.4 mg (70%) of DZ2-391. 'H NMR (500 MHz, CDC1 3 ) 8 8.22 (s, IH), 7.79 (s, 3H), 7.12 (s, IH), 6.86 (s, 1H), 6.09 (s, 2H), 5.71 (br s, 2H), 4.07 (t, J= 6.6 Hz, 2H), 2.82 (septet, J= 6.2 Hz, 1H), 2.49 (t, J= 6.5 Hz, 2H), 1.95 (m, 2H), 1.12 (d, J= 6.3 Hz, 6H); ' 3 C NMR (125 MHz, CDCI 3 ) 8 154.1, 152.3, 151.5, 149.6, 148.6, 147.5, 142.1, 137.2, 131.2 (q, J = 33 Hz), 129.6, 123.1 (q, J= 270 Hz), 121.3, 119.6, 119.4, 114.9, 110.8, 102.4, 49.5, 42.8, 40.6, 28.8, 21.7; HRMS (ESI) mn/z [M+H]* calcd. for C 26

H

25

F

6

N

6 0 2 S, 599.1664; found 599.1653; HPLC: method A R, = 7.45, method B R, = 9.38.

WO 2011/044394 PCT/US2010/051872 80 8-(6-(4-(dimethylamino)phenyl)benzo[d] [1,3Jdioxol-5-ylthio)-9-(3 (isopropylamino)propyl)-9H-purin-6-aniine [DZ2-392J. 4-(Dimethylamino)phenylboronic acid (14.5 mg, 0.0877 mmol) was added to PU-H71 (30 ig, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2

C

CI

2 :EtOAc:MeOH-NH 3 (7N), 4:5:2:1) to give 25.3 mg (85%) of DZ2-392. 'H NMR (500 MHz, CDC1 3 ) 6 8.24 (s, 1H), 7.13 (d, J= 8.7 Hz, 211), 6.93 (s, iH), 6.83 (s, 1H), 6.67 (d, J= 8.7 Hz, 2H), 6.01 (br s, 2H), 5.98 (s, 2H), 4.02 (t, J= 6.7 Hz, 2H), 2.97 (s, 6H), 2.78 (septet, J= 6.3 Hz, IH), 2.44 (t, J= 6.7 Hz, 2H), 1.87 (m, 2H), 1.10 (d, J= 6.3 Hz, 6H); "C NMR (125 MHz, CDCl 3 ) 5 154.4, 152.4, 151.5, 149.9, 148.5, 148.0, 147.1, 139.6, 130.0, 127.8, 120.5, 119.7,112.8,111.7, 111.0,101.7,49.3,43.1, 40.9, 40.4, 28.9, 21.9; HRMS (ESI) m/z [M+H] calcd. for C 26

H

32

N

7 0 2 S, 506.2338; found 506.2330; HPLC: method A Rt = 5.72, method B R, = 5.12. 9-(3-(isopropylamino)propyl)-8-(6-(thiophen-2-yl)benzold] [1,3Jdioxol-5-ylthio)-9H purin-6-amine [DZ2-395]. 2-Thienylboronic acid (11.2 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2 C1 2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 5 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH2Cl 2 :MeOH-NH3 (7N), 12.5:1) to give 12.4 mg (45%) of DZ2-395. 'H NMR (500 MHz, CDC 3 /MeOH-d 4 ) S 8.17 (s, 1H), 7.33 (dd, J= 1.4, 4.9 Hz, 1H), 7.07 (s, 1H), 7.04 (s, 111), 7.00-7.02 (m, 2H), 6.09 (s, 211), 4.12 (t, J= 6.6 Hz, 2H), 2.95 (septet, J= 6.6 Hz, 1H), 2.62 (t, J= 6.8 Hz, 2H), 2.00 (m, 2H), 1.19 (d, J= 6.6 Hz, 6H); 13 C NMR (125 MHz, CDC13/MeOH-d) 8 154.2, 152.0, 151.1, 149.4,148.8,148.4,140.5, 132.9, 127.8, 126.9, 126.3, 119.2, 119.0, 114.6, WO 2011/044394 PCT/US2010/051872 81 111.8, 102.3, 49.6,42.5, 40.6, 27.8, 20.7; HRMS (ESI) n/z [M+H]* calcd. for C2H25N 6 0 2

S

2 , 469.1480; found 469.1461; HPLC: method A R, = 6.38, method B Rt = 7.18. 8-(6-(furan-2-yl)benzo[dJ [1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6 amine [DZ3-4]. 2-Furanylboronic acid (9.8 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2 Cl 2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90*C for 3.5 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2 Cl2:MeOH-NH 3 (7N), 12.5:1) to give 19.1 mg (72%) of DZ3-4. 'H NMR (500 MHz, CDCl3/MeOH-d 4 ) 6 8.18 (s, IH), 7.49 (d, J= 1.8 Hz, 1H), 7.25 (s, 1H), 6.96 (s, 1H), 6.71 (d, J= 3.3 Hz, 1H), 6.47 (dd, J= 1.8, 3.2 Hz, 1H), 6.06 (s, 2H), 4.20 (t, J= 7.0 Hz, 2H), 2.87 (in, 1H), 2.61 (t, J= 6.9 Hz, 2H), 2.00 (in, 2H), 1.14 (d, J= 6.3 Hz, 6H); "C NMR (125 MHz, CDCl 3 /MeOH-d4) 5 154.3, 152.2, 151.2, 150.9, 149.5, 148.14, 148.08, 142.4, 129.0, 119.2, 117.5, 114.5, 111.5, 110.0, 109.0, 102.3, 42.8, 41.0, 28.5, 21.2; HRMS (ESI) m/z [M+H] called. for CH 25

N

6 0 3 S, 453.1709; found 453.1705; HPLC: method A Rt = 6.23, method B R = 6.82. 9-(3-(isopropylamino)propyl)-8-(6-(4-methoxyphenyl)benzo[d [,3jdioxol-5-ylthio)-9H purin-6-amine [DZ3-3]. 4-Methoxyphenylboronic acid (13.3 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmcl) and NaHCO 3 (14.7 mg, 0.1755 nimol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2 C1 2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2 Cl 2 :MeOH-NH3 (7N), 12.5:1) to give 20.5 mg (71%) of DZ3-3. 'H NMR (500 MHz, CDCl 3 ) 8 8.25 (s, 1H), 7.19 (d, J= 8.7 Hz, 2H), 6.95 (s, 1H), 6.86 (d, J= 8.7 Hz, 2H), 6.82 (s, 1H), 6.00 (s, 2H), 5.92 (br s, 2H), 4.01 (t, J= 6.7 Hz, 2H), 3.82 (s, 3H), 2.75 (septet, J= 6.3 Hz, 1H), 2.43 (t, J = 6.7 Hz, 2H), 1.85 (in, 2H), 1.07 (d, J= 6.3 Hz, 6H); 1 3 C NMR (125 MHz, CDCl 3 ) 5 159.2, WO 2011/044394 PCT/US2010/051872 82 154.3, 152.5, 151.5, 148.6, 147.8, 147.5, 139.0, 132.5, 130.4, 120.6, 119.8, 113.5, 113.0, 111.0, 101.8, 55.3, 49.1, 43.2, 40.9, 29.2, 22.2; HRMS (ESI) m/z [M+H]* caled. for

C

25

H

2 9

N

6

O

3 S, 493.2022; found 493.2010; HPLC: method A R, = 6.57, method B Rt = 7.55. 9-(3-(isopropylamino)propyl)-8-(6-(pyridin-4-yl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin 6-amine [DZ3-5]. 4-Pyridinylboronic acid (10.8 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H 2 0 (0.1 mL) and Pd(PPh 3

)

2

C

2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90*C for 3.5 t Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2 C1 2 :MeOH-NH 3 (7N), 12.5:1) to give 14.8 mg (55%) of DZ3-5. 'H NMR (500 MHz, CDC1 3 /MeOH-d 4 ) 8 8.53 (dd, J= 1.6, 4.8 Hz, 2H), 8.19 (s, 1H), 7.25 (dd, J= 1.6, 4.5 Hz, 2H), 7.11 (s, 1 H), 6.89 (s, 1H), 6.11 (s, 2H), 4.07 (t, J= 6.8 Hz, 211), 2.82 (in, IH), 2.51 (t, J= 6.8 Hz, 2H), 1.91 (in, 2H), 1.13 (d, J= 6.3 Hz, 6H); 1 3 C NMR (125 MHz, CDCI 3 /MeOH-d 4 ) 8 154.1,152.0,151.2,150.0, 148.90, 148.85, 148.69, 137.9, 124.5, 119.1, 117.7, 115.3, 110.6, 102.5, 49.2, 42.8, 40.7, 28.4,21.2; HRMS (ESI) t/z [M+H]* called. for C23H 2 6

N

7 0 2 S, 464.1869; found 464.1848; HPLC: method A R, = 5.13, method B R, = 2.57. 8-(6-(4-bromophenyl)benzo[dj [1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H purin-6-amine [DZ3-61. 4-Bromophenylboronic acid (17.6 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H 2 0 (0.1 mL) and Pd(PPh 3

)

2 Cl 2 (4 mg, 0.00584 nmol) were added and the reaction mixture was heated under nitrogen at 90*C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2

CI

2 :EtOAc:MeOH-Ni3 (7N), 4:5:2:1) to give 13.9 mg (44%) of DZ3-6. H NMR (500 MHz, CDC13) 5 8.23 (s, IH), 7.44 (d, J= 8.2 Hz, 2H), 7.13 (d, J= 8.2 Hz, 2H), 7.01 (s, 1H), 6.81 (s, 1H), 6.05 (s, 211), 5.69 (br s, 2H), 4.08 (t, J= 6.0 Hz, 2H), 2.91 (m, 1H), WO 2011/044394 PCT/US2OO/051872 83 2.50 (t, J= 5.9 Hz, 211), 1.98 (m, 2H), 1.20 (d, J= 6.4 Hz, 6H); "C NMR (125 MHz, CDC13/MeOH-d 4 ) 6 154.2, 152.0, 151.2, 149.8, 149.1, 148.2, 139.8, 139.1, 131.2, 131.0, 122.0, 119.0, 117.9, 115.0, 111.1,102.4,50.1, 42.1, 40.2,27.3, 20.2; HRMS (ESI) m/z [M+H]t called. for C 24

H

26 BrN 6 0 2 S, 541.1021/ 543.1001; found 541.1016/543.1004; HPLC: method A Rt = 6.93, method B Rt = 8.30. 8-(6-(furan-3-yI)benzo[dJ [1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6 amine [DZ3-27]. 3-Furanylboronic acid (9.8 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2 C1 2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2

CI

2 :MeOH-NH 3 (7N), 20:1) to give 2 3 .9 mg (90%) of DZ3-27. 'H NMR (500 MHz, CDC3/MeOH-d 4 ) 8 8.17 (s, IH), 7.51 (s, IH), 7.44 (s, 1H), 7.07 (s, IH), 6.97 (s, 1H), 6.49 (s, 1H), 608 (s, 2H), 4.17 (t, J= 6.9 Hz, 2H), 2.93 (septet, J= 6.4 Hz, iH), 2.64 (t, J= 7.1 Hz, 2H), 2.02 (m, 2H), 1.17 (d, J= 6.4 Hz, 6H); "C NMR (125 MHz, CDCI 3 /MeOH-d 4 ) 6 154.1, 151.8, 151.0, 149.7,149.0, 147.8, 142.6, 140.4, 131.7, 124.2, 118.9, 117.8, 114.8, 111.5, 110.7, 102.1, 49.2, 42.6, 40.6, 28.0, 20.7; HRMS (ESI) m/z [M+H] 4 calcd. for C 22

H

25

N

6 0 3 S, 453.1709; found 453.1711; HPLC: method A R, = 6.18, method B R, = 6.67. 5-(6-(6-anino-9-(3-(isopropylamino)propyl)-9H-purin-8-ylthio)benzo[d] [1,3]dioxol-5 yI)furan-2-carbaldehyde [DZ3-33]. 2-Formyl-5-fuanylboronic acid (12.3 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H 2 0 (0.1 mL) and Pd(PPh 3

)

2 C1 2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2

CI

2 :EtOAc:MeOH-NH 3 (7N), 2:2:1:0.5) to give 9.5 mg (34%) of DZ3-33. 'H WO 2011/044394 PCT/US2010/051872 84 NMR (500 MHz, CDC1/MeOH-d4) 5 9.57 (s, 1H), 8.18 (s, IN), 7.36 (d, J= 3.8 Hz, IH), 7.32 (s, IH), 7.07 (s, 1H), 6.98 (d, J= 3.8 Hz, IH), 6.12 (s, 2H), 4.32 (t, J= 6.7 Hz, 2H), 3.31 (septet, J= 6.6 Hz, 1H), 2.93 (t, J= 6.8 Hz, 2H), 2.30 (m, 2H), 1.42 (d, J= 6.6 Hz, 6H); "C NMR (125 MHz, CDCl,/MeOH-d) 8 177.5, 156.8, 154.5, 152.2, 151.9, 151.4, 150.1, 149.7, 148.1, 127.5, 124.3, 119.2, 118.7, 115.7, 112.7, 109.9, 102.9, 51.3,41.8,40.4,26.4, 19.2; HRMS (ESI) m/z [M+H]* called. for C23H 2 sN 6

O

4 S, 481.1658; found 481.1657; HPLC: method A R, = 5.87, method B Rt= 5.93. 8-(6-(1H-pyrrol-2-yl)benzo[dJ [1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H purin-6-anine [DZ3-29]. 1-N-Boc-pyrrole-2-boronic acid (18.5 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H 2 0 (0.1 mL) and Pd(PPh 3

)

2 Cl 2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 4 h. DMF was removed under reduced pressure and to the resulting residue was added CH 2

CI

2 (1.5 mL) and TFA (0.3 mL). The mixture was stirred for 5 h at rt, then solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2 Cb2:EtOAc:MeOH-NH3 (7N), 4:9:2:1) to give 5.8 mg (22%) of DZ3-29. IH NMR (500 MHz, CDClj/MeOH-d) 8 8.17 (s, 1), 7.04 (s, 1H), 7.01 (s, 1H), 6.88 (m, 1H), 6.27 (m, 1H), 6.21 (m, 1H), 6.03 (s, 2H), 4.17 (t, J= 6.8 Hz, 2H), 3.29 (septet, J= 6.6 Hz, 1H), 2.80 (t, J= 6.7 Hz, 2H), 2.15 (m, 2H), 1.41 (dJ= 6.6 Hz, 6H); HRMS (ESI) m/z [M+H]*calcd. for C 22 H2 6

N

7 0 2 S, 452.1869; found 452.1872; HPLC: method A Rt = 6.13, method B Rt = 6.43. 8-(6-(1H-pyrazol-4-yl)benzo[dJ [1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propy)-9H purin-6-amine [DZ3-301. 1-Boc-pyrazole-4-boronic acid pinacol ester (25.8 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2

C

2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 4 h. Solvent was WO 2011/044394 PCT/US2Olo/051872 85 removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2 Cl2:EtOAc:MeOH-NH 3 (7N), 2:2:1:0.5) to give 13.7 mg (53%) of DZ3-30. 'H NMR (500 MHz, CDCl3/MeOH-d4) 8 8.17 (s, 1H), 7.58 (s, 2H), 7.10 (s, 111), 6.95 (s, 1H), 6.06 (s, 2H), 4.08 (t, J= 6.9 Hz, 2H), 2.89 (septet, J=6.4 Hz, IH), 2.57 (t, J= 7.2 Hz, 2H), 1.91 (m, 2H), 1.14 (d, J= 6.4 Hz, 6H); 13 C NMR (125 MHz, CDC13/MeOH-d4) 8 154.0, 152.1, 151.2, 149.7, 148.9,147.5,133.6, 132.0, 119.8, 119.1, 117.9, 115.3, 110.9, 102.1, 49.2, 42.9, 40.8, 28.3, 21.3; HRMS (ESI) m/z [M+H]* caled. for C 2 1

H

25

N

2 0 2 S, 453.1821; found 453.1819; HPLC: method A R, = 5.60, method B Re = 4.87. 9-(3-(isopropylamino)propyl)-8-(6-(5-methylfuran-2-yl)benzo[d] [1,3]dioxol-5-ylthio) 9H-purin-6-anine [DZ3-35]. 4,4,5,5-Tetramethyl-2-(5-methyl-furan-2-yl) (1,3,2)dioxaborolane (21.9 mg, 0.1053 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2 Cl2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 90*C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2 C1 2 :EtOAc:MeOH-NH 3 (7N), 4:9:2:1) to give 11.5 mg (42%) of DZ3-35. 'H NMR (500 MHz, CDC1 3 ) 8 8.25 (s, 1H), 7.19 (s, 1H), 6.84 (s, IH), 6.63 (d, J= 3.1 Hz, 1H), 6.07 (d, J= 2.5 Hz, 1H), 5.98 (s, 2H), 5.93 (br s, 2H), 4.22 (t, J= 6.6 Hz, 2H), 2.94 (in, 1H), 2.59 (t, J= 6.6 Hz, 2H), 2.34 (s, 3H), 2.05 (in, 2H), 1.20 (d, J= 6.3 Hz, 6H); HRMS (ESI) m/z [M+H) calcd. for C 23

H

2 7

N

6 0 3 S, 467.1865; found 467.1869; HPLC: method A R, = 6.49, method B Rt = 7.53. 2-(6-(6-ainino-9-(3-(isopropylamino)propyl)-9H-purin-8-ylthio)benzo[d] [1,3]dioxol-5 yl)acetonitrile [DZ3-39].4-Isoxazoleboronic acid pinacol ester (20.5 mg, 0.1053 mmol) was added to PU-H71 (30 mg, 0.0585 unol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H 2 0 (0.1 mL) and Pd(PPh 3

)

2

C

2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 90"C for 4 h. Solvent was removed under WO 2011/044394 PCT/US2010/051872 86 reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2

CI

2 :EtOAc:MeOH-NH 3 (7N), 2:2:1:0.5) to give 10.3 mg (%) of DZ3-39. 'H NMR (500 MHz, CDC 3 /MeOH-d 4 ) a 8.17 (s, 1H), 7.14 (s, IH), 7.12 (s, 1H), 6.10 (s, 2H), 4.35 (t, J= 6.9 Hz, 2H), 3.99 (s, 2H), 3.08 (septet, J= 6.5 Hz, 1H), 2.82 (t, J= 7.0 Hz, 2H), 2.25 (m, 2H), 1.27 (d, J= 6.5 Hz, 6H); "C NMR (125 MHz, CDCl 3 /MeOH-d4) 8 154.2, 152.1, 152.0, 151.5, 150.8, 148.6, 147.7, 129.5, 119.2, 117.6, 116.2, 110.3, 102.7, 49.8, 42.5, 40.7, 27.7, 22.9, 20.4; HRMS (ESI) m/z [M+H]> called. for C 20

H

24

N

7 0 2 S, 426.1712; found 426.1712; HPLC: method A R, = 5.69, method B R, = 4.57. 8-(6-(1H-pyrrol-3-yl)benzo[d] [1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H purin-6-amine [DZ3-411. 1-Boc-pyrrole-3-boronic acid pinacol ester (30.9 mg, 0.1053 imol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H 2 0 (0.1 mL) and Pd(PPh 3

)

2 C1 2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2

CI

2 :EtOAc:MeOH-NH3 (7N), 2:2:1:0.5) to give 7.9 mg (30%) of DZ3-41. 'H NMR (500 MHz, CDCI 3 /MeOH-d 4 ) 5 8.16 (s, 1H), 7.02 (s, IH), 6.99 (s, iH), 6.86 (m, 1H), 6.76 (in, IH), 6.21 (m, 1H), 6.02 (s, 2H), 4.07 (t, J= 6.9 Hz, 2H), 2.95 (septet, J= 6.4 Hz, 1H), 2.59 (t, J= 7.1 Hz, 2H), 1.96 (m, 2H), 1.19 (d, J= 6.4 Hz, 6H); "C NMR (125 MHz, CDC13/MeOH-d 4 ) 8 154.4, 152.1, 152.0, 151.0, 149.4,146.7, 135.9, 131.6, 122.1, 119.1, 117.8, 117.5, 114.6, 111.0,109.2,101.9,53.6,42.6,40.6, 27.8,20.6; HRMS (ES1) m/z [M+H]* called. for C2H2 6

N

7 0 2 S, 452.1869; found 452.1862; HPLC: method A R = 6.02, method B Rt = 6.27. 9-(3-(isopropylaniino)propyl)-8-(6-(1-methyl-1H-pyrazol-5-y)benzo[d] [1,3]dioxol-5 ylthio)-9H-purin-6-amine [DZ3-441. 1-Methyl-l-H-pyrazole-5-boronic acid pinacol ester (18.2 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the WO 2011/044394 PCT/US2010/051872 87 reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2

C

2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 2 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2 CI2:EtOAc:MeOH-NH 3 (7N), 2:2:1:0.5) to give 20.1 mg (74%) of DZ3-44. 'H NMR (500 MHz, CDCI 3 ) S 8.25 (s, 1H), 7.40 (d, J= 1.8 Hz, IH), 7.05 (s, I H), 6.80 (s, IH), 6.08 (s, 2H), 6.06 (d, J= 1.8 Hz, 1H), 5.91 (br s, 2H), 4.10 (t, J= 6.7 Hz, 2H), 3.67 (s, 3H), 2.85 (septet, J= 6.3 Hz, 1H), 2.53 (t, J= 6.7 Hz, 2H), 1.97 (in, 2H), 1.13 (d, J= 6.3 Hz, 6H);

'

3 C NMR (125 MHz, CDC1 3 ) 8 154.4,152.7, 151.7, 149.3, 149.0, 147.0, 140.6, 138.5, 127.7, 123.3, 120.0, 113.8, 111.7, 107.4,102.5, 49.6, 43.2, 41.1, 37.1, 29.1, 22.0; HRMS (ESI) n/z [M+H]* calcd. for C2H27NsO 2 S, 467.1978; found 467.1985; HPLC: method A R = 5.74, method B R4 = 5.20. 8-(6-(1H-pyrazol-3-yl)benzo[d] [1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H purin-6-amine [DZ3-46]. 1H-pyrazole-3-boronic acid (33 mg, 0.293 mmol) was added to PU-H71 (50 mg, 0.0975 mmol) and NaHCO 3 (24.6 mg, 0.293 mmol). DMF (2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.2 mL) and Pd(PPh 3

)

2

C

2 (7 mg, 0.0098 mmol) were added and the reaction mixture was heated under nitrogen at 90*C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2

CI

2 :EtOAc:MeOH-NH 3 (7N), 2:2:1:0.5) to give 3.7 mg (8%) of DZ3-46. 1H NMR (500 MHz, CDC1 3 /MeOH-d4) 5 8.17 (s, 1H), 7.59 (d, J= 2.0 Hz, 1H), 7.10 (s, I), 7.07 (s, 1H), 6.38 (d, J= 2.0 Hz, IH), 6.08 (s, 2H), 4.19 (t, J= 6.8 Hz, 2H), 3.31 (septet, J= 6.6 Hz, 1H), 2.89 (t, J= 7.2 Hz, 2H), 2.10 (in, 2H), 1.39 (d, J= 6.6 Hz, 6H); 3 C NMR (125 MHz, CDCI 3 /MeOH-d 4 ) 8 154.5, 152.2, 152.1, 150.7, 149.5, 148.5, 148.3, 119.3, 119.1, 114.6, 114.5, 111.0, 110.9, 106.1, 102.3, 51.1, 41.7, 40.3, 26.0, 18.7; HRMS (ESI) m/z [M+H]* calcd. for C 21

H

2 5N 3

O

2 S, 453.1821; found 453.1826; HPLC: method A Rt = 5.65, method B R, = 4.83. 9-(3-(isopropylamino)propyl)-8-(6-(isoxazol-4-yl)benzo[d] [1,3]dioxol-5-ylthio)-9H purin-6-amine [DZ3-49]. 4-Isoxazoleboronic acid pinacol ester (20.5 mg, 0.1053 mmol) was WO 2011/044394 PCT/US2010/051872 88 added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2

C

2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 60 0 C for 4 h. Solvent was removed under reduced pressure and the resulting residue was attempted to be purified by preparatory TLC (hexane:CH 2 Cl 2 :EtOAc:MeOH-NH 3 (7N), 4:7:2:1) to give 7.4 mg (28%) of an inseparable mixture of DZ3-49 and DZ3-39 in a ratio of approximately 71:29, respectively, as determined by HPLC. 'H NMR (500 MHz, CDCl3/MeOH-d4) 6 8.66 (s, IH), 8.45 (s, I H), 8.17 (s, I H), 7.18 (s, IH), 7.01 (s, IH), 6.13 (s, 2H), 4.37 (t, J= 7.0 Hz, 2H), 3.27 (septet, J= 7.1 Hz, IH), 2.89 (t, J= 7.1 Hz, 2H), 2.22 (in, 2H), 1.38 (d, J= 6.5 Hz, 6H); MS (ESI) m/z [M+H]* 454.1; HPLC: method AR, = 5.67 (DZ3-39, 29%) and 5.87 (DZ3-49, 7 1%); method B R, = 4.58 (DZ3-39, 34%) and 5.57 (DZ3-49, 66%). 4-(6-(6-amino-9-(3-(isopropylamino)propyl)-9H-purin-8-ylthio)benzo[d] [1,3]dioxol-5 yl)benzaldehyde [DZ3-50]. 4-Formylphenylboronic acid (13 mg, 0,0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2

C

2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 90*C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2 Cl 2 :EtOAc:MeOH-NH (7N), 2:2:1:0.5) to give 18.8 mg (66%) of DZ3-50. 'H NMR (500 MHz, MeOH-d4) 6 10.01 (s, IH), 8.15 (s, IH), 7.85 (d, J= 8.1 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.14 (s, IH), 6.93 (s, I H), 6.13 (s, 2H), 4.05 (t, J= 6.8 Hz, 2H), 2.99 (septet, J = 6.4 Hz, 1H), 2.62 (t, J= 6.9 Hz, 2H), 1.99 (m, 2H), 1.24 (d, J= 6.4 Hz, 6H); "C NMR (125 MHz, MeOH-d 4 ) 8 192.3, 154.1, 151.9, 151.0, 149.8, 148.8, 148.5, 146.4, 139.5, 135.3, 130.0, 129.4, 119.0,117.7,115.0, 110.8, 102.4, 49.9, 42.2, 40.3, 27.4, 20.2; HRMS (ESI) m/z [M+H]* called. for C 25 H27N 6 0 3 S, 491.1865; found 491.1877; HPLC: method A Rt = 6.23, method B R, = 6.83.

WO 2011/044394 PCT/US2010/051872 89 tert-Butyl 6-(3-(6-aniino-8-(6-(3,5-bis(tritluoromethyl)phenyl)benzo[d][1,3]dioxol-5 ylthio)-9H-purin-9-yl)propylamino)hexylcarbamate [TT-V-43A]. Bis(trifluoromethyl)phenylboronic acid (22.7 mg, 0.0878 mmol) was added to PU-H7 I -C6 linker (39.2 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (l mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2

C

2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90*C for 3 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2

C

2 :MeOH

NH

3 (7N), 10:1) to give 27.7 mg (63%) of TT-V-43A. 'H NMR (500 MHz, CDC 3 ) 5 8.17 (s, 1H), 7.78 (s, 3H), 7.14 (s, IH), 6.89 (s, IH), 6.12 (s, 2H), 5.80 (br s, 2H), 4.68 (br s, 1H), 4.16 (t, J= 6.3 Hz, 2H), 3.10 (m, 2H), 2.81 (t, J= 7.7 Hz, 2H), 2.67 (t, J= 6.2 Hz, 2H), 2.21 (m, 2H), 1.81 (m, 2H), 1.30-1.53 (m, 15H); HRMS (ESI) m/z [M+H]* called. for

C

34

H

40

F

6

N

7 0 4 S, 756.2767; found 756.2753; HPLC: method A 1, = 8.17, method B R 11.00. N'-(3-(6-aino-8-(6-(3,5-bis(trifluoromethyl)phenyl)benzo[dj [1,3]dioxol-5-ylthio)-9H purin-9-yl)propyl)hexane-1,6-diaine [TT-V-47B]. TT-V-43A (26 mg, 0.0344 mmol) was dissolved in CH 2

CI

2 (1.2 mL) and TFA (0.3 mL) was added and stirred at it for 45 min. Then solvent was removed under reduced pressure and residue dried under high vacuum for 2 h to give TT-V-47B. Purified by preparatory TLC (hexane:CH 2 C1 2 :MeOH-NH3 (7N), 7:1) to give mg (%) of TT-V-47B. 'H NMR (500 MHz, CDC1 3 /MeOH-d4) 8 8.04 (s, IH), 7.67 (s, IH), 7.64 (s, 2H), 7.12 (s, 1H), 6.84 (s, 1H), 6.04 (s, 2H), 3.97 (t, J= 6.7 Hz, 2H), 2.85 (t, J= 7.0 Hz, 21), 2.84 (t, J= 6.9 Hz, 2H), 2.77 (t, J= 7.0 Hz, 2H), 2.06 (m, 2H), 1.71 (m, 2H), 1.63 (m, 2H), 1.28 (m, 4H); HRMS (ESI) m/z [M+H]* called. for C 2 9 H32F6N 7 0 2 S, 656.2242; found 656.2242; HPLC: method A Rt = 6.98, method B R = 8.38.

WO 2011/044394 PCT/US2010/051872 90 -oo

NH

2

NH

2 FF Filsi F NHN HN HN PU-DZ13 Reagents and conditions: (a) RB(OI-I) 2 , PdCl 2 (PPh 3

)

2 , NaHC0 3 , H 2 0, DMF, 90*C. Scheme 4. Suzuki coupling of PU-DZ13. 2-fluoro-8-((6-(furan-2-yl)benzo[d] [1,3]dioxol-5-yl)methyl)-9-(2-(isobutylamino)ethyl) 9H-purin-6-amine [DZ3-25]. 2-Furanylboronic acid (9.8 mg, 0.0877 mmol) was added to PU-DZ13 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H 2 0 (0.1 mL) and Pd(PPh 3

)

2

C

2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2

C

2 :MeOH-NH3 (7N), 20:1) to give 19.1 mg (72%) of DZ3-25. 1H NMR (500 MHz, CDC13/MeOH-d4) 8 7.46 (d, J= 1.4 Hz, 1 H), 7.08 (s, 1H), 6.64 (s, 1H), 6.46 (dd, J= 1.4, 3.2 Hz, 1H), 6.34 (d, J= 3.2 Hz, 1 H), 6.00 (s, 2H), 4.34 (s, 2H), 4.08 (t, J= 6.3 Hz, 2H), 2.85 (t, J= 6.3 Hz, 2H), 2.38 (d, J= 6.8 Hz, 2H), 1.70 (m, 1H), 0.88 (d, J= 6.7 Hz, 6H); "C NMR (125 MHz, CDCIJ/MeOH d45) 158.9 (d, J= 208.5 Hz), 156.2 (d, J= 20.2 Hz), 152.6, 152.3 (d, J= 18.3 Hz), 151.9, 147.9, 147.1, 142.1,126.1, 124.3, 115.8, 111.3, 110.0,108.7,108.2,101.6,57.0,48.1,42.3, 32.0, 27.7, 20.2; HRMS (ESI) mn/z [M+H]* called. for C 23

H

26

FN

6 0 3 , 453.2050; found 453.2041; HPLC: method A R = 7.10, method B Re = 8.52.

WO 2011/044394 PCT/US2010/051872 91 2-fluoro-8-((6-(furan-3-yl)benzo[d] [1,3]dioxol-5-yl)methyl)-9-(2-(isobutylamino)ethyl) 9H-purin-6-amine [DZ3-26]. 3-Furanylboronic acid (9.8 mg, 0.0877 mmol) was added to PU-DZ13 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H 2 0 (0.1 mL) and Pd(PPh 3

)

2

C

2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90*C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2

CI

2 :MeOH-NH 3 (7N), 20:1) to give 23.4 mg (88%) of DZ3-26. 'H NMR (500 MHz, CDC 3 ) 8 7.49 (m, 1H), 7.46 (m, IH), 6.82 (s, iH), 6.63 (s, 1H), 6.46 (in, 1H), 5.96 (s, 2H), 5.70 (br s, 2H), 4.22 (s, 2H), 3.91 (t, J= 6.1 Hz, 2H), 2.75 (t, J= 6.1 Hz, 2H), 2.29 (d, J= 6.5 Hz, 2H), 1.70 (m, IH), 0.83 (d, J= 6.7 Hz, 6H); "C NMR (125 MHz, CDC 3 ) 5 158.9 (d, J= 208.5 Hz), 156.2 (d, J = 20.3 Hz), 152.7 (d, J= 18.2 Hz), 152.2, 147.5, 146.9, 143.1, 140.1, 127.0,125.7,124.7, 116.6,111.8, 110.2, 109.4, 101.4,57.5,48.5, 43.0,31.9,28.1, 20.4; HRMS (ESI) m/z [M+H]* called. for C 23

H

26

FN

6 0 3 , 453.2050; found 453.2044; HPLC: method A Rt = 7.10, method B R, = 8.50. 8-((6-(1H-pyrrol-2-yl)benzo[dJ [1,3]dioxol-5-ylmethyl)-2-fluoro-9-(2 (isobutylamino)ethyl)-9H-purin-6-amine [DZ3-31]. 1-N-Boc-pyrrole-2-boronic acid (18.5 mg, 0.0877 mmol) was added to PU-DZ13 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2

C

2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 4 h. DMF was removed under reduced pressure and to the resulting residue was added CH 2

CI

2 (1.5 mL) and TFA (0.3 mL). The mixture was stirred for 5 h at rt, then solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH2C1 2 :EtOAc:MeOH-NH 3 (7N), 4:15:2:1) to give 5.2 mg (20%) of DZ3-31. H NMR (500 MHz, CDCI 3 /MeOH-d) 8 6.91 (s, 1H), 6.84 (dd, J= 1.4,2.5 Hz, 1 H), 6.65 (s, 1H), 6.22 (m, IH), 6.08 (dd, J= 1.4, 3.3 Hz, 1H), 5.97 (s, 2H), 4.26 (s, 2H), 4.06 (t, J= 6.7 Hz, 2H), 2.80 (t, J= 6.7 Hz, 2H), 2.55 (d, J= 7.0 Hz, 2H), 1.88 (m, 1H), 0.96 (d, J= 6.7 Hz, WO 2011/044394 PCT/US2010/051872 92 611); "C NMR (125 MHz, CDC13/MeOH-d 4 ) 8 158.8 (d, J= 208.1 Hz), 156.4 (d, J= 20.0 Hz), 152.9, 152.3 (d, J= 21.2 Hz), 147.4, 129.8, 127.9, 126.7, 118.5, 110.5,109.3, 108.7, 108.6, 101.5,56.6,47.4,41.1, 31.6, 27.1, 20.2; FIRMS (ESI) m/z [M+H] calcd. for

C

23 H27FN 7

O

2 , 452.2210; found 452.2212; HPLC: method A R, = 7.02, method B R,= 8.30. 5-(6-((6-amino-2-fluoro-9-(2-(isobutylanino)ethyl)-9H-purin-8 yl)methyl)benzo[d][1,3]dioxol-5-yl)furan-2-carbaldehyde [DZ3-341. 2-Formyl-5 furanylboronic acid (12.3 mg, 0.0877 mmol) was added to PU-DZ13 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2

C

2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2 Cl 2 :EtOAc:MeOH-NH 3 (7N), 2:2:1:0.5) to give 2.0 mg (7%) of DZ3-34. 'H NMR (500 MHz, CDC1 3 /MeOH-d 4 ) 8 9.47 (s, 1H), 7.27 (d, J= 3.7 Hz, 111), 7.20 (s, 1H), 6.77 (s, 1H), 6.63 (d, J= 3.7 Hz, 111), 6.06 (s, 2H), 4.45 (s, 2H), 4.32 (t, J= 6.3 Hz, 2H), 2.83 (t, J= 6.3 Hz, 2H), 2.54 (d, J= 6.8 Hz, 2H), 1.83 (m, 1H), 0.93 (d, J = 6.7 Hz, 6H); HRMS (ESI) m/z [M+H]* calcd. for C 24

H

2 6

FN

6 0 4 , 481.2000; found 481.1984; HPLC: method A R = 6.61, method B R = 7.62. 8-((6-(1H-pyrazol-4-yl)benzo[dj [1,3]dioxol-5-yl)methyl)-2-fluoro-9-(2 (isobutylamino)ethyl)-9H-purin-6-amine [DZ3-32]. 1 -Boc-pyrazole-4-boronic acid pinacol ester (25.8 mg, 0.0877 mmol) was added to PU-DZ13 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1.5 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.15 mL) and Pd(PPh 3

)

2

C

2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 5 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2

CI

2 :EtOAc:MeOH-NH 3 (7N), 2:2:1:0.5) to give 10.6 mg (40%) of DZ3-32. 'H NMR (500 MHz, CDCl3/MeOH-d) 8 7.50 (s, 2H), 6.83 (s, 1H), 6.69 (s, 1H), WO 2011/044394 PCT/US2010/051872 93 5.98 (s, 2H), 4.18 (s, 211), 4.01 (t, J= 6.6 Hz, 2H), 2.78 (t, J= 6.6 Hz, 211), 2.40 (d, J= 7.0 Hz, 2H), 1.71 (m, 1H), 0.88 (d, J= 6.7 Hz, 6H); "C NMR (125 MHz, CDC1 3 /MeOH-d 4 ) S 158.6 (d, J= 208.3 Hz), 156.3 (d, J= 19.6 Hz), 152.3, 152.1 (d, J= 21.2 Hz), 147.3, 147.1, 126.4, 126.2,120.1, 115.8,110.7,109.9, 101.4,56.3,47.3,40.8,31.9, 27.0,20.0; HRMS (ESI) m/z [M+H]* calcd. for C 2 2

H

26

FN

8

O

2 , 453.2163; found 453.2162; HPLC: method A Rt = 6.23, method B R, = 6.55. 2-fluoro-9-(2-(isobutylamino)ethyl)-8-((6-(5-methylfuran-2-yl)benzo[d][1,3]dioxol-5 yI)methyl)-9H-purin-6-amine [DZ3-361. 4,4,5,5-Tetramethyl-2-(5-methyl-furan-2-yl) (1,3,2)dioxaborolane (21.9 mg, 0.1053 miol) was added to PU-DZ13 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H 2 0 (0.1 mL) and Pd(PPh 3

)

2

C

2 (8 mg, 0.0117 minol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2 C12;EtOAc:MeOH-NH 3 (7N), 4:15:2:1) to give 15.6 mg (57%) of DZ3-36. 'H NMR (500 MHz, CDC1 3 ) 8 7.04 (s, 1H), 6.53 (s, 1H), 6.26 (d, J= 3.1 Hz, 1H), 6.21 (br s, 2H), 6.05 (d, J= 3.1 Hz, 1H), 5.94 (s, 2H), 4.37 (s, 2H), 3.98 (t, J= 6.3 Hz, 2H), 2.80 (t, J= 6.2 Hz, 2H), 2.34 (s, 3H), 2.31 (d, J= 6.8 Hz, 2H), 1.64 (m, IH), 0.83 (d, J= 6.7 Hz, 6H); HRMS (ESI) m/z [M+H]* called. for C 24

H

28

FN

6 0 3 , 467.2207; found 467.2200; HPLC: method A Rt = 7.29, method B Rt = 9.13. 8-((6-(1H-pyrrol-3-yl)benzo[dj [1,3]dioxol-5-yl)methyl)-2-fluoro-9-(2 (isobutylamino)ethyl)-9H-purin-6-aine [DZ3-38]. 1-Boc-pyrrole-3-boronic acid pinacol ester (30.9 mg, 0.1053 mmol) was added to PU-DZ13 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H 2 0 (0.2 mL) and Pd(PPh 3

)

2 C1 2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 90*C for 4 h, then at 120 0 C for 6.5 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2

CI

2 :EtOAc:MeOH-NH 3 (7N), 4:7:2:1) WO 2011/044394 PCT/US2010/051872 94 to give 20.9 mg (79%) of DZ3-38. 'H NMR (500 MHz, CDCI 3 ) 5 8.72 (br s, 1H), 6.85 (s, 1H), 6.83 (in, IH), 6.76 (m, IH), 6.62 (s, IH), 6.34 (br s, 2H), 6.23 (in, IH), 5.91 (s, 2H), 4.29 (s, 2H), 3.84 (t, J= 6.3 Hz, 2H), 2.67 (t, J= 6.3 Hz, 2H), 2.28 (d, J= 6.8 Hz, 2H), 1.60 (in, 1H), 0.82 (d, J=6.6 Hz, 6H); "C NMR (125 MHz, CDC 3 ) 8 158.8 (d, J=208.0Hz), 156.4 (d,J= 19.8 Hz), 153.0, 152.9 (d, J=21.3 Hz), 146.82, 146.76, 130.0, 126.5, 123.3, 118.4, 116.9, 116.6, 110.6,109.8,109.3,101.3, 57.6, 48.7, 43.0, 32.0, 28.3, 20.7; HRMS (ESI) m/z [M+H]* calcd. for C 23 H27FN 7 0 2 , 452.2210; found 452.2204; HPLC: method A Rt = 6.77, method B R, = 7.93. 2-(6-((6-amino-2-fluoro-9-(2-(isobutylamino)ethyl)-9H-purin-8 yI)nethyl)benzo[dJ [1,3jdioxol-5-yl)acetonitrile [DZ3-40]. 4-Isoxazoleboronic acid pinacol ester (20.5 mg, 0.1053 mmol) was added to PU-DZ13 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2 Cl 2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2

CI

2 :EtOAc:MeOH-NH (7N), 4:7:2:1) to give 8.3 mg (%) of DZ3-40. 'H NMR (500 MHz, CDC13/MeOH-d 4 ) 5 6.94 (s, 1H), 6.70 (s, 1H), 6.00 (s, 2H), 4.39 (t, J= 6.7 Hz, 2H), 4.31 (s, 2H), 3.84 (s, 2H), 3.18 (t, J= 6.6 Hz, 2H), 2.65 (d, J= 7.1 Hz, 2H), 1.94 (in, iH), 0.99 (d, J= 6.7 Hz, 6H); "C NMR (125 MHz, CDC1 3 / MeOH-d 4 ) S 158.7 (d, J= 210.4 Hz), 156.6 (d, J= 20.1 Hz), 152.1 (d, J= 18.2 Hz), 150.5, 148.1, 147.7, 126.7, 122.4, 117.9, 116.1,110.6,109.9,101.8,56.5, 47.4, 41.2,31.3,27.1, 21.5, 20.0; HRMS (ESI) mlz [M+H]* calcd. for C 21

H

25 FN70 2 , 426.2054; found 426.2048; HPLC: method A Rt = 6.48, method B Rt = 7.10. 8-((6-(1H-pyrazol-3-yl)benzo[dJ [1,3]dioxol-5-yl)methyl)-2-fluoro-9-(2 (isobutylamino)ethyl)-9H-purin-6-amine [DZ3-43]. IH-pyrazole-3-boronic acid (11.8 mg, 0.1053 mmol) was added to PU-DZ13 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction WO 2011/044394 PCT/US2010/051872 95 mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2 Cl 2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 4.5 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2 C1 2 :EtOAc:MeOH-NH 3 (7N), 2:2:1:0.5) to give 3.5 mg (13%) of DZ3-43. 'H NMR (500 MHz, CDCly/MeOH-d) $ 7.63 (d, J= 2.15 Hz, 1H), 6.95 (s, IH), 6.82 (s, 1H), 6.34 (d, J= 2.15 Hz, 1H), 6.01 (s, 2H), 4.35 (t, J= 6.8 Hz, 2H), 4.29 (s, 2H), 2.98 (t, J= 6.9 Hz, 2H), 2.64 (d, J= 7.0 Hz, 2H), 1.96 (m, 1H), 0.99 (d, J= 6.7 Hz, 6H); 1 3 C NMR (125 MHz, CDCI 3 / MeOH-d 4 ) 6 158.8 (d, J= 208.7 Hz), 156.6 (d, J= 19.3 Hz), 152.4, 152.2 (d, J = 18.7 Hz), 148.3, 147.3, 127.1, 115.94, 115.93, 110.3, 110.1,105.6, 101.8,56.3, 47.4,40.5, 31.5, 27.0, 20.2; HRMS (ESI) m/z [M+H]* called. for C 22

H

26

FN

8 0 2 , 453.2163; found 453.2149; HPLC: method A R, = 6.37, method B R, = 6.93. 2-fluoro-9-(2-(isobutylamino)ethyl)-8-((6-(1-methyl-1H-pyrazol-5 yl)benzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-6-amine [DZ3-451. 1-Methyl-I-H-pyrazole 5-boronic acid pinacol ester (18.2 mg, 0.0877 mmol) was added to PU-DZ13 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2

C

2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 2 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2

CI

2 :EtOAc:MeOH-NH 3 (7N), 4:7:2:1) to give 26.5 mg (97%) of DZ3-45. 'H NMR (500 MHz, CDC 3 ) 6 7.49 (d, J= 1.5 Hz, IH), 6.76 (s, 1H), 6.74 (s, 1H), 6.28 (br s, 2H), 6.17 (d, J= 1.5 Hz, 1H), 6.01 (s, 2H), 3.99 (s, 2H), 3.90 (t, J= 6.3 Hz, 2H), 3.66 (s, 3H), 2.76 (t, J= 6.3 Hz, 2H), 2.31 (d, J= 6.8 Hz, 2H), 1.72 (m, 1H), 0.84 (d, J= 6.7 Hz, 6H); 1 3 C NMR (125 MHz, CDCl 3 ) 8 159.0 (d, J= 208.7 Hz), 156.4 (d, J= 20.0 Hz), 152.8 (d, J= 18.5 Hz), 151.5, 149.0, 147.1, 141.3, 138.8, 129.4, 123.4, 116.6, 110.7,109.9,106.9, 101.9, 57.8, 48.7, 43.1, 36.9, 31.8, 28.3, 20.6; HRMS (ESI) m/z [M+H]*calcd. for C 23

H

28 FNO2, 467.2319; found 467.2323; HPLC: methodA R,=6.37, method B R, = 6.90.

WO 2011/044394 PCT/US2Olo/051872 96 2-fluoro-9-(2-(isobutylamino)ethyl)-8-((6-(thiophen-2-yl)benzo[d] [1,3]dioxol-5 yl)methyl)-9H-purin-6-amine [DZ3-48]. 2-Thienylboronic acid (11.2 mg, 0.0877 mmol) was added to PU-DZ13 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H 2 0 (0.1 mL) and Pd(PPh) 2 Cl 2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 2 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2

CI

2 :EtOAc:MeOH-NH (7N), 2:2:1:0.5) to give 18.3 mg (67%) of DZ3-48. 'H NMR (500 MHz, CDC1 3 /MeOH-d 4 ) 6 7.31 (d, J= 5.0 Hz, 1H), 7.03 (dd, J= 3.1, 5.0 Hz, 1H), 6.92 (s, 1H), 6.87 (d, J= 3.0 Hz, 1H), 6.74 (s, 1H), 6.01 (s, 2H), 4.19 (s, 2H), 3.99 (t, J= 6.5 Hz, 2H), 2.78 (t, J= 6.5 Hz, 2H), 2.37 (d, J= 6.9 Hz, 2H), 1.70 (m, 1H), 0.88 (d, J= 6.7 Hz, 6H); ' 3 C NMR (125 MHz, CDC13/MeOH-d4) 8 158.7 (d, J= 209.4 Hz), 156.4 (d, J= 19.6 Hz), 152.21 (d, J= 18.4 Hz), 152.20, 148.1, 147.0, 141.5, 127.7, 127.3, 127.0, 126.0,125.8, 115.9,111.3, 110.0, 101.6, 57.1, 48.1, 42.2, 32.0, 27.8, 20.3; HRMS (ESI) m/z [M+H]* calod. for C23H26FNO 2 S, 469,1822; found 469.1830; HPLC: method A R, = 7.21, method B Rt = 8.93. 2-fluoro-9-(2-(isobutylamino)ethyl)-8-((6-(isoxazol-4-yl)benzo[d][1,3]dioxol-5 yl)methyl)-9H-purin-6-amine [DZ3-51]. 4-Isoxazoleboronic acid pinacol ester (20.5 mg, 0.1053 mmol) was added to PU-DZ13 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2 Cl 2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 60 0 C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH2Cl 2 :EtOAc:MeOH-NH (7N), 2:2:1:0.5) to give 7.8 mg (29%) of an inseparable mixture of DZ3-51 and DZ3-40 in a ratio of approximately 44:56, respectively, as determined by HPLC. MS (ESI) m/z [M+H]* 454.4; HPLC: method A Rt = 6.46 (DZ3-40, 56%) and 6.65 (DZ3-51, 44%); method B R, = 7.08 (DZ3-40, 65%) and 7.52 (DZ3-51, 35%).

WO 2011/044394 PCT/US2010/051872 97 NH, NH, N N N NN N N N >-s R S NN HN HN PU-HZ151 Reagents and conditions: (a) RB(OH) 2 , PdC 2 (PPh 3

)

2 , NaHCO 3 , H 2 0, DMF, 90*C. Scheme 5. Suzuki coupling of PU-HZ151. 8-(6-(furan-2-yl)benzo[d][1,3]dioxol-5-ylthio)-9-(2-(neopentylamino)ethyl)-9H-purin-6 amine [TT5-53A]. 2-Furanylboronic acid (42.4 mg, 0.379 mmol) was added to PU-HZ151 (66.4 mg, 0.126 nhmol) and NaHCO 3 (63.6 mg, 0.756 mmol). DMF (2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.4 nL) and Pd(PPh 3

)

2 Cl2 (17.6 mg, 0.025 mmol) were added and the reaction mixture was heated under nitrogen at 90*C for 3.5 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2

CI

2 :MeOH-NH 3 (7N), 20:1) to give 25.2 mg (43%) of TT5-53A. 'H NMR (500 MHz, CDCl3) 3 8.30 (s, IH), 7.49 (d, J= 1.3 Hz, 111), 7.17 (s, 1H), 6.84 (s, IH), 6.75 (d, J= 3.3 Hz, 1H), 6.48 (dd, J= 1.8, 3.3 Hz, IH), 5.97 (s, 2H), 5.89 (br s, 2H), 4.18 (t, J= 6.5 Hz, 211), 2.86 (t, J= 6.5 Hz, 2H), 2.25 (s, 211), 0.83 (s, 9H); 13 C NMR (125 MHz, CDC 3 ) 5 154.6, 153.0, 151.7, 151.1, 148.4, 147.9, 146.8, 142.2, 127.2, 120.8, 120.0,112.8,111.5, 110.0, 108.7, 101.9, 61.9, 49.6, 43.9, 31.5, 27.6; HRMS (ESI) m/z [M+H]* calcd. for C23H27N 6

O

3 S, 467.1865; found 467.1870; HPLC: method AR, = 6.78, method B R, = 7.83.

WO 2011/044394 PCT/US2010/051872 98 8-(6-(5-methylfuran-2-yl)benzo[d] [1,3]dioxol-5-ylthio)-9-(2-(neopentylamino)ethyl)-9H purin-6-anine [DZ3-56]. 4,4,5,5-Tetramethyl-2-(5-methyl-furan-2-yl)-(1,3,2)dioxaborolane (17.7 mg, 0.0853 mmol) was added to PU-HZ151 (30 mg, 0.0569 mmol) and NaHCO 3 (14.3 mg, 0.1707 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2 C1 2 (8 mg, 0.0113 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 4.5 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2 C12:MeOH-NH 3 (7N), 15:1) to give 9.3 mg (34%) of DZ3-56. 'H NMR (500 MHz, CDCl 3 /MeOH-d 4 ) 5 8.19 (s, 1H), 7.24 (s, 1H), 6.89 (s, IH), 6.62 (d, J= 3.2 Hz, 1H), 6.05 (d, J= 3.2 Hz, 1H), 6.03 (s, 2H), 4.36 (t, J= 6.0 Hz, 2H), 3.04 (t, J= 6.0 Hz, 2H), 2.47 (s, 2H), 2.33 (s, 3H), 0.95 (s, 9H); "C NMR (125 MHz, CDC 3 /MeOH-d 4 ) 8 154.5, 152.4, 152.3, 151.2, 149.4, 149.2, 148.5, 147.7, 129.1, 119.4, 117.4, 114.3, 111.2, 1086, 107.8, 102.2, 61.4, 49.3, 43.2, 31.4, 27.7, 13.7; HRMS (ESI) m/z [M+H]* calcd. for C2 4

H

29

N

6 0 3 S, 481.2022; found 481.2002; HPLC: method A R = 6.89, method B R, = 7.58. 9-(2-(neopentylamino)ethyl)-8-(6-(thiophen-2-yl)benzo[d] [1,3]dioxol-5-ylthio)-9H-purin 6-amine [DZ3-58]. 2-Thiopheneboronic acid (10.9 mg, 0.0853 mmol) was added to PU HZ151 (30 mg, 0.0569 mmol) and NaHCO 3 (14.3 mg, 0.1707 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2 C1 2 (8 mg, 0.0113 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2 C1 2 :MeOH-NH3 (7N), 20:1) to give 16.0 mg (58%) of DZ3-58. 'H NMR (500 MHz, CDC13/MeOH-d) 8 8.18 (s, 1H), 7.32 (dd, J= 1.6,4.7 Hz, 1H), 6.98-7.03 (m, 411), 6.07 (s, 211), 4.29 (t, J= 5.4 Hz, 2H), 3.03 (t, J= 5.4 Hz, 211), 2.48 (s, 211), 0.97 (s, 9H); "C NMR (125 MHz, CDCI 3 /MeOH d 4 ) 8 154.3, 152.0, 150.8, 149.2, 148.9, 148.3, 140.5, 132.5,127.8, 127.0, 126.3, 120.1, 119.2,114.4, 111.8, 102.2, 61.1, 49.0, 42.9, 31.2, 27.6; HRMS (ESI) nz [M+H]* calcd. for C23H27N602S2, 483.1637; found 483.1621; HPLC: method A R, = 7.14, method B R, = 7.73.

WO 2011/044394 PCT/US2010/051872 99 8-(6-(1H-pyrrol-3-yI)benzo[d] [1,3]dioxol-5-ylthio)-9-(2-(neopentylaniino)ethyl)-9H purin-6-amine [DZ3-59]. 1-Boc-pyrrole-3-boronic acid pinacol ester (25 mg, 0.0853 mmol) was added to PU-HZ151 (30 mg, 0.0569 mmol) and NaHCO 3 (14.3 mg, 0.1707 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2

C

2 (8 mg, 0.0113 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2

C

2 :MeOH

NH

3 (7N), 20:1) to give 10.1 mg (38%) of DZ3-59. 1 H NMR (500 MHz, CDC 3 /MeOH-ds) S 8.15 (s, 1H), 7.03 (s, 1H), 6.95 (s, iH), 6.85 (in, 1H), 6.76 (in, IH), 6.20 (dd, J= 1.7, 2.4 Hz, 1H), 6.01 (s, 2H), 4.24 (t, J= 5.7 Hz, 2H), 2.98 (t, J= 5.7 Hz, 2H), 2.50 (s, 2H), 0.98 (s, 9H); "C NMR (125 MHz, CDC1 3 /MeOH-d4) 8 154.3, 152.1, 149.6, 149.3, 146.8, 135.7, 122.3, 119.3, 118.6, 117.9, 117.4, 114.5, 111.1, 109.4, 101.9, 61.0, 49.3,42.7, 31.2, 27.7; HRMS (ESI) m/ 1 z [M+H]* calcd. for C23H 2 8

N

7 0 2 S, 466.2025; found 466.2016; HPLC: method A R = 6.86, method B R, = 7.20. 8-(6-(furan-3-yl)benzo[dJ [1,3]dioxol-5-ylthio)-9-(2-(neopentylamino)ethyl)-9H-purin-6 amine [DZ3-601. 3-Furanylboronic acid (9.5 mg, 0.0853 mmol) was added to PU-HZ151 (30 mg, 0.0569 mmol) and NaHCO 3 (14.3 mg, 0.1707 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2

C

2 (8 mg, 0.0113 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH2CI 2 :MeOH-NH 3 (7N), 20:1) to give 13.8 mg (52%) of DZ3-60. 'H NMR (500 MHz, CDCI3/MeOH-d4) 5 8.17 (s, 1H), 7:50 (s, 1H), 7.43 (d, J= 1.5 Hz, 1H), 7.02 (s, 1H), 6.94 (s, 1H), 6.49 (d, J= 1.5 Hz, I), 6.06 (s, 2H), 4.29 (t, J = 5.9 Hz, 2H), 3.02 (t, J= 5.8 Hz, 2H), 2.46 (s, 2H), 0.94 (s, 9H); ' 3 C NMR (125 MHz, CDC1/MeOH-d,) 8 154.3, 152.0, 151.1, 149.6, 149.3, 147.9, 142.8, 140.6,131.5, 124.3, 119.3,118.8, 114.7, 111.7, 110.9, 102.2, 61.4, 49.1, 43.0, 31.3, 27.6; HRMS (ES) m/z

[M+H]

t called. for C23H27N 6

O

3 S, 467.1865; found 467.1845; HPLC: method A R = 6.65, method B R, 7.09.

WO 2011/044394 PCT/US2010/051872 100 8-(6-(1H-pyrazol-3-yI)benzo[d] [1,3]dioxol-5-ylthio)-9-(2-(neopentylamino)ethyl)-9H purin-6-amine [DZ3-61]. 1H-Pyrazole-3-boronic acid (19 mg, 0.1707 mmol) was added to PU-HZ151 (30 mg, 0.0569 mmol) and NaHCO 3 (14.3 mg, 0.1707 umol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2

C

2 :MeOH-NH3 (7N), 15:1) to give 6.5 mg (25%) of DZ3-61. 'H NMR (500 MHz, CDCI 3 /MeOH-d 4 ) 6 8.18 (s, 1H), 7.58 (d, J= 2.0 Hz, 1H), 7.05 (s, 2H), 6.40 (d, J= 2.0 Hz, 1H), 6.06 (s, 2H), 4.36 (t, J = 6.0 Hz, 2H), 3.01 (t, J= 6.0 Hz, 2H), 2.51 (s, 2H), 0.97 (s, 9H; "C NMR (125 MHz, CDCI3/MeOH-d4) 5 154.6, 152.3, 150.8, 149.4,148.6,148.5,120.1, 119.2,114.5,110.9, 106.0, 102.3, 61.2, 49.1, 42.5, 31.1, 27.5; HRMS (ESI) m/z [M+Hf+ called. for C 22

H

27

N

8 0 2 S, 467.1978; found 467.1972; HPLC: method A R, = 6.50, method B Rt = 6.61.

WO 2011/044394 PCT/US2010/051872 101

NH

2 ab N N N

H

2 N I N N s6-1 S6-2 S6-3

NH

2 N Nf N 2 -S N H 0 N N 0 H 86-4 6-5 d, e d, e

NH

2 NN

NH

2 K > _\/ NN N (§,=12 0 N N RHN 1, 2)n1,2 RHN S64 PU-WS4 n= 2, R= isopropyl PU-WS9 n= 1, R= isobutyl PU-WS21 n= 1, R= neopentyl Reagents and conditions: (a) NaNO 2 , KI, AcOH/TFA, 0*C; (b) 8-mercaptoadenine, Cs 2

CO

3 , PdCl 2 (dppf), DMF, 80*C, 48h; (c) NIS, TFA, CH 3 CN, rt, 2h ;(d) 1,3-dibromopropane or 1,2 dibromoethane, Cs 2

CO

3 , DMF, rt; (e) isopropylamine or isobutylamine or neopentylamine, DNF, rt; (f) DDQ, dioxane, 100 0 C. Scheme 6. Synthesis of PU-WS4, PU-WS9 and PU-WS21. 6-iodo-2,3-dihydrobenzofuran (S6-2). A solution of 2,3-dihydrobenzofuran-6-amine (S6-1; 0.74 g, 5.5 mmol) in acetic acid (25 mL) and TFA (2 mL) was cooled in an ice bath for 5 minutes. NaNO 2 (0.454g, 6.6 mmol) was added in 3 portions followed by KI (2.73 g, 16.4 mmol). The resulting mixture was stirred at 0*C for 15 minutes and quenched with H20 (20 mL). The mixture was extracted with EtOAc (3 x 150 mL) and the organic layer was washed WO 2011/044394 PCT/US2010/051872 102 with NaS 2

O

3 , brine, dried over MgSO 4 and filtered. The filtrate was condensed under reduced pressure and the residue was purified by flash chromatography (hexane:EtOAc, 90:10 to 40:60) to yield S6-2 (0.82 g, 61%) as a pale-yellow solid. 'H NMR (500 MHz, CDC) 8 7.14 (d, J= 7.6 Hz, 1H), 7.11 (s, 1H), 6.89 (d, J= 7.6 Hz, iH), 4.54 (t, J= 8.7 Hz, 2H), 3.14 (t, J= 8.7 Hz, 2H); "C NMR (125 MHz, CDC1 3 ) 8 161.1, 129.4, 127.1, 126.4, 118.7,91.7,71.6, 29.4. 8-(2,3-dihydrobenzofuran-6-ylthio)-9H-purin-6-amine (S6-3). To a solution of S6-2 (50 mg, 0.2 mmol) in DMF (2 mL) was added 8-mercaptoadenine (34 mg, 0.2 mmol), Cs 2

CO

3 (99.4 mg, 0.3 mmol) and PdC1 2 (dppf) (33 mg, 0.02 mmol). The mixture was degassed for 5 minutes with argon and stirred at 80 *C under argon protection for 48 h. The resulting mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (CH 2 Cl 2 :MeOH, 100:0 to 90:10) to yield S6-3 (25 mg, 44%) as a yellow solid. 'H NMR (500 MHz, CD 3 0D) a 8.14 (s, 1H), 7.24 (d, J= 7.6 Hz, IH), 7.07 (d, J= 7.3 Hz, 1H), 6.97 (s, IH), 4.62 (t, J= 8.7 Hz, 2H), 3.25 (t, J= 8.7 Hz, 2H); MS (ESI) m/z 285.8 [M+H]; HRMS (ESI) m/z [M+H]* called. for C 13

H

1 2

N

5 0S, 286.0763; found 286.0768. 8-(5-iodo-2,3-dihydrobenzofuran-6-ylthio)-9H-purin-6-ainne (S6-4) To a solution of S6 3 (40 mg, 0.14 mmol) in 6 mL of acetonitrile was added TFA (40 pL) and NIS (63 mg, 0.28 mmol). The resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography

(CH

2

CI

2 :MeOH, 100:0 to 90:10) to afford S6-4 (48 mg, 53%) as a yellow gum. 'H NMR (500 MHz, CDCl 3 ) 8 8.26 (s, 1H), 7.79 (s, 1H), 7.12 (s, iH), 4.65 (t, J= 8.8 Hz, 2H), 3.28 (t, J= 8.7 Hz, 2H); MS (ESI) m/z 412.0 (M+H)*. 8-(5-iodo-2,3-dihydro-benzofuran-6-ylsulfanyl)-9-(3-isopropylaniino-propyl)-9H-purin 6-ylamine (PU-WS4). A mixture of S6-4 (54 mg, 0.13 mmol), Cs 2

CO

3 (127 mg, 0.39 mmol) and 1,3-dibromopropane (202 mg, 0.65 mmol) in anhydrous DMF (2 mL) was stirred at rt for 2 h. Solvent was removed under reduced pressure and the residue purified by chromatography (CH 2

C

2 :MeOH:AcOH). The resulting solid was dissolved in DMF (2 mL) and isopropylamine (0.347 g, 0.5 mL, 5.9 mmol) was added and the solution stirred overnight WO 2011/044394 PCT/US2010/051872 103 at rt. The reaction afforded PU-WS4 (13 mg, 20%; over two-steps) as a yellow solid after purification. 'H NMR (500 MHz, CDCI 3

/CD

3 OD) 8 8.26 (s, 1H), 7.77 (s, 1H), 7.07 (s, IH), 4.65 (t, J= 8.7 Hz, 2H), 4.47 (t, J= 6.9 Hz, 2H), 3.20-3.33 (m, 3H), 3.01 (t, J= 7.5 Hz, 2H), 2.33 (m, 2H), 1.34 (d, J= 6.5 Hz, 6H); MS (ESI) m/z 511.2 [M+H]*; HRMS (ESI) m/z [M+H]* calcd. for C 1 9H 2 4INOS, 511.0777; found 511.0779. 8-(5-iodo-2,3-dibydro-benzofuran-6-ylsulfanyl)-9-(2-isobutylamino-ethyl)-9H-purin-6 ylamine (PU-WS9). A mixture of S6-4 (30 mg, 0.073 mmol), Cs 2

CO

3 (71 mg, 0.22 mmol) and 1,2-dibromoethane (69 mg, 0.365 mmol) in anhydrous DMF (1 mL) was stirred at rt for 2 h. Solvent was removed under reduced pressure and the residue purified by chromatography

(CH

2 Cl 2 :MeOH:AcOH). The resulting solid was dissolved in DMF (2 mL) and isobutylamine (0.241 g, 0.33 mL, 3.3 mmol) was added and the solution stirred overnight at rt. The reaction afforded PU-WS9 (15 mg, 40%; over two-steps) as a pale yellow solid. 'H NMR (500 MHz, CDCl 3 ) 6 8.26 (s, 1H), 7.63 (s, 1H), 6.56 (s, 1H), 6.27 (br s, 2H), 4.57 (t, J= 8.5 Hz, 2H), 4.50 (t, J= 5.5 Hz, 2H), 3.20 (t, J= 8.5 Hz, 2H), 3.12 (t, J= 5.5 Hz, 2H), 2.59 (d, J= 7 Hz, 2R), 1.99 (m, 1R), 0.97 (d, J=7 Hz, 6H); HRMS (ESI) m/z [M+H]* called. for C19H24IN 6 OS, 511.0777; found 511.0790. 8-((5-iodo-2,3-dihydrobenzofuran-6-yl)thio)-9-(2-(neopentylamino)ethyl)-9H-purin-6 amine (PU-WS21). Following the procedure to make PU-WS9, compound PU-WS21 was obtained as a white solid. 'HNMR (500 MHz, CDC1 3 , 6): 7.56 (s, 1H), 6.60 (s, IH), 4.47 (t, J = 8.7 Hz, 2H), 4.37 (m, 2H), 3.06-3.11 (m, 4H), 2.45 (s, 2H), 0.83 (s, 9H); HRMS (m/z): [M+H]* calcd for C 20

H

2 INOS 525.0933; found 525.0927.

WO 2011/044394 PCT/US2010/051872 104

NH

2

H

2 N S b N--N N -/ HNN N S6-1 87-1 S7-2

NH

2

NH

2 -H N- O -s o N 2 N 1- _._b _ / N ,N N' N N HN S7-3 Br HN 87-4 PU-WS1o Reagents and conditions: (a) NIS, CH 3 CN, 0*C, 20 min.; (b) 8-mercaptoadenine, neocuproine, CuI, NaOt-Bu, DMF, I 10C; (c) NaNO 2 , KI, AcOH/TFA, 0*C; (d) 1,3-dibromopropane, Cs 2

CO

3 , DMF, rt; (e) isopropylamine, DMF, rt. Scheme 7. Synthesis of PU-WSIO. 5-iodo-2,3-dihydrobenzofuran-6-amine (S7-1). To a solution of 2,3-dihydrobenzofuran-6 amine (S6-1; 95 mg, 0.7 mmol) in acetonitrile (3 mL) cooled in an ice-bath was added NIS (158 mg, 0.7 mmol). After stirring at 0 *C for 20 min, the mixture was condensed and purified by flash chromatography (hexane:EtOAc, 90:10 to 20:80) to yield S7-1 (180 mg, 98%) as a yellow solid, 'H NMR (500 MHz, CDC1 3 ) 8 7.38 (s, 1H), 6.26 (s, 1H), 4.53 (t, J= 8.5 Hz, 2H), 3.09 (t, J= 8.4 Hz, 2H); MS (ESI) m/z 261.9 [M+H]*. 8-(6-amino-2,3-dihydrobenzofuran-5-ylthio)-9H-purin-6-amiine (S7-2). The mixture of S7-1 (80 mg, 0.31 mmol), 8-mercaptoadenine (52 mg, 0.3 nmol), neocuproine (7 mg, 0.03 mnol), CuI (7 mg, 0.03 mmol) and sodium t-butoxide (100 mg, 1.04 mnol) was suspended in 10 mL of DMF and stirred at 110 *C overnight. The mixture was concentrated under reduced pressure and the residue purified by flash chromatography (hexane:EtOAc, 90:10 to 20:80) to yield S7-2 (50 mg, 56%) as a pale yellow solid. 'H NMR (500 MHz, CDC1 3 ) 8 8.15 WO 2011/044394 PCT/US2010/051872 105 (s, 1H), 7.33 (s, 1H), 6.35 (s, IH), 4.57 (t, J= 8.5 Hz, 2H), 3.14 (t, J= 8.4 Hz, 2H); MS (ESI) m/z 301.0 [M+H]*. 8-(6-iodo-2,3-dihydrobenzofuran-5-ylthio)-9H-purin-6-amine (S7-3). To a solution of S7-2 (25 mg, 0.08 mmol) in acetic acid/TFA (5 mL/I mL) cooled in ice-bath was added NaNO 2 (7 mg, 0.1mmol) and KI (27 mg, 0.16 mmol). The mixture was stirred at 0 0 C for 10 minutes and condensed under reduced pressure. The residue was purified by flash chromatography (CH 2 CI2:MeOH, 100:0 to 90:10) to yield S7-3 (13 mg, 41%) as a yellow solid. 'H NMR (500 MHz, CD 3 0D) 8 8.13 (s, 1H), 7.57 (s, 1H), 7.44 (s, 1 H), 4.66 (t, J= 8.5 Hz, 2H), 3.22 (t, J= 8.6 Hz, 2H); MS (ESI) m/z 411.9 [M+H]*. 9-(3-bromopropyl)- 8-(6-iodo-2,3-dihydrobenzofuran-5-ylthio)-9H-purin-6-amine (S7 4). To a solution of S7-3 (13 mg, 0.03 mmol) in DMF (2 mL) was added 1,3-dibromopropane (16 ptL, 0.16 mmol) and Cs 2

CO

3 (20 mg, 0.06 mmol) and the resulting mixture was stirred at rt for 40 minutes. The mixture was condensed under reduced pressure and the residue was purified by flash chromatography to yield S7-4 (6.2 mg, 34%). 'H NMR (500 MHz, CDC 3 ) 8 8.31 (s, 1H), 7.37 (s, 2H), 6.00 (br s, 2H), 4.62 (t, J= 8.7 Hz, 2H), 4.36 (t, J= 6.7 Hz, 2H), 3.42 (t, J= 6.2 Hz, 2H), 3.18 (t, J= 8.9 Hz, 2H), 2.39 (m, 2H); MS (ESI) m/z 531.9/5 3 3.9 [M+H]*. 8-(6-iodo-2,3-dihydro-benzofuran-5-ylsulfanyl)-9-(3-isobutylamino-ethyl)-9H-purin-6 ylamine (PU-WS10). A solution of S7-4 (6.2 mg, 0.012 mmol) and isopropylamine (0.2 mL) in DMF (1 mL) was stirred for 12 h. Solvent was removed under reduced pressure and the residue purified by preparative thin layer chromatography (CHC1 3 :MeOH-NH 3 (7N), 20:1) to afford PU-WS1O (4.0 mg, 60%) as a pale yellow solid. 'H NMR (400 MHz, CDC 3 ) 8 8.27 (s, 1H), 7.69 (s, 1H), 7.27 (s, 1H), 5.93 (br s, 2H), 4.66 (t, J= 8.8 Hz, 2H), 4.29 (t, J= 7 Hz, 2H), 3.33 (t, J= 8.7 Hz, 2H), 2.74 (septet, J= 6.2 Hz, 1H), 2.58 (t, J= 6.8 Hz, 2H), 1.98 (in, 2H), 1.05 (d, J= 6.5 Hz, 6H); 3 C NMR (100 MHz, CDC1 3 ) 8 162.0, 154.4, 152.7, 151.9, 147.8, 141.7, 130.2, 128.6, 121.1, 120.0, 74.1, 71.7, 48.9, 44.0,41.6, 30.9, 30.2; MS (ESI) m/z 511.1 [M+H]*.

WO 2011/044394 PCT/US2010/051872 106

NH

2

NH

2 N a,b, c N N N X1 x N N x2 N or a, d,c ora,d,e,c /n=1,2 RHN RHN PU-DZ8 X 1

=CH

2 , X 2 =F, n= 2, R= isopropyl PU-WS3 X,=CH 2 , X 2 =F, X=CN, n=2, R= isopropyl PU-H71 X 1 =S, X 2 =H, n= 2, R= isopropyl PU-WSS X 1 =S, X 2 =H, X 3 =CN, n= 2, R= isopropyl PU-HZ150 X1=S, X2=H, n= 1, R= isobutyl PU-WS6 X1=S, X 2 =H, X 0=CCt-Bu, n= 2, R= isopropyl PU-HZ151 X 1 =S, X=H, n1, R= isopetyl PU-WS7 X 1 =S, X 2 =H, X 3 =CCPh, n= 2 R= isopropyl PU-Z151 X 1 =S, X2=H, n= 1, R= neopentyl PU-WS8 X1=S, X2=H, X 3 =CCH, n= 2, R= isopropyl PU-DZ13 Xi=C-, X 2 =F, n= 1, R= isobutyl PU-WSI X 1 =S, X2=H, X=CCH, n= 1, R= isobutyl PU-WS19 X 1 =S, X2=H, X=CCH, n= 1, R= neopentyl PU-WS20 X 1

=CH

2 , X 2 =F, X 3 =CCH, n= 1, R= isobutyl Reagents and conditions: (a) Boc 2 O, Et 3 N, THF, rt, 12h; (b) PdCl2(dppf), Zn(CN) 2 , Zn, DMF, 130*C; (c) 10% TFA-CH 2 C1 2 , rt, 2-5h; (d) CuI, PdCI 2 (PPh 3 )2, t-butylacetylene or phenylacetylene or trimethylsilanylacetylene, Et 3 N, DMF, 90*C, 24h; (e) KOH, MeOH, rt, 2h. Scheme 8. Synthesis of PU-WS3, PU-WS5, PU-WS6, PU-WS7 and PU-WS8, PU-WS16, PU-WS19 and PU-WS20. 6-[6-anino-2-fluoro-9-(3-isopropylanino-propyl)-9H-purin-8-ylmethyl] benzo[1,3]dixole-5-carbonitrile (PU-WS3). A solution of PU-DZ8 (118 mg, 0.231 mmol), (Boc) 2 0 (55 mg, 0.254 mol) and triethylamine (16 mg, 0.231 mmol) in THF (2 mL) was stirred at room temperature for 12 h. Following solvent removal, the residue was purified by preparative thin layer chromatography (CHC 3 :MeOH-NH 3 (7N), 20:1) to afford Boc protected PU-DZ8 (120 mg, 85%; MS (ESI) m/z 613.05 [M+H]'). To a solution of Boc protected PU-DZ8 (26 mg, 0.04 mmol) in DMF (3 mL) was added PdCl 2 (dppf) (17 mg, 0.02 mmol), Zn(CN) 2 (10 mg, 0.08 mmol) and Zn (3 mg, 0.04 mL) and the resulting mixture was stirred at 130"C overnight. The reaction mixture was condensed under reduced pressure and the residue was purified by flash chromatography (CHCI 3 :MeOH-NH 3 (7N), 20:1) to yield Boc-protected PU-WS3 as a white solid. To a solution of this in 2 mL of CH 2 Cl 2 was added WO 2011/044394 PCT/US2Olo/051872 107 0.2 mL of TFA and the mixture was stirred at room temperature for 5 h. The reaction mixture was condensed under reduced pressure and the residue purified by flash chromatography

(CHCI

3 :MeOH-NH 3 (7N), 20:1) to yield PU-WS3 as a white solid in quantitative yield (12 mg, 59% for three steps). 'H NMR (500 MHz, CD 3 0D) 8 7.13 (s, 1H), 6.96 (s, IH), 6.03 (s, 2H), 4.31 (s, 2H), 4.25 (t, J= 7 Hz, 211), 3.26 (m, 1H), 3.01 (t, J= 7.5 Hz, 2H), 2.14 (m, 2H), 1.23 (d, J= 6.5 Hz, 6H); 13 C NMR (125 MHz, CD 3 0D) 5 160.4 (d, J= 208 Hz), 158.5 (d, J 19 Hz), 153.8, 153.5 (d, J= 19 Hz), 151.7, 149.1, 137.2, 119.1, 117.4, 112.6,112.4,106.3, 104.4, 52.3, 43.4, 40.8, 33.2, 27.7, 19.3; MS (ESI) m/z 412.3 [M+H]*. 6-[6-amino-9-(3-isopropylamino-propyl)-9H-purin-8-ylsulfanyl]benzo [1,3]dixole-5 carbonitrile (PU-WS5). The procedure for the preparation of PU-WS3 was followed starting from PU-H71. The reaction afforded PU-WS5 (6.5 mg, 32% for three steps) as a white solid. H NMR (500 MHz, CDC1 3

/CD

3 0D) $ 8.21 (s, 1 H), 7.22 (s, 1H), 7.19 (s, 1H), 6.19 (s, 2H), 4.40 (t, J= 7 Hz, 2H), 3.09 (septet, J= 6.5 Hz, 1H), 2.83 (t, J= 7.5 Hz, 2H), 2.26 (m, 2H), 1.25 (d, J= 6.5 Hz, 6H); MS (ESI) m/z 412.2 [M+H]*; HRMS (ESI) m/z [M+H]* calcd. for Cj 9 H22N 7 0 2 S, 412.1556; found 412.1560. 8-[6-(3,3-dimethyl-but-1-ynyl)-benzo[1,3]dioxol-5-ylsulfanyl]9-(3-isopropylamino propyl)-9H-purin-6-ylamine (PU-WS6). A solution of PU-H71 (70 mg, 0.137 mmol), (Boc)2O (35 mg, 0.161 mmol) and triethylamine (13 mg, 0.137 mmol) in THF (2 mL) was stirred at room temperature for 12 h. Following solvent removal, the residue was purified by preparative thin layer chromatography (CHC 3 :MeOH-NH 3 (7N), 20:1) to afford Boc protected PU-H71 (74 mg, 88%; MS (ESI) m/z 612.89 [M+H]*). To a solution of Boc protected PU-H71 (0.24 g, 0.39 mmol) in DMF (2 mL) was added CuI (4 mg, 0.1 mmol), PdC1 2 (PPh 3

)

2 (14 mg, 0.02 mmol), t-butylacetylene (72 pL, 0.59 mmol) and triethylamine (137 gL) and the mixture was stirred at 90 *C for 24 h. The reaction mixture was condensed under reduced pressure and purified by chromatography to afford a solid. To a solution of the solid in 15 mL of CH 2 C1 2 was added TFA (1.5 mL) and stirred at RT for 2 Irs. The mixture was condensed and purified by flash chromatography to afford PU-WS6 (97 mg, 52 % for three steps) as a white solid. 'H NMR (500 MHz, CDCl 3

/CD

3 0D) 8 8.25 (s, 1 H), 6.99 (s, 1H), 6.97 (s, 1H), 6.05 (s, 2H), 4.41 (t, J= 7 Hz, 2H), 3.29 (m, 1H), 2.98 (t, J= 7.5 Hz, 2H), WO 2011/044394 PCT/US2010/051872 108 2.24 (m, 2H), 1.34 (d, J= 6.5 Hz, 6H), 1.18 (s, 9H); "C NMR (125 MHz, CDCl 3

/CD

3 OD) 8 50.5, 41.3, 40.2, 30.3, 27.8, 25.9, 18.5; MS (ESI) mlz 467.3 [M+H]*; HRMS (ES) t/z [M+H]* calcd. for C 2 4H31N 6 0 2 S, 467.2229; found 467.2233. 9-(3-isopropylamino-propyl)-8-(6-phenylethynyl-benzo [1,3]dixool-5-ylsulfanyl)-9H purin-6-ylamine (PU-WS7). The procedure for the preparation of PU-WS6 was followed with phenylacetylene (65 pL, 0.59 mmol) to afford PU-WS7 (46 mg, 34% in three steps) as a white solid. 'H NMR (500 MHz, CDC 3

/CD

3 0D) S 8.2 (s, 1H), 7.30-7.40 (m, 5H), 7.08 (s, 111), 6.96 (s, IH), 6.06 (s, 211), 4.27 (m, 2H), 2.69 (m, IH), 2.51 (m, 2H), 1.97 (m, 2H), 1.01 (d, J= 6.5 Hz, 6H); "C NMR (125 MHz, CDCI 3

/CD

3 OD) 8 154.3,152.3,151.1,148.8, 147.3, 131.3, 128.7, 128.3, 124.4,122.4,120.4, 119.3, 112.9, 112.4,102.3, 94.2, 86.6, 50.5, 43.1, 41.3, 29.2, 21.7; MS (ESI) m/z 487.2 [M+H]*; HRMS (ESI) m/z [M+H]* calcd. for

C

26 H27N 6

O

2 S, 487.1903; found 487.1913. 8-(6-ethynyl-benzo[1,3]dioxol-5-ylsulfanyl)-9-(3-isopropylanino-propyl)-9H-purin-6 ylamine (PU-WS8). The procedure for the preparation of PU-WS6 was followed with trimethylsilanylacetylene (82 pLL, 0.59 mmol), and following coupling a white solid was obtained and used without further purification. To this was added MeOH (10 mL) and KOH (90 mg) and was stirred at rt for 2 hrs. The reaction mixture was concentrated under reduced pressure and to the resulting residue was added 2 mL of 10% TFA-CH 2

CI

2 and was stirred at rt for 2 hrs. The mixture was concentrated under reduced pressure and the residue chromatographed to afford PU-WS8 (5.2 mg, 26% for four steps) as a pale yellow solid. 'H NMR (500 MHz, CDC 3 ) 8 8.32 (s, 1H), 6.99 (s, IH), 6.84 (s, IH), 6.00 (s, 2H), 5.61 (br s, 2H), 4.31 (t, J=7 Hz, 2H), 3.31 (s, IH), 2.71 (m, 1H), 2.56 (t, J = 7 Hz, 2H), 1.97 (m, 2H), 1.02 (d, J = 6.5 Hz, 6H); MS (ESI) m/z 411.2 [M+H]*; HRMS (ESI) m/z [M+H]* calcd. for

C

2 0 H23N 6 0 2 S, 411.1603; found 411.1605. 8- ((6-ethynylbenzo[d][1,3]dioxol-5-yl)thio)-9-(2-(isobutylamino)ethyl)-9H-purin-6 amine (PU-WS16). Following the procedure to make PU-WS8, PU-WS16 was obtained as a white solid. 'H NMR (500 MHz, CDC 3 ) 8 8.24 (s, IH), 6.91 (s, 1H), 6.77 (s, 1H), 6.01 (s, 2H), 5.78 (br s, 2H), 4.33 (t,J= 6.1 Hz, 2H), 3.24 (s, 1H), 2.92 (t, J= 6.1 Hz, 2H), 2.38 (d, J WO 2011/044394 PCT/US2010/051872 109 = 6.8 Hz, 2H), 1.63 (m, 1H), 0.77 (d, J= 6.6 Hz, 6H); "C NMR (125 MHz, CDCl 3 ) 155.1, 153.5, 151.9, 149.6, 148.5, 147.0, 128.0, 124.1, 117.0,114.8,111.3, 102.6, 82.9, 81.4, 57.9, 49.3, 44.2, 28.8, 28.4, 20.9; HRMS (ESI) m/z [M+H]* calcd. for C 2 0H22N 6

O

2 S, 411.1603; found 411.1606. 8-(6-ethynylbenzo[d] [1,3]dioxol-5-ylthio)-9-(2-(neopentylamino)ethyl)-9H-purin amine (PU-WS19). Following the procedure to make PU-WSS, PU-WS19 was obtained as a white solid. 'H NMR (500 MHz, CDC1 3 ) 8 8.32 (s, 1H), 6.97 (s, 1H), 6.83 (s, 1H), 5.98 (s, 2H), 5.76 (br s, 2H), 4.35 (m, 2H), 3.06 (s, 1H), 2.97 (m, 2H), 2.33 (s, 2H), 0.82 (s, 9H); 1 3 C NMR (125 MHz, CDC1 3 ) 8 154.5, 152.9, 151.5, 149.1, 147.9, 146.5, 120.1, 117.7, 112.9, 111.9, 102.2, 82.3, 81.0, 61.9, 49.8, 43.9, 31.5, 27.7; HRMS (ESI) m/z [M+H] t called. for C21H 25

N

6

O

2 S, 425.1760; found 425.1753. 8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9-(2-(isobutylamino)ethyl)-9H purin-6-amine (PU-WS20). Following the procedure to make PU-WS8, PU-WS20 was obtained from PU-DZ13 as a white solid. 'H NMR (MeOH-d 4 , 500 MHz) 8: 6.98 (s, 1H), 6.70 (s, 1H), 6.02 (s, 2H), 4.36 (s, 2H), 4.20 (t, J = 6.4 Hz, 2H), 2.92 (t, J = 6.4 Hz, 2H), 2.42 (d, J = 6.9 Hz, 2H), 2.03 (s, 1H), 1.69 (m, 1H), 0.87 (d, J = 6.8 Hz, 6H); "C NMR (MeOH d4, 125 MHz) 8: 159.8, 158.1, 152.6, 151.4, 149.8, 147.2, 134.3, 116.2, 114.2, 112.5, 109.8, 102.3, 80.9, 57.5, 43.0, 32.6, 29.8, 28.2, 20.5.

WO 2011/044394 PCT/US2010/051872 110

NH

2 HNON ' b> HN0 -- / N\ S9-1 89-2 S9-3 0

NH

2

NH

2 N ON W- >-S e N x0 X ) Br 0 NHR O PU-HT165 X=CH 2 , R= isobutyl S9-4 X=CH 2 PU-HT175 X=CH 2 , R= neopentyl 89-5 X=CH 2

CH

2 PU-RK11 X=CH 2

CH

2 , R= isopropyl PU-RK12 X=CH 2

CH

2 , R= 1-imidazoyl Reagents and conditions: (a) NaNO 2 , 10% HCl, 0*C; KI, 0*C to rt; (b) 8-mercaptoadenine, neocuproine, Cul, NaOt-Bu, DMF, 110*C, 24 h; (c) NIS, TFA, CH 3 CN, rt; (d) 1,2-dibromoethane or 1,3-dibromopropane, Cs 2

CO

3 , DMF, rt; (e) isobutylamine or neopentylamine or isopropylamine or imidazole, DM1, rt. Scheme 9. Synthesis of PU-HT165, PU-HT175, PU-RKI 1, PU-RK12. 6-Iodo-2,3-dihydrobenzo[b][1,4]dioxine (S9-2). 2,3-dihydrobenzo[b][1,4]dioxin-6-amine (S9-1; 5 g, 33 mmol) was dissolved in 10% HCl solution and cooled to 0*C. Then, 30 mL of a cold aqueous solution of NaNO 2 (4.6 g, 66 mmol) was added over a period of 15 min and thereaction mixture was stirred at 0*C for an additional 10 min, followed by the addition of urea (1.6 g, 27 mmol). After 15 min, 40 mL of a suspension of KI (16.5 g, 100 mmol) in water/CH 2

CI

2 (1:1) was added. The reaction mixture was stirred overnight at room temperature then extracted with CH 2 C1 2 , dried over MgSO 4 . And condensed under reduced pressure and the residue was purified by flash chromatography (hexane:EtOAc, 100:0 to 90:10) to afford S9-2 (7.4 g, 86%) as a colorless oil. 1H NMR (500 MHz, CDC 3 ) S 7.28 5 (s, 1H), 7.13 (d, J= 8.5 Hz, 1H), 6.63 (d, J= 8.5 Hz, 1H1), 4.27-4.24 (in, 4H).

WO 2011/044394 PCT/US2010/051872 111 8-(7-Iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-9H-purin-6-amine (S9-3). To a solution of S9-2 (1.26 g, 4.8 mmol) in DMF (15 mL) was added 8-mercaptoadenine (0.400 g, 2.4 mmol), neocuproine (0.056 g, 0.24 mmol), CuI (0.044 g, 0.24 mmol) and NatOBu (0.460 g, 4.8 mmol). The reaction mixture was stirred at 110 *C for 24h. Solids were filtered and the filtrate was condensed under reduced pressure. The residue was flash chromatographed (CHC1 3 :MeOH:AcOH, 60:0.5:0.5 to 30:0.5:0.5) to yield 0.578 g (80%) of intermediate coupling product (MS (ESI) n/z 301.9 [M+H]). To 0.400 g (1.4 mmol) of this and NIS (0.945 g, 4.2 mmol) in acetonitrile (15 mL) was added TFA (540 pL, 0.800 g, 7 mmol) and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography

(CHC

3 :MeOH:AcOH, 60:0.5:0.5 to 30:0.5:0.5) to give S9-3 (0.436 g, 73%). 'H NMR (DMSO-d 6 , 500 MHz) 6 8.37 (s, 1H), 8.03 (br s, 2H), 7.47 (s, 1H), 7.10 (s, 1H), 4.25-4.27 (in, 4H); MS (ESI) m/z 427.9 [M+H]*. 9-(2-Bromoethyl)-8-(7-iodo-2,3-dihydrobenzo[b] [1,4]dioxin-i-ylthio)-9H-purin-6-amine (S9-4). A mixture of S9-3 (0.213 g, 0.5 mmol), 1,2-dibromoethane (0.500 g, 2.5 mmol) and Cs 2

CO

3 (0.184 g, 0.75 mmol) in anhydrous DMF (6 mL) was stirred at room temperature for 3h. Solids were filtered and the filtrate was condensed under reduced pressure to give a residue that was purified by preparative thin layer chromatography (CHC 3 :MeOH-NH 3 (7N), 20:1) to give S9-4 (0.107 g, 40%). 'H NMR (CDC 3 , 500 MHz) 8 8.29 (s, 1H), 7.36 (s, 1H), 7.00 (s, 1H), 6.23 (br s, 2H), 4.62 (t, J= 7.0 Hz, 2H), 4.16-4.24 (m, 4H), 3.69 (t, J= 7.0 Hz, 211); MS (ESI) m/z 533.9/535.9 [M+H]*. 9-(3-Bromopropyl)-8-(7-iodo-2,3-dihydrobenzo[b] [1,4]dioxin-6-ylthio)-9H-purin-6 amine (S9-5). A mixture of S9-3 (0.213 g, 0.5 mmol), 1,3-dibromopropane (0.512 g, 2.5 mmol) and Cs 2

CO

3 (0.184 g, 0.75 mmol) in anhydrous DMF (6 mL) was stirred at room temperature for 3h. Solids were filtered and the filtrate was condensed under reduced pressure to give a residue that was purified by preparative thin layer chromatography

(CHC

3 :MeOH-NHs (7N), 20:1) to give S9-5 (0.104 g, 38 %). 'H NMR (CDC1s, 500 MHz) a 8.26 (s, IH), 7.32 (s, IH), 6.94 (s, 1H), 5.6 (br s, 2H), 4.27 (t, J= 7.0 Hz, 2H), 4.10-4.17 (in, 4H), 3.32 (t, J= 7.0 Hz, 2H), 2.26 (in, 2H); MS (ESI) m/z 547.9/549.8 [M+H]*.

WO 2011/044394 PCT/US2010/051872 112 8-(7-Iodo-2,3-dihydrobenzojb] [1,4]dioxin-6-ylthio)-9-(2-(isobutylamino)ethyl)-5,9 dihydro-4H-purin-6-amine (PU-HT165). S9-4 (0.052 g, 0.097 mmol) and isobutylamine (0.354 g, 4.9 mmol) in DMF (1 ml) was stirred overnight at rt. Solvent was removed under reduced pressure and the resulting residue was purified by chromatography (CH 2 Cl2:MeOH) to give 0.040 g, 78%) of PU-HT165 as a yellow solid. 'H NMR (500 MHz, CDCI 3 ) 8 8.24 (s, iH), 7.37 (s, 1H), 6.94 (s, 1H), 6.24 (br s, 2H), 4.44 (br s, 2H), 4.22-4.24 (m, 4H), 3.08 (m, 2H), 2.52 (d, J= 5.7 Hz, 2H), 1.92 (in, 1H), 0.92 (d, J= 6.0 Hz, 6H); "C NMR (125 MHz, CDC1 3 ) 6 155.4, 152.8, 151.4, 147.7,145.5,145.2, 128.9, 127.5, 122.0, 120.5, 91.6, 64.9, 64.7, 57.3,49.0,43.9,28.0,21.0; MS (ESI) m/z 527.1 [M+H]*. 8-(7-Iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-9-(2-(neopentylamino)ethyl)-5,9 dihydro-4H-purin-6-amine (PU-HT175). S9-4 (0.052, 0.097 mmol) and neopentylamine (0.426 g, 4.9 mmol) in DMF (1 mL) was stirred overnight at rt. Solvent was removed under reduced pressure and the resulting residue was purified by chromatography (CH2CI 2 :MeOH) to give 0.038 g (73%) of PU-HT175 as a yellow solid. 'H NMR (500 MHz, CDC1 3 ) 6 8.31 (s, 1H), 7.37 (s, 1H), 6.94 (s, 1H), 5.79 (br s, 2H), 4.33 (t, J= 6.5 Hz, 2H), 4.204.24 (m, 4H), 2.99 (t, J= 6.5 Hz, 2H), 2.34 (s, 2H), 0.84 (s, 9H); "C NMR (125 MHz, CDC 3 ) S 154.5, 152.9, 151.7, 147.0, 144.7, 144.6, 128.2, 127.8, 121.2, 120.2, 90.7, 64.3, 64.2, 62.0, 49.8, 44.0,31.6,27.7; MS m/z 541.1 [M+H]*. 8-(7-Iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-9-(3-(isopropylamino)propyl)-9H purin-6-amine (PU-RK11). S9-5 (0.045 g, 0.082 mmol) and isopropylamine (0.242 g, 4.1 mmol) in DMF (1 mL) was stirred overnight at it. Solvent was removed under reduced pressure and the resulting residue was purified by chromatography (CH 2 C1 2 :MeOH) to give 0.038 g (88%) of PU-RK11. 'H NMR (500 MHz, CDC 3 ) 5 8.30 (s, 1H), 7.38 (s, iH), 6.95 (s, iH), 5.65 (br s, 2H), 4.32 (t, J= 6.9 Hz, 2H), 4.22-4.24 (m, 4H), 2.80 (septet, J= 6.7 Hz, iH), 2.61 (t, J= 6.7 Hz, 2H), 2.07 (m, 2H), 1.11 (d, J= 6.7 Hz, 6H); 3C NMR (125 MHz, CDCl 3 ) 5 154.4, 152.8, 151.7, 146.7, 144.8, 144.6, 128.3, 127.8, 121.3, 120.1, 91.0, 64.3, 64.2, 49.0, 43.6, 41.6, 29.8, 22.5; MS (ESI) n/z 527.1 [M+H]*.

WO 2011/044394 PCT/US2010/051872 113 9-(3-(1H-imidazol-1-yl)propyl)-8-(7-iodo-2,3-dihydrobenzo[b [1,4]dioxin-6-ylthio)-9H purin-6-amine (PU-RK12). S9-5 (0.045 g, 0.082 mmol) and imidazole (0.056 g, 0.82 mmol) in DMF (1 mL) was stirred overnight at it. Solvent was removed under reduced pressure and the resulting residue was purified by chromatography (CH2C12:MeOH) to give 0.029 g (67%) of PU-RK12. 'H NMR (500 MHz, CDC1 3 ) 8 8.34 (s, 1H), 7.62 (s, iH), 7.39 (s, 1 H), 7.09 (s, 1H), 6.98 (s, 1H), 6.94 (s, 1H), 5.70 (br s, 2H), 4.194.28 (in, 6H), 4.00 (t, J= 7.5 Hz, 2H), 2.25 (in, 2H); "C NMR (125 MHz, CDC 3 ) 8 154.5, 153.2, 151.8, 146.3, 145.0, 144.7, 137.1, 129.6, 128.3, 126.9, 121.3, 120.1, 118.7, 90.9, 64.3, 64.2, 44.3, 41.0, 31.8; MS (ESI) m/z 536.1 [M+H] . 0 0/-00 0a, b c Nd NN N

H

2 N F N S10-1 S10-2 H2 NINF I H SI-3 104 0 0 0 0 0 0 H 2

NH

2 / N14 2 Ng N F N F N N F H S10-6 Br R S10-6 Z3-3R= isobutyl DZ4R= t-butyl Reagents and conditions: (a) sulfur, morpholine, 140*C, 14 h; (b) 10% KOH (aq.), reflux, 12 h; (c) 2,4,5,6-tetraaminopyrinidine, triphenyl phosphite, pyridine, microwave irradiation at 220*C, 75 min.; (d) HF/pyridine, NaNO 2 , 0 *C to rt, 1 h; (e) NIS, TFA, CH 3 CN, rt ovemight; (f) Cs 2

CO

3 , 1,2 dibromoethane, DM1F, rt, 3.5 h; (g) isobutylamine or t-butylamine, DMF, overnight, rt. Scheme 10. Synthesis of DZ3-73 and DZ4-84. 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetic acid (S1O-2). A mixture of 1,4 benzodioxan-6-yl methyl ketone (S10-i; 5.5 g, 30.9 mmol), sulfur (1.98 g, 61.8 nmmol) and morpholine (6.73 g, 6.76 mL, 77.3 mmol) was refluxed at 140 0 C for 14 h. After cooling to rt, WO 2011/044394 PCT/US2010/051872 114 the reaction mixture was diluted with 150 mL of CH 2 C1 2 , transferred to a seperatory funnel and washed with 25 mL of ice-cold brine. The aqueous layer was further extracted with

CH

2 C1 2 (2 x 75 mL). The organic layers were combined, dried with Na 2

SO

4 , and filtered. Activated charcoal was added to the filtrate and after several minutes was filtered and concentrated to give 12.7 g of a brown oil. A mixture of this in 75 mL of 10% KOH (aq.) was refluxed for 12h. After cooling the reaction mixture was transferred to a seperatory funnel and washed with ether (30 mL), The aqueous layer was acidified with 6N HCl (-25 mL) to pH 2 and extracted with CH 2 C1 2 (4 x 100 mL). The organic layers were combined, washed with distilled water (100 ml), dried with Na 2

SO

4 and filtered. This was treated with charcoal, filtered, and solvent removed under reduced pressure and the resulting residue was purified by chromatography (hexane:EtOAc, 90:10 to 70:30) to give 3.90 g (65%) of S10-2. 'H NMR (500 MHz, CDC1 3 ) 8 6.80-6.82 (m, 2H), 6.74 (dd, J= 2.0, 8.2 Hz, 1H), 4.24 (s, 4H), 3.53 (s, 2H); MS (ESI) m/z 195.1 [M+H]*. 8-((2,3-dihydrobenzo[bi1,4]dioxin-6-yl)methyl)-9H-purine-2,6-diamine (S10-3). A mixture of S10-2 (1.00 g, 5.15 mmol), 2,4,5,6-tetraaminopyrimidine (0.868 g, 6.19 mmol), triphenyl phosphate (1.92 g, 1.63 mL, 6.19 mmol) in 15 mL of pyridine was sonicated for several minutes. It was then subjected to microwave irradiation at 220 0 C for 75 minutes. The mixture was concentrated and the resulting residue was purified by chromatography

(CH

2 C1 2 :MeOH:MeOH-NH 3 (7N), 60:0.5:0.5 to 20:0.5:0.5) to give 1.12 g (73%) of S10-3. 'H NMR (500 MHz, CDCl 3 /MeOH-d4) 5 6.75-6.84 (in, 3H), 4.24 (s, 41), 3.98 (s, 2H); MS (ESI) m/z 299.3 [M+H]*. 8-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2-fluoro-9H-purin-6-amine (S1O-4). To a solution of S10-3 (1.00 g, 3.35 mmol) in HF/pyridine (2A mL) at 0 *C, NaNO 2 (0.3 g, 4.36 mmol) was slowly added. The reaction was brought to room temperature and further stirred for I h. Following dilution with CH 2 C1 2 (20 mL), the excess HF was quenched by stirring for I h with CaCO3 (1.19 g). The mixture was dried under reduced pressure and subsequently purified by chromatography (CH 2 C1 2 :MeOH:AcOH, 90:1:0.5) to give 1.15 g (96%) of S10-4. H NMR (500 MHz, CDC1 3 /MeOH-d4) 8 6.75-6.84 (n, 3H), 4.24 (s, 4H), 4.04 (s, 2H); MS (ESI) m/z 302.3 [M+H]*.

WO 2011/044394 PCT/US2010/051872 115 2-fluoro-8-((7-iodo-2,3-dihydrobenzo[b] [1,4]dioxin-6-yl)methyl)-9H-purin-6-amine (S1O-5). S1O-4 (0.310 g, 1.03 mmol), NIS (0.301 g, 1.34 mmol), CH 3 CN (20 mL), TFA (2.34 g, 1.56 mL, 20.5 mmo was stirred at rt overnight. The mixture was dried under reduced pressure and the residue chromatographed (CH 2

CI

2 :MeOH:AcOH, 120:1:0.5 to 90:1:0.5) to give 0.340 g (77%) of a mixture of S10-5 (m/z 428.2 [M+H]) along with diiodinated compound (m/z 554.1 [M+H]). LC-MS shows ratio of S10-5 to diiodinated compound to be 83:17. This mixture was not separated but used further in the following step. 'H NMR (500 MHz, CDCI 3 /MeOH-d4) 6 7.37 (s, iH), 6.82 (s, 1H), 4.25 (s, 4H), 4.18 (s, 2H); MS (ESI) m/z 428.2 [M+H]+. 9-(2-bromoethyl)-2-fluoro-8-((7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-9H purin-6-amine (S1O-6). S10-5 (0.340 g, 0.796 mol), Cs 2

CO

3 (0.337 g, 1.035 mmol), 1,2 dibromoethane (0.747 g, 0.343 mL, 3.99 mmol) in DMF (10 mL) was stirred at rt for 3.5 h. The mixture was dried under reduced pressure and the residue chromatographed

(CH

2 Cl 2 :MeOH:AcOH, 200:1:0.5 to 120:1:0.5) to give 0.360 g (85%) of a mixture of S10-6 (m/z 534.0/536.2 [M+H]) along with diiodinated compound (m/z 659.5/661.9 [M+H]). LC MS shows ratio of titled compound to diiodinated compound to be 80:20. This mixture was not separated but used further in the following step. 2-fluoro-8-((7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-9-(2 (isobutylamino)ethyl)-9H-purin-6-amine [DZ3-731. S10-6 (0.360 g, 0.674 mmol) and isobutylamine (2.46 g, 3.38 ml) in DMF (8 mL) was stirred overnight at rt. Solvent was removed under reduced pressure and the resulting residue was chromatographed

(CH

2 C1 2 :MeOH:MeOH-NH 3 (7N), 120:0.5:0.5 to 60:0.5:0.5) to give 0.220 g of a mixture of DZ3-73 along with the diiodinated compound. This mixture was separated by reverse phase HPLC ((a) H20 + 0.1% TFA and (b) CH 3 CN + 0.1% TFA, 10 to 75% b over 22 minutes at 16 mL/min) to give 0.196 g (58%) of DZ3-73. 'H NMR (500 MHz, CDC 3 ) 6 7.35 (s, 1H), 6.57 (s, 1H), 6.37 (br s, 2H), 4.24 (s, 2H), 4.20 (s, 4H), 4.08 (t, J= 6.4 Hz, 2H), 2.91 (t, J= 6.4 Hz, 2H), 2.37 (d, J= 6.3 Hz, 2H), 1.64 (m, 1H), 0.85 (d, J= 6.2 Hz, 6H); 13 C NMR (125 MHz,

CDCI

3 ) 8 158.8 (d, J= 208.1 Hz), 156.4 (d, J= 19.5 Hz), 152.8 (d, J= 18.8 Hz), 151.2, WO 2011/044394 PCT/US2010/051872 116 144.2,143.6,131.5, 127.6,117.9, 116.7, 88.3,64.5, 57.8, 48.8,43.5, 38.6, 28.4,20.5; HRMS (ES 1n/z [MH]* calcd. for C 20

H

25

F]N

6 0 2 , 527.1068; found 527.1066; HPLC: method A R = 6.9 1, method B Rt = 8.48. 9-(2-(tert-butylamino)ethyl)-2-fluoro-8-((7-iodo-2,3-dihydrobenzo[b] [1,4]dioxin-6 yl)methyl)-9H-purin-6-amine [DZ4-841. S1O-6 (8 mg, 0.0149 mmol) and tert-butylamine (109 mg, 157 I) in DMF (0.5 mL) was stirred overnight at rt. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2

CI

2 :EtOAc:MeOH-NH 3 (7N), 7:2:1:0.5) to give 6 mg (77%) of DZ4-84. 'H NMR (500 MHz, CDC 3 ) 5 7.36 (s, 1H), 6.55 (s, IH), 5.86 (br s, 2H), 4.29 (s, 2H), 4.17-4.23 (m, 4H), 4.04 (t, J= 6.4 Hz, 2H), 2.85 (t, J= 6.4 Hz, 2H), 0.99 (s, 9H); MS (ESI) n/z 527.1 [M+H]*. N a N N Q( NHCHS r jd OH 0Br S1l-I S11-2 S11-3 S11-4 I NH, H2N B0 N e 2N N H2N )N N N " N BrI 0 cC) - IO IN sZ0 a11-5 S11-6 S11-7 S11-8 h NH NH N N N N N H 311-9 Br NHR S11-10 S11-11 Reagents and conditions: (a) NaBH 4 , AcOH, THF, rt; (b) dibromoethane, acetone, H 2 0, K 2 C0 3 , reflux; (c) NBS, DMF, 80*C; (d) KN03, H 2 S0 4 ; (e) Nal, Cut N,N'-dimethylethylenediamine, dioxane, 1 10 0 C; (f) Fe, NH 4 CI, isopropanol, reflux; (g) 8-mercaptoadenine, neocuproine, CuI, NaOtlu, DMF, 115*C; (h) NaNO 2 , KI, AcOH, 0*C; (i) Cs 2

CO

3 , 1,2-dibromnoethane or 1,3-dibromopropane, DMF, rt; 0) NH 2 R, DMF, rt.

WO 2011/044394 PCT/US2010/051872 117 Scheme 11. Synthesis of Morpholine-type compounds S11-11. H

O

2 N NH 2 a 0 2 N N b O2N N HN N HO 0 ( S12-1 S12-2 S12-3 S12-4 d NH 2

NH

2 _SSO N-N- .N N o N H NN> S12-5 S12-6 N 12 N

NH

2

NH

2 N - NS N N N Oh N N ,N 0 ~n=1,2 cn=1,2 /N ()NR2 Br NHR S12-8 S12-9 Reagents and conditions: (a) 1,2-dibromoethane, K 2 C0 3 , DMIF, 125 0 C; (b) Mel, DMF, 0*C then rt; (c) Pd/C, H2, MeOI-, rt; (d) NaNO 2 , AcOH, KI, 0*C; (e) 8-mercaptoadenine, neocuproine, CuI, NaOtBu, DMF, 115 0 C; (f) NIS, CH 3 CN, rt; (g) Cs 2

CO

3 , 1,3 dibromopropane or 1,2-dibromoethane, DMF, rt; (h) NH 2 R, DMF, rt. Scheme 12. Synthesis of Morpholine-type compounds S 12-9. 6-Nitro-3,4-dihydro-2H-benzo[b] [1,4]oxazine [S12-2]. To a solution of 2-amino-4 nitrophenol (S12-1; 1.5 g, 9.7 mmol) in 50 mL of DMF was added K 2 C0 3 (4.04 g, 29.2 mmol) and 1,2-dibromoethane (1 mL, 11.7 mmol). The resulting mixture was stirred at 125 *C under argon overnight. The resulting mixture was concentrated under vacuum and purified by flash chromatography to give S12-2 (1.2 g, 68%) as a yellow solid. 'H NMR (CDC 3 , 500 MHz) 8 7.55-7.58 (dd, J= 2.7, 8.9 Hz, 1H), 7.48 (d, J= 2.6 Hz, 1H), 6.81 (d, J= 8.9 Hz, WO 2011/044394 PCT/US2010/051872 118 1H), 4.34 (m, 2H), 4.12 (br s, 1H), 3.47 (n, 2h); "C NMR (CDC1 3 , 125 MHz) 8 149.4,141.8, 133.8, 115.0, 114.8, 110.2, 65.6, 40.0. 4-Methyl-6-nitro-3,4-dihydro-2H-benzo[bl,4]oxazine [S12-31. To a solution of S12-2 (0.66 g, 3.7 mmol) in 30 mL of DMF was added NaH (106 mg, 4.4 mmol) and stirred at 0 *C for 30 min. To the resulting mixture was added Mel (229 pL, 3.7 mmol) and kept stirring at rt for 2 h. The reaction mixture was concentrated in vacuum and purified by flash chromatography to give compound S12-3 (564 mg, 79%) as yellow solid. 'H NMR (CDCl 3 , 500 MHz) 5 7.56 (d, J= 8.8 Hz, IH), 7.45 (s, IH), 6.76 (d, J= 8.8 Hz, IH), 4.36 (in, 2H), 3.32 (in, 2H), 2.95 (s, 3H); "C NMR (CDC1 3 , 125 MHz) 6: 149.7, 142.2, 136.5, 115.4, 114.5, 106.9, 65.3, 47.9, 38.6; MS (ESI) m/z 194.8 (M+H)t. 4- Methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-anine [S12-4]. To a solution of S12-3 (560 mg, 2.9 mmol) in 20 mL of methanol was added Pd/C powder (10%, 96 mg). The resulting suspension was stirred at rt under hydrogen overnight. The reaction mixture was filtered, concentrated in vacuum and purified by flash chromatography to give S12-4 (420 mg, 89%) as a yellow solid. 'H NMR (CDC1 3 , 500 MHz) 6 6.56 (d, J= 8.3 Hz, 1H), 6.04 (d, J= 2.5 Hz, 1H), 5.98 (dd, J= 2.5, 8.3 Hz, 1H), 4.19 (t, J= 4.4 Hz, 2H), 3.21 (t, J= 4.5 Hz, 2H), 2.82 (s, 3H); 3 C NMR (CDC 3 , 125 MHz) 8 140.8, 137.4, 137.0, 116.2, 104.8, 100.4, 64.6, 49.5, 38.7. 6-Iodo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine [S12-5]. To solution of S12-4 (2.1 g, 12.8 mmol) in 50 mL of acetic acid cooled in ice bath was added NaNO 2 (1.77g, 26.9 mmol) slowly in portions. The resulting mixture was stirred at 0 *C for 10 min and was added KI (4.24 g, 38.4 mmol) in portions. The reaction mixture was stirred at 0 *C for 30 min, allowed to warm up to it and stirred for 2 h. The resulting mixture was quenched with 100 ml of water, extracted with ethyl acetate (3 x 150 nL). The organic layer was combined, treated with Na 2

S

2 0 3 , washed with brine, dried over MgSO 4 and purified by flash chromatography to give S12-5 (1.86 g, 53%) as a yellow solid. 'H NMR (CDC 3 , 500 MHz) 8 6.64 (d, J= 8.3 Hz, 1H), 6.56 (s, 1H), 6.48 (d, J= 8.4 Hz, 1H), 4.25 (in, 2H), 3.24 (in, 2H), 2.85 (s, 3H); "C NMR (CDCl 3 , 125 MHz) S 138.1, 126.6, 120.5, 117.6, 111.9, 83.7, 64.8, 48.7, 36.5.

WO 2011/044394 PCT/US2010/051872 119 M COOH NHBoc bNH 2 S13-1 13-2 S13-3

NH

2

H

2 N

NH

2 N NN

-

N N\ / H N S13-4 S13-5

NH

2

NH

2 N-g N\> N>~ N NN> Br HN S13-6 DZ4-52-NS Reagents or conditions: (a) (C 6

H

5 0)2P(O)N 3 , t-BuOH, Et 3 N, toluene, reflux; (b) t-BuLi, THF, -20 0 C, then ICH 2

CH

2 I, -78 0 C to rt; (c) TFA, CH 2

CI

2 , rt; (d) 8-mercaptoadenine, neocuproine, Cul, NaOtBu, DMF, 115*C; (e) KI, NaNO 2 , HCI, H20, < 5"C; (f) 1,3-dibromopropane, Cs 2

CO

3 , DMF, rt; (g) isopropylamine, DMF, rt. Scheme 13. Synthesis of DZ4-52-N9. tert-Butyl naphthalen-2-ylcarbamate (S13-2).2-Naphthoic acid (S13-1; 2.5 g, 14.3 mmol) in tert-BuOH (85 mL) and toluene (85 mL) was treated with Et 3 N (2.3 mL, 16.4 mmol), 3 A molecular sieves (16.7 g) and diphenyl phosphorylazide (3.5 mL, 16.4 mmol). The reaction mixture was refluxed for 24 h. After cooling to rt, solid was filtered off through Celite and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (75 mL) and washed with IN aqueous HCl (2 x 50 mL), saturated aqueous NaHCO 3 (2 x 50 mL), dried over sodium sulfate and concentrated under reduced pressure. Chromatography (10% EtOAc in hexanes) afforded 2.5 g (71%) of S13-2. 'H NMR (500 MHz, CDCI 3 ) 8 7.99 (s, WO 2011/044394 PCT/US2010/051872 120 IH), 7.72-7.78 (m,3H), 7.44 (t,J= 7.8 Hz, IH), 7.31-7.38 (in, 2H), 6.61 (brs, 1H), 1.55 (s, 9H); MS (ESI) m/z 244.02 [M+H]*, 2-Amino-3-iodonaphthalene (S13-3). To a solution of S13-2 (1.0 g, 4.11 mmol) in 20 mL dry THIF under argon at -20 0 C was added tert-butyl lithium (1.5 M solution in pentane, 6.9 mL, 10.27 mmol) dropwise and was stirred for 2 h at -20 *C. After cooling to -78 0 C, a solution of diiodoethane (2.9 g, 10.27 mmol) in 10 mL dry THF was added dropwise and then allowed to warm to t for 3 h. A saturated aqueous NH 4 Cl solution was added, and the solution was extracted with diethyl ether. The organic layer was washed with 10% sodium thiosulfate solution and dried over MgSO 4 . The solvents were evaporated under reduced pressure and the residue was purified by chromatography (3% EtOAc in hexanes) to afford 1.1 g of a 79/21 mixture (NMR) of regioisomeric 3-iodo and 1 -iodo Boc-protected 2 aminonaphthalene, respectively. This mixture (1.1 g) was dissolved in dichloromethane (12.5 mL), and trifluoroacetic acid (12.5 mL) was added dropwise at rt. After stirring for 1 h at rt, the solution was neutralized with a concentrated NaOH solution. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over MgSO 4 , concentrated under reduced pressure and the resulting residue was purified by chromatography (0.5% EtOAc in hexanes) to afford 0.50 g (45%) of S13-3. 'H NMR (500 MHz, CDCl 3 ) 5 8.25 (s, 1H), 7.59 (d, J= 8.3 Hz, 1H), 7.56 (d, J= 8.3 Hz, IH), 7.37 (dt, J= 1.0, 7.5 Hz, 1H), 7.22 (dt, J= 0.8, 7.5 Hz, 1H), 7.09 (s, IH), 4.23 (br s, 2H); "C NMR (125 MHz, CDC 3 ) 8 144.3, 139.5, 135.3, 129.9, 127.5, 127.2, 126.3, 123.7, 109.0, 88.7; MS (ESI) m/z 269.96. 8-(3-aminonaphthalen-2-ylthio)-9H-purin-6-amine (S13-4). A mixture of 8 mercaptoadenine (20.7 mg, 0.124 mmol), neocuproine hydrate (3.9 mg, 0.0 185 mmol), CuI (3.5 mg, 0.0185 mmol), sodium tert-butoxide (23.7 mg, 0.24 mmol), S13-3 (100 mg, 0.37 mmol) and DMF (2 mL) were heated at 115'C for 20 h. The solvent was removed under reduced pressure and the residue was purified by preparatory TLC (CH 2 Cl 2 :MeOH-NH 3 (7N), 10:1) to give 14 mg (37%) of S13-4 as a solid. 'H NMR (500 MHz, CDC13/MeOH-d 4 ) 6 8.18 (s, 1H), 8.12 (s, 1H), 7.71 (d, J= 8.3 Hz, 1H), 7.62 (d, J= 8.1 Hz, 1H), 7.40-7.46 (in, 1H), 7.24-7.30 (in, 1H), 7.20 (s, 1H); MS (ESI) mz 308.95 [M+H].

WO 2011/044394 PCT/US2010/051872 121 8-(3-iodonaphthalen-2-ylthio)-9H-purin-6-aine (S13-5). To a suspension of S13-4 (14 mg, 0.0454 mmol) in water (150 gL) at 5'C was added 6 M HCl (140 pL) over 5 min. Then a solution of NaNO 2 (6.3 mg, 0.0908 mmol) in water (70 pL) was added dropwise over 30 min. at below 5'C. The mixture was stirred for an additional 10 min., then urea (1.9 mg, 0.0317 mmol) was added slowly. After 10 minutes, a solution of KI (22.6 mg, 0.136 mmol) in water (70 IL) was added dropwise over 5 min. and the mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by preparatory TLC

(CH

2 CI2:MeOH-NH 3 (7N), 8:1) to give 8 mg (42%) of S13-5 as a solid. 'H NMR (500 MHz, CDCl3/MeOH-d 4 ) 8 8.51 (s, 1H), 8.17 (s, 2H), 7.75-7.80 (m, 2H), 7.52-7.60 (m, 2H); MS (ESI) mn/z 420.01 [M+H]*. 9-(3-bromopropyl)-8-(3-iodonaphthalen-2-ylthio)-9H-purin-6-amine (S13-6). S13-5 (8 mg, 0.019 mmol), Cs 2

CO

3 (7.4 mg, 0.0228 mmol), 1,3-dibromopropane (19.2 mg, 9.7 pL, 0.095 nmmol) in DMF (0.2 mL) was stirred for 30 min. Then additional Cs 2

CO

3 (7.4 mg, 0.0228 mmol) and 1,3-dibromopropane (19.2 mg, 9.7 pL, 0.095 mmol) was added and the mixture stirred for 30 min. The mixture was dried under reduced pressure and the residue purified by preparatory TLC (CH 2

CI

2 :MeOH:AcOH, 15:1:0.5) to give 4.6 mg (45%) of S13 6. 'H NMR (500 MHz, CDC1 3 /MeOH-d 4 ) 8 8.51 (s, 1H), 8.27 (s, 1H), 8.05 (s, 1H), 7.74-7.80 (m, 2H), 7.53-7.60 (m, 2H), 4.42 (t, J= 7.1 Hz, 2H), 3.45 (t, J= 6.6 Hz, 2H), 2.45 (m, 2H); MS (ESI) m/z 539.84/541.89 [M+H]*. 8-(3-iodonaphthalen-2-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6-amine IDZ4 52-N9]. S13-6 (4.6 mg, 0.0085 mmol) and isopropylamine (100 PL) in DMF (100 pL) was stirred overnight at rt. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2 C1 2 :MeOH-NH 3 (7N), 10:1) to give 4.0 mg (91%) of DZ4-52-N9. 'H NMR (500 MHz, CDC1 3 ) 8 8.44 (s, 1H), 8.34 (s, I H), 7.77 (s, 1H), 7.70-7.74 (m, 1H), 7.64-7.68 (m, 1H), 7.45-7.54 (m, 2H), 4.36 (t, J= 6.9 Hz, 2H), 2.74 (septet, J= 6.1 Hz, 1H), 2.58 (t, J= 6.8 Hz, 2H), 2.06 (m, 2H), 1.05 (d, J= 6.3 Hz, 6H); MS (ESI) m/z 518.82 [M+H]*.

WO 2011/044394 PCT/US2010/051872 122 a b 2N c

M

2 N 814-1 S14-2 S14-3

NH

2

H

2 N NH2I H2N,1: N ," N, I- f N I' N NN N H Nb H t S14-4 S14-5 S14-6

NH

2 I NH 2 I N -N, -N N s N N N N Br n=1,2 n= 1, 2 Br RHN S14-7 S14-8 Reagents and conditions: (a)Ac 2 O, dioxane, 0*C to rt; (b) KNO 3 , H 2

SO

4 , 0"C to rt; (c) NaNO 2 , KI, AcOH, 0*C to rt; (d) Fe, NH 4 CI, isopropanol, reflux; (e) 8-mercaptoadenine, CuI, nBu 4 NBr, NaOt Bu, my; (f) NaNO 2 , KI, AcOH, 0*C; (g) 1,3-dibromopropane or 1,2-dibromoethane, Cs 2

CO

3 , DM1, rt; (h) amine, DMF, rt. Scheme 14.

WO 2011/044394 PCT/US2010/051872 123 ab 0 2 N~oc 0 2 N

H

2 N S15-1 S15-2 S15-3

NH

2

H

2 N NH 2 H2Ny <.e N N-f N N KN N N N H H 815-4 s15-5 s15-6

NH

2 I NH 2 [NH2I N N N _ N, ~~NAL >>S /

.

II, g 1 h > N N N N ; N n=1,2 RH n= 1,2 HN Br RHN S15-7A n= 1 PU-WS25 n= 1, R= neopentyl 815-7B n=2 PU-WS26 n= 1, R= isobutyl PU-WS29 n= 2, R= isopropyl PU-WS27 Reagents and conditions: (a)Ac20, dioxane, 0*C to rt; (b) KNO 3 , H 2 SO4, 0*C to rt (c) NaNO 2 , KI, AcOH, 0*C to rt; (d) Fe, NH 4 CI, isopropanol, reflux; (e) 8-mercaptoadenine, CuI, nBu4NBr, NaOt Bu, my; (f) NaNO 2 , KI, AcOH, O 0 C; (g) 1,3-dibromopropane or 1,2-dibromoethane, Cs 2

CO

3 , DMF, rt; (h) isopropylamine or isobutylamine or neopentylamine, DMF, rt; (i) Cul, PdCl 2 (PPh 3

)

2 , trimethylsilanylacetylene, Et 3 N, DMF, 90"C. Scheme 15. Synthesis of PU-WS25, PU-WS26, PU-WS29 and PU-WS27. 5-amino-6-nitro-indane (S15-2). A solution of 5-aminoindane (S15-1; 10 g, 75 mmol) in 100 mL of dioxane cooled in ice bath was added acetic anhydride (15 mL) dropwise and kept stirring at room temperature for 2 days. The resulting mixture was condensed and dried under vacuum. The residue was dissolved in 100 mL of concentrated H 2

SO

4 , cooled in ice bath.

KNO

3 in 15 mL of concentrated H 2 SO4 was added dropwise. The resulting solution was stirred at 0 *C for 2 h and then at rt for 2 h. The reaction mixture was poured into 150 g of ice and the resulting yellow precipitate was filtered and washed with cold water to give S15-2 (7.1 g, 43%). 'H NMR (500 MHz, CDC1 3 ) 8 7.94 (s, IH), 6.65 (s, 1H), 6.02 (br, 2H), 2.83 (in, 4H), 2.06 (m, 2H); "CNMR (125 MHz, CDCI) S 154.4, 144.2, 134.1, 131.2, 120.8, 113.5, 33.1, 31.4, 25.7.

WO 2011/044394 PCT/US2010/051872 124 5-iodo-6-nitro-indane (S15-3). To a solution of S15-2 (0.14 g, 0.78 nmol) in acetic acid cooled in ice bath was added NaNO 2 (65 mg, 0.94 nmol). The reaction mixture was stirred for 2 minutes. KI (0.39g, 2.45 mmol) was added and the mixture was stirred at rt for 20 minutes. The resulting suspension was quenched with water (15 mL) and extracted with ethyl acetate (2 x 20 mL). The organic layer was washed with saturated aqueous Na 2

S

2 0 3 solution, brine and dried over MgSO4 and evaporated to dryness to give a residue that was purified by flash chromatography (ethyl acetate/hexane, gradient 0 to 50%) to give S15-3 (0.12 g, 65%) as a yellow solid. 'HNIR (500 MHz, CDCI 3 ) S 7.83 (s, IH), 7.71 (s, IH), 2.95 (m, 4H), 2.11 (m, 2H).

5-amino-6-iodo-indane (S15-4). To a solution of S15-3 (1.65 g, 5.7 mmol) in isopropanol (100 mL) and saturated aqueous NH 4 CI solution (20 mL) was added ironpowder (1.1 g). The resulting suspension was refluxed for lh. The reaction mixture was filtered and the filtrate was condensed and purified by flash chromatography (ethyl acetate/hexane, gradient 0 to 50%) to give S15-4 (1.36 g, 92%) as a pale yellow solid. 1 H NMR (500 MHz, CDCl 3 ) 8 7.44 (s, IH), 6.59 (s, iH), 3.88 (s, 2H), 2.74 (m, 4H), 1.98 (m, 2H); "CNMR (125 MHz, CDCl 3 ) 8 146.2, 144.9, 136.5, 134.1,111.0,32.8,31.8,26.1; MS (ESI): m/z 259.99 [M+H]t. 8-((6-amino-2,3-dihydro-1H-inden-5-yl)thio)-9-H-purin-6-amine (S15-5). The mixture of 8-mercaptoadenine (64 mg, 0.38 mmol), S15-4 (100 mg, 0.38 mmol), CuI (14.7 mg, 0.07 mmol), sodium t-butoxide (111 mg, 1.15 mmol) and tetrabutylammonium bromide (24.9 mg, 0.07 mmol) in anhydrous DMF (4 mL) was vortexed and heated at 190 *C under microwave for 1h. The resulting mixture was condensed and purified by flash chromatography (methylene chloride/methanol, gradient 0 to 10%) to give S15-5 (54 mg, 47%) as a while solid. 'HNMR (500 MHz, MeOH-d4/CDC 3 ) 8 8.11 (s, 1H), 7.36 (s, iH), 6.81 (s, IH), 2.85 (m, 4H), 2.06 (m, 2H); MS (ESI): m/z 299.02 [M+H]*. 8-((6-iodo-2,3-dihydro-1H-inden-5-yl)thio)-9-H-purin-6-amine (S15-6). To a solution of S15-5 (54 mg, 0.18 mmol) in acetic acid (5 mL) cooled in ice bath was added NaNO 2 (15 mg, 0.22 immol) followed by KI (90 mg, 0.54 mmol). The reaction mixture was stirred at 0 "C for 15 min and quenched with water (10 mL). The resulting mixture was extracted with WO 2011/044394 PCT/US2Olo/051872 125 methylene chloride (2 x 20 mL). The organic layer was washed with saturated aqueous Na 2

S

2 0 3 , brine, dried over MgSO 4 and evaporated to dryness. The residue was purified by flash chromatography (methylene chloride/methanol, gradient 0 to 10%) to give S15-6 (42 mg, 56%) as a white solid. HNMR (500 MHz, CDCI 3 ) 5 8.12 (s, 1H), 7.84 (s, IH), 7.39 (s, iH), 2.91 (m, 4H), 2.11 (m, 2H); MS (ESI) m/z 410.10 [M+H]*. 9-(2-bromoethyl)-8-((6-iodo-dihydro-1H-inden-5-yl)thio)-9H-purin-6-amine (S15-7A). To a solution of S15-6 (70 mg, 0.17 mmol) in DMF (3 mL) was added 1,2-dibromoethane (74 uL, 0.86 mmol) and Cs 2

CO

3 (111 mg, 0.34 mmol). The resulting mixture was stirred at rt for 2 h. S15-7A (36 mg, 41%) was obtained following preparatory TLC (methylene chloride/methanol, 20/1) as a white solid. 'HNMR (500 MHz, CDCl 3 ) 8 8.36 (s, 1H), 7.75 (s, iH), 7.18 (s, 1H), 4.62 (t, 2H), 3.68 (t, 2H), 2.88 (t, 2H), 2.81 (t, 2H), 2.06 (m, 2H); "CNMR (125 MHz, CDCl 3 , 5): 155.9, 153.9, 152.4, 149.8, 148.9, 148.1, 137.6, 132.8, 131.1, 101.7, 46.3, 33.9, 29.7, 26.8; MS (ESI): m/z 516.15, 518.16 [M, M+2]. 8-((6-iodo-2,3-dihydro-1H-inden-5-yl)thio)-9-(2-(neopentylamino)ethyl)-9H-purin-6 amine (PU-WS25). To a solution of S15-7A (31 mg, 0.06 mmol) in DMF (1.5 mL) was added neopentylamine (250 uL). The reaction mixture was stirred at rt overnight and condensed under vacuum. PU-WS25 (28 mg, 89%) was obtained following preparatory TLC (methylene chloride/methanol, 10/1) as a white solid. 'H NMR (500 MHz, CDCl3) S 8.32 (s, 1H), 7.73 (s, IH), 7.1 (s, IH), 5.63 (br, 2H), 4.38 (m, 2H), 3.03 (m, 2H), 2.87 (t, J=7.4 Hz, 2H), 2.78 (t, J= 7.4 Hz, 2H), 2.37 (s, 2H), 2.04 (m, 2H), 0.93 (s, 9H); "C NMR (125 MHz, CDCl 3 , 6):154.7, 152.9, 151.6, 147.1, 146.7, 146.4,135.9, 133.5, 127.5, 120.2, 97.7, 61.8, 50.7, 49.7, 43.9, 32.5, 32.2, 31.5, 27.7, 25.5; HRMS (m/z): [M+H]* calcd for C2tH28IN 6 S, 523.1141; found 523.1140. 8-((6-iodo-2,3-dihydro-IH-inden-5-yl)thio)-9-(2-(isobutylamino)ethyl)-9H-purin-6 amine (PU-WS26). To a solution of S15-7A (6 mg, 0.01 mmol) in DMF (1 mL) was added isobutylamine (150 uL). The reaction mixture was stirred at rt overnight and condensed under vacuum. PU-WS26 (5.9 mg, 99%) was obtained following preparatory TLC (methylene chloride/methanol, 10/1) as a white solid. 'HNMR (500 MHz, CDC 3 ) 8 8.31 (s, 1H), 7.74 (s, WO 2011/044394 PCT/US2010/051872 126 1H), 7.11 (s, IH), 5.73 (br, 2H), 4.43 (m, 2H), 3.04 (m, 2H), 2.87 (t, J= 7.4 Hz, 2H), 2.78 (t, J= 7.4 Hz, 211), 2.49 (d, J= 6.6 Hz, 211), 2.05 (in, 2H), 1.81 (m, 1H), 0.92 (m, 6H); HRMS (m/z): [M+H]* calcd for C 20 H2 6 lN 6 S 509.0984; found 509.0990. 9-(3-bromopropyl)-8-((6-iodo-2,3-dihydro-1IH-inden-5-yl)thio)-9H-purin-6-amine (S15 7B). To a solution of S15-6 (30 mg, 0.07 mmol) in DMF (3 mL) was added 1,3 dibromopropane (37 pL, 0.86 mmol) and Cs 2

CO

3 (46 mg, 0.14 mmol). The resulting mixture was stirred at rt for 2 h. S15-7B (8 mg, 21%) was obtained following preparatory TLC (methylene chloride/methanol, 20/1) as a white solid. 'H NMR (500 MHz, CDC 3 ) 3 8.27 (s, IH), 7.75 (s, 1H), 7.12 (s, 1H), 6.55 (br s, 2H), 4.33 (m, 2H), 2.88 (m, 2H), 2.79 (t, J= 7.4 Hz, 2H), 2.29 (m, 2H), 1.97 (m, 2H); MS (ESI): m/z 530.3, 532.3[M, M+2]. 8-((6-iodo-2,3-dihydro-1H-inden-5-yI)thio)-9-(3-(isopropylamino)propyl)-9H-purin-6 amine (PU-WS29). To a solution of S15-7B (8 mg, 0.015 mmol) in DMF (3 mL) was added isopropylamine (100 gL), stirred at rt overnight and condensed under vacuum. PU-WS29 (5.9 mg, 99%) was obtained following preparatory TLC (methylene chloride/methanol, 10/1) as a white solid. 'H NMR (500 MHz, CDC1 3 )8 8.32 (s, IH), 7.75 (s, 1H), 7.12 (s, iH), 5.73 (br s, 2H), 4.29 (t, 2H), 2.87 (t, J= 7.4 Hz, 2H), 2.7-2.79 (m, 3H), 2.55 (t, 2H), 2.03-2.09 (m, 4H), 1.05 (d, J= 11.2 Hz, 6H); 13 C NMR (125 MIHz, CDC1 3 ) 5 154.5, 152.9, 151.7, 147.2, 146.5, 135.9, 133.1, 127.6, 120.2, 97.9, 48.8, 43.7, 41.7, 32.5, 32.2, 30.0, 25.5, 22.7; HRMS (m/z): [M+H]* calcd for C 20

H

2 6 1N 6 S 509.0984; found 509.1003. 8-((6-ethynyl-2,3-dihydro-1H-inden-5-yl)thio)-9-(2-(neopentylamino)ethyl)-9H-purin-6 amine (PU-WS27). Following the procedure to make PU-WS8, PU-WS27 was obtained from PU-WS25 as a white solid. 1 H NMR (CDC1 3 , 500 MHz) S 8.32 (s, I H), 7.41 (s, 1H), 7.13 (s, IH), 5.67 (br s, 2H), 4.42 (m, 2H), 3.48 (s, iH), 3.02 (m, 2H), 2.77-2.91 (in, 4H), 2.39 (s, 2H), 2.06 (mn, 2H), 0.89 (s, 9H); HRMS (ESI) m/z [M+H]* calcd. for C2H 2 gN 6 S, 421.2174; found421.2164.

WO 2011/044394 PCT/US2010/051872 127 COOEt OH HO COOEt O_ EtOOC HOOC OOEt COOFt S13-4 S13-1 S13-2 S13-3 13-3 NH HOOC N HOOCNH S16-6 S16-6 S16-7

NH

2 NH 2 K-- h_1% F N H F N N S16-8 S16-9

NH

2 NH 2 I F NF Br RHN S16-10A n=2 PU-WVS8 n= 2, R= isopropyl S16-10B n=1 'PU-WS17 n= 1, R= isobutyl PU-WS22 n= 1, R= neopentyl - Reagents and conditions: (a)EtOH, H 2 S0 4 , reflux; (b) 2-bromomethylmalonate, NaH, DMF, 11 0*C; (c) PPA, toluene, reflux; (d) NaOH, MeOH, rt, then HCI; (e) Pd/C, H 2 (2 atm.), MeOH; (f) 2,4,5,6-tetraaminopyrimidine, triphenyl phosphite, pyridine, microwave, 21 0*C; (g) HF/pyridine, NaNO 2 , O4C to rt; (h) NIS, TFA, ACN; (i) 1,3-dibromopropane or 1,2 dibromoethane, Cs 2

CO

3 , DMF, rt; (h) isopropylamine or isobutylamine or neopentylamine, DMF, rt. Scheme 16. Synthesis of PU-WS17, PU-WS18, PU-WS22. Ethyl 2-(3-hydroxyphenyl)acetate (S16-2). To a solution of 2-(3-hydroxyphenyl)acetic acid (S16-1; 10 g, 65.8 mmol) in 200 mL of ethanol was added 8 mL of concentrated sulfuric acid. The resulting mixture was refluxed overnight and condensed under vacuum. The residue was dissolved in ethyl acetate and washed with water. The organic layer was combined, washed WO 2011/044394 PCT/US2010/051872 128 with brine, dried over MgSO 4 , evaporated to dryness and purified by flash chromatography to give S16-2 as a colorless oil in quantitative yield. 'H NMR (500 MHz, CDC 3 ) 8 7.35 (br, IH), 7.12 (in, 1H), 6.69-6.78 (in, 3H), 4.12 (in, 2H), 3.53 (s, 2H), 1.21 (in, 3H). Diethyl 2-((3-ethoxy-2-oxoethyl)phenox)methyl)malonate (S16-3). To a solution of S16-2 (11.8 g, 65.5 nmol) in 150 mL of DMF cooled in ice bath was added NaH (2.36 g, 98 minmol) and stirred at 0 "C under argon for 20 min. To the resulting mixture was added diethyl 2 bromomethylmalonate (11.8 mL, 78 mmol) dropwise. The reaction mixture was stirred at 110 >C overnight, evaporated to dryness and purified by flash chromatography to give compound S16-3 (15.2 g, 66%) as a colorless oil. 'H NMR (500 MHz, CDCI 3 ) 8 7.19 (t, 1H), 6.80-6.86 (in, 3H), 4.81 (in, 1H), 4.12 (in, 2H), 3.97 (in, 2H), 3.74 (in, 2H), 3.63 (in, 2H), 3.55 (s, 2H), 1.19 (in, 9H); 3 C NMR (125 MHz, CDC 3 ) 8 171.3,158.8,135.6,129.5, 121.8,115.6,113.3, 100.5,68.5, 62.5,60.7,41.3,15.4,14.1. Ethyl 2-(benzofuran-6-yl) acetate (S16-4). To a solution of S16-3 (6 g, 17 mmol) in 100 mL of toluene was added 3 g of polyphosphoric acid. The resulting mixture was refluxed overnight, condensed and purified by flash chromatography to give S16-4 (1.42 g, 41%) as colorless oil. 'H NMR (500 MHz, CDC 3 ) 6 7.31-7.42 (in, 3H), 6.95 (in, 1H), 6.51 (s, 1H), 3.94 (in, 2H), 3.51 (s, 2H), 1.02 (in, 3H); "C NMR (125 MHz, CDC1 3 ) 8 171.6,155.2,145.1, 130.6, 126.4, 124.3, 121.1, 112.2, 106.4, 60.9, 41.5,14.2. 2-(benzofuran-6-yI) acetic acid (S13-5). To a solution of S16-4 (3 g, 14.7 nnol) in 100 mL methanol was add 25 mL of 1 N NaOH. The resulting mixture was stirred at rt for 2 h, neutralized with concentrated HC, and adjusted pH to 2. The reaction mixture was condensed, purified by flash chromatography to yield S16-5 as a white solid in quantitative yield. 'H NMR (500 MHz, MeOH-d 4 ) 6 7.73 (s, 1H), 7.53 (d, J=7.9 Hz, 1H), 7.43 (s, 1H), 7.15 (d, J= 8.0 Hz, 1H), 6.79 (s, 1H), 3.70 (s, 2H); 1 3 C NMR (125 MHz, MeOH-d 4 ) 6 175.7, 156.6, 146.6, 132.5, 127.7, 125.4, 121.9, 113.0, 107.4, 41.9. 2-(2,3-dihydrobenzofuran-6-yl)acetic acid (S16-6). To a solution of S16-5 (1.8 g, 10 mmol) in 20 mL of methanol was added Pd/C (10%, 120 mg) and stirred at rt under H 2 (2 atm) WO 2011/044394 PCT/US2010/051872 129 overnight. The reaction mixture was filtered, washed with cold methanol, evaporated to dryness and purified by flash chromatography to give S16-6 (1.6 g, 88%) as a white solid. 'H NMR (500 MHz, MeOH-d 4 ) 6 7.12 (d, J= 7.6 Hz, IH), 6.73 (d, J= 7.9 Hz, 111), 6.71 (s, IH), 4.55 (m, 2H), 3.56 (s, 2H), 3.16 (in, 2H); "C NMR (125 MHz, MeOH-d 4 ) 8 177.9, 160.4, 133.3, 126.2, 124.8, 121.5, 110.5, 71.5, 41.1, 29.4. 8-((2,3-dihydrobenzofuran-6-y)methyl)-9H-purine-2,6-diamine (S16-7). The mixture of 2,4,5,6-tetraaminopyrimidine (200 mg, 1.4 mmol), S16-6 (254 mg, 1.4 mmol) and triphenyl phosphite (451 piL, 1.7 nmol) in 2 mL of pyridine was irradiated in the microwave for 15 min at 210 "C. After cooling, the reaction mixture was concentrated under vacuum and the residue purified by flash chromatography to give S16-7 (350 mg, 89%) as a yellow solid. 'H NMR (500 MHz, MeOH-d4) 6 7.16 (in, iH), 6.79 (in, 1H), 6.73 (s, 1H), 4.57 (in, 211), 4.12 (s, 211), 3.18 (in, 2H); MS: m/z 283.2 (M+H). 8-((2,3-dihydrobenzofuran-6-yl)methyl)-2-fluoro-9H-purin-6-amine (S16-8). A plastic tube charged with S16-7 (0.72 g, 2.5 mmol) was cooled in ice bath, added HF/pyridine (73%, 1.76 mL) and stirred to dissolve. To the resulting mixture was added NaNO 2 (0.23 g, 3.3 mmol) in portions and kept stirring for 5 min. The reaction mixture was allowed to warm up to rt and stirred for 3 h. CaCO 3 (0.68 g) was added to quench excess HF. The resulting suspension was stirred for I h, filtered, concentrated in vacuo and purified by flash chromatography to give S16-8 (0.45 g, 62%) as a yellow solid. 'H NMR (500 MHz, MeOH 4) : 7.16 (in, 1H), 6.77 (in, 1H), 6.71 (s, 1H), 4.57 (in, 2H), 4.12 (s, 2H), 3.19 (in, 2H); MS: m/z 286.0 (M+H)*. 2- fluoro-8-((5-iodo-2,3-dihydrobenzofuran-6-yl)methyl)-9H-purin-6-amine (S16-9). To a suspension of S16-8 (0.45 g, 1.6 mmol) in 50 mL acetonitrile was added 1 mL of TFA. To the resulting solution was added NIS (1.06 g, 4.7 mmol) and the reaction mixture was stirred at A for 3 h. It was then evaporated to dryness and purified by flash chromatography to give S16-9 (0.408 g, 63%) as a yellow solid. 'H NMR (500 MHz, MeOH-dt) 8 7.67 (s, 1H), 6.76 (s, 1H1), 4.59 (in, 2H), 4.28 (s, 2H), 3.21 (in, 211); MS: m/z 412 (M+H)*.

WO 2011/044394 PCT/US2010/051872 130 9- (3-bromopropyl)-2-fluoro-8-((5-iodo-2,3-dihydrobenzofuran-6-yl)methyl)-9H-purin 6-amine (S16-10A). To a solution of S16-9 (50 mg, 0.12 mmol) in 2 mL of DMF was added 1,3-dibromopropane (150 pL) and Cs 2

CO

3 (80 ng, 0.24 mmol). The resulting mixture was stirred at rt for 2 h, evaporated to dryness and purified by preparatory TLC to give S16-1OA (23 mg, 36%) as a white solid. 'H NMR (500 MHz, MeOH-d4) 6 7.48 (s, IH), 6.31 (s, 1H), 4.35 (in, 2H), 4.12 (s, 2H), 3.92 (in, 2h), 3.14 (in, 2H), 3.01 (in, 2H), 2.03 (in, 2H); MS: m/z 530, 532 (M, M+2). 2-fluoro-8-((5-iodo-2,3-dihydrobenzofuran-6-yl)methyl)-9-(3-(isopropylamino)propyl) 9H-purin-6-amine (PU-WS1S). To a solution of S16-1OA (15 mg, 0.03 mmol) in 1 mL of DMF was added isopropylamine (0.5 mL), stirred at rt overnight, evaporated to dryness and purified by flash chromatography to give PU-WS18 (13 mg, 90%) as a white solid. 'H NMR (500 MHz, MeOH-d 4 ) 8 7.67 (s, 1H), 6.72 (s, iH), 4.63 (in, 2H), 4.26 (in, 4H), 3.22-3.29 (in, 3H), 2.93 (t, J= 7.1 Hz, 2H), 2.27 (t, J= 7.0 Hz, 2H), 1.38 (d, J= 6.5 Hz, 6H); HRMS (ESI) m/z [M+H]* calcd. for C 2 0

H

25

N

6 0F1, 511.1119; found 511.1103. 2-fluoro-8-((5-iodo-2,3-dihydrobenzofuran-6-yl)methyl)-9-(2-(isobutylamino)ethyl)-9H purin-6-amine [PU-WS17]. To a solution of S16-9 (70 mg, 0.17 mmol) in 2 mL of DMF was added 1,2-dibromoethane (150 pL) and Cs 2

CO

3 (110 mg, 0.34 mmol). The resulting mixture was stirred at rt for 2 h, evaporated to dryness and purified by preparatory TLC to give bromide intermediate S16-10B. To a solution of S16-10B (10 mg, 0.19 mimol) in I mL of DMF was added isobutylamine (100 uL), stirred at rt overnight, evaporated to dryness and purified by flash chromatography to give PU-WS17 as a white solid. 'H NMR (MeOH d 4

/CDC

3 , 500 MHz) 6: 7.67 (s, 1Hl), 6.62 (s, 1H), 4.59 (t, J = 8.7 Hz, 2H), 4.29 (s, 2H), 4.15 (t, J = 6.5 Hz, 2H), 3.22 (t, J = 8.7 Hz, 2H), 2.93 (t, J = 6.5 Hz, 2H), 2.45 (d, J - 6.9 Hz, 2H), 1.69 (in, 111), 0.88 (d, J = 6.8 Hz, 6H); HRMS (ESI) m/z [M+Ht] called. for C 20

H

2 5 FINO, 511.1119; found 511.1113. 2-fluoro-8-((5-iodo-2,3-dihydrobenzofuran-6-yl)methyl)-9-(2-(neopentylaino)ethyl) 9H-purin-6-amlne [PU-WS22]. To a solution of S16-9 (70 mg, 0.17 mmol) in 2 mL of DMF was added 1,2-dibromoethane (150 pL) and Cs 2 C0 3 (110 mg, 0.34 mmol). The resulting WO 2011/044394 PCT/US2010/051872 131 mixture was stirred at rt for 2 h, evaporated to dryness and purified by preparatory TLC to give bromide intermediate S16-10B. To a solution of S16-1OB (65 mg, 0.13 mmol) in I mL of DMF was added neopentylamine (50 pL), stirred at rt overnight, evaporated to dryness and purified by flash chromatography to give compound PU-WS22 as a white solid. 'H NMR (CDCl 3 , 500 MHz) 5 7.46 (s, 1H), 6.53 (s, 1H), 5.79-(s, 2H), 5.52 (br, 2H), 4.52 (m, 2H), 4.09 (m, 2H), 3.19 (m, 2H), 2.94-3.02 (m, 2H), 2.34(s, 2H), 0.91 (s, 9H); HRMS (ESI) m/z [M+H]* caic& for C 21

H

2 7

FIN

6 0, 525.1275; found 525.1249. Br02b 0 2 N C H 2 N . BrBr I S171 S17-2 817-3 S17-4 S17-5 817-4

NH

2 / iiNH2 N N N\ 0 IL r 5 KJ N N (N N n=1,2 n=1,2 NHR Br S17-7 17 Reagents and conditions: (a) H-NO 3 , H 2

SO

4 ; (b) NaI, Cul, N,N'-dimethylethylenediamine, dioxane, 11 CO; (C) Fe, H1; (d) 8-mercaptoadenine, neocuproine, CuI, NaOtBu, DMF, 1 15*C; (e) KI, NaNO 2 , HC1, < 5*C ; (f) Cs 2

CO

3 , 1,3-dibromopropane, DMF, rt; (g) isopropylamine, DMF, rt Scheme 17.

WO 2011/044394 PCT/US2010/051872 132 H2N ACHN AcHBr S18-1 SS-2 S18-3 8184 O O NH 2

H

2 N e ~~ I. IIN AcHN H 2 N N N S18-6 818-6 S18-7

NH

2

NH

2

NH

2 N N% _S_/ St N5 NN N N O n=1,2 ( n=1,2 Br Br 316-8 S18-9 S18-10 Reagents and conditions: (a) Ac 2 O, CH 2

C

2 , rt; (b) Br 2 , AcOH, 10*C; (c) CrO,, AcOH/H 2 0, 50-55cC; (d) NaI, CuI, N,N'-dimethylethylenediamine, dioxane, 110 0 C; (e) 6M HC (aq.), reflux; (f) 8 mercaptoadenine, neocuproine, Cul, NaOtlu, DMF, 115*C; (g) KI, NaNO 2 , HC, < 5*C; (h) Cs2CO 3 , 1,3-dibromopropane, DME, rt; (i) isopropylamine, DMF, rt. Scheme 18.

NH

2 i NH 2 X _Z a or b (NZ_ X N N oXIN N ( ) )n 1,2 ( ,= 1,2 NHR NHR PU-HJPI8 X= H, Z= S, n= 2, R= isopropyl, X= 2-furanyl PU-RKII X= H, Z= S, n= 2, R= isopropyl PU-HJP19 X= H, Z= S, n= 2, R= isopropyl, X= 3-pyrazolyl PU-HTI65 X= H, Z= S, n= 1, R= isobutyl PU-HJP23 X= H, Z= S, n= 1, R= isobutyl, X= 2-furanyl DZ3-73 X= F, Z= CH2, n= 1, R= isobutyl TT-VI-63A X= F, Z= CH 2 , n= 1, R= isobutyl, X= 2-furanyl Tr-VI-64A X= F, Z= CH 2 , n= 1, R= isobutyl, X= 3-pyrazolyl PU-HJP20 X= H, Z= S, n= 2, R= isopropyl, X= 2-oxazolyl Reagets or conditions: (a) boronic acid, PdCI 2 (PPh3)2, NaHCO3, H20, DMF; (b) XSn(Bu) 3 , LiCl, Pd(PPh3) 4 , DMF, 90*C .

WO 2011/044394 PCT/US2010/051872 133 Scheme 19. Cross-coupling reactions of PU-RK11, PU-HT165 and DZ3-73. 8-((7-(furan-2-yl)-2,3-dihydrobenzo[b [1,4]dioxin-6-yI)thio)-9-(3 (isopropylamino)propyl)-9H-purin-6amine [HJPI1. 2-Furanylboronic acid (8 mg, 0.0712 mmol) was added to PU-RK11 (25 mg, 0.0475 mmol) and NaHCO 3 (12 mg, 0.1425 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2 C1 2 (6.7 mg, 0.0095 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 12 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC

(CH

2

CI

2 :MeOH-NH3 (7N), 20:1) to give 10.2 mg (45%) of HJP18. 'H NMR (500 MHz, CDCl3/MeOH-d 4 ) 8 8.29 (s,1H), 7.47 (s, 1H), 7.26 (d, J= 3.8 Hz, IH), 6.89 (s, 1H), 6.73 (d, J= 3.9 Hz, 1H), 6.46 (m, IH), 4.25 (in, 4H), 4.16 (t, J= 6.2 Hz, 2H), 2.67 (in, 1H), 2.47 (t, J = 7.1 Hz, 2H), 1.86 (in, 2H), 1.01 (d, J= 6.2 Hz, 6H); "C NMR (125 MHz, CDC1 3 /MeOH d4) 8 154.4,152.8,151.7,151.0,146.7, 144.2,143.7,142.2,126.6,122.1,119.9,119.3, 117.6,111.5,109.5,64.4,64.3,48.6, 43.8, 41.6, 30.1, 22.8; MS (ESI) n/z 467.14 [M+H]*. 8-((7-(1H-pyrazol-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9-(3 (isopropylamino)propyl)-9H-purin-6-amine [HJP19]. IH-Pyrazole-3-boronic acid (6.4 mg, 0.057 mmol) was added to PU-RK11 (20 mg, 0.038 mmol) andNaHCO 3 (9.8 mg, 0.117 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh) 2

C

2 (5.3 mg, 0.0076 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 12 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC

(CH

2 Cl2:MeOH-NH 3 (7N), 15:1) to give 7.6 mg (43%) of HJP19. Additionally, 15.9 mg of unreacted PU-RKI 1 was recovered for an actual yield of 86%. 'H NMR (500 MHz, CDCl 3 /MeOH-d4) 8 8.18 (s, 1H), 7.53 (d, J= 2.4 Hz, 1H), 7.15 (s, 1H), 7.14 (s, 1H), 6.36 (d, J= 2.4 Hz, 1H), 4.29 (in, 4H), 4.19 (t, J= 6.6 Hz, 2H), 2.75 (septet J= 6.1 Hz, 1H), 2.52 (t, J= 6.6 Hz, 2H), 1.93 (in, 2H), 1.06 (d, J= 6.1 Hz, 6H); MS (ESI) m/z 468.0 [M+H]*.

WO 2011/044394 PCT/US2010/051872 134 8-((7-(furan-2-yl)-2,3-dihydrobenzo[b] [1,4]dioxin-6-yl)thio)-9-(2-(isobutylamino)ethyl) 9H-purin-6-amine [HJP23]. 2-Furanylboronic acid (5.4 mg, 0.0486 mmol) was added to PU-HT165 (9 mg, 0.0171 mmol) and NaHCO 3 (5.7 mg, 0.0684 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2 C1 2 (2.4 mg, 0.0034 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 12 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2 Cl 2 :MeOH-NH 3 (7N), 20:1) to give 1.8 mg (23%) of HIP23. 'H NMR (500 MHz, CDCl 3 ) 5 8.29 (s, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.26 (s, 1H), 6. 90 (s, 1H), 6.74 (d, J = 3.2 Hz, 11), 6.47 (in, 1H), 5.63 (br s, 2H), 4.20-4.30 (in, 6H), 2.90 (t, J= 6.0 Hz, 2H), 2.38 (d, J= 6.8 Hz, 2H), 1.65 (in, IH), 0.85 (d, J= 6.9 Hz, 6H); HRMS (ESI) m/z [M+H]* calcd. for C23H 27

N

6

O

3 S, 467.1865; found 467.1884. 2-fluoro-8-((7-(furan-2-yl)-2,3-dihydrobenzo[b] [1,4]dioxin-6-yl)methyl)-9-(2 (isobutylamino)ethyl)-9H-purin-6-anine [TT-VI-53A]. 2-Furanylboronic acid (8 mg, 0.0712 mmol) was added to DZ3-73 (25 mg, 0.0475 mmol) and NaHCO 3 (12 ing, 0.1425 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2

C

2 (6.7 mg, 0.0095 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 12 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC

(CH

2 C1 2 :MeOH-NH3 (7N), 20:1) to give 20.9 mg (94%) of TT-VI-53A. 1H NMR (500 MHz, CDCl/MeOH-d4) 6 7.45 (d, J= 1.8 Hz, 1H), 7.13 (s, lH), 6.60 (s, 1H), 6.44 (dd, J= 1.8, 3.3 Hz, 1H), 6.35 (d, J= 3.3 Hz, 1H), 4.34 (s, 2H), 4.26 (s, 4H), 4.05 (t, J= 6.4 Hz, 2H), 2.85 (t, J= 6.4 Hz, 2H), 2.35 (d, J= 6.9 Hz, 2H), 1.67 (in, 1H), 0.85 (d, J= 6.7 Hz, 6H); "C NMR (125 MHz, CDC13/MeOH-d4) 6 158.8 (d, J= 209.1 Hz), 156.3 (d, J= 19.5 Hz), 152.8, 152.2, 143.9, 142.9, 142.2, 126.0, 124.1, 118.7, 117.7, 117.6, 116.3, 111.6, 108.2, 64.6, 57.5, 48.6, 43.1, 31.8, 28.2, 20.6; HRMS (ESI) m/z [M+H]* calcd. for C 24

H

2

FN

6 0 3 , 467.2207; found 467.2203; HPLC: method A R, = 7.05, method B R = 8.74.

WO 2011/044394 PCT/US2010/051872 135 8-((7-(1H-pyrazol-3-yl)-2,3-dihydrobenzo[b] [1,4]dioxin-6-yl)methyl)-2-fluoro-9-(2 (isobutylamino)ethyl)-9H-purin-6-anine [TT-VI-54A]. lH-Pyrazole-3-boronic acid (26 mg, 0.228 mmol) was added to DZ3-73 (30 mg, 0.0570 mmol) and NaHCO3 (29 mg, 0.342 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H 2 0 (0.2 mL) and Pd(PPh 3

)

2 C1 2 (8 mg, 0.0114 mmol) were added and the reaction mixture was heated under nitrogen at 900C for 12 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC

(CH

2 Cl 2 :MeOH-NH 3 (7N), 15:1) to give 11.3 mg (42%) of TT-VI-54A. Additionally, 15.9 mg of unreacted DZ3-73 was recovered for an actual yield of 90%. 'H NMR (500 MHz, CDC1 3 /MeOH-d4) 8 7.60 (d, J= 2.1 Hz, IH), 7.02 (s, iH), 6.82 (s, iH), 6.33 (d, J= 2.1 Hz, lH), 4.32 (t, J= 6.8 Hz, 2H), 4.29 (s, 2H), 4.28 (s, 4H), 2.96 (t, J= 6.8 Hz, 2H), 2.59 (d, J= 7.0 Hz, 2H), 1.92 (in, 1H), 0.96 (d, J= 6.7 Hz, 6H); "C NMR (125 MHz, CDCI 3 /MeOH-ds) 5 158.2 (d, J= 210.1 Hz), 156.5 (d, J= 19.9 Hz), 152.6, 152.2, 152.1, 144.0,143.0,126.5, 119.1, 118.9, 115.94, 115.91, 105.4, 64.65, 64.56, 56.5,47.7,41.0, 31.1, 27.2, 20.3; HRMS (ESI) m/z [M+H]* called. for C 23

H

22

FN

2

O

2 , 467.2319; found 467.2323; HPLC: method A Rt 6.39, method B R = 7.03. 9-(3-(isopropylamino)propyl)-8-((7-(oxazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6 yI)thio)-9H-purin-6-amine [HJP20]. 2-(Tributyltin)oxazole (54 mg, 0.1518 mmol) was added to PU-RK11 (20 mg, 0.038 mmol) and LiCl (3.2 mg, 0.076 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then Pd(PPh 3

)

4 (6.7 mg, 0.0095 mmol) was added and the reaction mixture was heated under nitrogen at 90"C for 12 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH2CI 2 :MeOH-NH 3 (7N), 20:1) to give 4.7 mg (27%) of HJP20. Additionally, 7 ing of unreacted PU-RK11 was recovered for an actual yield of 45%. 'H NMR (500 MHz, CDC1 3 ) 8 8.32 (s, 1H), 7.70 (s, 1H), 7.54 (s, 1H), 7.26 (s, 1H), 6.59 (s, 1H), 5.79 (br s, 2H), 4.20-4.34 (in, 6H), 2.67 (in, J= 6.1 Hz, 1H), 2.50 (t, J= WO 2011/044394 PCT/US2010/051872 136 6.8 Hz, 211), 1.93 (in, J= 7.1 Hz, 2H), 0.99 (d, J= 6.4 Hz, 6H); MS (ESI) m/z 468.15 [M+H]*.

NH

2

NH

2 R aorb

OCH

3

OCH

3 HN HN EC102 Reagents or conditions: (a) RB(OH) 2 , PdCI 2 (PPh 3

)

2 , NaHCO 3 , H20, DMF; (b) CuL, PdC 2 (PPh 3

)

2 , trimethylsilanylacetylene, Et 3 N, DMF, 90*C. Scheme 20. Cross-coupling reactions of EC102. 8-(2-(furan-2-yl)-5-methoxyphenylthio)-9-(2-(neopentylamino)ethyl)-9H-purin-6-amine [TT-V-138]. 2-Furanylboronic acid (8.2 mg, 0.0732 mmol) was added to EC102 (25 img, 0.0488 mmol) andNaHCO 3 (12.3 mg, 0.1464 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2 Cl 2 (6.8 mg, 0.00976 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 5 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2 Cl 2 :MeOH-NH 3 (7N), 20:1) to give 20.7 mg (94%) of TT-V-138. 'H NMR (500 MHz, CDC1 3 ) 8 8.31 (s, 1H), 7.62 (d, J= 8.7 Hz, IH), 7.50 (d, J= 1.8 Hz, 111), 6.86 (dd, J= 2.6, 8.7 Hz, IH), 6.70-6.73 (m, 2H), 6.49 (dd, J= 1.8, 3.3 Hz, 1H), 5.98 (hr s, 2H), 4.26 (t, J= 6.2 Hz, 2H), 3.70 (s, 3H), 2.89 (t, J= 6.2 Hz, 2H), 2.28 (s, 2H), 0.84 (s, 9H); 1 3 C NMR (125 MHz, CDC1 3 ) 8 159.4,154.8,153.2,151.6,151.2, 145.4, 142.0, 130.9, 130.2, 124.3, 120.1, 116.5, 113.4, 111.4,109.1, 61.8,55.3, 49.6,43.9, WO 2011/044394 PCT/US2010/051872 137 31.5, 27.6; HRMS (ESI) m/z [M+H]*calcd. for C 23

H

29

N

6 0 2 S, 453.2073; found 453.2071; HPLC: method A R, = 6.76, method B Rt = 7.29. 8-(5-methoxy-2-(thiophen-2-yl)phenylthio)-9-(2-(neopentylamino)ethyl)-9H-purin-6 amine [TT-V-139]. 2-Thiopheneboronic acid (18.8 mg, 0.147 imol) was added to EC102 (25 mg, 0.0488 mmol) and NaHCO 3 (24.6 mg, 0.293 nimol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.25 mL) and Pd(PPh 3 )2Cl 2 (10.4 mg, 0.0148 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 5 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH2C12:MeOH-NH 3 (7N), 20:1) to give 16.2 mg (71%) of TT-V-139. 'H NMR (500 MHz, CDCI 3 /MeOH-d) 8 8.19 (s, 1H), 7.45 (d, J= 8.5 Hz, IH), 7.30-7.33 (m, IH), 6.99-7.04 (m, 3H), 6.97 (dd, J= 2.6, 8.5 Hz, iH), 4.24 (t, J= 6.1 Hz, 2H), 3.82 (s, 3H), 2.97 (t, J= 6.1 Hz, 2H), 2.41 (s, 2H), 0.91 (s, 9H); 3 C NMR (125 MHz, CDCl3/MeOH-d4) 8 159.9, 154.6, 152.4, 150.9, 147.6, 140.4,133.2, 130.8, 129.3, 127.6, 127.1, 126.2, 119,5,118.9,114.6,61.4,55.6,49.3,43.3, 31,3, 27.6; HRMS (ESI) m/z [M+H]* called. for C 2 3 H2 9

N

6

OS

2 , 469.1844; found 469.1830; HPLC: method A R = 6.84, method B R = 7.48. 8-(5-methoxy-2-(1H-pyrazol-3-yI)phenylthio)-9-(2-(neopentylamino)ethyl)-9H-purin-6 amine [TT-V-140]. 1H-Pyrazole-3-boronic acid (26.2 mg, 0.234 mmol) was added to EC102 (30 mg, 0.0585 mmol) and NaHCO 3 (29.5 mg, 0.351 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.2 mL) and Pd(PPh 3

)

2 Cl 2 (8.2 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 7 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH2Cl 2 :MeOH-NH3 (7N), 15:1) to give 6.2 mg (23%) of TT-V-140. Additionally, 16.

4 mg of unreacted EC102 was recovered for an actual yield of 52%. 'H NMR (500 MHz, CDC1 3 /MeOH-d4) 8 8.19 (s, iH), 7.58 (d, J= 2.1 Hz, 1H), 7.50 (d, J= 8.5 Hz, 1H), 7.03 (d, J= 2.4 Hz, 1H), 6.99 (dd, J= 2.6, 8.6 Hz, 1H), 6.40 (d, J= 2.1 Hz, IH), 4.42 (t, J= 6.1 Hz, 2H), 3.81 (s, 3H), 3.02 (t, J= 6.1 Hz, 2H), 2.52 (s, 2H), WO 2011/044394 PCT/US2010/051872 138 0.98 (s, 9H); "C NMR (125 MHz, CDC1 3 /MeOH-d 4 ) 5 154.6, 152.3, 150.8, 149.4, 148.6, 148.5, 120.1, 119.2,114.5,110.9, 106.0, 102.3, 61.2, 49.1, 42.5, 31.1, 27.5; HRMS (ESI) m/z [M+H]* called. for C22H 2 9

N

8 OS, 453.2185; found 453.2186; HPLC: method A Rt = 6.61, method B R, = 6.82. 8- ((2-ethynyl-5-methoxyphenyl)thio)-9-(2-(neopentylamino)ethyl)-9H-purin-6-amine (PU-WS31). Following the procedure to make PU-WS8, PU-WS31 was obtained from EC1O2 as a white solid. 'H NMR (CDC1 3 , 500 MHz) 5: 8.35 (s, IN), 7.46 (d, J= 8.4 Hz, 1H), 6.75 (m, 2H), 5.65 (br, 2H), 4.35 (t, J = 6.3 Hz, 2H), 3.72 (s, 3H), 3.30 (s, 1H), 2.97 (t, J = 6.3 Hz, 2H), 2.31 (s, 2H), 0.87 (s, 9H); MS (ESI) m/z 411.3 (M+H)*.

NH

2 NH 2 R S S IN$N 0 I N N 0 NH NH PU-471

NH

2

/\NH

2 /\ N N FAN1 N I- R F F NR HN HN PU-DZ13 Reagents and conditions: (a) RSn(Bu) 3 , LiC1, Pd(PPh) 4 , DMF, 90 0

C.

WO 2011/044394 PCT/US2010/051872 139 Scheme 21. Stille coupling of PU-171 and PU-DZ13. 9-(3-(isopropylamino)propyl)-8-(6-(oxazol-2-yl)benzo[d [1,3jdioxol-5-ylthio)-9H-purin 6-amine [DZ4-20]. A mixture of PU-H71 (30 mg, 0.0585 mmol), 2-(tri-n butylstannyl)oxazole (83.8 mg, 49 g1, 0.234 mmol), LiC1 (5 mg, 0.117 mmol) and Pd(PPh3)4 (6.7 mg, 0.0058 mmol) in DMF (1 mL) was evacuated and back filled with nitrogen. This was repeated four times then the reaction mixture was heated under nitrogen at 90 0 C for 18 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2

C

2 :EtOAC:MeOH-NH3 (7N), 2:2:1:0.5) to give 20.8 mg (78%) of DZ4-20. 'H NMR (500 MHz, CDCl3/MeOH-d) & 8.25 (s, 1H), 7.75 (s, 111), 7.46 (a, 1H), 7.27 (s, 1H), 6.71 (s, iH), 6.06 (s, 2H), 4.26 (t, J= 6.9 Hz, 2H), 2.75 (septet, J= 6.3 Hz, 1H), 2.53 (t, J= 6.9 Hz, 2H), 1.98 (in, 2H), 1.06 (d, J= 6.3 Hz, 6H); HRMS (ESI) m/z [M+HJ* called. for C 21 11 24

N

7 0 3 S, 454.1661; found 454.1650; HPLC: method A 1, = 5.77, method B Rt = 5.28. 9-(3-(isopropylamino)propyl)-8-(6-(thiazol-2-yl)benzo[d] [1,3jdioxol-5-ylthio)-9H-purin 6-amine [DZ4-21]. A mixture of PU-H71 (30 mg, 0.0585 mmol), 2-(tri-n butylstannyl)thiazole (87.6 mg, 72.4 pl, 0.234 mmol), LiC1 (5 ing, 0.117 mmol) and Pd(PPh 3

)

4 (6.7 mg, 0.0058 mmol) in DMF (1 mL) was evacuated and back filled with nitrogen. This was repeated four times then the reaction mixture was heated under nitrogen at 90 0 C for 18 h. Then additional 2-(tri-n-butylstannyl)thiazole (21.9 mg, 18 pi, 0.0585 mmol) was added and the reaction mixture was heated under nitrogen at 90*C for an additional 18 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2 Cl 2 :EtOAC:MeOH-NH3 (7N), 2:2:1:0.5) to give 17.6 mg (64%) of DZ4-21. 'H NMR (500 MHz, CDCl3/MeOH-d) S 8.20 (s, 1H), 7.87 (d, J= 3.3 Hz, 1H), 7.45 (s, 1H), 7.44 (d, J= 3.3 Hz, 1H), 6.98 (s, 1H), 6.11 (s, 2H), 4.21 (t, J= 6.9 Hz, 2H), 2.78 (septet, J= 6.3 Hz, 1H), 2.55 (t, J= 6.9 Hz, 2H), 1.98 (in, 2H), 1.09 (d, J= 6.3 Hz, 6H); HRMS (ESI) m/z [M+H]* called. for C 21

H

2 4

N

7 0 2

S

2 , 470.1433; found 470.1438; HPLC: method A Rt = 5.86, method B R = 5.66.

WO 2011/044394 PCT/US2010/051872 140 2-fluoro-9-(2-(isobutylamino)ethyl)-8-((6-(oxazol-2-yl)benzo[d [1,3Jdioxol-5-yl)methyl) 9H-purin-6-amine [DZ4-23]. A mixture of PU-DZ13 (20 mg, 0.039 mmol), 2-(tri-n butylstannyl)oxazole (55.9 mg, 32.7 pl, 0.156 mmol), LiC1 (3.3 mg, 0.078 mmol) and Pd(PPh) 4 (4.5 mg, 0.0039 mmol) in DMF (1 mL) was evacuated and back filled with nitrogen. This was repeated four times then the reaction mixture was heated under nitrogen at 90 0 C for 18 h. Then additional LiC (3.3 mg, 0.078 mmol) and Pd(PPh 3

)

4 (4.5 mg, 0.0039 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for an additional 18 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC two times (hexane:CH 2 Cl 2 :EtOAC:MeOH-NH 3 (7N), 2:2:1:0.5 then CH 2 Cl2:MeOH-NH3 (7N), 20:1) to give 5.5 mg (31%) of DZ4-23. 'H NMR (500 MHz, CDCl 3 /MeOH-d 4 ) 5 7.68 (s, 1H), 7.53 (s, 1H), 7.12 (s, iH), 6.84 (s, 1H), 6.07 (s, 2H), 4.74 (s, 2H), 4.41 (t, J= 6.4 Hz, 2H), 3.15 (t, J= 6.4 Hz, 211), 2.59 (d, J= 6.9 Hz, 2H), 1.88 (m, 1H), 0.96 (d, J= 6.8 Hz, 6H); HRMS (ESI) n/z [M+H]* calcd. for C22H 2 5

FN

7

O

3 , 454.2003; found 454.1995; HPLC: method A R = 6.61, method B Rt = 7.58. 2-fluoro-9-(2-(isobutylamino)ethyl)-8-((6-(thiazol-2-yl)benzo[d] [1,3Jdioxol-5-yI)methyl) 9H-purin-6-amine [DZ4-24]. A mixture of PU-DZ13 (20 mg, 0.039 mmol), 2-(tri-n butylstannyl)thiazole (58.3 mg, 48.2 pl, 0.156 mmol), LiC1 (3.3 mg, 0.078 mmol) and Pd(PPh 3

)

4 (9 mg, 0.0078 mmol) in DMF (1 mL) was evacuated and back filled with nitrogen. This was repeated four times then the reaction mixture was heated under nitrogen at 90*C for 18 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC two times (hexane:CH 2 C1 2 :EtOAC:MeOH-NH3 (7N), 2:2:1:0.5 and

CH

2

CI

2 :MeOH:AcOH, 20:1:0.5) to give 10.2 mg (56%) of DZ4-24. 'H NMR (500 MHz,

CDC

3 /MeOH-d 4 ) 5 7.77 (d, J= 3.3 Hz, 1H), 7.36 (d, J= 3.3 Hz, 1H), 7.17 (s, 1H), 6.80 (s, 1H), 6.05 (s, 2H), 4.58 (s, 2H), 4.15 (t, J= 6.6 Hz, 2H), 2.85 (t, J= 6.6 Hz, 2H), 2.35 (d, J= 6.8 Hz, 211), 1.64 (m, 1H), 0.86 (d, J= 6.8 Hz, 6H); HRMS (ESI) mz [M+H]* calcd. for C22H 2 sFN 7 0 2 S, 470.1774; found 470.1770; HPLC: method A Rt = 6.68, method B R = 7.79.

WO 2011/044394 PCT/US2010/051872 141

NH

2 I

NH

2 R N 0 N N __X N N 0 1 N N 0 NH NH PU-H71 Reagents and conditions: (a) alkene (R), Pd(PPh3) 4 , i-Pr 2 NEt, NMP, 55-100*C. Scheme 22. Heck coupling of PU-H71. 8-(6-(cyclopent-2-enyl)benzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H purin-6-amine [TT-VI-116]. A solution of PU-H71 (30 mg, 0.0585 mmol) in NMP (1 mL) was evacuated and back filled with nitrogen. This was repeated four times, then DIEA (15.1 mg, 21 gL, 0.117 mmol), cyclopentene (80 mg, 103 gL, 1.171 mmol) and Pd(PPh) 4 (6.8 mg, 0.00586 nimol) were added and the reaction mixture was heated under nitrogen at 100*C for 20 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC two times (CH 2

CI

2 :MeOH-NH 3 (7N), 15:1 then CH 2 CI2:MeOH, 7:3) to give 9.2 mg (35%) of TT-VI-116. 'H NMR (500 MHz, CDCI 3 /MeOH-d 4 ) 8 8.16 (s, 1fH), 6.99 (s, 1H), 6.82 (s, 1H), 6.01 (s, 2H), 5.98 (in, 1H), 5.63 (in, 1 H), 4.41 (t, J= 6.4 Hz, 2H), 3.39 (in, 1H), 3.34 (septet, J= 6.6 Hz, 1 H), 2.95 (t, J= 6.4 Hz, 2H1), 2.22-2.52 (m, 5H), 1.50-1.59 (in, 1H), 1.44 (d, J= 6.6 Hz, 6H); HRMS (ESI) m/z [M+H]* calcd. for C23H 2 9N 6 0 2 S, 453.2073; found 453.2064; HPLC: method A R = 6.51, method B Rt = 7.79. 8-(6-(2,5-dihydro-1H-pyrrol-2-yl)benzo[d] [1,3]dioxol-5-ylthio)-9-(3 (isopropylamino)propyl)-9H-purin-6-amine [DZ3-141]. A solution of PU-H71 (30 mg, 0.0585 mmol) and N-Boc-2,3-dihydro- 1 H-pyrrole (19.8 mg, 20.2 pL, 0.117 mmol) in NMP (1.5 mL) was evacuated and back filled with nitrogen. This was repeated four times, then DIEA (15.1 mg, 21 sL, 0.117 mmol) and Pd(PPh 3

)

4 (13.5 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 100*C for 20 h. Solvent was removed WO 2011/044394 PCT/US2010/051872 142 under reduced pressure and the resulting residue was purified by preparatory TLC

(CH

2

C

2 :MeOH-NH 3 (7N), 15:1) and the resulting residue was dissolved into 2 mL of

CH

2

C

2 :TFA (4:1) and stirred for 1 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2 C1 2 :MeOH-NH 3 (7N), 10:1) to give 6.0 mg (23%) of DZ3-141. 1H NMR (500 MfHz, CDCI 3 /MeOH-d 4 ) 6 8.19 (s, IH), 6.98 (s, 2H), 6.04 (in, 1H), 6.01 (s, 2H), 5.74 (in, 1H), 5.62 (d, J= 2.0 Hz, 1H), 4.31 (t, J= 6.9 Hz, 2H), 3.81-3.88 (in, 1H), 3.89-3.95 (in, 1H), 2.87 (septet, J= 6.3 Hz, 1H), 2.68 (t, J= 6.7 Hz, 2H), 2.14 (in, 2H), 1.15 (d, J= 6.3 Hz, 6H); HRMS (ESI) mlz [M+H]' called. for

C

22

H

2 8

N

7 0 2 S, 454.2025; found 454.2046; HPLC: method A R = 5.27, method B Rt = 2.72. 8-(6-(2,3-dihydrofuran-2-yl)benzo[d] [1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl) 9H-purin-6-amine [DZ3-142]. A solution of PU-H71 (30 mg, 0.0585 mmol) in NMP (1.5 mL) was evacuated and back filled with nitrogen. This was repeated four times, then DIEA (15.1 mg, 21 gL, 0.117 mmol), 2,3-dihydrofaran (82 mg, 88 pL, 1.17 mmol) and Pd(PPh 3

)

4 (13.5 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 55 0 C for 20 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC two times (hexane:EtOAc:CH 2 C1 2 :MeOH-NH3 (7N), 2:1:2:0.5, then CH 2

CI

2 :MeOH-NH 3 (7N), 15:1) to give 7.0 mg (26%) of DZ3-142. 1 H NMR (500 MHz,

CDC

3 ) 6 8.23 (s, 1 H), 7.06 (s, 1 H), 6.96 (s, 111), 6.43 (in, 1 H), 6.01 (s, 2H), 5.94 (dd, J= 8.1, 10.8 Hz, 1H), 5.72 (br s, 2H), 4.93 (in, 1H), 4.35 (t, J= 6.8 Hz, 2H), 2.95-3.55 (in, 2H), 2.70 (t, J= 6.5 Hz, 2H), 2.39-2.47 (i, 1H), 2.22 (in, 211), 1.25 (d, J= 6.2 Hz, 6H); HRMS (ESI) m/z [M+H]* called. for C 2 2 H27N 6

O

3 S, 455.1865; found 455.1865; HPLC: method A Rt = 6.07, method B R = 6.49. 8-(6-(2,3-dihydrofuran-3-yl)benzo[d] 1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl) 9H-purin-6-amine [DZ3-143]. A solution of PU-H71 (30 mg, 0.0585 mmol) in NMP (1.5 mL) was evacuated and back filled with nitrogen. This was repeated four times, then DIEA (15.1 mg, 21 pL, 0.117 minol), 2,5-dihydrofuran (82 mg, 88 gL, 1.17 mmol) and Pd(PPh 3

)

4 (13.5 ing, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 55 0 C for 20 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC two times (CH 2 Cl 2 :MeOH-NH 3 (7N), 10:1, then WO 2011/044394 PCT/US2010/051872 143 hexane:EtOAc:CH 2 Cl 2 :MeOH-NH 3 (7N), 2:1:2:0.5) to give 5.0 mg (19%) of DZ3-143. 'H NMR (500 MHz, CDCl3/MeOH-d4) 8 8.18 (s, 1H), 7.02 (s, IH), 7.00 (s, iH), 6.55 (m, iH), 6.04 (s, 2H), 4.99 (m, IH), 4.64-4.69 (m, 1H), 4.45 (m, 1H), 4.31 (t, J= 6.8 Hz, 2H), 4.05 (dd, J= 6.2, 9.2 Hz, 1H), 3.40 (m, 1H), 2.67 (t, J= 6.4 Hz, 2H), 2.14 (m, 2H), 1.16 (d, J= 6.1 Hz, 6H); HRMS (ESI) ,n/z [M+H]* called. for C22H 2 7

N

6

O

3 S, 455.1865; found 455.1862; HPLC: method A R, = 6.04, method B Rt = 6.32.

NH

2 I NH 2 R N -S / aorb,c N N N N 0 N N 0 HN HN PU-WS23 R= 2-furanyl PU-.WS21 PU-WS24 R= 2-thiophenyl PU-WS28 R= CCH Reagents and conditions: (a) RB(OH) 2 , PdCl 2 (PPh 3

)

2 , NaHCO 3 , H 2 0, DMF, 90*C; (b) CuI, PdC1 2 (PPh 3

)

2 , trimethylsilanylacetylene, Et 3 N, DMF, 90*C; (c) KOH, MeOH, rt. Scheme 23. Cross coupling reactions of PU-WS21. 8-(5-(furan-2-yl)-2,3-dihydrobenzofuran-6-ylthio)-9-(2-(neopentylamino)ethyl)-9H purin-6-amine [PU-WS23]. Following the procedure to make PU-DZ3-4, compound PU WS23 was obtained as a white solid. 'HNMR (500 MHz, CDC1 3 ) 8 8.31 (s, IH), 7.49 (s, 2H), 6.68 (d, J= 3.4 Hz, IH), 6.58 (s, 1H), 6.49 (m, 1H), 5.60 (br s, 2H), 4.58 (t, J= 8.7 Hz, 2H), 4.25 (m, 2H), 3.22 (t, J= 8.7 Hz, 2H), 2.86 (m, 2H), 2.25 (s, 2H), 0.86 (s, 9H); HRMS (m/z): [M+H]* calcd for C 24

H

29

N

6 0 2 465.2073; found 465.2077.

WO 2011/044394 PCT/US2010/051872 144 9-(2-(neopentylamino)ethyl)-8-(5-(thiophen-2-yl)-2,3-dihydrobenzofuran-6-ylthio)-9H purin-6-amine [PU-WS24]. Following the procedure to make PU-DZ2-395, compound PU WS24 was obtained as a white solid. 'HNMR (500 MHz, CDC 3 ) 8 8.31 (s, 1 H), 7.32 (m, 1H), 7.27 (s, 1H), 7.03-7.07 (m, 2H), 6.67 (s, IH), 5.59 (br s, 2H), 4.58 (t, J= 8.7 Hz, 2H), 4.15 (m, 2H), 3.21 (t, J= 8.7 Hz, 2H), 2.86 (m, 2H), 2.25 (s; 2H), 0.83 (s, 9H); HRMS (m/z): [M+H]* daled for C 2 4H 29

N

6 0 2 481.1844; found 481.1825. 8-(5-ethynyl-2,3-dihydrobenzofuran-6-ylthio)-9-(2-(neopentylamino)ethyl)-9H-purin-6 amine [PU-WS28]. Following the procedure to make PU-WS8, compound PU-WS28 was obtained as a white solid. 'HNMR (500 MHz, CDC 3 , 5): 8.33 (s, IH), 7.36 (s, 1H), 6.59 (s, IH), 5.70 (br, 2H), 4.58 (t, J= 8.7 Hz, 2H), 4.41 (m, 2H), 3.33 (t, J= 8.7 Hz, 2H), 3.49 (m, 2H), 3.02 (s, 2H), 2.44 (s, 2H), 0.91 (s, 9H); HRMS (m/z): [M+H]* calcd for C22H 27

N

6 OS 423.1967; found 423.1968. H2N 0 AHN Q0 b ACHN Co H2N S2-1 524-2 S24-3 S24-4 NH NH 2 -N NH 2 -N

-,

2 N-N N--',Y e N N N N tt>N N N N 24-5 1, 2 n=1, 2 5 24-6 Br ' RHN S24-7 S24-8 Reagents and conditions: (a) Ac 2 O, AcOH rt; (b) ICI, CH 2 C1 2 , AcOH, rt; (c) NaOH, EtOH, H 2 0, reflux; (d) parafornaldehyde, NaBH 3 CN, MeOH, 5 0 C; (e) 8-mercaptoadenine, neocuproine, Cul, NaOtBu, DM1F, 115*C; (f) Cs 2

CO

3 , 1,3-dibromopropane or 1,2-dibromoethane, DM1F, rt; (g) amine, DMF, rt. Scheme 24. Similarly, WO 2011/044394 PCT/US2010/051872 145

H

2 N H 2 N H N 0 H 2d e g N N H 2 - N N' N H2N Hl RH n= 1,2 5 or 6-membered ring IRHN corresponding to appropriate 2-jodoamine H2N H2N IN Scheme 25. Synthesis of various bromides required for alkylation of the purine skeleton.

NH

2 X

NH

2 X2 CsR-Br N HCs 2

CO

3 ,DIMF X 4 N N H R 5 or 6- 5 or 6 membered ring membered ring WO 2011/044394 PCT[US2OIO/051872 146 HC(OEt) 3 H Br Sr OH COI1-Br n = 1 ,2 P h P , C B r 4 T A C H 3 = 1 ,2 N Mo NBOC NH oz4\

CH

3

SO

2 OI rx,fBr BrJ n=1,2 OH Hr~/~l1. =1,2 0Br N) Bw0 rN rBr S 11 -~ 0s

-N

WO 2011/044394 PCT/US2010/051872 147 0 0+BAo- Su TIPS H H HIP tHtlpo q TP6 t-butylpterN n-BU 4 NF N 10% d/C LiAH Pd{(Ac) 2 / COOn-Bu COOn-Bu coon-Bu HO Bo Boo H HA P0O2B N N N HO HO Br Br

SO

2 NCO HC(OEt~h AcCq CHaS 2 Ci H O 0 N N 2 N N Br Br Br Br 00 O -N 1 T CI N NH, 6 2) LiBr 00 -N BrO HHO Br-NH 2 NHj Br -- q NH4 2 000 O 0 MeNH 2 Br 0 08r WO 2011/044394 PCT[US2OIO/051872 148 Table IA No. Name lA-i PU-WS1O 8-((6-iodo-2,3-diliydrobenzofuran-5-yl)thio)-9-(3 (isopropylamino)propyl)-9H-purin-6-amine lA-2 8-((6-iodo-2,3-dilaydrobenzofliran-5-yl)thio)-9-(2-(isobutylamino)ethyl) 9H-purin-6-amine tA-3 1 -(6-amnino-8-(6-iodo-2,3-dihydrobenofura-5-ylthio)-9H-purm-9-yl)-3 (tert-butylamino)propan-2-ol lA-4 2-fluoro-8-((6-iodo-2,3-dihydrobenofuan-5-yl)methyl)-9-(2 _(isobutylamino)ediyl)-9H-purin-6-amine lA-5 2-chloro-8-((6-(Ihran-2-yl)-2,3-dihydrobenofuran-5-yl)methyl)-9-(3 (isopropylamino)propyl)-9H-purin-6-amine lA-6 2-fluoro-8-((6-iodo-2,3-dihydrobenofura-5-yl)methyl)-9-(3 (isopropylarnino)propyfl-9H-purin-6-anmine 1A-7 8-((6-(furan-2-y1)-2,3-dihydrobenofum-5-y1)thio)-9-(3 - (isopropylamino)propyl)-9H-purin-6-amine 1A-8 8-((6-ethynyl-2,3-dihydrobenzofliran-5-yl)thio)-9-(3 - ~(isopropytamino)propyl)-9H-purin-6-anmine, 1A-9 5-((6-arnino-9-(3-(isopropylamino)propyl)-9H-purin-8-yl)thio)-2,3 dihydrobenzofuma-6-carbonitrile IA-10 8-((6-(azixidin-1I-yl)-2,3-dilaydrobenzofiaa-5-yl)methyl)-2-fluoro-9-(2 _________(neopentylanmino)ethyl)-9H-purin-6-amine IA-1l 8-((6-iodo-2,3-dihydrobenofuran-5-yl)thio)-9-(2-(isobutylamino)ethyl) _________9H-purin-6-amine lA-12 3-(2-(6-ainino-8-(6-(5-methylfuran-2-yl)-2,3-dihydrobenzofLaran-5 ylthio)-9H-purin-9-yl)ethyl)piperidine-1-sulfonamide IA-13 ] -(3-(2-(8-(6-(1 H-pyrazol-3-yl)-2,3-dihydrobenzofura-5-ylthio)-6 anuino-9H-punin-9-yt)ethyl)pipenidin-1I -yl)ethanone IA-14 4-(3-(6-aznino-8-(6-ethynyl-2,3-dihydrobenzfinan-5-ytthio)-9H-putin-9 - yl)propyl~piperidine- I -carbaldehyde lA-i5 1-(3-(2-(6-amino-2-fluoro-8-((6-fura-2-yl)-2,3-dihydrobenofuran-5 yl)methyl)-9H-purin-9-yl)ethyl)piperidin-1I -yl)ethanone lA-16 N-(2-((2-(6-axnino-8-((6-(fura-2-yI)-2,3-dihydrobenofuira-5-yl)hio) 9H-purin-9-yl)ethyl)amino)ethyl sulfamide lA-17 3-((2-(6-amino-8-((6-(fuiran-2-yl)-2,3-diaydrobenzofura-5-yl)tio)-9H purin-9-yl)ethyt)ainino)-N-hydroxypropanamide lA-18 2-fluoro-8-((6-iodo-2,3-dihydrobenzofuran-5-yl)tliio)-9-(3 (isopropylamnho)propyl)-9H-purin-6-amine WO 2011/044394 PCT[US2OIO/051872 149 -4 IA-19 2-chiloro-8-((6-iodo-2,3-dihydrobenofura-5-yl)methyl)-9-(2 (isobutylamino)ethyl)-9H-purin-6-amine IA-20 9-(2-am-inoethyl)-2-fluoro-8-((6-iodo-2,3-dihydrobenzofuran-5 yl)methyl)-9H-purin-6-amme IA-21 9-(3-aminopropyl)-8-((6-iodo-2,3-dihydrobenzobran-5-yl)thio)-9H _________purin-6-am ire IA-22 9-(2-aininoethyl)-8-((6-iodo-2,3-dihydrobenzofLiran-5-yl)thio)-9H-purin _________6-amine IA-23 9-(3-(tert-butylam-ino)pmopyl)-8-((6-iodo-2,3-dihydrobenzofuran-5 _________Yl)thio)-9H-purin-6-amine IA-24 i-(6-amino-8-((6-iodo-2,3-dihydrobenzofhm-5-yl)thio)-9H-purin-9-yl) _________3-(isopropylamnino)propan-2-ol 1A-25 1-(3-(6-amiino-2-fluoro-8-((6-iodo-2,3-dihydroeofuiran-5-yl)methyl) ______ 9H-purin-9-yl)propyl)pyrrolidin-3-one IA-26 I -(3-(6-amino-8-(6-iodo-2,3-dihydrobenzofuran-5-ylthiio)-9H-purin-9 _________yl)propyl)pymrlidin-3-one IA-27 5-(6-aniino-8-(6-iodo-2,3-dihydrobenzoftwran-5-ylthio)-9H-purin-9 yl)pentane- 1-sulfonamide IA-28 I -(6-amino-2-fluoro-8-((6-iodo-2,3-diliydrobenzoftiran-5-yl)methyl)-9H __________purin-9-yl)-3-(isopropylamino)propan-2-ol IA-29 8-((6-ethynyl-2,3-dihydrobenofhra-5-yl)methyl)-2-fluoro-9-(5 (methylsulfonyl)pentyl)-9H-purin-6-amine 1A-30 2-fluoro-8-((6-iodo-2,3-dihydrobenzofuran-5-y1)methyl)-9-(2-(1 (methylsulfonyl)pyrrolidin-3-yl)ethyl)-9H-purin-6-amine IA-31 N-(4-(6-amino-2-fluoro-8-((6-iodo-2,3-dihydrobenzofhran-5-yl)rnethyl) - 9H-purin-9-yl)butyl)methanesulfonanide 1A-32 l-(6-amino-8-((6-ethynyl-2,3-dihydrobenzofuran-5-yl)methyl)-2-fluoro 9H-purin-9-yl)-3-(isopropylamiao)propan-2-ol 1A-33 6-(6-amino-8-((6-ethynyl-2,3-dihydrobenofhran-5-yl)methyl)-2-fluoro ________9H-purin-9-yl)hexanmde IA-34 1 -(4-(2-(6-amino-8-((6-ethynyl-2,3-dihydrobenzofhran-5-yl)methyl)-2 fluoro-9H-purin-9-yl)ethyl)piperidin-I -yl)ethanone IA-35 8-((6-ethynyl-2,3-dihydrobenzofura-5-yl)methyl) 2-fluoro-9-(2-(I -(metliylsulfonyl)piperidin-3 _________yl)ethyl)-9H-purin-6-amine 9-(3-(isopropylamino)propyl)-8-((6-(5 niethylfuran2 yl) 2,3-dihydrobenzoir-5 yl)thio)-9H-punin-6-amine 9-(3-(tert-butylamino)propyl)-8-((6-(5-methylfuiran 2-yl)-2,3-dihydrobenzoftiran-5-yl)thio)-9H-purin-6 amine __________9-(3-(tert-butylamino)propyl)-8-(( 6- WO 2011/044394 PCT[US2OIO/051872 150 -4 (diinethylamino)-2,3-dihydrobenzofiaa-5-yl)thio) 9H-purin-6-wmine WO 2011/044394 PCT[US2OIO/051872 151 I -(4-(2-(6-amiino-8-((6-(dimethylamino)-2,3 dihydrobenzofiira-5-yl)thlio)-9H-purin-9 yl)ethiyl)piperidin-1-yl)ethanone IA-40 8-((6-(dimethylanaino)-2,3-dihydrobenzofuran-5-yl)thio)-9-(2-(1 __________(methylsulfonyl)piperidin-3-yl)ethyl)-9H-purin-6-amine 1A41l 4-(3-(6-amino-8-(6-(aziuidin-1-yl)-2,3-dihydrobenzofliran-5-ylthio)-9H _________purin-9-yl)propyl)piperidine-1 -carbaldehyde 1A-42 8-((6-(fflan-2-yl)-2,3-dihydrobenzofhra-5-yl)thio)-9-(2-(1 1(methylsulfonyl)piperidin-3-yl)ethyl)-9H-purin-6-ainine IA-43 8-((6-(dnrnethylamino)-2,3-dihydobenzofin-a-5-yl)methyl)-2-fluoro-9-(2 (isobutylamio)ethyl)-9H-purin-6-amine 1A-44 8-((6-(dimnethylamnino)-2,3-dihydrobenzfiaa-5-yl)thio)-9-(2 ___________(neopentylanaino)ethyl)-9H-purin-6-amine IA445 9-(3-(tert-butylamino)propyl)-8-((6-(oxazol-2-yl)-2,3-dihydrobenzofuran-5 ___________yl)thio)-9H-purin-6-amine IA-46 1-(3-(2-(6-aniino-8-(6-(oxaol-2-yl)-2,3-dihydrobenzofura-5-ylthio)-9H-purin __________9-yI)ethyl)piperidin-1 -yl)ethanone IA447 4-(3-(6-amino-S-(6-(oxazol-2-yl)-2,3-dihydrobenofura-5-ylthio)-9H-purin-9 yI)propyl)piperidine- 1-carbaldehyde 1A4-48 9-(2-(1-(methylsulfonyl)piperidin-3-yl)ethyl)-8-((6-(oxazol-2-yl)-2,3 dihydrobenzofiira-5-yI)thio)-9H-purin-6-amine 1.A49 1-(2-(3-(6-anmino-8-(6-iodo-2,3-dihydrobenzofura-5-ylthio)-9H-purin-9 ______ yl)propyl)pyrrolidin-1-yI)ethanone IA4-50 9-(3-(tert-butylamio)propyl)-8-((6-(5-methyloxazol-2-yl)-2,3 Sdihydrobenzofi ar5-yl)thio)-9H-purin-6-amine 1A4-51 9-(3-(tert-butylamino)propyl)48-((6-(thiazo-2-yl)-2,3-dihydrobenzofiira-5 - ~yl)thio)-9H-purin-6-ammne IA-52 9-(3-(tert-butylamiino)propyl)-S-((6-(5-methylthiazo-2-yl)-2,3 Idihydrobenofinan-5-yl)thio)-9H-purin-6-atine Table 1B No. Name lB-1 PU-WS9 8-((5-iodo-2,3-dihydrobenzofinn-6-yl)thio)-9-(2-(isobutylaaino)ethyl)-9H-purin 6-amine 1B-2 PIJ-W84 8-((5-iodo-2,3-dihydrobenzofurn-6-yl)thio)-9-(3-(isopropylanmino)propyl)-9vH _________purin-6-amine WO 2011/044394 PCT[US2OIO/051872 152 -41B-3 PU-WS17 2-fluoro-S-((5-iodo-2,3-dihydrobenzfuiran-6-yl)methyl)-9-(2 (isobutylamino)ethyl)-9H-purin-6-anmrne 1B-4 PU-WSl8 2-fluoro-S-((5-iodo-2,3-dihydrobetzfura-6-y1)methyl)-9-(3 l B-5 2h-8-((5-po3y-2,3-dihydberofara-6-yl)ethio)-9-(2 (isobutylamino)thyl)-9H-purin-6-amine 1-6 8-((5-cyclopenyi-2,3-dihydrobenzofuran-6-yl)thio)-9-(3-(isopropylarino)propyl) 9H-purin-6-amine lB-7D 8-((5-diethylao-2,3-dihydrobera -6-yl)methyl)-2-o-9-(2 (isopetylamino)ethyl)-9H-purin-6-nrne lB-li 6-((6-atin-2-tuor--l(3-ioproylmiomproyl)9Hi-un-8-ylmty)23 dihyobenzyl~an-5hl-carbonirile-nin lB-9l 2-oh lo-9-(3 -(ioynilnof~rop yl)((-thylf93-in-2-yl2,3- opl) dhdoezfun--lmty)9H-purin-6-aniine lB-19 4-2(-n--((5 hyy -chynyl-,3-ihrobnfia-6-yl) thi2-lo-9-purn ylsoetylapierineh- -carbaldehyde 3-14 1-(2(6nuino-2-fluoro-8-((5-(iiryan-2-yly)-2-dihy rpin-6-yl)neyl) 19dh-prin9yIeybiemofirn-1-yIbethanon 1B-12 N2hl-((-(-mopylino-8(5-f r pl-455-ehlun-2-yl)-2,3-dyroezfa--Iti)--pi 9-yrethyfaninoeyl)ufmel-Hprn6aa 1B-13 3-((2-(6-anmino-8-((5-thynyl-2,3-dihydrobenzofuran-6-yI)thio)-9H-purin-9 yl)ethyl)amprin--hydroxdyppa de 1B-14 9-(-(2-(obtylainoetyl)-r8-((5-(thiph-2-yl)-2,3-dihydrobezofuran-6-yl)thio) ______9H-purin-9-anleypieii-ylthne 1B-15 3-(3--(6-amin8-(5-o 2yl-2,3-dihydrobea -6-y~hio)-9H-p in-oy)2 oxointhylaoliinoe1-cslarbldhde lB-19 32-lor ~o-8-((5-ethynyl-2,3-dihydrobefran--yl6etyl)b-9- n isb9 lmn-eh1 9-urin-6-amine lB-18 6-(3(6-anino--hloo--(3-ioproylmofpropylt)-9H-purin--yl)topyl-2 _______ dindaezodin--cattonitrile lB-19 2-chloro-8-((5-diethylam3-inyreo)-,diyrbczour-y)methyl)-9-(2 (neopetylaiino)ethyl)-91-purin-6-axine IB-22 8-((5-cyclopentyl-2,3-dihydrobenofiian-6-yl)thio)-2-fluoro-9-(3 I(isopropylanaino)propyl)-9H-purin-6-ainine 1B-23 1-(3-(6-amino-8-(5-iodo-2,3-dihydrobenzfurn-6-ylthio)-9H-purin-9 yI)propyl)pyrrolidin-3 -one IB-24 PU-WS21 8-((5-iodo-2,3-dihydrobenzofhr-6-yI)thio)-9-(2-(neopentylanmino)ethyl)-9H _________purin-6-amine I-25 PU-WS22 2-fluoro-8-((5-iodo-2,3-dihydrobenofura-6-yl)methyl)-9-(2 __________(neopentylanmino)ethyl)-9H-purin-6-anmine WO 2011/044394 PCT[US2OIO/051872 153 L4 IB-26 PUJ-WS23 8-((5-(fira-2-yl)-2,3-dihydrobenzofirn-6-yl)thio)-9-(2-(neopentylamino)ethyl) _________9H-purin-6-amine IB-27 PU-WS24 9-(2-(neopentylamino)ethyl)-8-((5-(thiophen-2-yl)-2,3-dihydrobezofhan-6 _________yl)thio)-911-purin-6-amine N IB-28 PU-WS28 8-((5-ethyny1-2,3-dihydrobet~oftua-6-y1)thio)-9-(2-(neopentylamino)ethy1)-9H purin-6-aniine 1IB-29 9-(3-amiinopropyl)-8-ff5-iodo-2,3-dihydrobcnzfiua-6-yl)thio)-9H-purin-6-armine 1B-30 9-(2-aniinoethyl)-2-fluoro-S-((5-iodo-2,3-dihydrobenzofinan-6-yl)methyl)-9H __________purin-6-ainine lIB-31 9-(2-amioethyl)-8-((5-iodo-2,3-dihydrobenzoffia-6-ylthio)-9H-purin-6-mine IB-32 9-(3-(tert-butylamino)propyl)-8-(f5-iodo-2,3-dihydrobenzofiaa-6-yl)tbio)-9H _________purin-6-aniine 1B-33 2-fluoro-8-((5-(5-methylfuran-2-yl)-2,3-dihydrobenzofua-6-yl)methyl)-9-(2-( __________(methylstilfonyl)piperidin-3-yl)ethyl)-9H-puuin-6-amine IB-34 1-(3-(6-amino-8-(5-iodo-2,3-dihydrobenzofura-6-ylthio)-9H-purin-9-yl)propyl)-4 ________I hydroxypyolidir,-2-one IB-35 N-(3-(6-amino-8-((5-iodo-2,3-dihydrobenzofura-6-yl)thio)-9H-purin-9 __________ l)propyl)niethanesulfonanide 1B-36 1-(3-(6-amino-8-(5-ethynyl-2,3-dihydrobeiiofiarn-6-ylthio)-9H-purin-9 __________yI)propyl)pynolidin-3-one IB-37 8-(5-iodo-2,3-dihydrobenzofura-6-ylthio)-9-(2-(l -(methylsulfonyl)pyrrolidin-3 yI)ethyl)-9H-purin-6-amine IB-38 N-(3-(6-anaino-8-((5-ethynyl-2,3-dihydrobenzofuira-6-yI)thio)-9H-purin-9 yl)propyl)methanesulfonamide IB-39 I -(4-(2-(6-amino-84(5-ethynyl-2,3-dihydrobrioffiran-6-yl)thio)-9H-parin-9 _______ I yl)ethyl)piperidin-1 -yl)ethanone WO 2011/044394 PCT[US2OIO/051872 154 -4 IB40l 8-((5-ethynyl-2,3-dihydrobenofuran-6-yl)thio)-9-(2-(1 -(methylsulfonyl)piperidin __________3-yl)ethyl)-9H-purin-6-amine IR-41 5-(6-anmino-8-(5-ethynyl-2,3-dihydrobenofuran-6-ylthio)-9H-pmin-9-yl)pentae 1-sulfonamide IB-42 I -(4-(2-(6-amino-8-((5-(fura-2-yl)-2,3-dihydrobenzfurn-6-yl)thio)-9H-purin-9 yl)ethyl)pipeiidin- 1-yl)ethanone IB43i 8-(5-(5-methylfiuran-2-yl)-2,3-dihydrobenzofiian-6-ylthio)-9-(2-(1 __________(methylsdfonyl)piperidin-3-yl)ethyl)-9H-purin-6-anine I-44 2-(3-(6-anaino-8-(5-(5-methylfuran-2-yl)-2,3-dihydrobenzfura-6-ylthio)-9H Ipudin-9-yl)propyL)pyrrolidine-1I -earbaldehyde 1-45 N-(2-(6-anuiino-S-((5-ethynyl-2,3-dihydrobenzofuran-6-yl)thio)-9H-purin-9 yl)ethyl) N'-methyl-sulfiric diamide IB-46 9-(3-(tert-butylamnno)propyl)-8-((5-(oxzo-2-yl)-2,3-dihydobenzofiian-6 yl)thio)-9H-purin-6-amine 1-47 9-(3-(tert-butylamino)propy1)-8-((5-ethyny1-2,3-dihydrobenzfiran-6-y1)thio)-9H __________purin-6-amine IB-48 9-(3-(tert-biatylarnino)propy1)-8-((5-(dimethylamlino)-2,3-dihydrobenzfiaa-6 ______ yl)thio)-9H-purin-6-aniine IB-49 1-(6-amino-8-((5-iodo-2,3-dihydrobenzofura-6-yl)thio)-9H-purin-9-yl)-3 _________(isopropylamino)propan-2-ol IB-50 1-(4-(2-(6-amino-8-((5-(oxazol-2-yl)-2,3-dihydrobenfuran-6-yl)thio)-9H-purin __________9-yI~ethylbpiperidin- 1 -yl)ethanone _________dihydrobenzofiura-6-yl)thio)-9H-purin-6-anine IB-52 3-(3-(6-anino-8-(5-iodo-2,3-dihydobenofurn-6&ylthio)-9H-pmin-9 __________yl)propyl)pyrrolidine- 1 -sulfonamde lB-53 9-(3-(tert-butylamino)propyl)-8-((5-(5-methyloxazol-2-yl)-2,3-dihydrobenzofia ______ 6-yflthio)-9H-purin-6-aninc IB-54 9-(3-(ter-butylatno)propyl)-8-((5-(thizol-2-yl)-2,3-dihydrobezoflsra-6 __________yl)thio)-9H-purin-6-amine IB-55 9-(3-(tert-butylamino)propyl)-8-((5-(5-methyltizo1-2-yl)-2,3-dihydrobenzfiamn __________6-yl)thio)-9H-purin-6-amine 1-56 6-(6-amino-8-(5-iodo-2,3-dihydrobenofijra-6-ylhio)-9H-purin-9-yl)hexanatmde 1-57 5-(6-aniino-8-(5-iodo-2,3-dihydrobenofisa-6-ylhio)-9H-purin-9-yl)pentane- ________sulfonamde IB-58 3-(6-amiino-8-(5-ethynyl-2,3-dihydrobenzfurn-6-ylthio)-9H-purin-9-yl)propyl __________ sulfanite Table IC No. Name ic-i 8-((6-iodo-2,3-dihydrobenzorblthiophen-5-yl)thio)-9-(3 _____________(isopropylamiino)Dropyl)-9H-ui-6 -Amine iC-2 8-((6-iodo-2,3-dihydroberio[blthiophen-5-yl)thio)-9-(2-(isobutylanino)ethyl) 9H-puui-6-amine 1C-3 84(6-iodo-2,3dhydobno[b]thiophen-5-yl)thio)-9-(3 ____________(isopropylamno)propyl)-9H-purin-6-amine 1C-4 2-fluoro-8-((6-iod,-diyrbnobtipen5yehl-- WO 2011/044394 PCT[US2OIO/051872 155 -4 (isobutylanmino)ethyl)-9H-purin-6-anmine iC-S 2-chloro-S-((6-(fura-2-yl)-2,3-dihydroben[b]thiophen-5-yl)methyl)-9-(3 (isopropylanino)propyl)-9H-purin-6-amine 1C-6 S-((6-(IH-iniidzol-4-yl)-2,3-dihydrobezo[bltiophen-5-yl)methyl)-2-fluoro-9 ____________(3-(isopropylanmino)propypl)-9H-purin-6-amine 1C-7 8-((6-(ffiir-2-yl)-2,3-dihydrobenzo[b~thiophen-5-yl)thio)-9-(3 (isopropylamino)propyfl-9H-purin-6-ainine iC-8 8-((6-ethynyl-2,3-dihydrobenzo[blthiophen-5-yl)thio)-9-(3 (isoprpylaynno)propyl)-9H-purin-6-amine LC-9 5-((6-amino-9-(3-(isopropylarmino)propyl)-9H-purin-8-yl)thio)-2,3 dihydrobenzo[b]tbiophene-6-carbonitrile IC-10 8-((6-(aziridin-1 -yI)-2,3-dihydrobenzo]thiophn--y)methy)-2-fluoro-9-(2 (en ~ilaniino ethyI -9-p rin-6-amine ic-li 8-((6-iodo-2,3-dihydrobenzo[blthiophen-5-yl)thio)-9-(2-(isobutylaimino)ethyl) 9H-purin-6-amine iC-12 1 -(4-(2-(6-anmino-8-((6-(fuiran-2-yI)-2,3-dihydrobenz[b]thiophen-5-yl)thio)-9H purin-9-yl)ethyl)piperidin-1-yI)ethanone. 1C-13 4-(2-(8-((6-(1H-pyrazol-3-y)-2,3-dihydobeno[blthiophen-5-y)thio)-6-amino 9H-purin-9-yI)ethyl)piperidire-l1 cabaldehyde 1C-14 4-(2-(6-amino-8-((6-ethyny1-2,3-dihydrobenzothiophen-5-y)thio)-9H-purin-9 yl)ethyl)piperidine-l1 cabaldehyde IC-is 1-(4-(2-(6-amino-2-fiuoro-8-((6-(furan-2-yI)-2,3-dihydrobenzo[bjthiophen-5 yI)methyl)-9H--puin-9-yl)ethyl)piperidin-1-yI)ethanone IC-16 N-(2-((2-(6-amino-8-((6-(fura-2-yl)-2,3-dihydrobenzofblthiophen-5-yI)thio) 9H-purin-9-yI)ethy)amino)etyl)sulfamide 1C-17 3-((2-(6-amino-8-<(6-(fiiran-2-yl)-2,3-dihydrobenz[bjthiophen-5-y)thio)-9H Ipurin-9-yl)ethyl)amino)-N-hydroxypropanamide iC-i8 9-(3-anminopropyl)-8-((6-iodo-2,3-dihydrobeno[bjthiophen-5-yl)thio)-9H-purin 6-amine LC-19 9-(2-arniinoethyl)-2-fluoro-8-((6-iodo-2,3-dihydrobenzo[blthiophen-5-yI)metlyl) ___________9H1-purin-6-amine IC-20 9-(2-arminoethyl)-8-((6-iodo-2,3-dihydrobenzo[blthiophen-5-yl)thio)-9H-purin-6 amine 1C-21 9-(3-(tet-butylamino)propyl)-8-((6-iodo-2,3-dihydrobenzo[bthiophen-5-yl)thio) _________9H-purin-6-amine Table iD NO. Name 1D-1 8-((5-iodo-2,3-dihydrobenzo[blthiophen-6-yl)thio)-9-(2-(isobutylamino)ethyl) ______________9H-purin-6-ammne iD-2 8-((5-iodo-2,3-dihydroberio[b]thiophen-6-yI)thio)-9-(3 ______________(isopropylaraino)propyl)-9H-purin-6-amine 1D-3 2-fluoro-8-((5-iodo-2,3-dihydrobenzo[b]thiophen-6-yl)methyl)-9-(2 (isobutylaniino)ethyl)-9H-purin-6-amine 1D-4 2-fluoro-8-((5-iodo-2,3-dihydrobenz[bjthiophen-6-yI)methyl)-9-(3 (isopropylanmino)propyl)-9H-purin-6-anine liD-5 8-((5-iodo-2,3-dhydrobenzo[bjthiophen-6-yl)thio)-9-(2-(isobutylamino)ethyl) 9H-puri-6-aine LD-6 8-((5-(furan-2-yl)-2,3-dihydrobenz[blthiophen-6-yl)thio)-9-(3- WO 2011/044394 PCT[US2OIO/051872 156 -4 (isopropylantino)propyl)-9H-purin-6-amine 1D-7 8-((5-(dimethylanmino)-2,3-dihydrobcnz[b]thiophen-6-yI)methyl)-2-fluoro-9 (2-(neopentylamino)ethyl)-9H-purin-6-anine 1D-8 8-((5-(IH-pyrazol-3-yl)-2,3-dihydrobeno[b]thiophen-6-yl)thio)-9-(2 (isobutylamino)ethyl)-9H-purin-6-amine 1D-9 S-((5-cyclopenty1-2,3-dihydrobenzo[b~thiophen-6-y1)thio)-9-(3 (isoprpylamino)propyl)-9H-purin-6-anaine 1D-10 8-((5-ethyny1-2,3-dihydrobenz[b]thiophx-6-y1)methyl)-2-fluoro-9-(2 (isobutylamino)ethyl)-9H-purin-6-aniine ID-11 6-((6-aniino-2-fluoro-9-(3-(isopropylanmino)propyl)-9H-purin-8-yl)methyl)-2,3 dihydrobenzolblthiophene-5-cabonitrile 1D-12 2-chloro-8-((5-(fuira-2-yl)-2,3-dihydrobenz[b~thiophen-6-yl)methyl)-9-(3 (isopropylanmino)propyl)-9H-purin-6-aniine 1D-13 4-(2-(6-amino-8-((5-ethnyl-2,3dihydrobenzo[b]thiophen-6-yl)thio)-9H-purin 9-yl)ethiyl)piperidine- 1-cabaldehyde ID-14 1-(4-(2-(6-amino-2-fluoro-8-((5-(fin-2-yl)-2,3-dihydrobenzo[b]hiophen-6 ylmethyl-9H-purin-9-y)ethy1)piperidin-1 -yflethanone 1D-i5 N-(2-((2-(6-amino-S-((5-(furan-2-yl)-2,3-dihydrobenzo[b]thiophen-6-yl)thio) ______________911-p urin-9-yI)ethyl)amino)ethyl)sulfanmide 1D-16 3-((2-(6-amino-8-((5-ethynyl-2,3-dihydrobenzo[b]thiophen-6-yl)thio)-9H ______________purin-9-yI)ethyl)amino)-N-hydroxypropanide WO 2011/044394 PCT[US2OIO/051872 157 -4 1D-17 2-chloro-8-((5-iodo-2,3-dihydrobeno[b]thiophen-6-yl)methyl)-9-(3 ______________(isopropylamino)propyl)-9H-purin-6-liae 1D-18 9-(3-aminopropyl)-8-((5-iodo-2,3-dihydrobeno[b]thiophen-6-yl)thio)-9H _____________pmrn-6-axnine 1D-19 9-(2-aininoethy1)-2-fluoro-8-((5-iodo-2,3-dihydrobenzo~b]iiophen-6 ylmethyl)-9H-purin-6-amine ID-20 9-(2-amiinoethyl)-8-((5-iodo-2,3-dihydrobeno[blthiophen-6-yl)thio)-9H-purin 6-amine ID-21 9-(3-(tert-butylamino)propyl)-8-((5-iodo-2,3-dihydrobenzo[b]thiophen-6 Iyl)thio)-9H-purin-6-amine Table 1E No. Name lE-1 1-(6-amiino-8-(6-iodo-2,3-dihydro-IH-inden-5-ylthic)-9H-purin-9-yl)-3-(tert butylanmino)propa-2-ol 1E-2 PU-WS26 8-((6-iodo-2,3-dihydro-IH-inden-5-yl)thio)-9-(2-(isobutylammno)ethyl)-9H-punn-6 amine 1E-3 1-(3-(6-anaino-8-(6-iodo-2,3-diydro1H-inden-5-yltaio)-9H-purin-9 yl)prcopyl)pyfrolidin-3 -one 1E-4 2-fluor-S-((6-ioo-2,3-dihydro-H-inden-5-y)methy)-9-(2-(iobutyamiino)ethyl)-9H p=r-6-ame 1E-5 2-chloro-S-((6-(fiua-2-yl)-2,3-dihydro-IH-inden-5-yl)methyl)-9-(3 - (isopropylamino)propyl)-9H-puriii-6-amine 1E-6 2-fiuoro-8-((6-iodo-2,3-dihydro-1H-ndex-5-yl)methyl)-9-(3-(isopropylamino)propyl) ______9H1-purin-6-aniine lE-7 8-((6-(fiimn-2-yl)-2,3-dihydro-1H-inden-5-yl)thio)-9-(3-(isoprpylamino)propyl)-9H purin-6-ammne l-S 8-((6-ethynyl-2,3-dhydro-1H-inden-5-yl)thio)-9-(3-(isopropylamino)propyl)-9H-purin I6-amine JE-9 6-((6-amino-9-(3-(isopropylaniino)propyl)-9H-purin-8-yl)thio)-2,3-dihydro1H-indene ________5-carbonitrile IF-b0 8-((6-(azetidin-1 -yI)-2,3-dihydro-1H-inder-5-yl)methyl)-2-fluoro9-(2 ________(neopentylamino)ethyl)-9H-purin-6-amine iF-il 9-(3-(isopropylanmino)propyl)-8-((6-(oxaol-2-yl)-2,3-dihydro-H-inden-5-yl)thio)-9H purin-6-amine lE-12 1-(3-(2-(6-amiino-8-(6-(oxaol-2-yl)-2,3-dihydro-IH-inden-5-ylthio)-9H-purin-9 ________yl)ethyl)piperidin- I -yl)ethanone WO 2011/044394 PCT[US2OIO/051872 158 1E-13 3-(2-(8-(6-(1H-pyrazol-3-yl)-2,3-dihydro-1H-nden-5-ylthio)-6-amino-9H-purin-9 _______yl)ethyl)piperidine-1-cabaldehyde 1E-14 1-(3-(2-(6-aniino-S-(6-ethynyl-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9 - yl)ethyl)pipefidin- 1-yl)ethanone IE-15 2-fluoro-9-(3.-(1-(methylsulfonyl)pyrrolidin-3-yl)propyl)-8-((6-(oxazol-2-yl)-2,3 - ~dihydro-1H-inden-5-yl)methyl)-9H-purin-6-anmine N IE-16 N-(2-((2-(6-aino-S-(6-(oxazo-2-yl)-2,3-dihydro-1H-inden-5-yl)thio)-9H-puin-9 ________yl) ethyl) ainn ethyl) sul faniide 1E-17 3-(2-(6-amino-8-(6-(oxazo-2-yl)-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9 _______yl)ethylamino)-N-hydroxypropanamide IE-18 1-(34(3-(6-amnino-8-(6-iodo-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9 _______yl)propyl)pyrrlidin- 1-yl)ethanone 1E-19 1-(3-(3-(6-antno-S-(6-ethynyl-2,3-dihydro-H-inden-5-ylthio)-9-purin-9 _______ lropyl)pyrrolidin-1-yl)ethanone IE-20 2-chloro-8-((6-ethynyl-2,3-dihydro-1H-inden-5-yl)methyl)-9-(3 I____ (isopropylamino)propyl)-9H-purin-6-amine IE-21 PIJ-WS25 8-((6-iodo-2,3-dihydro-1H-indei-5-yl)thio)-9-(2-(neopentylamino)ethyl)-9H-purin-6 amine IE-22 PIJ-WS27 8-((6-ethynyl-2,3-dihydro-1H-inden-5-yl)thio)-9-(2-(neopentylanmino)ethyl)-9H-puin 6-amine IE-23 PU-WS29 8-((6-iodo-2,3-dihydro-1H-inden-5-yl)thio)-9-(3-(isopropylamino)propyl)-9H-purm-6 amne 1F,24 9-(3-aminoproyl)-8-ff6-iodo-2,3-dhydro-1H-inden-5-yl)thio)-9H-purin-6-amine IE-25 9-(2-amiinoethyl)-8-((6-iodo-2,3-dihydro-1H-inden-5-yl)thio)-9H-purin-6-amme 1E-26 9-(3-(tert-butylatnino)propy1)-8-((6-iodo-2,3-dihydro-lH-inden-5-yl)thio)-9H-puin-6 amine 1E-27 9-(3-(isopropylaiino)propyl)-8-((6-(5-methyloxaol-2-yl)-2,3-dihydro-1H-inden-5 _______yl)thio)-9H-purin-6-amine IE-28 1-(4-(3-(6-amino-8-(6-(dimethylamino)-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9 yl)propyl)piperidin- 1 -yl)ethanone 1E-29 1-(3-(2-(6-amino-2-fluoro-8-((6-(4-methylthiazol-2-yl)-2,3-dihydro-1H-inden-5 _______yl)inethyl)-9H-purin-9-yl)ethyl)piperidin-l1-yl)ethanone IE-30 8-((6-(5 -methyloxaol-2-yl)-2,3-dihydro- 1H-indcn-5 -yl)thio)-9(2-( I(rnethylsulfonyl)piperidin-3-yl)ethyl)-9H-purin-6-antine IE-31 9-(3-amninopropyl)-S-((6-(5-methyloxazol-2-yl)-2,3-diydro-1H-inden-5-yl)thio)-9H purin-6-amine IE-32 9-(3-(tet-butylanino)propyl)-2-luoro-8-((6-(4-methylthizol-2-yl)-2,3dihydro-1H inden-5-yl)naethyl)j-9H-purin-6-amine 1F,33 8-((6-(1H-pyrazol-3-yl)-2,3-dihydro-1H-inden-5-yl)inethyl)-9-(3-(tert butylamino)propyl)-2-fluoo-911-purin-6-ammne IE-34 8-(6-(aziridin-1-yl)-2,3-dihydro-1H-inden-5-ylthio)-9-(3-(1-(methylsulfonyl)pyrrolidin - 3-yl)propyl)-9H-purin-6-amie IE-35 1-(3-(6-amiino-2-fluoro-8-((6-iodo-2,3-dihydro-1H-inden-5-yl)methyl)-9H-purin-9 Il propyl)pyrrolidin-3-one 1E-36 8-((6-(5-methyloxazol-2-y1)-2,3-dihydro-1H-inden-5-y1)thio)-9-(2 (neopentylamio)ethyl)-9H-purin-6-aine IE-37 1-(6-amiino-S-((6-(5-methytokazo-2-yl)-2,3-dihydro-1H-inde--yl)thio)-9H-purin-9 WO 2011/044394 PCT[US2OIO/051872 159 _______yl)-3-(isopropylamimo)propan-2-ol 1E-38 5-(6-aniino-8-(6-iodo-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9-yl)-N-methylpentane 1-sulfonamide IE-39 5 -(6-amino-8-(6-iodo-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9-yl)pentne-I _______sulfonamide 1E-40 5-(6-aniino-S-(6-ethynyl-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9-yl)pentane-1 sulfonamide IE-41 1-(2-(4-(6-amnino-S-(6-(5-methylfiiran-2-yI)-2,3-dihydro-1H-inden-5-ylthio)-9H-purin _______9-yl)butyl~pyrolidin-t-yl)ehaione IE-42 I -(3-(6-amino-8-(6-iodo-2,3-dihydro-1H-inden-5-ylthio)-9H-puri-9 _______yl)propyl)pymrlidin-3-ol IE-43 6-(6-amiino-S-(6-iodo-2,3-dihydro-IH-inden-5-ylthio)-9H-purin-9-yl)hexanamide 1E-44 1-(3-(3-(6-arnilno-2-fluoro-8-((6-iodo-2,3-dilhydro-1H-inden-5-yl)methyl)-9H-purin-9 yl)propyl)pyrrlidin- 1-yl)ethanone IE-45 5-(6-anaino-2-fluoro-S-((6-iodo-2,3-dihydro-1H-inden-5-yl)methyl)-9H-purin-9-yl)-N niethylpentane- 1 -sulfonamide IE-46 5-(6-anino-2-fluoro-8-((6-iodo-2,3-dihydro-IH-inden-5-yl)methyl)-9H-puin-9 Iyl)pentane- 1-sulfonanoide 1E-47 9-(3-(tert-butylamiino)propyl)-2-tluoro-8-((6-iodo-2,3-dihydro1H-inden-5-yl)methyl) 9H-purin-6-amine 1E-48 2-fluoro-8-((6-iodo-2,3-dihydro-1H-inden-5-yl)methyl)-9-(2-(neopentylamino)ethyl) 9H-pmrn-6-anaine IE-49 I -(4-(3-(6-amiino-8-(6-ethynyl-2,3-dihydro-IH-inden-5-ylthio)-9H-purin-9 yI)propyl)piperdin- 1-yl)ethanone 1E-50 1-(3-(2-(6-amino-8-((6-etlaynyl-2,3-dihydro-1H-inden-5-yI)mthyl)-2-fluoro-9H-purin 9-yI)ethyl)piperidin-1 -yl)ethanone 1E-51 9-(3-(tert-butylamino)propyl)-S-(6-ethynyl-2,3-dihydro-IH-inden-5-ylthio)-9H-purin-6 amine IE-52 9-(3-(tert-butylamino)propyl)-8-((6-ethynyl-2,3-dihydro-1H-inden-5-yl)methyl)-2 fluoro-9H-purin-6-aniine IE-53 6-(6-amino-8-((6-ethynyl-2,3-dihydro-IH-rnden-5-yl)niethyl)-2-fluoro-9H-punin-9 yl)hexananmide 1E-54 1-(3-(6-amino-8-((6-ethyrnyI-2,3-dihydro-1H-inden-5-yl)methyl)-2-fluorc9H-purin-9 yl)propyl)pymrlidin-3-one 1E-55 4-(6-amiino-8-((6-ethynyl-2,3-dihydro-1H-inden-5-yl)methyl)-2-tluoro-9H-purin-9 yl)butane-1 -sulfonamde 1E-56 8-((6-ethynyl-2,3-dihydro-1H-inden-5-yl)methyl)-2-fluoro-9-(3 (isopropylanmino)propyl)-9H-purin-6-amine IE-57 8-((6-ethynyl-2,3-dihydro-1H-inden-5-yI)methyl)-2-fluoro-9-(2 (neopentylamino)ethyl)-9H-purin-6-amine IE-58 1-acetyl-3-(3-(6-amino-8-(6-ethynyl-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9 yl)propyl)imidazlidin-2-one IE-59 9-(3-(tert-butylamnino)propyl)-8-(6-(oxaol-2-yl)-2,3-dihydro-1H-inden-5-ylthio)-9H _____ prn-6-amin IE-60 9-(3-(tert-butylamino)propyl)-8-(6-(5-methyloxaol-2-yl)-2,3-dihydro-1H-inden-5 - ylthio)-9H-pRin-6-amine IE-61 8-(6-(1H-pyraol-3-yl)-2,3-dihydro-1H-inden-5-ylthio)-9-(3-(tert-butylamino)propyl) 9H-purin-6-aniine IE-62 1-(3-(2-(6-amino-8-(6-(5-methyloxaol-2-yl)-2,3-dihydro-1H-inden-5-ylthio)-9H-purin _______9-yl)ethyl)piperidin-1-yl\ethanone WO 2011/044394 PCT[US2OIO/051872 160 IE-63 6-(6-atniino-8-(6-(oxazo-2-yl)-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9 ylffhexanmde 1E64 1-(3-(6-amino-8-(6-(4-methyloxazo-2-yl)-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9 yl)propyl)pyrrolidin-3-one LE-65 6-(6-amino-2-fluoro-8-((6-(oxazol-2-yl)-2,3-dihydxo-1H--inden-5-yl)methyl)-9Hf-purin - 9-yl)hexanamde 1E-66 1-(3-(6-amiino-2-fluoro-8-((6-(oxaol-2-yl)-2,3-dihydro-1H-inden-5-y)mehyl)-9H - purin-9-yl)propyl)pyrrolidin-3-one 1E-67 5-(6-amino-2-fluoro-8-((6-(oxazol-2-yl)-2,3-dihydxo1H-inden-5-yl)methyl)-9H-purin 9-yl)pentane-1-sulfonaniide IE-68 8-((6-iodo-2,3-dihydro-IH-inden-5-yI)thio)-9-(2-(1-methylpiperidin-2-y)ethyl)-9H ________purin-6-amine IE-69 8-((6-iodo-2,3-dihydro-1H-inden-5-yl)thio)-9-(2-(1 -naethylpiperdin-3-yl)ethyl)-9H _______purin-6-amine 1E-70 8-((6-io-2,3-dihydro-H-inden-5-yl)thio)-9-(2-(1 -(methylsulfonyl)piperidin-3 ________yl)ethyl)-9H-purin-6-anaine 1E-71 3-(2-(6-amiino-8-((6-iodo-2,3-dihydro-IH-inden-5-yl)thio)-9H-purin-9 _____I yl)ethyl)piperidine-1-sulfonanmide IE-72 2-fluoro-8-((6-iodo-2,3-dihydro- 1H-inden-5-yl)methyl)-9-(2-( I -methylpipenidan-2 _______ ylethyl)-9-purin-6-amine iE-73 2-fluoro-8-((6-iodo-2,3-dihydro-1H-inden-5-yl)naethyl)-9-(2-( t-methylpiperidin-3 _______yl)ethyl)-9H-purin-6-amine IE-74 2-fluoro-8-((6-iodo-2,3-dihydro-1H-inden-5-yl)naethyl)-9-(2-(1 _____ (methylsulfonyl)piperidin-3-yI)ethyl)-9H-purin-6-amine IE-75 3-(2-(6-amiino-2-fluoro-8-((6-iodo-2,3-dihydro-1H-indern5-yl)methyl)-9H-purin-9 yl)ethyl)piperidine- I -sulfonamide 1E-76 9-(3-(tert-butylamino)propyl)-2-fluoro-8-((6-iodo-2,3-dihydro-IH-inden-5-y)naethyl) 9H-purin-6-amine IE-77 8-((6-ethynyl-2,3-dihydro-IH-inden-5-yI)thio)-9-(2-(1-methylpiperidin-2-yl)ethyl)-9H _____ purin-6-amine IE-78 8-((6-ethynyl-2,3-dihydro-IH-inden-5-y)thio)-9-(2-(1-methylpiperidin-3-yl)ethyl)-9H ________puin-6-amine IE-79 3-(2-(6-amino-8-((6-ethynyl-2,3-dihydro--H-inden-5-yl)methyl)-2-fluoro-9H-pudin-9 Iyl)ethyl)piperidinc-1-sulfonamide 1E-80 8-((6-ethynyl-2,3-dihydro-IH-inden-5-yl)thio)-9-(2-(I -(methylsulfonyl)piperidin-3 ________ y)ethyl)-9H-purn-6-amine IE-81 8-((6-ethynyl-2,3-dihydro-IH-inden-5-yI)methyl)-2-fluoro9-(2-( -methylpiperidin-2 ________yl)ethyl)-9H-purin-6-amine IE-82 8-((6-ethynyl-2,3-dihydro-1f-inden-5-yI)naethyl)-2-fluoro-9-(2-(1-methylpiperidin-3 - yI)ethyl)-9H-purin-6-anaine 1E-83 9-(3-(tert-butylamino)propyl)-8-(6-(4-methylthiazol-2-yl)-2,3-dihydro-1H-inden-5 ylthio)-9H-purin-6-amine 1E-84 2-fluoro-9-(2-(1 -methylpiperidin-2-yI)ethyl)-8-((6-(oxaol-2-yl)-2,3-dihydro-IH-inden ________5-yl)methyl)-9H-purin-6-anmine IE-85 2-fluoro-9-(2-(1 -methylpiperidin-3-yl)ethyl)-8-((6-(oxazol-2-yl)-2,3-dihydro-1H-inden _______5-flmethyl)-9H-pumi-6-an~ine Table IF INo. Name WO 2011/044394 PCT[US2OIO/051872 161 -4IF-i 8-(f6-iodoindolin-5-yl)thio)-9-(2-(isobutylamino)ethyl)-9H-purin-6-anine iF-2 2-fluoro-8-q(6-iodoindolin-5-yl)methyl)-9-(2-(isobutylamino)ethyl)-9H-pmin-6-amine 1F-3 8-((6-(YH-pyrazol-3-yl)indolin-5-yflthio)-9-(2-(isobutylamiino)ethyl)-9H-purin-6-anine 1F-4 8- (6-thynIindolin-5-yI thio)-9- 2-(isobutylaino ethyI -9H-purin-6-amine 1F-5 8-((6-(1H-pyrroI-3-yl)indolin-5-y1)methyI)-2-fluoro-9-(2-(isobutylamino)ethy)-9H _______purin-6-aniine N1F-6 5-((6-amino-9-(3-(isopropylamino)propyl)-9H-purin-8-yl)thio)indoline-6-carbonitrile WO 2011/044394 PCT[US2OIO/051872 162 -4 1F-7 8-((6-(furan-2-yl)-1I -xnethylindolin-5-yl)thio)-9-(3-(isopropylamino)propyl)-9H-purin 6-amiune IF-B 8-((6-cyclobutyl-1 -methyhindolmn-5-yl)methyl)-2-fluoro-9-(2-(isobutylammio)ethyl) ____ 9H-purin-6-atnine IF-9 I -(5-((6-amino-2-fluoro-9-(2-(neopentylamino)ethyl)-9H-purin-8-yl)methyl)-6 ____ (aziridin- 1-yl)indolin- 1 -yI)ethanone N 1F-10 I-(4-(2-(6-amiino-8 -((6-(fiuran-2-yl)indolin-5-yl)thio)-9H-pudin-9-yl)ethyl)piperidin-1I _______yl)ethanone 1F-11 4-(2-(S-((6-(1H-pyraol-3-yI)indolin-5-yI)thio)-6-amiino-9H-purin-9 ____ yI)ethyl)piperidine- 1 -carbaldehyde 1F-12 4-(2-(6-amino-8-((6-ethyxiyl-1-mthylindolin-5-yl)thio)-9H-purin-9 -~~ th I A~ipridine-1I -carbaldehyde iF-13 I -(4-(2-(6-amino-2-fluoro-8-((6-(fuiran-2-yl)indolin-5-yl)methyl)-9H1-purin-9 y~ethy1)piperidin- 1 -yl)ethanone IF-14 N-(2-((2-(6-amino-S-((6-(fhran-2-yl)indolin-5-yl)thio)-9H-purin-9 ____yl)ethyl)amino)ethyl)sulfaniide IF-15 3-((2-(6-amnino-8-((6-(fiara-2-yl)indolin-5-yI)tbio)-9H-purin-9-y)ethyl)amino)-N - ~hydroxyropanamide IF-16 2-chloro-8-((6-iodoindolin-5-yl)methyl)-9-(2-(isobutylamino)ethyl)-9H-prn6-a une iF-i7 9-(3-amiinopropyl)-8-((6-iodoindolin-5-yflthio)-9H-purin-6-anmine iF-i8 9-(2-aminoethyfl-8-((6-iodoindoin-5-y1)thio)-9H-purin-6-am-ine iF-19 9-(3-(tert-butylanuino)propyl)-8-((6-iodoindolin-5-yl)thio)-9H-purin-6-amine IIF-20 I8-((6-iodoindolin-5-yI)thio)-9-(3-(isopropylamino)propyl)-9H-purin-6-amine Table 1G No. Name 10-1 1-(6-(6-amino-9-(3-(isopropylaxnino)propyl)-9H-purin-8-ylthio)-5-iodoindolin-1 _______yI)ethanone 1G-2 2-fluoro-8-((5-iodoindolin-6-y1)methy1)-9-(2-isobut1amino)ethyfl-9H-purin-6-anmine 1G-3 S-((5-(1H-pyrazol-3-yI)indolin-6-yl)thio)-9-(2-(isobutylam-ino)ethyl)-9H-purin-6amine 1G-4 S-q(5-thynylinolin-6-yl)thio)-9-(24isobutylaino)efiyl)-9H-purin-6-anine 10-5 S-((5-(I--pyrrol-3-yl)indolin-6-yl)methyl)-2-fluoro-9-(2-(isobutylamino)ethyl)-9H _______purin-6-amine WO 2011/044394 PCT[US2OIO/051872 163 -4 16-6 6-((6-amino-94-3.-(isopropylamino)propyl)-9H-purin-X-yl)thio)indoline-5-carbonitrile 16-7 8-((5-(furan-2-yl)-1 -methylindolin-6-yl)thio)-9-(3-(isopropylamiino)propyi)-9H-purin 6-amine 1G-8 8-((5-cyclobutyl-1-niethylindolin-6-yl)methyl)-2-fluoro-9-(2-(isobutylamino)ethyl) ____ 9H-purin-6-amine 1G-9 1 -(6-((6-ammno-2-fluoro-9-(2-(neopxtylamino)ethy1)-9H-purin-8-y)methy)-5 _____(zridin-1 -yI)indoh-I -yl)ethanone IG-10 1-(4-(2-(6-amino-8-((5-(fiiran-2-yl)indolin-6-yl)thio)-9H-purin-9-yl)ethyl)piperidin- ________yl)ethanone 1G-11 8-(5-(1H-pyraol-3-yl)indolin-6-ylthio)-9-(2-(1-(methylsulfonyl)piperidin-3-yI)ethyl) _____ 9H-purin-6-amine 1G-12 3-(2-(6-amino-S-(1 -othyl-5 -ethynylindolin-6-ylthio)-9H-purin-9-yl)ethyl)pipedidine- 1 ________carbaldehyde IG-13 1-(3-(2-(6-amino-2-tluoro-8-((1 -inethyl-5-(5 -methylfiira-2-yl)indolin-6-yI)methyl) ________9H-purin-9-yl)ethyl)piperidin-1 -ylethanone IG-14 N-(2-((2-(6-amino-8-((5-(furan-2-yl)indolin-6-yl)thio)-9H-purin-9 ________yl)ethyl)amino)ethyl)sulfamide IG-15 3-(2-(6-amino-8-(5-(5-methylfiura-2-yl)mndolin-6-ylthio)-9H-punin-9-yI)ethylamiino) N-hydroxypropanmde IG-16 1-(3-(4-(6-amiino-8-(5-iodo-1-methylindolin-6-ylthio)-9H-purin-9-yl)butyl)pyrrolidin 1 -yl)ethanone 1G-17 9-(3-aniinopropyl)-8-((5-iodoindolin-6-yl)thio)-9H-prin-6-a re IG-18 92-aminoethyl)-8-((5-iodoindolin-6-yl)thio)-9H-purin-6-amine 10G-19 9-(3-(tert-butylamino)propyl)-8-( lhyl-5-iodoindolin-6-ylthio)-9H-purin-6-amine 10G-20 S-(5-iodo-1 -methylindolfi-6-ylthio)-9-(3-(isop-opylamlino)propyl)-9H-purin-6-ami'ne 1G-21 1-(3-(6-amnino-8-(5-iodo--nethylindolin-6-ylthio)-9H-purin-9-yl)propyl)pyrrolidin-3 one Table 1H No. Name 1H-1 6-((6-amino-9-(2-(isobutylamino)ethyl)-9H-purin-S-yl)thio)-5-iodo-2,3-dihydro-1H indmx-1-one IH-2 6-((6-amiino-9-(3-(isopropylamino)propyl)-9H-purin-8-yl)thio)-5-iodo-2,3-dihydro 1H-inden-1-one 1H-3 6-((6-amino-2-tluoro-9-(2-(isobutylamino)ethyl)-9H-purrn-8-yl)methyl)-5-iodo-2,3 _______dihydro-IHl-inden-1 -ne 1H-4 6-((6-amino-2-fluoro-9-(3-(isopropylaxnino)propyl)-9H-purin-8-yl)methyl)-5-iodo ____ 2,3-dihydro-1H-indmr-1 -one 1H-5 6-(6-amino-9-(2-hydroxy-3-(isopropylanaino)propyl)-9H-purin-8-ylthio)-5-iodo-2,3 1____ dihydro-1H-inden-1 -one 1H-6 6-((6-amino-9-(3-(isopropylamino)propyl)-9H-purin-S-yl)thio)-5-(furan-2-yl)-2,3 dihydro-1H-mnden-1-one IH-7 6-((6-amino-2-fiuoro-9-(2-(neopentylamino)ethyl)-9H-purin-8-yl)methyl-5 _____ (dimethylamino)-2,3-dihydro-IH-inden-1-one 1ff-S 6-((6-amino-9-(2-(isobutylamiino)ethyl)-9H-purin-S-y)thio)-5-(H-pyazol-3-y) _____2,3-dihydro-I H-indn-1 -oneH 1H-9 6-ff6-amino-9-(3-6isopropylamino)propyl)-9H-punin-8-yl)thio)-5-cyclopropy-2,3- WO 2011/044394 PCT[US2OIO/051872 164 -4 ______dihydro-1H-inden-1I-one 1H1-10 6-((6-amino-2-fluoro-9-(2-(isobutylamino)ethyl)-91-purin-8-yI)methyl)-5-ethynyl ______2,3-dihydro-1IH-inden-1I -one IH-11 6-((6-amino-2-fluoro-9-(3-(isopropylamino)propyl)-9H-purin-8-yl)methyl)-I -oxo _______2,3-dihydro-1 H-indene-5-carbonitrile 1IH-12 6-((6-aino-2-chloro-9-(3-ioppylamino)propy)-9H-puri-8-y)methy'I)-5 _____ (fiirn-2-yl)-2,3-dihydro- 1H-inden-1 -one IH-13 4-(2-(6-amino-8-((6-ethynyl-3-oxo-2,3-dihydro-1E-indern5-yl)thio)-9H-purin-9 _______ l)ethyl)piperidine- I -earbaldehyde 1H-14 6-((9-(24(1 -acetylpiperidin-3-yI)ethyl)-6-amiino-2-fluoo-9H-purin-S-y)methyl)-5 _______(5-methylftira-2-yl)-2,3-dihydro-IH-inden-t-one IH-15 N-(2-((2-(6-aniino-8-((6-(fura-2-yI)-3-oxo-2,3-dihydro1-lHden-5-y)thio)-9H _____ purim-9-yI)ethyl)AMinoethyl)sulfamde 1H1-16 3-((2-(6-anaino-8-((6-ethynyl-3-oxo-2,3-dihydro-IH-inden-5-yl)thio)-9H-purin-9 yI)ethyl)amino)-N-hydroxypropamide 1H-17 6-((6-amino-9-(2-(isobutylamino)ethyl)-9H-purin-8-yI)thio)-5-iodo-2,3-dihydro-IH indene-1-thione IH-18 6-((6-amino-2-fluoro-9-(3-(isopropylamnino)propyl)-9H-purin-8-yI)methyl)-5-iodo I2,3-dihydro-1H-indene-I-thione IH1-19 6-((6-amino-9-(3-aminopropyl)-9H-pmin-S-y)thio)-5-iodo-2,3dihydr-1H-iiden 1-one IH1-20 6-((6-aniino9-(2-aminoethyl)-2-fluoro-9H-purin-8-yI)methyl)-5-iodo-2,3-dihydro IHl-inden-1-one IH-21 6-((6-amino-9-(2-aminoethyl)-9H-purin-8-yflthio)-5-iodo-2,3-dihydro-1H-inden-1 one IH-22 6-((6-amino-9-(3-(tert-butylamino)propyl)-9H-pudin-8-yI)thio)-5-iodo-2,3-dihydro 1 H-inden-1-one 1H-23 3-(2-(6-amino-8-(6-iodo-3-oxo2,3-dihydro-IH-rnden-5-ylthio)-9H-punin-9 yI)ethyl)pyn-lidine- I -carbaldehyde 1IH-24 6-(6-amino-9-(2-(I -(methylsulfonyl)pynfolidin-3-yl)ethyl)-9H-purin-8-ylthio)-5 iodo-2,3-dihydro-1H-inden-1-one 1H1-25 N-(3-(6-amino-2-fluoro-8-((6-iodo-3-oxo-2,3-dihydro-IH-inden-5-y)methyl)-9H purin-9-yI)propyl)methanesulfonanide 1IH-26 6-((6-anaino-9-(2-(1 -(methylsulfonyl)piperidin-3 -yl)ethyl)-9H-purin-8-yl)thio)-5 (1H-pyrazol-3-yI)-2,3-dihydro-1H-inder-1-one IH-27 6-((6-amino-9-(3-(tert-butylamino)propyl)-9H-purin-8-yl)thio)-5-(5-methylfuran-2 yl)-2,3 -dihydro- IH-inden-1 -one IH-28 6-((6-amino-9-(3-(tert-butylamino)propyl)-9H-purin-8-yI)thio)-5-(5-methylthiazol I___ 2-yI)-2 ,3-dihydro-1H-inden-I-one 1IH-29 6-((6-amino-9-(3-(tert-butylamino)propyl)-9H-purin-8-y)thio)-5-(thiophen-2-y) 2,3-dihydro-1H-inden-1-one IH-3O 2-(3-(6-amino-8-(6-iodo-3-oxo-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9 Syl)propyl)azetidinae-lI cabaldehyde 111-31 6-((6-amino-9-(3-(tert-butylamino)propyl)-2-fluor-9-purin-8-yl)methyl)-5 ethynyl-2,3-dihydro-1H-inden-I-one 1IH-32 6-((6-amino-9-(2-(l -(methylsulfonyl)piperidin-3-yI)ethyl)-9H-purin-8-yl)thio)-5 (dimethylamino)-2,3-dihydro-1H-inden-1 -one IH-33 6-((6-amiino-9-(3-(tert-butylam~ino)propyl)-2-fluoro-9H-purin-8-yl)methyl)-5-(5 1methyloxazo-2-yl)-2,3-dihydro-l H-iden- I -one IH-34 6-((9-(2-(I -aeetylpiperidbn-4-y)ethyl)-6-amino-2-fluoo-9H-purin-8-y)methyl)-5- WO 2011/044394 PCT[US2OIO/051872 165 -4 (5-nathyltiazol-2-yI)-2,3-dihydr-1H-inden-1 -one 111-35 N-(3-(6-amino-2-fluoro-8-((6-(5-methyloxaol-2-yl)-3-oxo-2,3-dihydro-IH-inden - 5-yl)medhyl)-9H-purin-9-yI)propyl)methanesulfonamide 111-36 1-(3-(6-amiirn-8-(6-iodo-3-oxo-2,3-dihydro-1H-inden-5-ylthio)-9H-puin-9 yl)propyl)pyrrolidin-3-one IH11-37 1 -(3-(6-amino-8-(6-iodo-3-oxo-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9 _______yl)propyl)pyrrolidin-2-one WO 2011/044394 PCT/US2010/051872 166 Table 2A Compound # Name EC 5 0 ; binding to EC 5 o; binding JNPL3 brain to SKBr3 cell Hsp9O(nM) Hsp9O(nM) 1B-1| PU-WS9 5.5 ND 1B-2 PU-WS4 8.0-14 ND IA-1 PU-WS10 132.9-346 ND Table 2B Compound # Name EC 50 ; binding to EC 5 0 ; binding JNPL3 brain to SKBr3 cell Hsp9O(nM) Hsp9O (nM) 1B-3 PU-WS17 17.3 ND 1B-4 PU-WS18 33.3 ND 1B-24 PU-WS21 10.8 ND 1B-25 PU-WS22 8.0 ND Table 2C Compound # Name EC 50 ; binding to EC 5 0 ; binding JNPL3 brain to SKBr3 cell Hsp9O(nM) Hsp9O(nM) 1B-26 PU-WS23 12.2 ND 1B-27 PU-WS24 25.4 ND Table 2D Compound # Name ECso; binding to EC 5 o; binding JNPL3 brain to SKBr3 cell E Hsp9O (nM) Hsp9O (nM) 1B-28 PU-WS28 | 8.1 ND Table 2E Compound # Name ECso; binding to EC 5 0 ; binding JNPL3 brain to SKBr3 cell - Hsp9O (nM) Hsp9O (nM) IE-2 PU-WS26 3.6 ND IE-21 PU-WS25 7.2 ND IE-23 PU-WS29 4.5 ND Table 2F Compound # Name ECo; binding to EC 5 0 ; binding JNPL3 brain to SKBr3 cell Hsp90 (nM) Hsp9O (nM) 1E-22 | PU-WS27 |___15 ND WO 2011/044394 PCT/US2010/051872 167 Table 2G Compound # Name ECso; binding to ECso; binding JNPL3 brain to SKBr3 cell Hsp9O (nM) Hsp9O (nM) 4A-1 DZ2-388 270 645 4A-2 DZ2-390 2,666 6,240 4A-3 DZ2-391 >100,000 >100,000 4A-4 TT-V-47B 8,287 15,010 4A-5 DZ2-392 1,388 2,520 4A-6 DZ3-3 438 1,030 4A-7 DZ3-6 732 1,385 4A-8 DZ3-50 2,333 >3000 4C-1 DZ3-4 11 22 4C-2 DZ3-27 48 86 4C-3 DZ3-25 3.9 5.2 4C-4 DZ3-26 14 26 4C-5 TT5-53A 5.3 6.5 4C-6 DZ3-33 56 141 4C-7 DZ3-34 82 142 4C-8 DZ3-35 23 37 4C-9 DZ3-36 6.0 12 4C-10 DZ3-49 >300 >300 4C-11 DZ3-51 153 185 4C-14 DZ3-60 ND 10.1 4C-16 DZ3-56 ND 10.2 4C-38 DZ4-20 ND 7.9 4C-39 DZ4-23 ND 11.4 4C-40 DZ3-142 ND 509 4C-41 DZ3-143 ND 2,081 4D-1 DZ2-395 43 80 4D-2 DZ3-48 24 59 4D-3 DZ3-58 ND 18.5 4D-16 DZ4-21 ND 47 4D-17 DZ4-24 ND 19.7 4F-1 DZ3-5 4,120 9,620 WO 2011/044394 PCT/US2010/051872 168 Table 2H Compound # Name EC 5 0 ; binding to EC 5 o; binding JNPL3 brain to SKBr3 cell Hsp90 (nM) Hsp9O (nM) 4B-1 PU-WS8 19.1 ND 4B-2 PU-WS6 403 ND 4B-3 PU-WS7 731 ND 4B-4 PU-WS16 13.7 ND 4B-13 PU-WS19 8.6 ND 4B-14 PU-WS20 <200 ND Table 21 Compound # Name ECso; binding to ECso; binding JNPL3 brain to SKBr3 cell Hsp9O (nM) Hsp9O (nM) 4E-1| PU-WS3 218.8 ND 4E-2 PU-WSS 285 ND 4E-3 DZ3-39 542 1126 4E-4 DZ3-40 46 93 Table 2J Compound # Name EC5o; binding to EC 50 ; binding JNPL3 brain to SKBr3 cell Hsp9O (nM) Hsp90 (nM) 41-12 | TT-VI-11 ND 394 WO 2011/044394 PCT/US2010/051872 169 Table 2K Compound # Name ECso; binding to EC 5 0 ; binding JNPL3 brain to SKBr3 cell Hsp9O(nM) Hsp90(nM) 4G-1 DZ3-30 374 1024 4G-2 DZ3-32 107 128 4G-3 DZ3-43 2.6 7.2 4G-4 DZ3-44 >300 >300 4G-5 DZ3-45 >300 >300 4G-6 DZ3-46 4.0 5.5 4G-9 | DZ3-61 ND 5.5 Table 2L Compound # Name EC 5 o; binding to EC5o; binding JNPL3 brain to SKBr3 cell Hsp9O(nM) Hsp9O (nM) 4H-1 DZ3-29 309 740 4H-2 DZ3-31 89 121 411-3 DZ3-41 57 161 411-4 DZ3-59 ND 24.6 411-6| DZ3-38 23 47 411-7 DZ3-141 ND 26,653 Table 2M Compound # Name EC5o; binding to ECso; binding JNPL3 brain to SKBr3 cell Hsp90 (nM) Hsp90 (nM) 5A-1 PU-RK11 ND 34.5 5A-2 PU-HT165 ND 34.6 5A-3 PU-HT175 ND 34.8 5A-4 PU-RK12 ND 62.8 5A-5 DZ3-73 ND 9.4 5A-6 DZ4-84 45.1 ND WO 2011/044394 PCT/US2010/051872 170 Table 2N Compound # Name EC 5 o; binding to EC 50 ; binding JNPL3 brain to SKBr3 cell Hsp9O (nM) Hsp9O (nM) SB-I HJP18 ND 6.9 5B-7 TT-VI-53A ND 5.3 5B-33 HJP23 46.3 ND 5B-34 HJP20 ND 3.5 Table 20 Compound # Name EC 5 o; binding to EC 5 o; binding JNPL3 brain to SKBr3 cell Hsp90 (nM) Hsp9O (nM) 5D-2 HJP19 ND 11.2 5D-4 TT-VI-54A ND 7.7 Table 2P Compound # Name ECso; binding to ECso; binding JNPL3 brain to SKBr3 cell F Hsp9O (nM) Hsp9O (nM) 6B-25 DZ4-52-N9 ND 97.0 Table 20 Compound # Name EC 5 o; binding to EC 5 o; binding JNPL3 brain to SKBr3 cell Hsp9O (nM) Hsp9O (nM) 7A-20 PU-WS31 <200 ND 7C-13 TT-V-138 ND 84 7D-3 TT-V-139 ND 240 7E-6 TT-V-140 ND 32 WO 2011/044394 PCT[US2OIO/051872 171 Table 3A No. Name 3A-1 2-fluoro-8-((5-(furan-2-yI)benzofura-6-yl)methyl)-9-(2 ______________(neopentylanmino)ethyl)-9H-purin-6-ancn 3A-2 2-fluoro-8-((5-iodo-iH-indol-6-yl)mthyl)-9-(2-(neopentylamino)ethyl) ______________9H-puz-in-6-arnine 3A-3 N-(2-((2-(6-amino-8-((5-(fura-2-yl)benzo[b]thiophen-6-yl)thio)-9H ______________purin-9-yl)ethyl)amino)ethyl)sulfamide 3A-4 3-((2-(8-((1-acetyl-5-(fiiran-2-yl)-IH-indol-6-yl)thio)-6-ainiino-9H ______________ pur-9-yl)ethyl)amino)-N-hydroxypropananiide 3A-5 8-((5-(azetidin-1 -yl)benzfiirn-6-yl)thio)-9-(2-(isobutylamino)ethyl) 9H-purin-6-aniine 3A-6 8-((5-iodobenz[b]thiophen-6-yI)thio)-9-(2-(isobutylamino)ethyl)-9H purin-6 -amnme 3A-7 8-((5-( IH-pyrazo-3-yl)-IH-indol-6-yl)thio)-9-(3 (isopropylamio)propyl)-9H-puin-6-anmine 3A-8 8-((5-ethynyl-IH-indol-6-yl)thio)-9-(2-isobutylamino)ethyl)-9H-purin 6-amine 3A-9 6-((6-anaino-9-(2-(isobutylamino)ethyl)-9H-purin-8-yl)thio)-1 -methyl IH-indole-5-carbonitrile 3A-10 9-(3-aninopropyl)-8-(fS-iodobenzfin-6-yl)thio)-9H-purin-6-anine 3A-11 9-(2-aminoethyl)-8-((5-iodobenzofura-6-yl)dhio)-9H-purin-6-anine 3A-12 9-(3-(tet-buylanmino)propyl)-8-((5-iodobenzofinn-6-yl)thio)-9H-purin 6-amine 3A-13 2-fluoro-8-((5-iodobenofuran-6-yl)methyl)-9-(2 (neopentylamino)ethyl)-9H-purin-6-anmrne 3A-14 I -(4-(2-(6-anmino-2-fluoro-8-((5-(5-methylfuran-2-yl)benofuran-6 ______________yl)methyl)-9H-purn-9-yl)ethyl)piperidin-1-yI)ethanone 3A-15 9-(3-(tert-butylamino)propyl)-8-((5-thynylbenzfiira-6-yl)thio)-9H _____________punn-6 -amine 3A-16 2-fluoro-8-((5-(5-nietliyloxazol-2-yl)benofuran-6-y)methYl)-9(2 (neopentylanmino)ethyl)-9H-purin-6-anvine 3A-17 9-(3-(tert-butylamino)propyl)-8-((5-(dimethylamino)benzofra-6 yl)thio)-9H-pmrn-6-amie 3A-18 8-((5-iodobenzofura-6-yl)thio)-9-(2-(1 -(methylsulfonyl)piperidin-3 yl)ethyl)-9H-purin-6-aniine 3A-19 8-((5-(1H-pyrazo-3-yl)benzofiiran-6-yl)thio)-9-(2 (neopentylanmino)ethyt)-9H-purin-6-anmine 3A-20 N-(3-(6-amino-8-((5-(aziridin-l-yl)benzofura-6-yl)thio)-9H-purin-9 _____________yl)propyl)inethanesulfonamde 3A-21 3-(6-anino-8-((5-iodobenzofura-6-yl)thio)-9H-purin-9-yl)propy sulfamte 3A-22 9-(3-(tert-butylamiino)propyl)-8-((5-(oxaol-2-yl)benzofura-6-yl)thio) 9H-puri-6-amine 3A-23 8-((5-ethyiiylenzofiia-6-yl)thio)-9-(2-(neopentylatmino)ethyl)-9H ______________purin-6-aniine 3A-24 I -(6-amiino-8-((5-iodobenzofbran-6-yl)thio)-9H-purin-9-yI)-3-(tert- WO 2011/044394 PCT[US2OIO/051872 172 butylamio)propan-2-o 3A-25 8-((5-iodobenzfiura-6-yl)thio)-9-(3-(isopropylanmino)propyl)-9H __________purin-6-ainine 3A-26 9-(3-(tert-butylamino)prcpyl)-8-((5-(5-methylthiazo-2-yl)benzofuran-6 yl)thio)-9H-purin-6-amine Table 3B No. Name 3B-i 5-((6-anaino-9-(2-(isobutylamino)edhyl)-9H-purin-8-yl)thio)bnofara 6-caibonitrile 3B-2 8-((6-iodobenzfuran-5-yI)thio)-9-(2-(isobutylamino)ethyl)-9H-purin-6 amie 3B-3 8-((6-(firan-2-yl)benzfiua-5-yl)thio)-9-(2-(isobutylamino)ehyl)-9H puri-6-amine 3B-4 N-(2-((2-(6-armino-8-((6-(fianm-2-yl)benzofuran-5-yl)thio)-9H--purin-9 - ~yl)ethyl)aznino)teeth)sulfaide 3B-5 3-((2-(6-amino-S-((6-(ffiirn-2-yl)benzofura-5-yl)thio)-9H-puin-9 Iyl)ethyl)amino)-N-hydroxypropanamide 3B3-6 2-luoro-S-((6-(fira-2-yl)-IH-indol-5-yl)methyl)-9-(2 (neopentylamino)ethyl)-9H-purin-6-anmine 3B-7 8-((6-(aztidin-1 -yl)-IH-indol-5-yl)thio)-9-(2-(isobutylaniino)ethyl)-9H - purin-6-arnine SB-8 9-(2-(isobutylarnino)ethyl)-8-((6-(pyrrolidin-1 -yl)-1H-indol-5-yl)thio) - 9H-purin-6-ainine - (isopropylamino)propyl)-9H-purin-6-ainine 3B-10 2-fluoro8-((6-iodo-1-isopropyl-1H-indol-5-yl)methyl)-9-(2 I(isobutylainino)ethyl)-9H-purin-6-anmine 3B-11 2-fluoro-S-((6-(finn-2-yl)benzo[blthiophen-5-yl)methyl)-9-(3 ____________(isopropylamino)propyl)-9H-purin-6-anmine 3B-12 2-fluoro-8-((6-iodobenzo[blthiophen-5-yl)methyl)-9-(2 ________ (neoPentYlamino)edhyl)-9H-purin-6-amine 3B-13 8-((6-(]IH-pyrrol-3-yl)benz[b]thiophen-5-yl)methyl)-2-fluor-9-(2 ________ (isobutylamno)ethyl)-9H-purin-6-anmine 3B-14 8-((6-ethynylbenzo~b]thiophen-5-yI)methyl)-2-fluoro-9-(2 - ~(isobutylarmino)ethyl)-9H-purin-6-anaine SB-15 2-chloro-8-((6-ethynylbeno[b]thiophen-5-yl)methyl)-9-(2 _________I (isobutylanmino)ethyl)-9H-purin-6-anine 3B-16 S-((6-(azetidin-1-yI)-1H-indol-5-yl)thio)-9-(2-(isobutylamino)ehyl)-9H ___________purin-6-amine 3B-i7 8-((6-(aziridin-1-yl)-1H-indol-5-yl)thio)-9-(2-(isobutylamino)ethyl)-9H ____________purin-6-ammne SB-i8 9-(3-amnopropyl)-8-((6-iodobenzofiara-5-yl)thio)-9H-purin-6-amine 3B-19 9-(2-anainoethyl)-8-((6-iodobenofumxn-5-yl)thio)-9H-purin-6-armine 3B-20 9-(3-(tert-butylamino)propyl)-8-((6-iodobezofisn-5-yl)thio)-9purin-6-amine 3B-21 1-(4-(2-(6-amio-2-fluoro-8-((6-(5-methylfira-2-yl)benzfura-5 y l)methyl)-9H-purin-9-yI)ethyl)piperidin-1-yflethanoe 3B-22 9-(3-(tert-butylamino)propy1)-8-(f6ethynlbenzofimr-5-y1)tho-H WO 2011/044394 PCT[US2OIO/051872 173 L4 puxn-6-amine 3B-23 2-fluoro-8-((6-(5-methyloxaol-2-y)benzofizra-5-yl)methyl)-9-(2 ____________(neopentylanmino)ethyl)-9H-purin-6-anaine 3B-24 9-(3-(tert-butylanino)propyl)-8-((6-(dimethylaimino)benofiia-5 ____________yl)thio)-9H-purin-6-aine 3B-25 8-((6-iodobenofura-5-yl)thio)-9-(2 -(I -(methylsulfonyl)piperidin-3 ________ yl)ethyfl-9H-purin-6-amine 3B-26 8-((6-(IH-pyrazol-3-yl)benofura-5-yl)thio)-9-(2 ___________(neopentylamino)ethyl)-9H-purin-6-aie 3B-27 N-(3-(6-anaino-8-((6-(azridin-1I -yl)benzofim-5-yl)thio)-9H-purin-9 ___________ l)propyl)inethanesulfonamide 3B-28 3-(6-arnino-8-((6-iodobenzfiaa-5-yl)thio)-9H-punin-9-y)propyl ____________sulfamte 3B-29 9-(3-(tert-butylamino)propyl)-8-((6-(oxazo-2-yl)benofiirn-5-yl)thio) _________9H-purin-6-amine 3B-30 8-((6-ethynylbenzofura-5-yI)thio)-9-(2-(neopentylanaino)ethyl)-9H _______ purin-6-arnrne 3B-31 I -(6-amino-8-((6-iodobt~ofi a-5-y1)thio)-9H-purin-9-y1)-3-(tert butylaniino)propan-2-ol 3B-32 S-((6-iodobenofuran-5-yl)thio)-9-(3-(isopropylaxniino)propyl)-9H __________1 pmrn-6-amine 3B-33 9-(3-(tert-butylanuino)propyl)-8-((6-(5-niethylthiazol-2-yl)benzofuran-5 YI)thio)-9H-puri-6-amine 3B-34 I -(3-(6-axnino-8-(6-iodobenzfizran-5-ylthio)-9H-purin-9 ____________yl)propyl)pyrrolidin-3-ol 3B-35 1-(3-(6-amiino-8-(6-iodobenzofuran-5-ylthio)-9H-purin-9 ____________yl)propyl)pyrrolidin-3-one Table 3C No. Name 3C-1 6-((6-anaio-9-(2-(isobutylarmino)ethyl)-9H-purin-8-yl)thio)berio[djoxaole-5 carbonitie 3C-2 8-((5-(furan-2-yl)benzo[dlthiazo-6-yI)thio)-9-(2-(neopentylamino)ethyl)-9H purin-6-anaine 3C-3 2-fluoro-8-((5-(fura-2-yl)benzodjoxaol-6-yl)methyl)-9-(2 (neopentylaniino)ethyl)-9H-purin-6-anmine 3C-4 8-((5-(azetidin-1 -yl)benzo[d~oxazol-6-yl)thio)-9-(2-(isobutylanaino)ethyl)-9H purin-6-ame purin-6-amine 3C-6 8-((5-ethynylbenz[dlthiazol-6-yI)methiyl)-2-fluoro-9-(2-(isobutylamino)ethyl) _________9H-purin-6-amnine 3C-7 N-(2-((2-(6-amino-8-((5-iodobt~o[dloxao1-6-y1)thio)-9H-purin-9 ________I yflethiyl)amino)ethyl) sulfamide 3C-8 3-((2-(6-amino-8-((5-(fiiran-2-yl)benz[dloxazol-6-yl)thio)-9H-purin-9 _________yl)ethyl)anilno)-N-hydroxypropannide WO 2011/044394 PCT[US2OIO/051872 174 Table 3D No. Name 3D-I 5-((6-amino-9-(2-(isobutylamino)ethyl-9H-puin-8-y)thio)- IH ______ ______benzo[dlirnidaz.ole-6-carbrnitrile 3D-2 8-((6-(furan-2-yl)-1H1-benzo[d]irnidazol-5-yl)thio)-9-(2 (neopentylamino)ethy)-9-purin-6-anrine 3D-3 2-fluoro-8-((6-(ffiran-2-yl)-1H-benzold]itnidazol-5-yl) ethyI)-9-2 ____________(neopentylamino)ethyl)-9H-piirin-6-anine 3D-4 8-((6-(azetidin-1-yl)-IH-benzo[dlimidazol-5-yl)thio)-9-(2 ____________ isobutylamino)ethyfl-9H-purin-6-anmine 3D-5 9-(2-(isobutylaznino)ethyl)-S-((6-(pyrrolidin-1 -yl)-l H-benzo[d]imidaz.ol-5 ____________yl)thio)-91f-purin-6-amrne 3D-6 j8-((6-ethynyl-I -rnethyl-iH-benzo[d]imidazol-5-yl)methiyl)-2-flmIuro-9-(2 ____________(isobutylamiino)ethyl)-9H-rpurin-6-ariine 3D- 7 iN((((8(iaei--o-iH-benzod]imidazol-5-y1)thio)-6-airano ____________ 9H-purin-9-yl)cthyl)arnino)ethyl)rnethanesuiforamide 3D-8 3-((2-(6-amino-8-((6-(furan-2 -yi)-iII-ezrhmdzl5y~ho-1I 3 -t purirn-9-yl)eth yl)amino)-N-hydroxyropanamide 3D-9 ~5-((6-amino-9-(2.-(isotutylamino)ethyl)-9H-puiri-S ____________ yfthio)be io N] oxaole-6-carbonitrile 3D-10 8-((6-iodobenzo[d]oxazoi-5-yI)thiio)-9-(2-(neopentylamino)ethyl)-9H jpurin-6-ami 3D-li 5-((6-amino-9-(2-(isobutylamino)etbyl)-9H-purin-8 yflthio~benzo[dithiazole-6-carbonitrile 3D-1 2 8-((6-(furan-2-yl)benzo[djthiazol-5-yI)thio)-9-(2-(neopentylanmino)ethyl) QH1-purin-6-amnine 3D-13 2-fluoro-8-((6-(fiurax-2-yl)beno[d]oxazo1-5-y1)mnethyl)-9-(2 (neopentylarnino)ethyfl-9H-pnrin-6-arninec 3D-14 8-((6-(azetidin-1 -y1)benzo~d]oxazo1-5 -y)thio)-9-(2-(i sobutylamino)ethy1) ________ 9 1 i-purin-6-anaine 3D-15 9-(2-(isobutylamino)ethyl)-84((6-(pyrrolidin-1I -yl)beno[d]thiazol-5 _____________yI)thio)-9H-prin-6-annine 3D-16 8-((6-ethynylbeno[djthiazcl-5-yl)mcthyl)-2-luoro-9-(2 ____________(isobutylamino)ethyl)-9H-purin-6-anmine Table 3E No, Name 3E-1 6-((6amino-9-(2-(tsobu-ylarmno)ethyl)-9H-purin--y)thio)benzo[d][ l,2,3]oxadiazole-> ___________ arb nrle 3E-2 845(ua--y.ez~J12,3]thiadiazol-6-y)thio)-9-(2-(nieopcntvlarnino)ethyl)-9H-purin 6-amine 3F,3 2-f4luoro-8-(fiwan-2-yl)betno[d][1 ,2,3]oxadiaawl-&-yI)rnethvl)-9-}2 ___________(neopentylamino)ethyl)-9H-purin-6-aminre 3E-4 8-((5-(azetidin-I -yl)benzo~d] [I ,2,3]oxadiazol-6-yl)thio)-9-(2-(isobutylamino)ethyl)-9H ___________purin-6-arnine 3F-5 9-2(sbtlmn~ty)S-(-~roii--yDbenzojdlA3]thiadiazo-6-y)thio-_911 WO 2011/044394 PCT/US2OIO/051872 175 __________ purin-6-amine 3E-6 j8-((5--effynylbenzo[d][ i,2,3]thiadiazol6-vl)methyl-2-lnoro-9-(2-(isobuiylamino)ethyl)-9H ___________puin-6-amine 3E-7 IN-(2-((2-(6-amino-8-((5-iodobenzo[d [ 1,2,3joxadisuol-6-yl)thio)-91{-purin-9 ___________ jyl)ethyl)amino)ethflsulfamide SE-S 3-((2-(6-amino-S-((5-(fiian-2-y)bezo~d]l,2,3]oxadiazol-6-yl)thiio)-9H-purin-9 ___________I y)ethyl)am~ino)-N-hydroxypropananjde 3E-9 J5-((6-amino-9-(2-(isobutylamino)ethyl)-9H-purin-8-yl)thio)-3--indazole-6-carbonitrile 3E-10 8-((6-(furan-2-yl)-31--indazol-5-yl)thio)-9-(2-(neopentylanino)ethyl)-.H-purin-6-anine 3E-11 2-fluoro-8-((6-(funn-2-yl)-3H-indazol-5-yI)meihyl)-9-(2-(neopentylamino)ethyl)-9H-puin __________ j6-amnine 3E-12 j8-(6-(azetidin-1-y1)-31--indao-5-ylthio)-9-isobutylamino)ethy)9H-purin-6-amine Table 3F No. jName 3F-I 5-((6-aniino-9-(2'-isobutylamino)ehyl)-91-purin-8 ________________y!)tlhio)berzofdl(1.2,3)oxadiazole-6&carbonitrilc 3F-2 8-((641IH-pyazol-3-yl)benzo~d][1 .,,3]oxadi:azol.-5-yflthie)-9-(2 _____________(neopentylaniino)ethyl)-9H-purin-6-anine 3F-3 2-foro-8-(6-(furan-2-vl)-IH-benzo(d] [1,2 ,3ltriazo'i-5-yl)rnethyl)-9-(2 ______________(neopentyl~arino)ethyl)-9H-paurn-6-amin.e 3F-4 S-((6-(azetidin-1 -yl)tenzo[d]( F, I2,3]thiadiazoi-5-yl)thio)-9-(2 (isobutyianiino)ethyl)-91-i-puin-6-anmine 3F-5 9-(2-(isobutylamino)ethyI)-S-((5-(pynolidin-1 -yl)-3H-indazol-6-yl)thio)-9H purin-6-amine 3F-6 8-((6-ethynyl- I-metihy1-IH-benzo(d]r 1,2,3] tiaol-5-yl)rnethyl)-2-fluoro-9 jL sbutIIVaminoctbyO-9H-purin-6-amine 3F-7 N-(2-((2-(6-aniino-8-((6-iodobenzo[d] [1 ,2,3]oxadiazol-5-yl)thio)-9H-puri 9-yI)ethyl)an~ino)ethyl)sulfaraide 3F-8 3-((2-(6-amino-8-((5-(ffiran-2-yl)-3H-indazol-6-yl)thio)-91-purin-9 yI)ethyl)amino)-N-hydroxypropa .......-.......... i 3F-9 6-((6-amino-9-(2-(isobutylamino)ethyl)-9H-ptuin-8-yIithio)-3H-indazole-5 _______________ oatbon it rile 3F-to 8-((6-iodobenzo[d][1 ,2,3loxadiazol-5-yl,'thio)-9-(2-(neopentylain o)ethyl) 3F-1I1 5-((&arnino-9-(2-(isobntylam~ino)ethiyl)-9H-purin-8 _______________ Iyi)thio)benzo[d][i ,2,3]thiadiazole-6-carbonitrile 3F-12 8-((6-(furan-2 -yl)terazo[d] '[1,2,3]thiadiazol-5-yl)th io)-9i(2 SF432-fuoro8-(6-(frar-2-y~tezordr[1,2,3]oxadiaol-5-yl)rnethyl)-9-(2 I(rneopentvlamino)ehyi)-91-I-pwin-6-amre 3F-14 i. -((6-(azetidin- 1-yl~benzo[d] f 1 ,2,3]loxadiazcP-5-yl)thio)-9-(2 ___________ (isobutvlatnino~eh yl)-9H-purin4-- Aiie 3F-15 9 2(sbr~iioehl-46(yr Iid -yl)beno[d] [ I231lthiadiazol ______________5 yl)thio)-9H-piixin-6-amine 315-16 8-((5-ethyrtyi-3Hi-indazoI-6-y1)niethyl)-2-flnoro-9-(2-(isobutylaiino)ethyl) 9-punin-6-ain WO 2011/044394 PCT[US2OIO/051872 176 Table 4A No. ____Name 4A-1 D--38 9-(3-(isopropylatnino)propyl)4-(6-phenylbenzo[d][ 1,3]dioxol-5-ylthio) ______________914-piuri-6-araine 4A-2 DZ2-390 8-(6-(4-tert-butylphenyl)bezo[dJ[1,31drnxoI-5-ylthio)-9-(3 _______________ =iopoplaI-oppy)9pui6am 4A-3 DZ2-391 S-(6-(3,5-bis~trifluoromethyl)phenyl)bcnzo[dJ[ 1 ,jdioxol-5-ylthio)-9-(3 ................... (isopropylanmino)propyl)-9H-purin-6-anmine 4A-4 TT-V-47B NI -(3-(6-amino-S-(6-(3,5-bis(trifluorornethyl)phenyl)henzo[d][ 1.3]dioxol __________ ___ -lti)9HpI In9y)propyl)hxxe-l .6-dianrine 4A-5 DZ2-392 8-(6-(4-(dirnethxilami no)ph.enyl)be~o[d][ I,3)dioxob-5-ylthio)-9-{3 I_________ (isopropylamino)propyl)-9H-p rn-6-anine 4A-6 DZ3-3 9-(3-}isopropylarni no)propyl)-8-(6-(4-methoxyvphenyl)benzo[d][ 1,3]dioxol _______________5-yithio)-9H-purtn4,-ane~ 4A-7 DZ3-6 8-(6-(4-bromnoplhenyl)berno[d] [1,3]dioxol-5-ylthio)-9-(3 ______________(isopropyiamiino)propyl)-91-puin-6-arnne 4A.8 DZ3-5O 4-(6-(6-amino-9-(3-(isopropylamino)propyl)-9H-purin-8 ylthio)benzo[dli I ,3ldioxol-5-ylbezaldehyde 4A-9 4-(2-(6-arnino-8-(6-phenylbcnzordi[I ,3]dioxoI-5-ylthio)-9H-purin-9 ________- _ yijehyjpidn1 -c adchyde__-______________ 4A-10 1}(4-(2-(6-amino-2-fluoro-8-((6-pheniylbeno[d)[1 .3]dioxol-5-yl)methyl) ______________ 9-puiin --yethyl)piperidin-1 -yI)ethanone 4A-11 N-(2-((2-(6-arnino-8-((6-phenylbenzotd]i1 ,3]dioxol-5-yl)tlio)-9H-pmin-9 4A-I12 3(-6ain--6peyb od]1 ,3]dioxol-5-ylthio)-9--pm-in-9 ___________ylje hyIa miiio)-f drop To amidc 4A-13 9-(13-aminooropyl)-8-(6-phenylbenzo[d][1,3]dioxol-5-yltliio)-9H-un amine Table 4B No _ __ _ _ __ _ _ __ _ _ _ Nam e 484- PLJ-WSS 8-(6-ethymylbenzo[d][i,3]dioxo-5-ylthio)-9-(3-(isopopylanino)propy) 9H-pnurin--amine _____________ 4B-2 PIJ-WS6 i8-(6-(3,3-6meilbut-1-y,yl)beiio[d~rl,3]dioxol-5-ylti.o)-9-(3 4R-3 PU-WS7 9-(3-(isopropylamino)propyI)-8-(6-4phenylethynyI)benzo[d]I ,3]dioxol-5 -ylthio)9WpurIE-r~nl _________________ WO 2011/044394 PCT[US2616/051872 177 L44B-4 PUj-WSL6 S-(6-ethyybezo~d)(1 ,3]dioxol-5-ylthio)-942-(isobutylan.ino,)ethyI)-9H ______________purin-6-amrne 4B-5 I -(3-(2-(6-amino-8-(6ethynylbero[d][ 1,3]dioxol-5-ylthio)-9v-purin-9 _______________yl)ethyl)pipedidin-1I -yl)ethanone __________ 4B-6 8}(6-ethynylbenzc~dj[ 1,3]dioxol-5-ylthio)-9-(2-( I N________ (me thylsulfonyl)piperidin-3-yi)ethyl)-9H-purin-6-arnnne 6B3-7 1 -(3-(4-(6-anino-8-((6-ethynylbenzo[d][I,3]dioxol-5-yl)methyl)-2-fluoro ___________ ____ Hprnin-9-yi)butyl)pynolidin-1-yflethanone 4B3-8 5-(6-amino-8-((6-ethynylbenzo~d][ t,3]dioxol-5-y)methyl)-2-fuoro-9 ______________purn 9-yI)pentane-1 -sulfonamide 4B3-9 3-(2-(6-amino-2-chloro-8-((6othynylbezod)[1I,3)dioxo1--5-yl)methy) ______________9H-purin-9-yl)ethyl)pipedidine-1-cabaldehyde 4B3-10 3-(2-(6-arino-8-((6-ethynylbeto[d] r1,3]dioxol-5-yl)rnethyl)-2-fluoro ______________9-purin-9-y)ehyl)pipefidnpe-1 -sulfonamide 4B-1I N-(2-((2-(6-amino-S-((6-ethyybenzo~d)[1 ,3):dioxol-5-yflthio)-9H-pmrn 9 yI)ethvl)amino)ethyl)sulfamide 4B9-12 ' (2-(6-amino-8-(6-eihynylbenzo[d][ 1,3] dioxol-5-ylthio)-9H-pudin-9 _______________ )ethyainoNbdoyrpnme 4B3-13 PU-WS19 8-(6-ethynylhenzo[d][1,3]dioxol-5-ylthiO)-9-(2}-neopen ylamino)ethyql) ______________9H-jpurin-6-ainine 4B3-14 PU-WS20 8-((6 ethynylbenzod] [ I ,3]dioxol-5-yI)methyl)-2-fluoro-9-(2 _______________(isobuitylminio)ethyl)-9H-puhin-6-amine 413159-(3-aminopropyb-8-(6-ethynylbenofd]I ,3] dioxol-5 -ylthio)-9H-pmin-6 amine 4B3-16 9-(2 -aminoethyl)-8 -(6-ethynylbenzo[d [1 ,3]dioxol-5-ylthio)-9H-purin-6 amine 4B3-17 9-(3-(tert-butylamino)propyl)-S-(6-ethymylbenzo[d] [ 1,3]dioxol-5 -ylthio) ______________9H-purin-6-amine 4B-18 1-(3 -(6-amino-8-(6-ethynylbenzo[d] [ 1,3]dioxoI-5 -y4thio)-9H-purin-9 yl)propyl)pyrrolidin-3 -one 4B3-19 3-(2-(6-aiino1-8-((6-ethynylbenzo[d][1 ,3idioxol-5-yl)thio)-9H-purin-9 _____________vl)etliyl)piperidine-1I -sulfonaide 4B3-20 6-(6-amino-8-(6-cthynylbenzo[d][1 ,3]doxol1-5-vlthio)-9H-purin-9 ________________yl)lhexmaaride 4B3-21 1-(&-amino-8-(6-ethvnyb enzo[d][ 1 .3] dioxol -5-ylthio)-9H-purin-9-yl)-3 41-22 6-(6-amino-8-((6-e~hynylben2o [d] [ 1,31]di oxol-5-yl)methyl)-2-fluoro-9H _______________pur~h-9-yI)hexanamide 4B3-23 1 -(2-((2-(6-amnino-8-(6-ethvnylbenzo[dFrI1,3] dioxol-5-ylthio)-9-1-pui-9 yl)ethylamainolrnethy!) LpyrLIdin--yLeLhanone_-____ 4B1-24 T-(6anno8(&-ethynybro[di[1 ,3]dioxo1-5-ythio>. 9H-purin-9 _______________yI)pentane-1 -sulfonamide 4B3-25 1-(3-(2-(6-amino-8-((6-ethynylbenzo[d)[ 1,3]dioxol-5-yl)methiyl)-2-fluoro _______________9H-purin-9-yl~lethyI)piperidin-1-y1)ethanone 4B-26 8-~6-tbyny~benz[fI 3jdioxol WO 2011/044394 PCT[US2OIO/051872 178 (neopentylarnino)ethyl)-9H-purin-6-armine 4B-27 8-((6-ethvylbeazo[d]![I .3]dioxol-5-vI)methyl)-2-fluoro-9-(3 _________ --- _ (isopropylarmino)propyi)-9H-purin-6-amine 4B-28 9-(3-(tert-bulylamino)propyl)-8-((6-ethynylbenzo[d[ I ,3)dioxol-5 vI)nwthyl)-2-fluoro-9H-purin-6-anmine 4B-29 8-((6-ethynylbeno~di[1 ,3]dioxol-5-yI)nmethyl)-2-fluoro-9-(2-( 1 N imethylstilfonylip Ieridin-3-yl)ethy)-9H-purin-6-amne 4B-30 I -(3-(6-amino-8-((6-ethynylbezord]1[1 ,3]dioxoI-5-yl)methyl)-2-fluoro _______________9H-purin-9-yl)propyl)pyrrolidin-3-one 4B-31 8-((6-ethynylbenzo[d][I,3]dioxol-5-y)methyl)-2-fluoro-9-(2-( ____.........._ methylpiperidin-3-yI)ethyl)-9H-purin-6-amine 4B-32 8-(6-ethynylbenzo[di[1 ,Sjdioxol-5-ylthio)-9-(2-( 1-methylpiperidin-2 ____________________________ u n-6-arnine 4B-33 1 -(2-((9-(6-amino-8-((6-ethynylberzo[d]1[1 ,3]dioxoI-5-yI)methyl)-2 ______________ flnoro-9H-purin-9-yi)ethyiaminpo)methvflnyno idin-1 -Lhhone_] 4B-34 8-(6-ethyriylbenzo[d][ 1,3]dioxoi-5-ylthio)-9-(2-( i-tnethIylpiperidin-3 _______________ y)ethyl'i-9H-purin-6-amine 4B-35 j -(-tyybnod] 1,]ixl5yfnehl-4ur--2( _____________ nethylpircridin-2-y1)ethyl)-9W-purin46-ainin Table 4C No. Name 4C-1 DZ3-4 8-((6-(Thran-2-yl)benzo[dfli ,3]dioxol-5-yl)thio)-9-(3-(isopropylamino)propyl)-9H p~rin-6-ann 4C-2 DZS-27 8-((6-(fura-3-yl'ibeno[J][1 ,3]dioxo1-5-yl)thio)-9-(3-(isopropylan~ino)propy)-9H __________purin- 6-ammoe 4C-3 D73-25 I2-flnoro-S-((6-(ftira-2-yl)benw[d][i,3]dioxol-5-yl)metlhyl)-9-(2-(isobutylamino)ethyl) ________I 9H-purin-6-aniine 4C-4 DZ3-26 2-fluoro-S-((6-(furarn3-yl)benzo[d][1 ,3]dioxol-5-yl)methyl)-9-(2-(isobutylamino)ethyl) 9H-purin-6-arnne 4C-5 TT5-53A 8-((6-(faa-2-yI)benzo[d][I ,3]dioxol-5-yl)thio)-9-(2-(reopcntylamnino)ethvyl)-9H-purin __________6-amine 4C-6 DZS-33 5-(6-((6-amiino-9-(3-}isopropyamino)propyl)-9H-purin-S-y)tbiooenzo[d[ 3ldio-5 yl)furan-2-oarbaldehyde--- - -- 4C-7 D7,3-34 5-(6-((6-amino-2-tluoro-9-(2-(isoburylamino)cthyl)-9H-purin-8 ______~~~.. .f~ z ......... .,3 d. ............. balch o 4C-8 0Z3-35 9-(3-(isopropylaminc~propyl)-8-((6-(5-methylfuran-2-y)benzo[d [1 ,31dioxoi.5-y1)thio) ___________9H-purin-6-amine 4C-9 DZ3-36 _________ -fluoro-9-(2-(isohutylamino)ethyl)-8-((6-(5-niethvlfhran-2-yl)benzoLd r ,3]dioxol-5- WO 2011/044394 PCT/US2OIO/051872 179 _______ yl)methyl)-9H-purin-6-a-nine 4C-11 DZ3-51 2-fluoro-9-(2-(isobutylan~jno)ethy1)-8-((6-(isoxazo1-4-yl)benzo[d][1 ,3]dioxol-5 4C42 Lhnethyfl-9H-purin-6-amine F -4C-12 8-((6-(5-(ainhomethyl)fiiran-2-yl)benzo[d][ 1 ,3]dioxol-5-yl)thko)9-3 ________ -(isopropyl~mino)propyl)-9H-:p"-am 4C-13 8-((6-(5-(ainomethyl)furan-2-yl)benzo[d][1 ,3]dioxol-5-yI)rnethyl)-2-fluoro-9-(2 4C44 (isoutyamin~ethfl-H-:F~Pf-6-amine 4C-14 0Z3-60 S-((6-(fhra-3-yl)benzo[d]Il ,3]dioxol-5-yi)thio)-9-(-(neopentyamino)ethA)-9H-pnrin 6-amine 4C-15 8-(&-(5-rnethyloxa.zoi-2-yl)benzo[d][1,3]dioxol-5-ylthio)-9-(2-(neopentylanino)ethyl) __________ 9H-rin-6- amne 4C-16 i 072-56 8-((6-(5-methylffi.ran-2-yl)benzo[d][ 1,3]dioxol-5-yl)thio)-9-(2-(neopenylainho)ethyl) __________9Hpurin-6-amino 4C-17 1 (3-(6-anilno-2-flnoro-8-((6-(5-methiyloxazol-2-y1)berazo[dlrl ,3ldioxol-5-yl)rnethyl> _________91-ptan-9-vy~p1.oidi-3-one 4C-18 8-((6-(5-(aniinonethyl)furan-2-yl)benzo(d]rl,3]dioxol-5-yl)thiio)-9-%2 ___________(neopentylarniiokthyl)-9H-urin-6-mn 4C-19 1 (3-(t(6anno-S-(6(5-mehylffira-2-y1)benzo~d] F",3]dioxi-5-ylthi0)-9H-purin-9 ____________yi)ethyflpiperidin-1-yl)ethanonie 4C-20 8-(6-(5-methylftra-2-y1)benzo[d) 1 ,3]dioxol-5-yltbio)-9-(2-( 1 (methy lsulfonyl)*piipefldin-3-yl~ethyl)-9H-purin-6-amine 4C-21 1-(3-(2-(6-anmino-2-fluoro-8-((6-(5-methylfiira-2-yl)beno(d][1 ,3]dioxol-5-yl)methyl) __________ 9H1i~:.ehlpprdn~!ebnn 4C-22 4-(2-(6-amino-2-fluoro-8-((6-(furan-2-y)benzold][1 ,3]dioxol-5-yI)rnethyl)-9H-puin-9 ____________ y~L)ethyl)piperidine-l1 carbleye _____ ___ 4C-23 I -(3-(6-amino-S-(6-(oxazol-2-yl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-9 _________ __________ yl~p pyDryrolidin-3-onc 4C-24 1 66amino-8-(6-45-methylxaol-2-yI)benzo[d][1,3)dioxol-5-ylthio)-9H-pnrin-9 _________yI)hexanamide 4fC-25 6-(6-amiino-2.fluoro-SK(6-(5-methvloxazol-2-yl)benzo[dI[1I,3)dioxoi-5-yl)methyl)-9H ___________purin-9-yi~lhexananmide 4C-26 I 44-(2-(6-.mi~o-2-fluoro-8-((6-(5-methylfaran-2-yI)benzo[d][i,3)dioxol-5-y)mety) 4C-27 1 ~~~9H-pmrin9yey1ipii-tyIthoe 4C-271-(4(2-4(6-amino-2-obloro-8-((6-(5-methytffiran-2-y)benzodF I,3]dioxol-5-yI)tnethyl)i __________91H-pmt-9- ADethyI)pipertdin-I -yl~ethanne 4C-28 T1.(3-(2-(6-arnino-S-(6-(5-niethvloxazol-2-yI)bezo [d][1 ,3]dioxol-5-ylthio)-9H-purin-9 _______ j _____________ __ yl)ethyl)piperidin-1-yl)ethanone 4C-29 I (3-(2-(6-amino-2.-fluoro-S-((6-(5-mehyklxazol-2-yl)bezo[d[1,3]dioxol-5 4C-36 3-(' (6-amino-2-chkro-84(&-(5-mehyoxzo-2-yl)benzo[d] [I,3]dioxoi-5-yi)rnethqyl) ___________ ~9H-purin:9:y1)ethyl~pipeidine1-sulfounmde ______ 4C-31 J1 (4 ( 9 -(6-amiino-S-((6-(5-(amninomethyl)ffira-2-yl)benzo[d) [1 ,3]dioxol-5-yl)thio)-9- 4C-32 ...-.-.... (..-arioety~xzo--lhez~I(13doxl5y~mty) WO 2011/044394 PCT/US2OIO/051872 ________2-f uoro,-911-purin-9-y;i~qtvl)pipeiidin-1I -yflethan.... 4C-33 S-6aio2fur--t41etyoao-~1tnod~I,3]dioxol-5-yi)rnetwflj-QH puin-9m Dpnae1-ufamd 2 -fluoro- 9 -(3-(isopropylamrino)propyl)--((6-(5-metyloxazo 2-yl)benzc~dfll 3]dioxol-5-yl)methyl)-9H-purin-6-amine 1.. 9-(3-(tert-butylaniino)propy)-2-fluoro-8-((6-(5-mthyoxzo-2 yl)benzo[d)j 1,3]dioxol-5-yl)methyl)-91{-purin-6-amiine N-(2-((2-(6-arno-84(6-(5-rnethylfurr-2 vl)ethyl)arnino)ethyl) sifamido 3-(2-(6-amino-S<-(5-rnethylforn-2-y1)benzo[dlr I,3]dioxo-5 ylthio)-9H-prin-9-yl)ehyian-o)-Nhydroxypropananide DZ4-20 9-(3-(isopropylamino)propyl)-8-((6-(oxazo1-2 yI)benzofd3[ I,3]dioxol-5-yl)thio)-911-pm-in-6-atnine DZ4-23 2-fluoro-9-(2-(isobutIainiino)ethy1)-g-((6-(oxazol-2 yl)benzo[d][1 ,3]dioxol-5-yl)methyl)-9H-purin-6-arnine DZ3-142 8-((6-(2,3-dihydrofura-2-yl)benzo~d][1 ,3]dioxoi-5-yl)thio)-9 (3-(isopropylanmino)propyl)-9H-purin-6-amine DZ34143 S-if 6-(2,3-dihydrofuran-3-yl)benzo[d[1,3 jdoxol-5-yl)thio)-9 (3-(isopropylamino)propyl)>9H-purin-6-amine yl)benzo[d][ I ,3]di.oxol-5-ylthio)-9H-puriu-6amine 9-(2-aminoethyl)v2-fluoro-8-((6-(5-mehlirn2 _______~~y 1 yD& ,Jodkf1, j i x15y1mi1) =nii--i I WO 2011/044394 PCT[US2OIO/051872 -4 9-(3-(rert-butylarmino)propyl)-8-(6-(5-nethylfuran-2 y?)benzord][1 ,3]dioxol-5-yhthio)-9H-purin-6-amine 9-(3-(tert-butylarnino)propyl)-8-((6-(oxzo2 yl)bcnzordjr 1,3]dioxo1-5-y1)tio)-9H-purin-6-amine 1-44-{2-(6-amiino-8-((6-(oxazol-2-yI)benzo~d [ 1,3]dioxol-5 yl)thio)-9H-purin-9-y1)ethyi)piperidin-I -yl)ethanone 8-((6-(5-methyloxazol-2-ylmenzo'd] [1 3]dioxol-5-yi)thkfl)-9-(2 (I -(meth~ylsulfonyI)piperidin-3-y1)ethyl)-9Ti-purin-6-aminie 9-(3-(tert-bntyIamino)propy1)-8-((6-(5-methyIoxzoi-2 yl)benzo~d][ 1 ,3jdioxol-5-yl)tio)-9H-pnrin-6-amrine I -(6-amino-8-(6-(5-methylfiiran-2-y1)benzo[d]r1 ,3]dioxol-5 ylthio)-9H-puin-9-yI)-3-(tert-bnTylaniio)propan-2-o1 I -(6-anmino-8-((6-(5-methiyloxazo1-2-yI)benzo[di(1,31dioxoI-5 yl)thio)-9H-purin-9-yl)-3-(isopropyLami no)propan-2-o 2-(3-(6-amiino-8-(6-(5-metbyftira-2-y)benzo[d]' LI,3]doxol-5 ylthio)-9H-purin-9-y)propylI)airidine-1-catbadehyde ---------- ---------------- - ----------------------- i~enan- -ulfonamide- 5-(6-amn"o-8-(6-(5-methylxao-2-yI)benzo[d][ 1,3]dioxol-5 __________ylthio)-9H-puirin-9-y)pentane-l-sulfonamide WO 2011/044394 PCT[US2OIO/051872 182 -4 846-(5-metyloxazo1-2-y1)benz ofd)[ I,3]dioxol-5-ylthio)-9-(3 (I -(methylsulfonyl)pyrrolidin-3-yl)propyl)-9H-purin-6-amine I -(3-(6-amino-S-(6-(5-mcthyloxazol-2-yl)benzo[d[ I ,3jdioxol 5-ylthio)-9H-purin-9-yl)propyl)pyrrolidin-3-one 9-(3-(tert-butylanaino)propyl)-2-fluoro-S-((6-(oxazol-2 ylbheruo[d][ I ,3]dioxol-5-y1)rnethyl)-9H-purin-6-arnine 5-(6-arnino-2l-fluoro-8-((6-(5-mehylffiran-2 yI)benzo~d]i 1 ,3Jdioxol-.5-yl)methyl)-9H-purin-9-yI)pentane-1 sulfonmide 6-(6-arnino-2-fluoro-8-((6-(5-methyifuran-2 vI)benzo [d)[i ,3]dioxoI-5-y1I)methyI)$9H-purin-9-y1)hexaiide 2-fluoro-9-(3-(isopropylamfio)propyl)-8-((6-(5-methylmrn-2 yI)benzo[d]r I,3]dioxoI-5-yI)metyI)-9H-p~irin-6-armine 9-(3-(tert-butylanino)propyl)-2-flnoro-8-((6-(5-methylfuran-2 yI)benzo[d][1I,3]dioxoI-5-y1)metyI)-9H-purin-6-amiine 9-$3-aminopropyl)-2-fluoro-8-((6-(5.niethyifkiran-2 ylI)benzo[d][I ,3]dioxol-$-yi)rnethyl)-9H-purin-6-amine 9-(3-anuinopropy)-2-fluoro-8-((6-(5-methyioxazol-2 yfl~benzo[d][I 3]dioxo1-5-y1)rneLhy1)-9H-purin-6-anine Table 4D1 WO 2011/044394 PCT/US2010/051872 183 No. Name 4D-1 DZ2-395 9-(3-(isopropylamino)propy1)-8-((6-(thiophen-2-yl)benzo[d][ 1,3]dioxol-5-yl)thio)-9H purin-6-amine 4D-2 DZ3-48 2-fluoro-9-(2-(isobutylamino)ethyl)-8-((6-(thiophen-2-yl)benzo[d)[1,3]dioxol-5 __________ylmethy1)-9H-purn-6-amine ___________________ 4D-3 DZ3-58 9-(2-(neopentylamino)ethyl)-8-((6-(thiophen-2-yl)benzo[d][1,3]dioxol-5-yl)thio)-9H purin-6-amine 4D-4 9-(3-(isopropylamino)propyl)-8-((6-(thiophen-3-y)benzo[d] [1,3]dioxol-5-yl)thio)-9H purin-6-amine 4D-5 2-fluoro-9-(2-(isobutylamino)ethyl)-8-((6-(thiophen-3-yl)benzo[d][,I 3]dioxol-5 yl)methvl)-9H-purin-6-anmine 4D-6 9-(2-(neopentylamino)ethyl)-8-((6-(thiophen-3-yl)benzo[d][ 1,3]dioxol-5-yl)thio)-9H purin-6-amine 4D-7 1-(4-(2-(6-amino-S-((6-(thiophen-2-yl)benzo[d][ 1,3]dioxol-5-yl)thio)-9HI-puiin-9 yl)ethyl)piperidin-1 -yl)ethanone 4D-8 4-(2-(6-amino-8-((6-(thiophen-2-yl)benzod][1,3]dioxoL-5-yl)thio)-9H-purin-9 yt)ethyl)piperidine-1 -carbaldehyde 4D-9 1-(4-(2-(6-amino-2-fluoro-8-((6-(thiophen-2-y)benzo[d][ 1,3]dioxol-5-yl)methyl)-9H purin-9-yl)ethyl)piperidin-1-yl)ethanone 4D-10 4-(2-(6-amino-2-fluoro-8-((6-(thiophen-2-yl)benzo[d][1,3]dioxoi-5-yl)methyl)-9H purin-9-yl)ethyl)piperidine-1-carbaldehyde 4D-11 4-(2-(6-amino-8-((6-(thiophen-3-yl)benzo[d][1,3]dioxol-5-yl)thio)-9H-purin-9 yl)ethyl)piperidine-1 -carbaldehyde 4D-12 4-(2-(6-amino-2-fluoro-8-((6-thiophen-3-yl)benzo[d][1,3]dioxol-5-yl)methyl)-9H purin-9-yl)ethyl)piperidine-1 -carbaldehyde 6D-13 4-(2-(6-amino-2-chloro-8-((6-(thiophen-3-yl)benzo[d][1 ,3]dioxol-5-yl)methyl)-9H purin-9-y1)ethyl)piperidine-1 -carbaldehyde 4D-14 N-(2-((2-(6-amino-8-((6-(thiophen-2-yl)benzo[d][ 1,3]dioxol-5-yl)thio)-9H-punrin-9 yl)ethyl)amino)ethyl) sulfamide 4D-15 3-((2-(6-amino-8-((6-(thiophen-2-yl)benzo[d][1,3]dioxol-5-yl)thio)-911-purin-9 _________yl)ethyl)amino)-N-hydroxypropanamide 4D-16 DZ4-21 9-(3-(isopropyiamino)propyl)-8-((6-(thiazoi-2-y)benzo[d][ 1,3]dioxol-5- yl)thio)-9H purin-6-amine 4D-17 DZ4-24 2-fluoro-9-(2-(isobutyamino)ethyl)-8-((6-(thiazol-2-yl)benzo[d][ 1,3]dioxoi-5 yl)mnethyl)-9H-purin-6-amine 4D-18 9-(3-aninopropyl)-8-((6-(thiophen-2-yl)benzo[d][i ,3]dioxol-5-yl)thio)-9H-purin-6 amnine 4D-19 9-(3-(tert-butylamino)propyl)-8-((6-(thiophen-2-yl)benzo[d][ 1,3]dioxol-5-yl)thio)-9H purin-6-amine 4D-20 9-(34tert-butylamino)propyl)-8-((6-(thiazoi-2-y)benzo[d][1,3]dioxol-5-yl)thio)-91 purin-6-amine 4D-21 9-(3-(tert-butylamino)propy)-8-((6-(5-methylthiophen-2-yl)benzo[d] [1,3]dioxol-5 yl)thio)-9H-purin-6-amine 4D-22 9-(3-(tert-butylamino)propyl)-8-((6-(5-methylthiazol-2-yl)benzofd][ 1,3]dioxol-5- WO 2011/044394 PCT[US2OIO/051872 184 41X23 I-( 3 -(t(6-amino--(6-(5-niethylthiazo1.2 yl)beofd [I .

3 ]dioxol-5-vlthio-1-ui 4D-24 I -(6-ainino-8-((6-(5-methylthiophen-2-yl)bepmo[d][1 ,3idoxol-5-yl)thio)-9H-purI n-9

-

_L)-

3 -(isopropyl nmoVpoan2o N ~ 4D-25 l-( 6 -anino-S-((6-(5-methythiaol-2-y)be~o[dJ[1,3jdioxov-Sy)tIio9a-purin-9-y> 4D-26 6 -(6-arnino-8-(6-(5-methylthiophern2-yI)bermo[d)r1 ,3ldioxol-5-ylthio)-9l-purin-9 4D-27 5-(6-amluno-8-(6-(5-methylthiazol-2-ylbenzofdJ[ I,3]dioxoI-5-ylthio)-9H-purin-9 yI~pentane- I -sulfonawfte 4ID-28 9)-(3-(1 -(mrthylsulfony)pvrrolidin-3-ylpropy1)-S-(6-(5-methyltiiiophen-2 y1)benzordj[1I,3]dioxo1-5-yltbio)-.9H-purin-6-amine _______ 4D-29 2

-(

2 -(6-amino-8-(6-(5-methylthiazoV2-yl)tenzo[d][l .3]dioxoi.-5-ylthio)-911.pudin-9 Iylbcthyi)pynoidne-1 -carbaldehyde 4D-.30 1 I-Ioo9(-iouyann~t~l--(-5wehihohn2y~eod[,3ldioxol-I 41Z-31 f8-((6-(5-rethylthiophen.,-2-yi)bezoid)[ !,3]dioxol-5-yl)thio)-9 (2 4D-32 12-fluoro-9-(2-(isobut ,amino)ezhyl)-8-((6-(5-methylthiazob-2-yl)benzo[d[ 1 3ldoxoi-5 ~ y~mehy)~~jpuin6-aniine _______________________ 4D3-33 R-((6-(5-methylthiazoi-2.-ylbenzold)(i,3]dioxo1-5-yl)tlhio)-9-(2-(neopentylaaino)ethy) 911L!P!36arn ne _______ _________ Table 4r No. Name 4E-1 Ptl-WS3 I6-((6-amnino-2-fluoro-9-(3-(isopropylanmino)propyl)-9H-prin-8 ___________ iy1)nithygbenzo~diU ,3]dioxole-5-carbonitrile 4E-2 PU-WS5 16-((6-amino-9-(3-isopropylanmino)propy)-9H-purin-S-yl)thio)benzo(d][1 ,3]dioxole-5 earbonitrile _____________________ IE-3 DZ3-39 2-(6--((6-anmino-9-(3-(isopropylaniino)propyl)-9H-purin-8-yI)thio)benzo[d[1I,3]dioxol-5 * 4E-4 ~ yl)acetouitrile 4E-4 DZ3-40 2-(6-((6-amninc -- fluoro-9-(2-(isobutyfamninofrthyl)-9H-puin-8 ___________ ylrnehyi~enztdi1. ,jdioxoI-5-ylbacetonitrile * 6E-5 r -2(24-nio8(6-caoehlbn 1) ,3]dioxol-5 -yI)zhio)-9H-pnurn-9 ____________yflethyl.)amnino)ethyl)suiffmide ________________ 4F,6 3 -((2 -<6-amo-8-((6-eyanobenzo[di 1 ,3]diOXol-5 -yl)thio)-9H-pirin-9-yl)ethyl) mino)-N 4E4 Ii droxvpropaand------------------------ 4E 6-((6-aino-2-choro-9-(3-(isopopylanino)propy)-9H-pitrn-8 yD-ehybms!WI& dAi1 ,3ldioxole-5-carbonitLre Table 4F No. Name WO 2011/044394 PCT[US2OIO/051872 185 9-4}isproyiaino)propyU)-8-(6-Cpyridin-yl~benzo[d][ I ,3]ixl Table 5A No. Name 5A-1 PU-RK11 S-((7-iodo-2.3-dihvdrobenzo[b][1 ,4]dioxin-6-yi)thio)-9-(3 5A-2PU-H1658-((7-iodo-2,3-dihydrobenzo[J[ 1 ,4ldioxin-6-yl)thio)-9 ____._.........._ (2-(isobutylanmino)ethyl)-9H-purin-6-amine PU -H T 175 8-((7-iodo-2,3-dihydxobenw[b][ 1,4]dioxin-6-y1)thio)-9 (2-(neopentyiamino)ethyfl-911-ptirin-6-aniine PU-RK12 9-(3-(TH-irnidazol-1 -yl)propyl)-8-((7-iodc-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9H-purin-6-am~ine PU-0Z3-73 2-tlhoro-8-(( ,7-iodo-2,3-dihiydrobenzc~b](i ,4]dioxin-6 yI)nietyi)-9-(2-(isobutylaniino)ethyl)-9H-purin-6-a.mine FU-DZ4-4 9-(2-(tert-butylarmino)ethiyl)-2-fluoro-8-((7-iodo-2, dihydrobenzo[b]L I,4)dlioxin-6-yl)methyl)-9H-purin-6 amnine 9-(3-aniinopropyl)-8-((7-iodo-2,3 dihydrobcnzo~bi[ I,4]dioxin-6-yI)thio)-9H-purin-6-amine 9-(2-aiminoethy1)-8-((7-iodo-2,3 dihydrobenzo[b][1.4]dioxin-6&yl)thio)-9H-puin-6-amine 9-(3-(tet-buylarnino)propyl)-8-((1-iodo-2 3 dihydroberio[bJ[ I,4]doxin-6-yl)thio)-9H-pnrin-6-arnine I -(6-aino-a-((7-iodo-2,3-dihydrobenzoib]rl ,4]dioxini 6-yI)tio)-9H-piirin-9-yI)-3-(isopropyi.arnino)propan-2-ol 5-(6-amiino-g-(7-iodo-2,3-dihydrobenzofb)[i ,4]dioxin-6 ylthio)-91--purin-9-yl)pentan-1I -sulfonaide WO 2011/044394 PCT[US2OIO/051872 186 dihydrobeno[b][1 ,4)dioxin-6-ylthio)-9ll-purin-9 yl)propyl)pynolidn-3 -ne 6-(6-amizio8-(7-iodo-2,3-diydro.c.zo[b]f I,4]d.ioxirx-6 N ylthio)-91{-purin-9-yI)bexaaide 9-(3-(tert-hutylarmno)propyl)-2-fluloro-S-((7-iod6-2,3- I dihydrobenzob]E1 ,4]dioxin-6-yl)methyl)-9H-pmin-6 amine dihydroben~o[b][ 1,4]dioxiiv6-ylthio}-911-pntrin-9 yl)hutyl)pyxrolidin- 1 wl)ethaome 2-fluoro-8-((7-iodo-2,3-dhydrohenzo[b][1,4]dioxin-6 yl)rrethyl)-9-(3-(isopropylaniino)propyl)-9Hi-purin-6 amine i-(3-(6-arnino-2-fluoro-8-((7-iodo-2,3 dihydrobenzo[b][1.,4]dioxin-6-yl)methyl)-9H-purin-9 yl)propyl)pyrolidin-3-one 6-(6-amino--fluoro-8-((7-iodo-2,3 dihydrobonzotbj(1,4]dioxin-6-yI)methyl)-YH-puin-9 yl)hexananide 546-amino-2-fluorw8g-((7-iodo-2,3 dihydrobenzo[h][I,4]doxin-6-yl)methyl)-9W-purin-9 yI~pentane-1 -sulfonamide Table 5B 5B-1 rHJPIS Nm R-((7-(finan-2-yl)-2,3-dihydrobenzo[bi1[.4]clioxin-6-yI)thio)-9-(3-(isopropylamino)prepyb-91 ___________pur~h-6-a mine 5B-2 1 (3-(6-arino4{-7-(oxzol-2-yl)-2,,3-dhydrobenzo*b[ t,4jdioxin-6-ylthio)-91-urn9 _________L yojopy lohdn-3-one ________ 9(-iprplinpop)--{-5rthfla-2-yJ)23:-diydobno b[I4ion WO 2011/044394 PCT[US2OIO/051872 187 ___________yl)thio)-9H-purn-6-armne 5B-4 6-(6-amino-2-fluoro8-((7-(5-ffetliyloxazol-2-yI)-2,3-dihydrobeao[,] [1.4]dioxin-6-yl)methyl) __________9H-purin-9-yl)hexanamide 5B3-5 6-(&5amaino-8-(7-(5-rnethyloxazol-2-yI)-2,3-diliydrobenzo[b][1,4]dioxin-6-y'thio)-91I-purin-9 ___________yl~hexanamide NS5-6 2-flaoro-R-((745-methylftran-2-yl)-2,3-dihydrobenzo[b][ 1,4]dioxin-6-vl)methyl)-9-(2-(b (rnethyisuiftiryl)piperidin-3-yl)cthy)-911-puirin-6-a-mne 5B-7 jTT-VI-SSA I2-fluoro-8-((7-(faan-2-yI)-2,3-dihydrobenzo[bJ[l 4]dioxin-6-yl)rnethyl)-9-(2 5B-8 I -(3-(2-(6-arnino-2-fl'uoro-8-((7-(5-rnethyifi-2-yI)-2.3-dihydrobenzohi[1,4]dioxim6 I y)mthyl)-9H-pnrin-9-vl)ethyl)piperidin-1-ybethanone 5B-9 8-(7-(5-methylfurarn2-yl)-2,3-dihydrohenzob[1,4]dioxin.-6-ylthiio)-9-Q -(1 (methylsulfo-nyl~pipEridini-3--yI)ethyf-9H-f,rnn-6-amine SB-10 12-iluoro-9-(2-(isobutylarnino)ethyl)-8-((7-(5-methylffixan-2-yl)-2,3 _________ Idihydrobenzol bll A,4dioin--yl)methyl)-9H-purn-6-amfine 5B-11 I I-(3-(6-amnino-2-fluoro-&-((7-(5-mcthyloxazob-2-yl)-2,3-dh ydrobez[bl[ t,4jdioxin-6 ________ limthyl)-9H-prin-9-yl)propyl)pynolidin-3(ne 5B3-12 18-((7-(5-(atninomethvl)furan-2-yl)-2,3-dihydrobenw[b][I 4idioxin-6-yI)methyl)-2-fluoro-9-Q2 _______(isobutylaiino)thyl) -911-puin-6- aiine - 5B-13 I8-(7-(5-methyloxazoi-2-yl)-2,3-dihydr-obeno[b][1,4]dioxin-6-ythio)-9-(2 ___________(neopentvlan~inio)ediyl)-9H-pnrin-6-amine 5B-14 - -(3-(2-(6-anino-(7-(5-nethylforan-yl)-2,3-dihydrobenzo[b][ I ,4]dioxin-6-ylthio)-9H .______ . purin-9-2 ehy iedi- vjehnn _____________________ SB-is 8-((7-(5-mnethylfiirn-2-yl)-2,3Wdihydrobenzo[b][I ,4]d.ioxim-6-yl)thio)-9-(2 5B-16 18-((7-f(isxazo14-y)-23-diydrobrio[b[ 1,4]dioxin-6-ylfthi)-9-(2-(ncopentylaniino)ethy) __________9H-purin-6-milne 5B-17 -(3-(2-(6-am~ino-8-(.7-(5-methyloxazol-2-yI)-2,3-dihydrobeazo[bj[ I.4]dioxiin-6-ykchio)-9Hi ___________ urin-9-yl)ethy1~piperidin-I -vl)ethano,,e SB-IS 8-(7-,-(5-(amhxnomethy1)fiwa-2-y1)-2,3-diiydrobe~o[b][I ,4]dioxin-6-yl)thio)-9-(2 5849 (ncpen~~moyth -911-purin-6-amine IB1 5-(6-ant.qo-8-(7-(5-rnethylfhraa-2-yl)-2,3-dihydrohenzo~b[ ,4]dioxin-6-ylthio)-9H-purin-9 ___________yl)pentatne-1-suxlfonarnide 5B-20 5-(6-amino-S-(7-(5-rnethyloxazo]-2-yI)-I,3-dihydrobero[b]1,4]dioxin-6-ylhio)-91-purin-9- ' 5B3-21 1 -(4-(2-(6-anrio-2-chloro-8-((7-(furan-2-yl)-213-dihydrobenzo[b][1,4]dioxin-6-yl)rnethyi)-9H ptuiti-9-yI)e hi)piperidin-1-yI)ethanone 5B-22 1 1-(4-(2-(6-ainjo-S-((7-(5-metiylfiiran-2-y)-2,3 -diliydrobenzo~t][1,4]dioxin-6-vi)thiio)-9H _________ purin-9-yl)ethvl)pindin-1-yl)ethanone 5B-3 -4-2-(6-amno-2-fluoro-8}((7-(5-methylfi~an-2-yl)-2,3-dihydrobenzo[b][ ,4]dioxin-6 m yImehl) -purin-9-y)ehy1)Jijperidin-1 -yI~ethanone SB-24 I -(3-(6-arnino-8-(7-(5-methylfhran-2-yl>-2,3-dihydrobenzo[iI ,]dioxin-6-ylthio)-9H-puhrn-9 58-25 9-(3-(tert-hutylamijno)oropyl)-8-(7-(5-rnetbylfuran-2-yl)-2,3-dihydrobezob]1,4]dioxin _________I ylthiol-911-purirn6-amne 5B-26 2-chioro-S-((7-(5-rnethylfura-2.-yI)-2,3-dihydrobenzo[b][1,4]dioxin-6&yI)nethyl)-9-Ql-(i __________ jreth Isnlfonyfprolidin-3-yl)ethyl)-911-purin-6-amine 5B-27 1-(3-(2-(6-aino-8-(7-(5-(aminonmethyl)fiixarn2-yi)-2,3-dihydrohenzo~b][ I,4]dioxin-6-yltIhio) __________9H-purin-9-y)tl)piperidin-1 -yl)ethanone WO 2011/044394 PCT[US2OIO/051872 188 513-28 1 -(3-(24(6-arnino-8-(7-(5-aniinomethy)furan-2-y)-2,3-dihydrobno[b][1 ,4]dioxin-6 __________yI~methyl)-2-fluoro-911-pmain-9-yI)etliDpieii--lehnn SB-29 5-(6-arnino-2-fluoro-8-((7-(5-methvlfuran-2-yl)-2,3-dihydobezoib][I,4]dioxin-6-y-i)methlyl)-I ___________9H-pumi-9-yI)penta..e-1 -su1Conarnide 51B-30 4-(2-(6-amino-2-ehioro4-((7-(soxazo-4-y1)-2,3-diliydrobeno~b][ i,4dioxin-6&y1)meihyl)-9[b _______ purini-9-yi)ethyl)piperidiiie-lcarbaldehivde 1 S-31 N-(24(2-(6-airino-8-(,7-(fiirah-2-yl)-2,3-dihydrobenzo[b][1 ,4]dioxin-& y)tio)-9--purin-9 1______ yletl1)amino'ethyl)sulfam~ide SB3-32 3-((2-(6-arnno-S-((Y7-(ltran-2 -yl)-2,3 -dihydoezoblE[ 1,4]dioxin-6-yl)thio)-911-purin-9 5B33 -yl)ethyl)arnino)-N-hydroxypropaanide ____________________ purin-6-am'ne 5B-34 HJP20 9-(3-(isopropylainno)propyI)-8-((7(oxazoi-2yl)-,3.dihydrobenzo[b[ 1,4]dioxin-6-yI)thi o) 9H--pmin-6-airnine 5B-35 9-{3-amiropropyl)-2-fluoro-8-((7-(5-mcthylfbnn-2-yl)-23-dihydrobenz[b][1,4dioxin-6 ___________ )."'ethyl)-9H-pwin-6-arnne 5B-36 9-(3-anTrnopropyl)-S-(7-(5-methylfura-2-yl)-2,3-dihydrobezo[l[1 ,4]dioxim-6-ylthio)-9fl 5B-37 9-(3-(tent-buylmi'no)propyl)--(7-(5-methylfuxan-2-y1)-2,3-dihydrobenz[b[1I,4]di;oxin-6 ________yltthio)-9H-pnrini-6-amine SB-38 9-(3-amiinoprop~yfl-8-((7-(oxazol-2-yl)-2.3-dihydroheiio[b][i ,4)dioxin-6-vl)thio)-9Hf-pvrin-6 amine 5B3-39 9-(3-(tert-butylamino)propyl)-S-((7-(oxazol-2-yl)-2,3-dihydrcbenzo[b[ I,4]dioxin-6-yl)ihio) 914-purin-6-amine _____ ___________________________ 511-40 9-(3-Qtert-'utylan- in)propyl)-8-((7-(5-methyioxazolb2-yI)-2,3-dihydrobezob[1 ,4]dioxin-6 _________ *yl)ihio)-9H-pur-6-amine 5B-41 1 -(4-(2-(6-arniio-8-((7-(5-methyloxazol-2-yl)-2,3-dihydrobenzo[b [ I ,4jdioxin-6-yi)thio)-9H __________ ID'rin-9-yI)ethvl)pi peridin-1I-yl~ethnofle 51342 -((45rnehylxaol-2-y)-2,3-cdi1ydroibenzo[b]l[ 1,4]dioxin-6-yI)thio)-9-(2 -(I1 -- (mthylulfonylpipedi-3-yjLh)etw-911-purin-6-anmine 5B-43 1-(6-aino-8-((7-(5-methylfra-2-yI)-2,3-dihydrobcnzo[h][1L4jdioxin-6-v)thio)-9H-purin-9 __________yl)-3-(isopropylamiino)propan-2-ol 51B44 1-(6-arnino-8-Q(7-(5-niethyloxazo-2-yl)-2,3-diiyrobenzo[b[1 4]dioxiri-6-yl)thio)-9H-purin-9 ___________yI)-3-(isopropylanin)propap.-2-ol 5B-45 6-(6-amino-2-fluoro-8-(7-(5-methylman-2-y)-2,3-dihydrobenzo[][,4dioxin-6-y)methyl) ___________________________________2put!:n:y9he, tayme 1 5B3-46 N-(3-(6-ami~no-8-((7-(5-methyloxazol-2.yl)-2,3-dihydrobenzo[][1 ,4jdioxin-6-yl)thio)-9H purin-y1K)propy1)methanesulfonanmid~e SH-41 i-(2-(4.-(6-arino-8-(7-(5-metltyloxazol-2-yl)-2,3-dihydrobenzorb]rl ,4)dioxin-6-yltbio)-9H I __________puin-9-yllbutyl)pyrrolidin-I -yl)ethanone SB3-48 - f-(3-aminopropyI)-2-fluoro-8-((7-(5-methyloxazoI-2-yI)-2,3-dihydrobonzo[bJ[1',4]dioxin-6 ____________~YE y[)thyb)-9H-2urin-6-amne ___-__ 5B3-49 2-fluoro-9-(3-(isopropylamino)propyl)-8-((7-(oxazo--yl)-2,3-dihydoberto[bI1[1,4ldioxin-6 ____________ yl)rnethvl)4-pni-tai S B-50 2-fluoro-9-(3-(isopropylarniino)propyi)-8-((7-(5-niethyloxazol-2-yl)-2,3 ________I dihydrobenzorb]rI,4]dioxin-6-yI)nmetbyl)-9H-purin-6-amine 513B-51 19-(3-(tert-butylamnino)propyI)-2-fiuoro-8- (7-(oxazo-2-yi)-2,3-dihydrobizo[bE i ,4]dioxin-6- WO 2011/044394 PCT[US2OIO/051872 189 58-529-(3-(tert-butylamnino)propyl)-2-fluoro-8-(Q-(5-rnethyexazol-2-y)-2,3 ______....... dihydrobeoobJ(,ldo -6-yl)mcthyl)-9H-pudin-6-anine 5B-53 I6-(6-amnino-2-flnoro-S-((7-(5--methyloxazol-2-y1)-2,3-dihydrobenzofl][1 ,4]dioxin-6-yl)methyl) 9I1-punin-9l-ylhexanarnidc 513-54 5-(6-amrno-2-ficoro-8-((7-(5-nethytoxazo1-2-yfl-2,3-dihydrobezoh] L,4ldioxin-6-yI)methyl) N 9H-purin-9-yI)pentne-1-sulfonamide 5B-55 -(3-(6-amino-2-flnoro-S-((7-(5-methyloxazo1-2-yl)-2-,3-dibydrobenzo[b][ I,4]diexin-6 __________ v)miethyl)-9H-pud.n-9-yi)propy1)pyrr.olidin-3-one 51-5 1-(3-{ami-2-fl.oro-8-((7-(oxazoal-2-yI)-2,3-diliydrobetxorblr I,4]dioxi-6-yI)rnehyl)-9H Table 5C No. 1 Nam 5C-i 9i(3-(isopropylarnino)propyi.)-S-((7-(thiophcen-2-ylfr2,3-dihydrobero[h][1 ,4jdioxin-6 ____________yl~tio)-911-purin-6-arniine SC-2 I2-fhioro-9-(2-(isohvtylamrino)ethyl)-S-((7-(Qhioplien-2-yI)-2,3 _________ I ihydrooenzolb][1 ,4ldioxin-6-yl)methyl)-9H-pmiii-&aminc 5C-3 9-(2-(neopentylarino)ethyl)-8-((7-(thiophcn-2-yl)-2,3-dihydobenzo[b][1,4]diox,-6 __________ IyI)tliio)-9H-purin-6-arnine SC-4 9-{3-(isoprpylaimino)propyl)-8-((7-(thiophen-3-yl)-2,3-dihydrobcnzo[b][1,4dioxin-6 5C-S 2-fluoro-9-42-(isobntylamlino)etl iyfl)-84(7-(thiophien-3-yl)-2,3 ___________dihydrobenzoyblrI,4ldioxin-6-yflmethyl)-911-pur-6-amine 5C-6 9-%2(neopentlamiio)ethyl)-8-((7-(thiophen-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6 ____________yi)thio)-9H-purin-6-amine 5C-7 1pu4in-1-lathipcddin(-(t -vlhetnone______________________________________io)-9H SC-8 4-(2-(6-amrino-8-((7-(thiopheon-2-yI)-2,3-dihydrobenzo~b][1 ,4]dioxin-6-yl)thlio)-9H- I - purin-9-yl)ethyl)piL'eridino-1-carbaIdehyde 5C-9? I-(4-(2-(6-arnno-4,luoro-S-((7-(thiophen-2-yl)-2,3-dihydrobenzojb][1I,4]dioxin-6 yI)methyl)-9H-prin-9-y)ethyllpipeidin-1 -yI)ezhanone 5C-11 4-(2-(6-amino-8-((1-(thiophien-3-yl),-2,3-dihydrobenmo~b][1 ,4]dioxin-6&yl)tio)-9 ________ p yui--lehlDpedidine- 1-carbaldehyde 5C-13 4-(2- 6-amino-2-chloro-8-((7-(thiophen-V yI>-2,3-dihydrohenzo[b]il1,4]dioxin-6 yi)methyl)-9H-parin-9-yI)ethiyl)pipedidine-1-earbaldehyde 5C-14 i -2((2-(6-amino-S-(C7-(thiophen-2-yl)-2.3-diliydrobenzo[b][1,4]dioxin-6-yl)thioV9H purin-9-vi)ethiyl)aniino)ethyl)sulfamiide SC-15 3-((2-(6-arnino-8-((7-(thiophen-2-yl)-2,3-dihydrobenzx[b][I ,4]dioxin-6-yI)thio)-9H1 - puxin-9-yl)ethyl)aino)-N-hy oxypropaamide SC.] 6 9-(3-animnopropyl)-8-((7-(thiophen,-2-yl%2,3-dihydsohei~o[b][1I,4]dioxin-6 yI)&hio)-911-punn-6-amine 5C-17 9-(3-(isonropylamiino)propyl)-8-4(7-(5-methylthiophen-2-yl)-2,3 dihydrob eno[b][1,4]dioxin-6-yI)th.io)-9H-purin-6-am,. scAis ]-(6-arnino-8-((7-(5-methylthiophen-2-yI)-2,3-dihydrobenzo~b][ I,4idioxin-6-yl)thio) _____ 9.H-putin-9-yl)-3-(isopropylanino)propan-2-o ____ ________ 5C-I.9 1-f2-(3-(6-anuino-8-(7-(5-methykthiazol-2-yl)-2,3-dihydrobenzoflrl :4idioxin-6-ylthio) .9H-put-in-9-yl)propyl)pvrrolidin-l -yl)ethanone WO 2011/044394 PCT[US2OIO/051872 190 5C-20 9-(2-alnmtyliloylp.eiino-S-((7-(5-methy45-iethythiazo!--1-,.iyoenfj 1 do-y)thio9H N 5C-22 9 -(S-(tert-bItyIanio)PropyI)-8-((-(thiao-2yI>2,34dihydrobenzo[ I,4]dioxin-6 J y.!th o -91-pain-6-amine 5C-23 9

(

3 (ten tlwmrno)propy)--(g-(5-nethytiophen2-y)2.3 Table 5D No. __________Name 5D-1 8 -((7-(i1--pyrazoi-4-yl)-2,3-dihydrobnzo~bl[l 4ldioxin-6-y1)thio)-9-(3 .. Qs2E2RopyAninOprOpyfl)9H-purin-6-anIne 5D-2 1HJP19 I 8-((l-(1l{-pyrazol-3-yl)-2,3-diliydrobenzo[b][ I,43dioxin-6-yl)thio)-9-(3 I (__isop~ropylaino)propyfl-9H-puriii-6-anmine _________ SD-3 I8-G(7-(1H-vyrazol-4-yT)-2,3-dihydrnbenzofb][ I 43dioxin-6-yI)metliyl)-2-fluoro-9-(2 fjou) n~t j 5D-4 TI-T-M5A I -((7-(1H-pyTazol-3-yI)-2,3-dihydrotenzo~b][ I 4]dioxin-6-y!)methyl)-2-Thioro-9-(2 __________(isobutyLfminto jtlylH-pwrin-6-anne ________________ 5D-5 l-(3-(X-(7-(1H-pyrazoI-3-yI)-2,3-dihydrobimobj I,4]dioxir-6-ylthio)-6-armn FSD-6 '8-((7-(1H-pyrazl-3-yl)-2,3-dihydrobenzo[b][1 ,4]dioxini-6-ylthio)-9<(2 I(neopenp1amino)eLiy)-9H-purin-6-ane 5D-7 I -4-(2-(8-((7,-(1H-pynzo-3-yI)-2,3-dihydrobcnzo[b][1 ,43dioxin-6-yl)zhio)-6-arni-9H ___________prin-9-yI)e Iy)niperidin-1-yI~ethanone SD-8 S ((7-(1H4-pyrs~ol-3-yl)-2,3-dilaydrobeno[b][1,4]dioxiru6-yI)rnethy!)-9-{2-anrinc'etliyl) 2-flioro-9-punn-6-amnc 5D-9 1-(4-(2-(8-((7-(iH-pyrazol-3-yI)-2,3-dihydroberiolt][1,4]ioaxin-6-yI)methyl)-6-ainino-I 2-fhioro-9H-purin-9-ylethyflpiperidin-l -yl)ethanone 5D-10 1 b(3-(2-(S-((7-(1 H-pyraol-3-yl)-2,3dihydrobenzoibJ[I ,4]dioxin-6y!)meth y1l)-arino. 5D-1I S-((7-( IH-pyrazol-3-yl)-2,3-dihydrobenzo[b] [ l,4]dioxin-6-y)methyl)-2-flu oro-9-(2-(1 _____-I(mettalfonyl~pipet*din-3-yjj4hfl-9H-pudin-6-anine S-l fluorop-9H-prlpyin-9-3 ne ylyxoii-3o e SD13f 8-(7-(1H-pyrazol-3-yI)-2,3-dihydrobenzob][1,4Jdioxin-6-ylthio)-9-(241 l ____________ ,ysulfony)iperidin-3-y1)ethyl)-9U-purin-6-amine _____ 5D4-14 N-(2-((2-(S-((7 -(IH-pyazol-3-yl}-2,3-dihydrobenzo~b][1 ,4]dioxin-6-yI)thio)-6-amino ___________ 9Hwpur~j4~ I amin)ethvl sulfaride ____ SD-15 3,-((2-(S-((7-(1II-pyrzo-3-l)-2,34ilydobezo[b]EI ,43dioxina-6-yI)tio)-6-amiino-9H 5W16 vtn9- 1 ethybaniro)-N-hydroxypropanairide -TD:F6S8((7-(1H-iinidazol-4-yO)-2,3-dihydrobenzo[b][ 1,4jdioxin-6-y)tlaio)-9-(3 __________J(isopropylamino)pzopyD-9H-purin-6-atnine 5D-17 8-{(7-(1 H-pyrazoI-3-yl)- ,3-dihydrobenzo[b1[1 ,4]dioxiiv6-y1)thio)-9-(3-aminopropyl) _________ 1911- uzin-6-amnne SD-18 8-((7-(l H-nyrazc-3-yQ)-2,3-dihydrobenzofhff I,4]4ioxin-6-yl)tbio)-9-(3-(tert butylarnino)propyl)-9H-purin-6-anmine WO 2011/044394 PCT[US2OIO/051872 5D-19 8-((7-(IH-pyrazo-3-yl)-2,3-dihydrobenzob][1 ,4]dioxin-6-yi)xrethvl)-9-(3-(tert butylaniino)propy)-2-fuor-91E r--mne_______________ 5D-20 9-(3-(isopropylainino)propyl)-8-((7(5-methyl- IWpyrazo-3-y}-2,3 5D-20 dihydrotenzobll 1.4ldioxin-6-y1)thio)-911-ptuin-6-arnine 5D-21 8-((7-(5-methyl-I H-pyrazol-3-yl)-2,3-diiydrobemo[b]l[ I ,4]dioxi-6-yi)thio)-9-(2 (neopentylarmino)ethvl)-9H-puyin-6-amine 5L)42 9-(3-(tcrt-tuylarino)propyl)-2-fluoro-8-((7-(5-rnethyiH-pyrazol-3-yl)-2,3 dihydrobenzorbjr i,4]dioxini-6-yl)methv)-9H-purin-6-amine 5D-23 I -(8-((7-(iIL-pyraol-3-yI)-2,3-dihydrobenzorb] [i,4]dioxin-6-y)thio)-6-aiino-9Hv SD-U I-(X-((7-(IH-pyrazoi-3-yi )-2,3.-dihydtobeno[b][I ,4]dioxin-6-yli)nethyl)-6-arnino-2 ___________ luoro-9H-purin-9-yI)-3-hter-butylainino)propan-2-oI 5D-25 5-(S-((7-(1H-pytazol-3-y)-2,3-dihydrobno[b][1,4]dioxin-6-yI)rncthyl)-6-arnr-2 ___________ fhoro-SH-prin-9- yI)pentaiie-l.-ulfenaride SD-26 6-(84(7-(1H-pyrazo-3-y)-2,3-dihydobezo[][1,4]dicxit-6-y)merliyl)-6-an-no-2 _________ fuoro-9H-puin-9-yI)hexanaide 5D-27 5-(8-(741IH-pyrazob3-yI)-2,3-dihydrohenzo[b] [1,4]dioxin-6-ylthio)-6-ani'no-9H-pvrin ____________9-ylbpentaie-1 -sulfonamnide SD-28 6-(S-(7-(1f--pyzol-3-yl)-2,3-dihydrohenzo[b] [1 ,4)dioxin-6-ylthio)-6-arnino-9H-purin I9-vl)hexanarnide Table 5E No. Name 5E-1 S-((7-ethyny1-2,3-dihydrobenzo[b]J 1,4]dioxin-6-yl)thio)-9-(3 - (isopropvlarmino)propyI)-9H-purin-6-amirne 5E-2 3-(3-(6-aino-8-(7-ethynyl-2 .3-dihydrobeno[][1,44ioxdn-6-ylthio)-9I1 _________ urin-9-yl)prop yyolidinc-l-carbaldehy4e 5E-3 S-((7-ethynyl-2,3-dihydrobenzofb)( I ,4]dioxin-6-yI)znethiyl)-2-fluoro-9-(2 - isohutylao~ino)eth D)-91{prn--amine SEA4 9-(2-aninoethyi)-8-(7-ethynyi-2,3-diliydrotewnofb][ 1,4]dioxin-6-yithio)-9H-pur-6 5E-5 84((7-ethyi~v-2 ,3-dihydrobenzo[b][1I,4]dioxio-6-yl)thioi-9-(2 S(neop-ntylarnino)ethyl)-911-purim-6-amine i SE-6 9-(2-aominoethyi)-8-((7-ethvny!-2,-dihydrobeonzob][1,4Jpoxin-6-y)tho)-9H1-pun 6-amine .mn 5E-7 1-(3-(2-(6-anilno-8-(7-ethynyl-2,3-dihydrobenzo[h][1 Aldioxin-6-ylthio)-9}{-purin-9 __________yl)ethyl)piperidin-1-yl)ethlanonec 1-(3(-( 6-nxi-S,-((7-ethynvl-2],-diobnzobI1,]ios( -- ylmty) ______ (fhluoo9u in9)epiperidin- i thl-vHpIipethanone 5E-9i 3-(2(-atynin-8,-(-hynyl-23-dbydobno(] I 4]dioxin-6-yI)=niethyl)uo.-2-fboro - Im9Hpurn-9yI th)ppeidi-1-cahldehyder,6amn 5E-l0 1-(3-(6-mino--((-ethynyl-2,3-diyrobeob,4]dioxin-6-ylnethyl)-2-o _________9H-omin-9-yI)propyl)pyrolidin-3-une SE- 13 6-(6-amiino-8-((7-cthyrtyi-2,3-dihiydrobenzob[ t,4]dioxin-6-yi)mcthyl)-2-flur- __________ ptuin-9-yl)hexan ide WO 2011/044394 PCT[US2OIO/051872 192 5E-14 N-(2-((2-(6-amino,-8-((7-ethynyI-2,3-dihydrobenzo[b)[1,4]dioxin-6-vfti)-H ___________ purin-9-yI)ethyl)amino)etlwl)sulfainide 5E-15 3-((2-(6-amino-S-(( -ethyiyI-2,3Aiiydrobenzo[b][1,4]dioxin-6-yl)tbio)-9H-purin-9 SE-16 9-(3-arninopropyl)-8-((7-ethynyl-2,3-dihydrobcnzo[b[1 ,4]dioxin-6-y)thio)-91 purin-6-anmine 5E-17 6-(6-atnino-8-(7-ethynyl-2,3-dihydrobenzo[b] P ,4]dioxin-6&ylthio)-9H-purin-9 _________yflhexanamide ________________________ SE-18 5-(6-aniino-S4(7-othynyb-2,3-dlihydxobeino[b][ 1 4]dioxin-6-yithio)-9H-purin-9 __________yl)pentane-1-sulfonamide 5E-1 9 1-(6-amino-8-((7-etvNmyi-2.3-dihvdrobenzo[b][i,4]dioxin-6-y)mothyl)-2-fluoo-9H _________puzn-?-yl)-3-(tert-butamino)propa-2-o E-20 1-(6-amino-8-((7-cthynyl-2,3-dihydrobcnzo[b][1,4]dioxin-6-yl)thio)-9H-puirin-9-yl) I _________ 34isopropyllanino prpan-2-ol 5E-21 1 -6amino-S-((7eth xy-2,3-dihydrobenzo[b][1,4]dioxin-6-y!)methy)-2-fiuoo-9H ________ punin-9-yi)pentare-1-suifonamide 5E-22 I8-(fT-ethynyl-2,$dilbydrobenzo[b][i 4]dioxin-6-y1)mcthyI)-2-flhoro-9-(3 _________ (isopropylamino)propy)-9H-purini-6-amine 5E-23 9-(3-(tert-butvlamrino)propyl)-S-((7-etbynyl-2,3-dihydrobevo~h][ 1,4]dioxin-6 SE-24 9-(3-amnnopropyl) 8-((7-ethynyl-2,3-dihydrobero~bE1,4]dioxin-6-yl)m.ethiyl)-2 __________fluoro-MIIpufin-6-amine 5E-25 9-(3-(tert,-butylamino)propyl)-8-(7-ethynyl-2,3-dhydrobenzo[b][1 ,4]dioxin-6-ylthio) _________i 9H-pmrn-6-amnne 5E-26 8-7-etliynyl-2,3-dihydrobenzo[b][1 ,4]ldioxin-6-ylthio)-9-(2-(1-methylpiperidin-2 5E-27 i8-{7-etiynyl-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthi}-9-(2-(1 -methylpipedidin-3 __________yI)ethl~y)-9H-Lurin-6-ammie 5E-28 8-((7 thynyi-2,3-dihydmbeo~b1,4]dioxin-yI)mthy)-2-floix'9-(2-( _________ neth~ylpiperidin-2-vl)ethyl)-9H-purin-6-armine SE-f 8-(7~thy~yl2,3dihydrobenzo[b1i,4]dioxin-6-y1)methyi)-2Aflhoro-94 2-(1 ________ Imetiypipddn--yl)ethyl)-9H-pu -6-amine Table 5F No. -Name SF-I. 7-((6-atmino-9-(3-(isopropylamino)nropy1)-9H-purt-8-yI)thio)-2,3 -dihydrotezorbE1,4]dioxine-6-carbonitdlc 5F2 7-((6-amino-9-(3-(isopropylamino)propyi)-9H-purin-8-yl)thio)-2,3 dihydrobeoofb][ I ,4]dioxine-6-carbonitrile 5F-3 7-((6-amino- -fkoro-9-(2-(isobrylanino)ethyl)-9H-purin-8-y)nnh.yl)-2,3 ________dihydrobeno[1,Jji Ajdioxine-6-carbonitrile I 5F-4 I 7-((6,-arnino-2-fluoro-9-(2-(isobutyamiDo)etbyl)-9H-pin--y)methvI)-2,3 Idihydrobenzo[b][1 ,4]dioxinc-6-cabonitrile 5F-5 7-((6-aminDo-9-(2-(noopentylawrino)ethyl)-9H-purin-8-y)thio)-2,3 _______ Idihydrobenzorh][i,4]dioxine-6-carbonitrile 5F-6 7-(6-no9-(-(nepeny1~no)ehy)-9H-pin--l)tho-2,3 _______ diydroeoz~bl I ,ldixin-6-caronilxile SF-7 I 2-(7-((6-armino-2-fluioro-9-(2-(isobutylamino)ethyl)-9H-pudin-8-y)metiyl)-2,3 * _______ Idihvdrobenzo[bl[ I ,4jdioxin-64yllacetonitdle WO 2011/044394 PCT[US2OIO/051872 193 ' F8N-(2-((2-(6-arnino-8-((7-(cyanonmethyI)-2,3-dihydrobenzo[b] [1 ,4]dioxin-6-yl)thio) sr9l-purin-9-ylethyI)arinoty)sulfamide SF9 3-((2-(6-ami~no-8-((7-(cyanometwl)-2,3-dihydrobenzo[b[1I,4]dioxin-6-yI)thio)-9H-I -..- puriD-9-ybethvi )amino)-N-liydroxypropanamidc 510 7-((6-arnino-2-chloro-9-{2-(isobutylamino)cthyl-9H-purin-8-yl)nethyl-2,3 ________dibvdpobenzo~b][ I 4]dioxine-6-carbonitrile WO 2011/044394 PCT[US2OIO/051872 194 Table 5G No. [_________Na me 56-1 S-((7-(azihidin- 1-yl)-2,3-dihydroberao[b][ I.,4jdioxin-6-yl)t hio)-9-(2 1 (neopentylarno)ethyl)-91-Tpurin-6-amine 50-2 I8-((7-(azefidin-1-vl)-2,3-dihydrohenzo[b][1,4]dioxirn6-vl)thio)-9-(2 * isohu~ylamino)ethy)-9H-purin-6-a~nine 5G-3 I[9-(2-(isobutyamnen)ethqyl)-8-((7-(prroidin- i-yi)-2,3-dihydxobcnzo[b][ I,4]jdioxin-6 ________yl)thio)-9H-purin-6-amine ________________ 5G-4 [8-((7-aziridin-1-y)-2,3-dihydroberz[b)( I,4]dioxin-6-yI)rnetliyl)-2-iluoro-9-(2 ______ (neope ntylarnio~ethy -91l-purin-6-amnie 50-5 8-((-(aoidi-1- 2,3Aiiydrobezo[h][1,4]dioxi-6-yl)mthyl)-2-fluoo-9-(2 ________(isobutvlanmino)eth yl)-91-I-prin-6-amine G0-6 L 2-fluoro-9-(2-(isobiutylaniino)ethyl)-8-((7-(pyrrolidin- 1 t 1

)-

2

.

3 _______ di ydoboenzotlbI ,4jdioxin-&-yl)methyl)-9TH-purin-6-arn ne 5C-7 7-chloo9-(2-(isobutylanmino)etiyl)-8-((1-(pyrrolidin-1 -yl)- 2

,

3 ________t dhydrb Enzbi[1,4]dioxir-6-vl)metliyl)-9H-purin-6-an!ne 1CS I-(4-(2-(6-arnino-8-((Q-(aziridin-1 -yl)-2,3-dihydrobeno[b]EI,4ldioxin-6-yi)thio)-9H _______ Ipnrin-9-vl)ethyl)piperidin-1 -ylethanone ____________ 5G-9 11-(3-(2{6-amrinio-8-(7-(azetidin-1 -yl)-2,3-dihydroh)enzo[b][l1&]~ioxin-6-ylthio)-9H _______ jpurin-9-yl)ethyl)piperidin-1-yl)ethanone 5G-10 4-(2-(6-amino-2-chloro-S-((7-(pyrrlidin-1-yI)-2.3-dibvdroteno[b[1 ,4]dioxin-6 _________yI)nethyI)-9H-purin-9-yI)cthyl)pipeiidine-1 -cabaldehyde 5011 8-((7-(dimethylamino)-2,3-dihydrobenzo[b][i,4]dioxin-6-y)thio)-9-(2 * _______(isobutylamhio)ethyl)-9Hi- uiu-6-amine 5 G-12 S-((7-(dirncthylamino)-2,3-dihydrobeno[b)i1,4dioxn-6-ybmefhyl)-2-fluioro-9-(2 I f____ isobutylarni.o)etbyl)-91H-puwin-6-amine 50-13 1-(3-(2-(6-an'Jno-8-(7-(dirnethylarniino)-2,3-dihydrobonzo[b](1.,4]dioxin-6-ylthio)-9H _________purin-9-ylI)etliyl)piperidin-1-yl)ethane I5Cr14 1-(3-(2-(6-air.ino4S-((7-(dimethylarnino)-2,3-dihydrobenzofb[1 ,4]dioxin-6-yi)methyl) 5G-I5 8-(7-(dinrthylarno)-2,3-dihydrobezorh] [1 ,4]dioxin-6-yltllio)-9-(24-(i -1 (rnethvlsufonvl piperidin-3-y1)eth.yI)-9H-puin-6-anline G168-((7-(dimethylamino)-2,3-diydobenzob]1 ,4)dioxin-6-yi)rnethyl)-2-fluorni-9(- I(methylsufn Ifonyperidin-3-yI ethyl)-9H~puht -- mne 50-17 S-((7-(ethylanmino)-2,3-dihydrobenzo[b]ri ,4]dioxin-6-yl)thio}-9-(2 (isobutL~amino)ethyrL)9H-ai--m purin-9-y)ethly)pipeidin-1-y1)ethanone i 0-19 R-(7-(ethylaniino)-2,3-dihydrobenz[b]j I,4]dioxin-6&yllhio)-9-( i 5G-20 2-fluorc-9-(2-(isobutylaimino)ethyl>8g-((7-(isoprcpylanino)-2,3 i ____ dihydrobenzobll,4dioxin-6-y1)methyl)-9H-puin-6-anmine 5G2 8-(7i-(isopropylamino)-2,3-dihydrobenzo~b][1,4doxin-6-ylthio)-9-2-(1 I _______ mediylsulfonyl)pipen -3-yl)ethyl)-9H-pvrn-6-anmine 15G-22 1-(3-(2-(6-arino-2-fkuoro-8-((7-(isopropylan'ino)-2,3-dihydrobezorb][ 1,4]dioxin-6 I _______yl2rnethl)l-9H-pR=n-9-yI)ethvl)piperidin-1-yI)ethanoe 50-2 S~(1-(dmetylamaino)-2,3-dibydrobenzo~bi 1 ,4]dioxiri-6-yl)thio)-9-(3 I (ioprpybino)propyl-91-Dun -6-amine _________ WO 2011/044394 PCT[US2OIO/051872 195 5G-24 8-((7-(dimethyiamiro)-2,3-dihydrobezo~b)[1 ,4]dioxin-6-yl)thio)-9-(2-(1 -I ________(methysulfonyl)piperidin-3-yl)ethyl)-9H-punn-6-amine 5G-25 5-(6-amino-8-(7-(dimethylamino)-2,3-dihydrobenofb][i,4]dioxin-6-ylthio)-9H-purn-7 9:21lpctane-1 -sulfonanmide 5G-26 6-}&arnino-8-(7-(dirnothiylam-ino)-2.3-dihydrobenzo[ ][i,4Jdioxn-6-ylthto)-9H-purn 9-yi)hexaraide 5G-27 9-(3-(tert-bntylamino)propyl)-8-((7-(dimnethylamino)-2,3-d.hydrbez[bF I ,4]dioxin SG-28 1-(3-6-arnino-8 -(7-4dimethylarniino)-2,3-diliydrobenzo[b][ I ,4]dioxin-6-ylthio)-9H __________pr- in-9-yI)propyI)pyrrolidin-3-one Table 511 No. Name 5H1-1 8-((7-cyclopropyl-2,3-dihydroheno[bI 1 14]dioxin-6-yl)thio)-9-(2-{neopentylamino)ethyl) 9H-pwrn6-ammne 5H1-2 8-((7-eyclobutyl-2,3Adihydrobenzo[b] [ I ,4]dioxinl-6-yI)thio)-9-(2-(i sobutylarino)thyl)-9{ purin-6-amine 5H1-3 S-((7-eyelopentyl-2,i-dihydrobenzo~b][i ,4]dieocin-6-yl)thio)-9-Q2-(isobutylarninofrthyl)-91[ ________ uvn-6-arnine 511-4 8-((7-eyelopropyl-2,3-dihydrobenzo[hI1[ 1,4]dioxin-6-yl)methyl)-2-fluoro-9 -(2 (neo!mpentyiao)etyl 9-rRn-. 6-amine 5-5 8}((7Aclobutyl-2,3-dihydrobezob][1I,4jdioxin-6-yl)methyl)-2-flnoro-9-(2 (isohtylamino)ethyl)-9H-ptrin-6-arine 511-6 S-((7-cyelopentyl-2,3-dihydroheno[b] 1 ,4]dioxin-6-yl)rnethvfl-2-fluoro-9-(2 ________(isobuitylanino)ethiyl)-9H-purin-6-amine 5H-71 1-(-(2-{6-aniino-8-((7-eyelopropyl-2,3-dhydrobezobl[1 ,4]dioxin-6-yl)thio)-9H-punin-9 ________ yIthyflpiperidin-1 -vl)etharorne 5-8 1 I -(4-(2-(6-arninPo-8-((7-cyelopropyl-2,3-dihydrobenzo~b)(1,4]dioxin-&-yl)tnethvl)-2-fhioro ________9H-prin-9-yflethyl)piperdin- I yl)ethanone 511-9 1 -(4-(2-(6-amino-2-chioro-8-((7-cyclobutyl-2,3-dihydrobeto[t][ ,4]dioxin-6-yl)methy)-9 ________puarin-9-yI)ethyl)piperidin-1.-yl)ethanone 5H-10 4-(2-(6-awino-8-((7-evciobutyl-2,3-dihydrobi~o[b[1,4]ioxin-6-yl)tio)-9H-puzin-9 yI)ethyb~piperidine-l -carbaldohyde 5H11 4-(2 -(6-an~ino-8-((7-oyclopenty-2,3-Aihydrobenzo~h][1,4]dioxi-6-v)mthy)-2-lhoro-9H 511-12 3-(6-amino-8-((-cyclopropyl-2,3-dihydrobenzo(b][ 1,4]dioxin-6-yI)thio)-9H-purin-9 ________yflpropyl sulfamae 5H1-13 8-(Q-cyclopropyl-2.3-dihydrobenzo[h][ I 4]dioxin-6-yl)thio)-9-(2-(1 ______(rnth slfnypiperdin-3-y~ty 9-ui.6ai SH-14 9-(3-(tert-hutylamiino)propyl)-8-(7o/yclopropyl-2,3-dihydrobezo[b] [1,4]dioxin-6-yl)thio) ________9}I-purin-6-amire 5H-15 2-(3-(6-an~ino-8-(7-cyclobutyl 2,3-dihydxobenzo( b][ i,4]dioxin-6-ylthi o)-9H-pudin-9 ________ yIrpoyflpyroldine-1-svl'onasie 5H1-16 3-(2-(6-amino-8-(7-eyclopemnv1-2,3-dihydrohenz[h][1,4]dioxin-6-ylthio)-9H-purin-9 ______ l)ethylI)pyrroidin-e-l -sulfoinmide 5H-17 8-(7-cyclopentyl-2,3-dihydrobcnzo[b][ I,4]dioxin-6-ylthio)-9-(2-(1 -(rnethylsuifonyl)piperidin _______3-yI)ethyl)-9H-puri-6-arnmne 511-18 9-3(ethtlniopoy)8(-yiootl23dhdoezn)14do~ -6-ybthio)-9H- WO 2011/044394 PCT[US2OIO/051872 196 rn-6-amin !5H-19 1I (6-amio-- (7-cyclopentyl-2,3-dihydrohenzo[t][1 ,4dioxin-6-yltio)-9H-purin-9-y)-3 (isopron lanrino pro an2-ol Table 6A R6A- I 8-(fl-iodo-2,3-dihydrobenizo[b][I ,4]oxathii-6-yl)thio)-9-(3-(isopropvlamino)propl) ________ 9H-ptirin-&amine 6A A 11 8-((7-ethynyl-2,3-4ihydrobenzo[h][1 ,4]oxathiin-6-yI)thio>-9-(3 I~ ('isoEpplarnino)propyl)-9H-purin-6-amine 6A-4 4-(2-(6-amino-8-((7-(fLxran--yl)-2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)thio)-91-purin 6A- 2'fluoro9-(2-isobutylaj'no)ethy1)%,S((7(pyrrdidin-1Lyl)-2,3 6 dibydrobonzo~b][l,4]oxathiin-6-yl)rnethyl)-9H-purin-6-amine 6A-6(Q-(azirdin-1-yI>-2,3-dihydrobenzo[bl[I ,4joxathiin-6-yl)thio)-9-(2 _______(neopentylamino thy1)-9H-prin-6-arnine 6A-7 i.8-((6-(ftira-2-yb)-23-tlihydrobenzo[hJ[i ,4joxathiin-7-yljthio)-9-(3 _____ I (isopropylarmino)proryl)-9H-purin-6-amine 6A-8 8-((6-.tliy-yl-,3-dydrobenzorb][ I,4]oxathiin-7-yl)thio)-9-(3 _______(isopropylamno)propyl)-911-purin-6-anmino 6A.-9 1 4.(2.(6-amino-8-((6-(furan-2.yI).2.3.dihydrobenzorblrl,4]oxathiin-7-yl)thio)-9H-purin 6 10___ -i)etylpierdine- I carbaldehvde 6A-l 2-loo9(}iobuy lamino)ethyl)-8-((6-(pyrolidin-1I -yl)-2,3 _____ dihy drobenzo[b][1,4]oxathiin--ylmethyl)-9H-purin-6-amne 6A-t1 1 8-((6-(aziridin-1I-yl)-2,3-dihydrobenzo[b][1I,4]oxathiin-'7-yI)thio)-9-(2 ______(necopent)1amino)ethyl)-9H-purin-6-arnine 6A12 d-(7-(furaiv2-yI)-4-tnethyl-34-ihydro-2H-ezo~b]E I,4]oxazin-&-yi)thiio)-9-(2 i ... .. L(neopenryian~ino)ethyl)-9H-puin-6-anine 6A-13 i8-((4-m ethyl-7-(1H-pyrazol-3-yl)-3,4-diivdro-ZH-benzo[hJ[1,4]oxazin-6-yI)thio)-9-(2 ________(neopentylamiiilo)ethyl)-911-purin-6-amine 6A-14 S-((7-ethynyI-4-methy1-3,4-dihydro-2H-bonz[b 1[ I,4]oxazin-6-yl)thio)-9-(2 _______(isobutylamino)ethyl)-911-prin-6-anaine 6A-15 2- floio-8-((7-(fira-2-yl)-4-rnetty-34-dtydo-2-be-zo[b][1.4]oxazin-6y)methy> I 1k e9 ( (neopiernylamnino)ethyi~l)-9H-purin-6-arnine 6A-16 4-(z-(6-amnino-8-((7-(fura-2-yI)-4-methyl-3,4-dihydo-21-heno[b][r i4]thiazin-6-I _______yl)thio)-9H-pr--letypiidn- cbaehe 6A-17 8-((6-(furan-2-y1)-4-mnethy-3,4-dihydro-2H-benzo'b[1,4]oxazin-i-yI)thio)-9-(3 _______(isopropylaniino~propyl)-91-purin-6-amine 6A-18 9N3-(scpropylaniino)propy)-8-((4-metliyl-6{biophn-2-yl)-3,4-diydro-.H _____ benzo[b][ 1.4]oxazin-7-yl)thio)-9H-puin--amine 6A-19 I.4-2-(6-amino-S-((6-(ftiran-2-yl)-4-mefiyl-3,4-dihydr-21-benzo[b] I,4]oxazin7 6K0 yi!)thio)-911-pudin-9-yl)ethyl)piperidine-t -arbaldehyde 6204-(2-(6-amino-8-((6-ethyny1-4-methy1-3,4-dihydro-H-boi [b][1 ,4]oxazin-7-yI)thio) 6A-2 , 9H((-(ptnin:9 1ety)pipmeidine3I-dehyd2-e~ob[,]xzn7y~bo- ________ jjbtylatino)ethvl)-9H-purin-6-amine WO 2011/044394 PCT[US2OIO/051872 -4 197 6A-22 I8-((6-(furan-2-yl)-4-methyl-3,4-dihydro-211-benzor'bi[ I,4]thiazin-7-yi)thio)-9-(3 I ______(isopropylanino)prop~yl)-9H-pudin-6-omine 6A-23 8-((6-iodochromn-7-yl)thio)-9-(3-(isopropylamino)propyl)-911-pain-&-amine 6A-24 8-((6-(furan-2-yI)chroman7-yI)thio)-9-(3-(isop~ylarino)propyi)-9H-puin-6-anine 6A-25 846ehyticroa--1ti)9(3(spoyann)propyl)-9H-pin-6-aincn 6A-26 4-(2-(6-am~ino-S-((6-(Thxan-2-yl)thiocbromnx7-yl)thio)-9H-prnin9-y~eth'vl)piprddine ________1-carhaldchyde 6A-27 i2-fluoro-9-(2-(isobnitylarniino)ezhiyl)-8-((1-methyl-6-(pynolidin-1 -yl)-1 2,3,4 _______ terogtiqinoin-7-yl)methy)-9H-prin-6-amine i6A-28 4-(2-(6-arnino-S-((6-(Thran-2-y)-1 ,2,3.,4-tetraihydroquinoiin-7-vI)thio)-9H-purin-9 ________yflethvflpiperidinc-l-carbaldehyde 6A-29 8-((7-iodoohroman-6-yI~thio)-9-(3-(isooropylamino)propyl)-9H-puin-6amine 6A-30 8-((7-(fi~ran-2-y)ehroman-6-yl)thio)-9-(3-(isopropyamito)propy)-9H-pin-6-amin 6A-31 8}((7-ethynylthiochron)9H-ulinan.ne 6A-32 4-(2-(6-amuio-S-((7-(faran-2-yl)thiochromn-6-yl)thio)-9H-pmin-9-yl)ethyl)piperidine I _____1-earhaldehyde1 6A-33 2-fluoro-9-(2-(isobutylanino)ethy)-84(7"-(pyffoidii-1-y1)-1,2,3,4-tetrahydroquinolin-6 ________yl)metlxy)-9fl-prxwn-6-amine 6A-34 4-(2-(6-arno-8-((7-(fiaran-2-yi)-l1-methyl-1,2,3.4-tetrahydroqninolin-6-vl)thio)-9H- I pnurin-9-y1)ethyl~pidirc-1-carbaidehyde 6A-35 2-ehloro-S-((7-iodo-2,3Adihydrobenzo[b][1 ,4]oxathiin-6-yi )rnerhyl)-9-(2 I ______(isobutylanio)ethv)-91-1pudn-6-armne I6A-36 2-chtoro-S-((6-iodo-2,3-iiydrobnzo[b][1,4]oxathiin-7-y!)nehy1)-9-(2 _______(isobuttylamiino)cthyfl-9H-purin-6-arninc 6A-37 2-chloroM-8-(joohrm 7-yrnethy)-9-(2-(isobutylamino)ethyV-9H~purin 6-amine 6A-38 9-(3-(tertbuyanino)propy)-8-4(6-iodochromn-7-y)thio)-9H-nrdin-6-atrine CA-39 N-(3-(6-ariino-S-((6 iodochromar-7-y)thio)-YH-purin-9-yl)pop'1)rethanesulfonaiide 6A-40 3-6- mi o- -f6-iodoc ro an 7jIthio)-911-purin-9-Yl)propy solfam ate I6A_41 I 46ino-8-((6-iodochrman-7-y)ti)-9H-prin-9-y)-3-(isopropylamino)propan-2 I6A-42 9-(34tert-butylamino~propyb)-8-((6-ehnyi chota-'j t -- urn-6-aminc 16A-43 N-(3-(6-amino-8-ftE-ethynylhronan-7-v)thio)-9H-purin-9 __ __ _ ypropyfl eh n sif n m 6A-44 3-(6-amino-8-((6-(ffiran-2-yI)chroman-7-yl)thio)-9H-purin-9-yflpropy sulfanrnte 6A-45 1 -(6-=rnino-8-((6-(5-methyloxazoI-2-yI)ehwtan-7-yI)thio)-9H-pmin-9-y)-3 ______ (sopropylamin)propan-2-oI 64,46 9-(3-Qert*butylaminqo)propyl)--((6iodo-4-methyl-3,4-dihydro-ZH-benzo~b][ ,4]oxazin y-lftlc9H-purin-6-amne 6A-47 N-(3 (6 a ,ino ((6-iodo-4-methvl-3,4-dihydro-2HT-benzo~h][1.4]o ai-7-yl)thio)-9H ______pur 9 lpoy)methanesulfonarnde4 6A-48 i 3-(6-aniino-S-((6-iodo-4-meihyl-3,4-dihydro-2H-benzo[b][l,4]oxazin-7-yl)thio)-9H _____ ram9 yl)propyl sulfamato 6A-49 1 -(6-arino-8-((6-iodo-4-medhyl-3,4-dihydro-2H-betzo[b][1 4]oxazin-7-yI)thio)-9H _____ purin-9 yl)-3-(isopropyian~no)propan-2-oi I 6A-50 9-(3-(tert4butylamino~propyI)-8-((6-ethynvI-4-methyl-3,4-dihydro-2H _______benzorblii,Alcxnin-7-vI)thio)-9H-puxin-6-amine IA5 N4(3-(6-aino-8-((6-ethynyl-4-methyl-3,4-dihiydro-2H-ez[b]1 ,4]oxazin-7-yl)thio) 6 A 1 pHunin-9-yl)propylmethanesulfoitnide 6A-52 3-(6-amino-8-(f6-(finan-2-y}-4-rncthvl-3,4-dihydro-2F1-bezt I 4oxan-7-yl)lhio)- WO 2011/044394 PCT[US2OIO/051872 198 _____ 9H-ptuin-9-yl)proIy snifamate 6A-53 I 1-(6-amino-8-.((4-methy1-6-(5-meffiyloxazoI-2-y1)-3,4-dihydro-2H-beno[hJ[ 1 4]oxazin _____ 7-y1)thio)-9H-purin-9-yJ)-3-(isopropylamino)propan-2-o 6A-54 9-(3-(tert-bntylaniino)propy)-S-((4-methyl6-(5-nethyoxzo-2-yi)-3,4-dihydo-21 _______benzo~b][ I,4]oxazin-7-yl)thio)-911-purin-6-armne Table 6B No. I Na me 6B-1 i 8-if 3-iodo-5,6,7,8-tctrahydironaphthalen-2-ylthio)-9-(3-(isopropyamino)propyl}-9H _______purin-6-aniine 6B1-2 1 -((3-Th&o-5,6 ,",8-tetraliydronaphzhalen-2-yl)thio)-9-Q-.(isobulylarino)ethyi,)-911-puin amne 6B3-3 8-((3-iodo-5,6,7,8-tetrabydronaphthlen-2-yl)thio)-9-(2-(neopentyamino)ethiyl)-9H-purin i- 6-amine 16B-4 2-fluoro-8-if3-iodo-5,6,7.8-tetrahydroaptbien-21-y)methv1)-9-(2-isobityla.no)ethy) ________91--puin-6-aniine S6B-5 2-chloro-8-((3-(fiwan-2-yl)-5,6,7,8-tetrahydronaphthalen-2-yI)methyl)-9-(3 * _______(isopropylarnino)propyl)-9H-tuin-6-amnine 6B-6 2-fluoro-8-if3-iodo-5,6,7,8-tetiahydromnphthakon-2-vI methy)-9-(3 * (isoropylaino)propyi)-9H-purin-6-amine 6B-7 8(3(ap--l-,,,-e~~doahhln2y~bo--3( rplm poy) _______911-purin-6-armine 6B-8 8-((3-ethynyl-5,6,7,&-tetrahydronaphthalen-2-yI)thio)-9-(3-(isopropylarnino)propyl)-9H ________purn-6-anuine 681-9 3-((6-amino-9-(3-<isopropylamino)propyl)-9H-purin-8-vl)thio)-5,6,7,8 ________tetrahydron~aplthaiene-2-carbonitrile4 _21() 8-((3-(azetidin-I -vI)-5,6,7,8-tetralbydronaphthalen-2-yl)rnethyl)-2-fluoro-9-(2 ________(neopentylanirinoethyl)-QH-nirin-6-amine 6-t 8-((3-iodo-5,6,7,8-tetrabydronaphithaIen-2-yI)thio)-9-(2-(isobutylamino)ethyl)-9Ei-purin-6 amine 6B-12 6-(6-amino-8-(3-(oxazol-2-yl)-5,6,78-terahydronaphthaleta-2-vltbio)-9H-pudn-9 6B-13 I -(3-(2-(8-(3-(lH-pyrzo-3-yl)-56,7,-terahydronaphthaen-2-yltlhio)-6-amino-9H-purin 9-yh~ethyflpiperidin-i -yilethanorcve________ 6B-14 1-(3-(2-(6-amino-S-(3-thynlyl-5,6,7,8-tetrhydronaphthalen-2-ylthio)-9H-purin-9 ________yl)ethyl)piperidin-1-yl)cthanone 6B-15 1-(3-(2-(6-arniino-2-flnoro-S-((3-(5-metbylfiiran-2-yl)-5,6,7,S-tetrahydronaphthaen-2 1 ,xnethyl)-9H- win-9-yl)ethy)piperidin-1-yl)ethanone 6B-16 N,-(2-((2-(6-arnino---i3-(fttra-2-yI)-5,6,7,8-tetrahydronaphthalen-2-yl)zhioi)-9H-purin-9 ________yl)ediyl)anilno)ethyl~methanesufonamide 6B-17 3-(f2-(6-amino-8-((3(fuamn-2-yI)-5,6.7,8-tetrahvdronaphthaIen-2-y)thio)-9H -punin-9 62-18 9-(3-aminovropylD-8-((3-iodo-5,6,7,8-terahvdronapithaen-2-y)thio)-9-purin-6-amine 6B_19 9-(3-(isopropylamin~o)propyl)-8-((3-(oxazol-2-y1V-5,6.7,S-tetrahvdronaphthalern2-yl)thio) ________9H-purin-6-atndne 6B-20 9-(3-(tcrt-butylarnino)propyl)-8-((3-iodo-5,6,7,8-Letrahydronaphthalen-2-yl)thio)-9H ________purin-6-amnine 6B_21 _ILZ§ain-4-5mtyfrn2y)5679tn~ma tam2yti)91 WO 2011/044394 PCT[US2OIO/051872 -4 199 ______ pm [un-9-vl)ethyl)pipehidin-i-y)ethaione 6-22 1-(3-(2-(6-amino-8-(3-(oxazoI-2-yi)-5,6,7.8-tetrahydronaplitalen2-ythio)-9H-puri-9 yl)ethyl)pipeniiin-I.-yI)ethanone 6B-23 8-((3-4dimctlhylamino)-5,6,7,8-tetahydronapi,thalen-2-yI)thio)-9-(2 (nieopentyi amito)ethyl)-9I1-purin-6-anine I _______tetrahydronaphthalen -yI)tliio)-9H-purin-6-ammne 6B3-25 DZA-52-N9 _____ 8-((3-iodonaphthalen-2-yl)thio)-9-(3-(isopropylanmino)propyl>9H-purin-6amine 6B3-26 Sg-((3-(dirnethylair~o)naphithalen-2-yl)tlo)-9-(2-(neopentylamino)ehyl)-9H-pnin-6 armne 6B-27 1 -(3-(2-(6-arnino-8-(3-(5-methylfiuran-2-yl)naphthalen-2-yltlhio)-9H-puin-9 ________ y)ethyl)piperidi.n-i -yflethanone 6B-28 9-(2-(l -(metliyls tlfonyl)piperidin-3-yl)ethyl)-8-((3-(5-methylthiazol-2-yl)naphthaien-2 _______yl)thio)-9H-puxin-6-amine 6B-29 8-((3-<thynylnphthalen-2w1l)thio)-9-(34isoptopylamino)propyl)-9HWpihm.-amine 6Bl-30 R-((3-(ll-pyrazob3-yl)naphthalen-2-yl)thio)-9-(3-(isopropylanino)propyl)-9H-pnn-6 amine 6B-31 1-(6-amnino-S-((3-iodonaplithalen-2-yl)tliio)-9H-pndin-9-yi)-34isopropylamino)propan-2 Sol -6B-32 5-(6-amino-S-(3-otiwnylnaphthaken-2-ylthio)-9H-pudin9yl)pentane- -sulfonamide i6B3-33 9-(3-(tert-butylainro)propyl)-8-((3-iodonaphthalen-2-yl)thio)-9J-purn-6-amin 16B-34 8-((3-(5-methyloxazoi-2-yl)naphthalei-2-yl)thio)-9-(2-(1 -(methylsulfonyl)piperidin-3 _______yl)ethyl)-9H-purnq-6-aniine 6B.-35 2-fluoro-8.( 3-fodonaphtlialen-2-vl)meth 'I -9-(2-(isobutylarnino ethy1)-91--urin--a in 6B-36 I -(3-(2-(6-aro~t-8-(3-(aziridin-1 -yl)napithalen-2-yk.hio)-9H-purin-9-yi)ethvl)piperidin-l _____ vI)etbanone 6B-37 6-(6-arino-8-(3-(5-methyloxazol-2-yI)-5,6,7,8-tehahydronaphthaleni-2-ylthio)-9H-puhn 69-38 6-(6aio83iodo-5,6,7,8-tetrahydronaphthalen-2-ylthio)-9H-pndiv-9-ylheunaniide 6B3-39 5 5-(6-arnino-S-(3 -iodo-5,6,7,Sdtetrahydronaphthaleen-2-ylthio)-91-purin-9-yl)pentane- I 1stlfonanude 16B-40 1-(3-46-amino-8-(3-iodo-5,6,78-tetra,ydronaphthalen-2-ythio)-9H-t tin-9 _____I yI)propyi)pyrroldin-3-one Table 7A No. Na me 7A-1 -L dinyI-5-methoxph ylthio)-93-(isopopylaino)propyl-9H-prin-6-amine -7A- 9(3 (isopropv lamino)propy1)-8-(5-methoxy-2-(prop-1-yny1)phcnylthio)-9H-Iudn-6-anineI 7A-3 I9-{3-( sopropylamiino)propyl)-8-(5-methoxy-2-4phenylethynlpenlho-9H-puri-6 mine 7A-4 18-(2-ethyIi-5-methoxyphenylthio)-9-(2-(isobutylamino)cthy)-9H-purin-6-alinire 7A-5 j1-(4-(2-(6-a ino-8-(2-ethynyl-5-methox3phenvlthi&) -9H-pvrin-9-yl)ethy1)piperidin-1 YI etharone 7A-6 4-2(aimno-8-(2-ethynyl-5-methoxypbenylthio)-9H-puariri-9-yl)ethyl)piperidinc-I I carba~ehd WO 2011/044394 PCT[US2OIO/051872 200) 7A-7 1.44-(2-(6-amaino-8-(2-cthyryl-5-methoxybenzyl)-2-fluoro9H-purin-9-yl)cthy)piperidin 1 -yl)etha~on 7A-8 4-(2-(6-amino-8-(2-ethynyl-5-methoxybenzyl)-2-luoro-911-purin-9-yI)etliyl)piperidine-l carbaldehyde 7A-9 1-(4-(2-(6-amiuo-2-ehloro-8-(2-etliyl-5-tnethoxybenzyl)-9H-purin-9-yl)ethiyl)pipeidini-I N ~ 1-yl)ethanone 7A-10 4-(2-(6-arnino-2-chloro-8-(2-ethyniyl-5-methoxybenzyi)-9H-purin-9-y)etiyl)piperidine-1 carbaldeiyde 7A-i1 N-(2-(2-(6-arrino-S-(2-ethvnyi-5-methoxyphenylti)9H-purini-9 yl)e thyl am ino ehy I)slf aide 7A-12 3-(2-(6-amnino-S-(2-ethynyl-5-methoxyphenylthio)-9H-puirin-9-yl)ethylamino)-N hydroxypropan ari de 7A-13 8-(5-ethoxy-?-ethyyphenyltbio)-9-(3-ispropylaninopropyl)-9{-purin-6-antne 7A-14 1 -(6-amino-8-(2-etlwnyl-5-methoxyphenylthio)911-purin-9-yl)-3-(isopropylamino)propanl 2-ol 7A-15 8-(2-ethynyl-5-methoxyphenylthio)-9-(2-QI-(methylsalfonyl)pipeaidn-3-y)ethyl)-9H _______pnrin-6-amine I7A-16 N-(3-(6-amino-S-(2-ethynyl-5-m-ethoxypheniylthio)-9H-purin-9 ________yl)propyl)methanesolfona~xude 7A-17 2-(3-(6-amifr.o-8}(2-ethynyl-5-rnethoxyphenylthio)-9H-pudin-9-yl)propyl)ryrolidine-I _______ cabaldehyde 7lA-IS 8-(2-try1--mtoxbe vi-2fiar-9-({propyla~Tino~propy1)-9H-puin-6-aniine 7A-19 l-(3-(6-arnino-g-(2-effiynyl-5-.methoxyphenylthio)-9H-puin-9-yI)propyl)pyrolidin-3-on 7A-20 PUJ-WS31 ________8-((2-ethypy-5-rnethoxypheny])thio)-9-(2-(neopentylamino)ethyl)-9H-puin-6-antn Table 7B No. Name ?B-1 2-((6-amino-2-fluoro-94(3-(isopropylamino)propyl)-9H-purin-8-yi)methyl-4 ___ ___ -m othoxybonzonitrile _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 7B3 2-(2-(6-aniino-9-(3-(isopropylanino)propyl)-9H-purin-8-ylthio)-4 -7B-4 2-(2-ff6-anmino-2-fluoro-9-(2-(isobtyla.nino)ethy1)-9H-purin-8-yI)methyI)-4 nmethioxypbenyfllacetonitrile 'lB-5 2-(9(-((k a iperidi4-)ethyl)-6-anno-9H-prin-8-yltio)-4-nethoxbezonitile 7B-6 2-((6-arnino-2-flnoro-9-(2-(i -foryiperdinA4-yl)etbyl)-91I-pmlin-8-y1)nmethyI>-4 -nothOXY bnZOnitrl 7B-7 2-((42-(1.aoetylpiperidin-4-y)ethy)-6-amino-2-chloo-9H-puin-8-y)methy)-4 methoxybenonitrile 7B-8 2-(2-(6-arnino-9-(2l-(I -formylpipenidmn4-yI)eth-yl)-9H-purin-8-ylio)V4 ________me tho xypheiy l~aet o it rile 7B3-9 242!-((9-(2-(l -acetylpipedidinA-y1)ethyl}-6-a~rrino-2-fluoro-9H-pnrin--yl)metl) _________ et hojxyp eny I)aceton it rile 7B-10 2-((6-aniino-2-fluoro-9-(3-(isopropylamino)propyl)-9H-pnin-8-yl)mety) - etboxybenzonitrilc WO 2011/044394 PCT[US2OIO/051872 201 711 N-(X{k'2-&arninro-8(2-yano-5-methoxvphenYlthio)-9H-prin-9 I yl)etlhylamaino)ethy)mrethtieplfoniamide 7BW12 3-(2-(6-amino-8-(2-cyano-5-rnethoxyphenylthio)-9H-purin-9-y1)ethylamino)-N Ihydroxypropanamide Table 7C No. Name 7C-1 8-(2-(furan-2-yl)-5-rnethoxyphenylthio)-9-(3-(isopropylamino)propyl)-9H-puin-6-anine 7C-2 9-(3-(isopropylarnino)propyl)-S-(5-mcthoxy-2-(5-mcthylfura-2-yl)phenylthio)-91l-pnin ________6-amnine 7C-3 9-(3-(isopropylamino)propyl)-8-(2-(isoxazolA4-yl)-5-rnethoxyphienylthio)-9H-pnrin-6 _________ n el F7C-4 $-(2-(5-(aminowethyl)furan-2-yi)-5-methoxypheinvlthio)-9-(3-(isopropylamino)propyl) 9H-purin-6-amine 7C-5 2-fluoro-8-(2-(furan-2-vl)-5-methoxybezy)-9-(2-(isobuty~arnino)ethy)-9H-purin-6 amine 7E-6 2-flhoro,-3-(2-(fiura-3-yl1)-5-rnethoxybenzy)-9-(2-(isobntyia.nino)ethyl)-9H-purin-6 I amne 7C-7 2-fluoro-9-(2-(isobutylarmino)ethy1)-8-(5-rnethoxy-2-(5-.methylfinan-2-y)benzyl)-9H _______pmrn-6-amine 7C-8 [2-fluoro-92-(sobutyliarino)eth'I)-8-(2-(isoxaoi-4-yl)-5-methox),benzy1")-9H-puin-6 9H-ptuin-6-arxune 7C-10 I -(3-(6-arnino-8-(5-methoxy-2-(5-methylfuran-2-yl)phenylthio)-9H-purin-9 ________yl)propyl)pymrlidin-3-one 7C-11 8-(5-methoxy-2-(5-methylfiira-2-y!)phenylthio)-9-(2-(I-(methylsulfonyl)piperidin-S '7C-12 5-(6-atnino-8-(5-methoxy-2-(oxazol-2-yI)phenylthio)-9H-purin-9-yl)penane-I _______sulfonamnide 7C-13 f-V-138 ______ j8-(2-(fu-2-yl)-5-methoxyphenylthio)-9-(2-(neopentylanmino)ethy)-9H-purin-6-armine 7C-14 8-(2-(furan-3-yI)-5-metlioxyhenytthio)-9-(2-(neopentylamino)ethyl)-9H-prin-6-amine 7C-15 8-(5-methoxy-2-(5-inethylfuran-2-yI)phenyltbio)-9-(2-(neopentylamiino)ethyl)-9H-purin-& amine C-68-(2-(io--y)5-nethoxypLhyli)--2eoenylaino)ethyl)u',P-9-pur~nin 7C-18 8-(%-(5-(aninoPiethyl)ftiran-2-yI)-5-methoxyphenyl'thio)-9-(2-(neopetyanno)ehy)-9H ________pmunix -amine 7C2-19 1 -(3-(24(6-amino-S}5-methoxy-2-(oxazol-2-yljphenylthi o)-9H-purin-9vl)etliyl)piperii;n - byl)ethvl)piperidin-1-yl ethanone 7C2-21 3-(2-(6-anmino-2chloro-8-(5-nethqoxy-2-(5-methylfrn-2-y')benzy)-9H-puhin-9 7C2 yl)ethyl)piperidine-l -rbaldehyde 7-2 1-(3-(2-(6-amrino-8-(5-methoxy-2-(5-methylt'urai-2-yI)phenylthio)-9H-pmin-9 ____ ___ yyl)l~ieii- yIethanone WO 2011/044394 PCT[US2OIO/051872 202 7C-23 1-(4-(2-(6-aino-2-tluoro-8-(5-rnethoxy-2-(5-metlfiran-2-y)enzy)-QH-pur-9 yJ)ethyl)piperidin-1-yI)ethmaone 7C-24 1-(3-(6-aniao-8-(5-niethoxy-2-(thiazol-2-yl)phonylthio)-9H-purin-9-yI)propyl)pyxrolidini 3-one 7C-25 9-(3-arninopropy1)-8-(5-methoxy-2-(5-nmethylftura-2-yl)phenylIthio)-9H-purin-6-amine N 7C-26 9-(3-(isoprooylarnino)propyl}-8-(5-methoxv-2-(oxazol-2-yI)phenyltbio)-9H-prin-6-am .ine1 7C-27l I 4-(2-(6-anaino-8-(2-(5-(am nrnomethyl)furan-2-y1)-5-methoxyphenylthio)-9H-purin-9 ________yI)etixyrpipedidin-I -y)ethanone 7C-28 I -(4-(2-(6-antno--(2-(5-(aminomethyl)fiira-2-y)-5-metoxyhcnzyl)-2-fluoo-9H-purin i____ 9-yl)ethyVl)piperidin-1 -yI)ethanone XC-29 I4-(2-(6-amino-s-(2-(isoxzo-4-y--mehoxyphnylr iio)-9H-ptuixi-9-yl)ethyl)piperidine 1____ 1-oarhaldehivde 7C7-30 ~4-(2-(6-arino-2-ehloro-S-(2-(isoxazo1 4-yi)-5 -rnctloxyhenzl)-9H-purin-9 ________yl ethyflpipedidine- I -cabaldehydc ,C7-31 j N-(2-(2-(6-atnino-S-(2-(fara-2-y)-5-methoxyphenylhio)-911-pumin-9 1____ I l)ethylamino)ethyl)sulfarnide 7C7-32 [;(2,&amno44-(nran-2-y)--metloxypenylhi)-9H-prin-9-yehyaino)-N 7C3 I____ 8-(5-ethoxv-2-(ftira,-2-y[)phenylthio)-9-(3-(isopropylanino)propyI)-9H-purin-6-amine 7C-34 9

-(

3 <isopn-p.ylarniuo)prp[--5mthx--oao-2-yl) aey ti 2 -9-poi--mn 7C7-35 [ 9-(3-(tet-butyIaino)propyl)--(2-(fua-2-yi)-5-nethoxphenthio)-9H-puin-6-anmine rahie 7D N'o. Name D- I 9-(3-(isopropy1mino~pro y1mehx- 0hi en---.ylpe, Ithio-1-urn6ain 7DJ-2 2-fluoro-9-(2-(isobutylamino)ethyl)-8-(5-methoxy-2-(thiophern2-yl)benzyl)-9H-pain-6-amine 7D-1 TT-V-139 8-(5-methoxy-2-(thiophen-2-yflphonylth.io)-9-(2-(nopentyllrio)etl-9H-puin-6amnine 7D-4 -(3-(isopropylamino)propyl)-R-(5-tel x-th Iop -- yipe-ho)9J-nn6-mn 7D-5 N-(346-aniino-8-5-methoxy-2-(thize1-2-I)pI ,ythio-9H-pxin-9-y1)propyI)metbanesulfonaidc 7D-6 8 (5-rnetboxy-2-(zhiophen-3-y)pEnytio--((eojentylamino~et~yD-9H-pui--mn 718 7 1 (4-(2-(6-amino-8-(5-metioxy-2-(thiophen-2yl)phenythio)-9H-puirin-9-y)ethy)piperidin- ________ l)ethanone 7D-8 4-(2-(6-arnino-8-(5-methoxy-2-(thiophen-2-yl)phenylthio)-9H-purin-9-yl)ethyl)pipeidine- _____ carbaldehyde 7D-9 1 (4-(2-(6-amino-2-tluoro-8-(5-methoxy-2-(thiophen-2-ylhey)-911-puin-9-yI)ethyl)piperidin-1 _______yI)cthanone 7D-10 1 (6-amno-8-(5-meahoxy-2-(thiophen-2-yl)phenylthio)-9I-I-pain-9-y1)-3 (isopropylamlino)propan,-2 I _______ 7D-11 8-(5-methoxy-2-(5-metli.ylthi,.ophen-2-yl)phenylthio)-9-(2-(1-(m.eth.ylsulfonyl)piptidin-3-y)etyl) QH-prin-6-amine ' 7D-12 N-(2}2-(6-anmino-8-(5-nmethoxy-2-(thi'opien-2-yl)phenylthio)-9H-purin-9 yl~ethylarnino)ethyl)sulfamide 7-3 3-(2-(6-anino-g-(5-methoxy--(thophe-2-y)pienvlthio)-9H-puin-9-yl)ety',amino)-N- 7D-14 S-(5-etiioxy-2-(tliiophien-2-yI)benzyi)-2-fluoro-9- 2 Jsobut laino)ethy1)-9H-purin-6-arine 70-1 9*(3-arnnoprpy)S-(5-methoxy-2-(thiophen 2-y)phnyltbio)-9H-pmrn-6-a ie ,D_16 9-(3-(isopropylamino)propyl)-R-(5-nethoxy-2-(thizo-2-yl)phenylthio)-9H-purin-6amine WO 2011/044394 PCT[US2OIO/051872 203 Table 7E NO. [Name 7E-1 9-(3-(isopropylami-ino)propyl)-8-(5-methoxy-2-(1H-pyraol-4-yl)phenyilhio)-9H-purin-6 ________amine 7F-2 9-(3-(isopropylamino)propyl)-S-(5-methoxy-2-( tH-pyrazoi-3-yl)phenylthio)-9H-purin-6 amine 7E-3 2-fluoro-9-(2-(isobutylamino)ethyl)-8-(5-methoxy-2-(1fl-pyrazol-4-ybenzy)-91-prin 6-amine 7E4 2-flhioro-9-(2-(isobitylamnino)ethyl)-8-(5-methoxy-2-(H-praz1-3-y)bnzyl)-9H-puin ________6-amine 7E-5 I -(3-(2-(6-amino-8-(5-methoxy-2-(IH-pyrazol-3-y)phenylthio)-91-purin-9 Iyflehylyr) di- ylehnn 7E-6 TT-V-140 S-(5-rnethoxy-2-f IH-pyrazob-3-yl)plicnyfthio)-9-(2-(neopen.tylamin.,o)ethyl)-9H-pmin-6 7.Fr7 I1-(4-(2-(6-amino-8-(5-methoxy--(I1-pyazd-3-yl)phenyltio)-91T-prin-9 ______ Yoe yichlppdin-1 -yl~ethanone 7E-8 :14-(2-(6-amnino-8-(5-rnethoxy-2-(1H-pyrazoi-3-yI)phenylhio)-9H-purin-9 _ _ _ _ _ _ _ _ yI eth y~ pi erid in e -1 -carb ald eh y d e 7E-9 I j(4-(2-(6-aMo-2-fluoro-8-(5-methoxy-2-( IH-pvrazcd-3-vI)benzyI-Hpxrn-9 _______ y~ehvlppdi- -viIlethanone 7E-10 4-(2(-mio2uoro-8-(5-methoxy-2-( IfI-pyrazol-3-yi!)benzyl)-9H-purin-9 I )etlhyi)piperidine--calkeyd1e 7E-11 14(4-(2-(6-amino-2-chloro-8-(5-melhoxy-2-( 1H-pyrazo1-3-yI)benzyI)-9H-purin-9 _yI~eth2)piperidin-. -yl)ethanone __________________ 7E-12 4-(2-(6-amfino-8-(5-methoxy-2-(H-pyazo-4-y)phenylthio)-9H-purii-9 yl)ethyl)piperidine-l -artaldehyde 7E-13 I -(6-atnino-8-(5-methoxy-2-(IH-pyrazol-3-yl)phenylthio)-9H-purin-9-yI)-3 _________(isopropylamno)propan-2-ol 7E-14 N-(2-(2-(6-amino-S-(5-methoxy-2-(IH-pyrazol-3-yl)phenylthio)-9H-purin-9 yl)ethylamino)ethyflsulfamide 7E-15 3-(2-(6-amnino-8-(5-methoxy-2-(1H-pyrazol-3-yi)phenylthio)-9H-purin-9-yl)ethylarnino) N-hydroxypropanamide 7E-16 8-(5-ethoxy-2-(IH-pyrazol-3-vl)phenylthio)-9-(3-(isopropylamino)propyl)-91-purin-6 amine 7EF17 8(-hoy2Ipyal-3-yl)bezy)--fluoro-9-(2-(isobtyianlno)ethyl)-91-purin-6 7F 18 9-(3-(tert-butylainino)propvI)-8-(5-methoxy-2}i!H-pyio-3-y)pheiytio)-9H-puin-6 amine 7& 19 9-(3-aminopropvl)-S-(5-rnethoxv-241IH-pyrazol-3-yl)phenvi.thioj-Hnh--mn 7E-20 8-(5-rnethoxy-2-(1 1--pymzol-3-yl)phenylthio)-9-(2-(1 -(methylsuifonyP~piperidin-3 yl)propvl)inethanesulfonaride _______________________ 1.-22 9-(3-(isopropylarniino)propyl)-8-(5-rnethoxy- -(5-rnethyl-1H-pyrazol-3-yl)phenylthio) _______I 9H-purin-6-anline Table VF WO 2011/044394 PCT[US2OIO/051872 204 No. Name 7F-1 9-(3-(isopropylami no)propy1.)-8-(5-methcsQxy-2-(1H-pynolP3-y1)phenylthiQ)-9H ................ purin-6-anmine 7F-2 9-(3-(isopropylamino)propyl)-8-(5-methoxy-2-(IH-pyrol-2-yl)phenylthio)-911 purin-6-amine 7F-3 2-fluoro-9-(2-(isobutylarmino)ethyl)-8-(5-methoxy-2-(1fl-pyrrol-3-yl)benzyl) ______________9H-purin-6-arrine 7F-4 8-(5-naethoxy-2-(1 H-pyrroI-3-yl)phenylthio)-9-(2-(1 -(methyisulfonyl)pyrrolidin _______________2:y1)ethy)9H-p=rn~mn 7F-5 8-(5-methoxy-2-(I4-pyrrol-3-yl)phenylthio)-9-(2-(neopentylamino)thyl)-9H Spnrin-6-amine 7F-6 9-(isopropylamino)propyl)-8-(5-methoxy-2-(5-methyl-1 H-pyrrol-3 7F-7 4-(3-(6-aimino-8-(5-methoxy-2-(iH-pyrrol-3-yl phenylthio)-9H-purin-9 ______________ y)propyi)piperidinie-1 -cabaidehvde 7F-8 ~ 4-(2-Q5-amino-8-(5-nmezhoxy-2-(HD -- ;phnti)9-ur-9 ______________yl)ethyi)piperidine-i -carbaidehyde 7F-9 1 -(4-(2-(6-amino-2-fluaoro-8-(5-mehoxy-2-(1 -pyrrol-3-yl)benzy!)-9H-pnrin-9 , Dsthy1)pipeddin--y)ethanone 7F-10 14(4-(3-(6-aniino-2-fluoro-8-(5-methoxy-2-(1H-pyno-3-y)bezy)-9H-puin-9 _______________ yI)propyl)piperidin- 1-vl)ethanone 7F-11 I (4-(2-(6-arnino-2-chioro-8-(5-rnethioxy-2-( I H-pyrrol-3-yI)benzyt)-9H-prnin-9 ______________ yflethyt)piperidin- I -yI)ethanone 7F-12 N-(3-(6-amino-S-(5-methoxy-%<I1-pyrrTol-3-yI)phenylthio)-9H-purin-9 I propyl)methanesulfonamide ________ 7F-13 8-(5-rnethoxy-2-(1H-pyrrol3-yI)phenylthio)-9-(241 -(rnethylsulfonyI)piperidin 7F-14 Nq-(2-(2-(6-arnino-8-(5-rnethoxy-2-( 1H-pyrrol-3-yl)phenylthio)-9H-purin-9 _______________yi)ethylaniino)ethyl)sulfarnide 7F-].5 3-(2-(6-amino-S-(5-rncthoxy-2-(IH-pyrrol-3-yI)phenylthio)-911-purin-9 ____ __________yl)ethylamino)-N-hydroxypropanarnide 7F~-16 8-(5-ethoxy-2-(1H-pyrrol-3-yl)phenyltliio)-9-(3-(isopropylaniino)propyl)-9H ____________________puriii-6-ainiie 7F-17 8-(S5-ethoxy-2-(I H-pynol-3 -yl)benzyi)-2-fluoro-9-(2-(isobutylamino)ethyl)-9H1 __________-puxin-6-amine------ 7F!At 9-(3 -(tert-buitvIawno)p-opy)-8-(5-methoxy-2-( I H-pyrrol-3-yl)phenylthio)-9H _____________ puti-6-arnine 7F-19 9-(3-aminopropyl)-8-(5-mehloxy-2(1H--pynol-3-yl)phenylthio-9H-.pnrin-6 amne 7F 20 1-(6-amino-S-(5-methoxy-2-(IH-pyrrol-3-yl)phenylthio)-9H-puirin-9-yi)-3 _______________(isopropvlanmino)propan-2-oI WO 2011/044394 PCT/US2010/051872 205 Table 8 Options for R. I R is hydrogen, a C 1 to Cu. alkyl, alkenyl, alkynyl, or an alkoxvalky group, optionally including heteroatoms such as N or 0, or a targeting moiety connected to N9 via a linker, 2. R is hydrogen, straight- or branched-, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, in which one or more methylenes can be interrupted or terminated by 0, 5, 5(0), 502, N(R 28 ), C(0), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic; substituted or unsubstituted cycloalkyl; or -B Y M1-M2-M3-M4 R 210 B is a linker; R 2 ,, is selected from the group consisting of hydrogen, N(R2)COR 4 ,

N(R

2 )CON(%R4, N(R 2

)COOR

4

N(R

2 )S(0)SR 3 , N(R2)S(0),N(R 3

)R

4 ; where ie and i are independently selected from hydrogen, aliphatic or substituted aliphatic; R, is selected from the group consisting of: aryl, substituted aryl, heteroarvi, substituted heteroaryl, heterocyclic, substituted heterocyclic, cyloalkyl, substituted cycloaiky!, cycloalkenyl, substituted cycloalkenyl, and substituted or unsubstituted -Ci-CG alkyl, -C-C alkenyl, or -Cr Cc alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from 0, S or N; n is 1 or 2; Mi is absent or selected from substituted or unsubstituted -Ci-C 6 aikyl, -C 2 - Ct alkenyl, or -CrC 6 alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; M2 is absent, 0, 5, 50, 50, N(R 2 ) or CO; M, is absent, 0, 5, SO, SO,, N(Rz, CO, Ci-C alkyl, C-CG alkenyl, C 2

C

6 alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;

M

4 is hydrogen, NR 5

R

6 , CF 3 , O 4 , halogen, substituted or unsubstituted -C,- C 6 alkyl, -C 2

-C

6 alkenyl, or -Cr CsalkynyI, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl or substituted heteroaryl; where Rs and Re are independently selected from the group consisting of hydrogen, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl or substituted cycloalkyl; provided that -R and -Mi-MrMr M4 cannot be both hydrogen.

WO 2011/044394 PCT/US2010/051872 206 Table 8 cont'd 3 Ris N 32 R wherein R is (a) hydro; (b) CrC6 alkyl optionally substituted with 1, 2, 3, 4, or 5 substituents each independently chosen from the group of halo, hydroxyl, amino, cyano, and -C(=O)R wherein R 3 is amino; (c) -C(=O)R, wherein R 3 - is selected from the group consisting of: (1) hydro, (2) C,-C, 0 (e.g., C-C 6 ) alkyl optionally substituted with 1, 2, 3, 4, or 5 substituents each independently chosen from the group of (A) halo, (A) hydroxyl, (C) thiol, (D) cyano, (E) C-C 6 haloalkyl (e.g., trifluoromethyl), (F) Cr C, alkoxy (e.g., methoxy) optionally substituted with C,-C 6 alkoxy (e.g., methoxy), (G) C-amido, (H) N-amido, (I) sulfonyl, (J) -N(R")(R2) wherein R 2 1 and R 2 ' are independently hydro, Cr C 6 alkyl, sulfonyl, and C-carboxy, (3) C,-C 5 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents each independently chosen from the group of halo, hydroxyl, amino, cyano, and CI-C 6 haloalkyl (e.g., trifluoromethyl), and (4) C,-C 6 alkoxy optionally substituted with 1, 2, 3, 4, or 5 substituents each independently chosen from halo, hydroxyl, amino, cyano, and C-C haloalkyl (e.g., trifluoromethyl) (f) heterocycle or heterocycivialkyl, optionally substituted with 1, 2, 3, 4, or 5 substituents independently chosen from haio, hydroxyl, amino, cyano, trihalomethyl, and C-C 4 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently chosen from halo, hydroxyl, amino, cyano, CrCs haloalkyl (e.g., trifluoromethyl) (e.g., tetrazole-5-y! optionally substituted with 1, 2. 3, or 4 C-C, alkyl); (g) sulfonyl; and (h) optionally substituted heteroaryl Table 8, cont'd 4. R is -R " - Rss, wherein WO 2011/044394 PCT/US2010/051872 207 R is -(CH,)n- wherein n=0-3, -C(O), -C(S), -SO-, or -SO 2 N-; and R" is alkyl, aromatic, heteroaromatic, alicyclic, or heterocyclic, each of which is optionally bi-or tri-cyclic, and optionally substituted with H, halogen, lower alkyl, lower alkenyt, lower alkynyl, lower aryl, lower aflicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, -NI, -SR0 -O R% -CN, -CO 2 R", NO2, or -N R"Rs', RSS is hydrogen, lower alkyl, lower aryl, or -C(O) IR"; R' is lower alkyl, lower aryl, lower heteroaryl, -N R'3 R5' 0 or -ORm R" is independently hydrogen or lower alkyl; and R311 is 5. R is selected from the group consisting of H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alicyclic, optionally substituted araalkyl, optionally substituted aryloxyalkyl, optionally substituted alkoxyalkyl, alkylaminoalkyl, alkylcarbonylamnoalkyl, alkylcarbonyoxylalkyl, optionally substituted heterocyclic, hydroxyalkyl, haloalkyl, perhaloalkyl, C(O)Rn, S(O) 2 R", C(O)NHR6', and C(O)OR; where R" is 6. R is H, SRv;, SOR7,. SO-R 7 :. ORt. COOR 7 1 , CONR-,R,,, -CN, C alkyl, C alkenyl, C2, alkynyl, -RAOR,-, -RANR,, --RlAN?. , SRm, --RkASOR or -RASO 2 RR, cycloalkyl, heteroalkyl, heterocycloalkyl. aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl. heteroarylaikyl, NR,,R, 2 ,

--OSO

2 N(R7c)2, -N(R7c)S0 2 0H, -N(R7c)SO2R 7 c, --R7AOSO 2 N(Rwc)2, or -R-,N(R 7 c)OSO2R 7 c; R71 and R7 2 are independently seected from the group consisting of H, COORm, CON(R7,) 2 CIA alkyl, C26 alkenyl, C, , alkynyl, --RAOR, . .- R7ANRa, --R7NR71R, --RASR, --RASOR 3 or -R7ASO2Ra cycloalkyl, beteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylarl, arylalkyl, alkylheteroaryl. and heteroaryladkyl; each R7A is independently Cj 6 alkyl, C 2 -, alkenyl, C 2

-

6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl. heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, alkylheteroarylalkyl, or heteroarylalkyl; and each Rs is independently H1, C, 6 alkyl, C2. alkenyl, Cj.

6 alkynyt, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, --SO20H, --SO2N(R 7 A)2, --SO2NHRA or --SO 2

NH

2 ; and each R.sub.C is independently H, C 1

.

6 alkyl, C 2 < alkenyl, C2 6 alkyny1, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, or heteroarylalkyl; 7A. R is hydrogen, straight- or branched-, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, which one or more methylenes can be interrupted or terminated by 0, S, S(O), SO2, N(Rss), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic; substituted or unsubstituted cycloalkyl; where Rs, is hydrogen, acyl, aliphatic or substituted aliphatic. 7B. R is -MI-M2-M3-M4, wherein Mi is absent, C-C 6 alky., C-C alkenyl, C-Cs alkynyi, aryl or heteroaryl;

M

2 is absent, 0, S, SO, SO2, N(Res), or C=O;

M

3 is absent, C=0, 0, S, SO, 802 or N(Rs); and M4 is hydrogen, halogen, CN, N, hydroxy, substituted hydroxy, anino, substituted amino, CF 3 , C<C 6 alkyl, C2C alkenyl, C2C6 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl.

Claims

1. A compound of the formula: NH 2 X2 Z Z3 cyQ X X 4 A Z 2 I X R Xb wherein (a) each of Zi, Z 2 and Z 3 is independently CH or N; (b) Xa and Xb are 0 and Xc is CH 2 ; (c) Y is -CH 2 - or -S-; (d) X 4 is hydrogen or halogen; and (e) X 2 and R are a combination selected from: (i) X 2 is cyano-alkyl and R is a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, a trialkylammonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl, with the proviso that R does not include a piperidino moiety; or (ii) X 2 is an aryl, an alkynyl, a cycloalkyl, or a cycloalkenyl group and R is: (a) hydrogen; or (b) a straight-chain- or branched- C1 to Cio alkyl, C 2 to C 6 alkenyl, or C 2 to C 6 alkynyl, which is unsubstituted or substituted; or (c) aryl, heteroaryl, heterocyclic, cycloalkyl, alkylaryl, or arylalkyl, which is unsubstituted or substituted; or (d) -SR 71 , -S(O)R 71 , -S0 2 R 7 1 , -OR 71 , -COOR 71 , -CONR 71 R 7 2 , -CN, R7AOR7B, -R7ANR7B, -R7ANR71R7B, -R7ASR7B, -R7AS(O)R7B, -R7ASO2R7B, NR 71 R 72 , -OSO 2 N(R 7 c) 2 , -N(R 7 c)SO 2 OH, -N(R 7 c)SO 2 R 7 c, -R7AOSO2N(R7c)2, or -R 7 AN(R 7 )OS0 2 R 7 C, wherein each R 71 and R 7 2 is independently selected from the group consisting of hydrogen, COOR7B, CON(R 7 c) 2 , C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, -R7AOR7B, -R7ANR7B, -R7ASR7B, R7AS(O)R7B, -R7ASO2R7B, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, and heteroarylalkyl, each R7A IS independently C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to 209 C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl, and each R7B is independently hydrogen, C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, -SO 2 OH, SO2N(R7A)2, -SO2NHR7A, or -SO 2 NH 2 ; and each R 7 c is independently hydrogen, C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, or heteroarylalkyl; or (e) -Mi-M 2 -M 3 -M 4 , wherein: Mi is absent, C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, aryl, or heteroaryl, M 2 is absent, 0, S, S(O), SO 2 , N(Rss), or C(=0), M 3 is absent, C(=O), 0, S, S(O), SO 2 , or N(Rss), and M 4 is hydrogen, halogen, CN, N 3 , hydroxy, amino, substituted amino, CF 3 , C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein Rss is hydrogen, aliphatic, substituted aliphatic, or acyl.

2. The compound of claim 1, wherein X 2 is alkynyl.

3. The compound of claim 2, wherein the compound is selected from the group consisting of: 8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6 amine; 8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9-(2-(isobutylamino)ethyl)-9H-purin-6 amine; 1-(3-(2-(6-amino-8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9H-purin-9 yl)ethyl)piperidin-1-yl)ethanone; 8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9-(2-(1 (methylsulfonyl)piperidin-3-yl)ethyl)-9H-purin-6-amine; N-(2-((2-(6-amino-8-((6 ethynylbenzo[d][1,3]dioxol-5-yl)thio)-9H-purin-9-yl)ethyl)amino)ethyl)sulfamide; 3-(2-(6 amino-8-(6-ethynylbenzo [d] [1,3] dioxol-5-ylthio)-9H-purin-9-yl)ethylamino)-N hydroxypropanamide; 8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9-(2-(neopentylamino)ethyl) 9H-purin-6-amine; 8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9-(2- 210 (isobutylamino)ethyl)-9H-purin-6-amine; 9-(3-aminopropyl)-8-(6-ethynylbenzo[d][1,3]dioxol

5-ylthio)-9H-purin-6-amine; 9-(2-aminoethyl)-8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9H purin-6-amine; 9-(3-(tert-butylamino)propyl)-8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9H purin-6-amine; 1-(3-(6-amino-8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9H-purin-9 yl)propyl)pyrrolidin-3-one; 3 -(2-(6-amino-8-((6-ethynylbenzo [d] [1,3 ]dioxol-5-yl)thio)-9H purin-9-yl)ethyl)piperidine-1-sulfonamide; 6-(6-amino-8-(6-ethynylbenzo[d][1,3]dioxol-5 ylthio)-9H-purin-9-yl)hexanamide; 1-(6-amino-8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9H purin-9-yl)-3-(tert-butylamino)propan-2-ol; 1-(2-((2-(6-amino-8-(6 ethynylbenzo[d][1,3]dioxol-5-ylthio)-9H-purin-9-yl)ethylamino)methyl)pyrrolidin-1 yl)ethanone; 5-(6-amino-8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9H-purin-9-yl)pentane-1 sulfonamide; 8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9-(2-(1-methylpiperidin-2-yl)ethyl) 9H-purin-6-amine; 8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9-(2-(1-methylpiperidin-3 yl)ethyl)-9H-purin-6-amine; 1-(3-(4-(6-amino-8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl) 2-fluoro-9H-purin-9-yl)butyl)pyrrolidin-1-yl)ethanone; 5-(6-amino-8-((6 ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9H-purin-9-yl)pentane-1-sulfonamide; 3-(2 (6-amino-2-chloro-8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-9 yl)ethyl)piperidine-1-carbaldehyde; 3-(2-(6-amino-8-((6-ethynylbenzo[d][1,3]dioxol-5 yl)methyl)-2-fluoro-9H-purin-9-yl)ethyl)piperidine-1-sulfonamide; 8-((6 ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9-(2-(isobutylamino)ethyl)-9H-purin-6 amine; 6-(6-amino-8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9H-purin-9 yl)hexanamide; 1-(3-(2-(6-amino-8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9H purin-9-yl)ethyl)piperidin-1-yl)ethanone; 8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2 fluoro-9-(2-(neopentylamino)ethyl)-9H-purin-6-amine; 8-((6-ethynylbenzo[d][1,3]dioxol-5 yl)methyl)-2-fluoro-9-(3-(isopropylamino)propyl)-9H-purin-6-amine; 9-(3-(tert butylamino)propyl)-8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9H-purin-6- amine;

8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9-(2-(1- (methylsulfonyl)piperidin-3 yl)ethyl)-9H-purin-6-amine; 1-(3-(6-amino-8-((6- ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2 fluoro-9H-purin-9-yl)propyl)pyrrolidin-3 -one; 8- ((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl) 2-fluoro-9-(2-(1-methylpiperidin-3-yl)ethyl)-9H- purin-6-amine; 1-(2-((2-(6-amino-8-((6 ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9H- purin-9-yl)ethylamino)methyl)pyrrolidin 1-yl)ethanone; and 8-((6- 211 ethynylbenzo[d] [1,3]dioxol-5-yl)methyl)-2-fluoro-9-(2-(1 -methylpiperidin-2-yl)ethyl)-9H purin-6-amine. 4. The compound of claim 1, wherein X 2 is a heteroaryl group. 5. The compound of claim 4, wherein X 2 is furanyl. 6. The compound of claim 5, wherein the compound is selected from the group consisting of: 8-((6-(furan-2-yl)benzo[d][1,3]dioxol-5-yl)thio)-9-(3-(isopropylamino)propyl)-9H-purin 6-amine; 8-((6-(furan-2-yl)benzo[d][1,3]dioxol-5-yl)thio)-9-(2-(neopentylamino)ethyl)-9H purin-6-amine; 5-(6-((6-amino-9-(3-(isopropylamino)propyl)-9H-purin-8 yl)thio)benzo[d][1,3]dioxol-5-yl)furan-2-carbaldehyde; 9-(3-(isopropylamino)propyl)-8-((6 (5-methylfuran-2-yl)benzo[d][1,3]dioxol-5-yl)thio)-9H-purin-6-amine; 8-((6-(5 (aminomethyl)furan-2-yl)benzo[d][1,3]dioxol-5-yl)thio)-9-(3-(isopropylamino)propyl)-9H purin-6-amine; 8-((6-(5-methylfuran-2-yl)benzo[d][1,3]dioxol-5-yl)thio)-9-(2 (neopentylamino)ethyl)-9H-purin-6-amine; 8-((6-(5-(aminomethyl)furan-2 yl)benzo[d][1,3]dioxol-5-yl)thio)-9-(2-(neopentylamino)ethyl)-9H-purin-6-amine; 1-(3-(2-(6 amino-8-(6-(5 -methylfuran-2-yl)benzo [d] [1,3 ]dioxol-5-ylthio)-9H-purin-9-yl)ethyl)piperidin 1-yl)ethanone; 8-(6-(5-methylfuran-2-yl)benzo[d][1,3]dioxol-5-ylthio)-9-(2-(1 (methylsulfonyl)piperidin-3-yl)ethyl)-9H-purin-6-amine; 1-(4-(2-(6-amino-8-((6-(5 (aminomethyl)furan-2-yl)benzo[d][1,3]dioxol-5-yl)thio)-9H-purin-9-yl)ethyl)piperidin-1 yl)ethanone; N-(2-((2-(6-amino-8-((6-(5-methylfuran-2-yl)benzo[d][1,3]dioxol-5-yl)thio)-9H purin-9-yl)ethyl)amino)ethyl) sulfamide; 3-(2-(6-amino-8-(6-(5-methylfuran-2 yl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-9-yl)ethylamino)-N-hydroxypropanamide; 9-(3- (tert butylamino)propyl)-8-(6-(5-methylfuran-2-yl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6- amine; 1-(6-amino-8-(6-(5-methylfuran-2-yl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-9-yl)-3- (tert butylamino)propan-2-ol; 2-(3-(6-amino-8-(6-(5-methylfuran-2-yl)benzo[d][1,3]dioxol-5- ylthio) 9H-purin-9-yl)propyl)aziridine-1-carbaldehyde; 5-(6-amino-8-(6-(5-methylfuran-2 yl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-9-yl)pentane-1-sulfonamide; 1-(3-(2-(6-amino-2 fluoro-8-((6-(5-methylfuran-2-yl)benzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-9 yl)ethyl)piperidin-1-yl)ethanone; 4-(2-(6-amino-2-fluoro-8-((6-(furan-2- 212 yl)benzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-9-yl)ethyl)piperidine-1-carbaldehyde; 1-(4-(2 (6-amino-2-fluoro-8-((6-(5-methylfuran-2-yl)benzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-9 yl)ethyl)piperidin-1-yl)ethanone; 1-(4-(2-(6-amino-2-chloro-8-((6-(5-methylfuran-2 yl)benzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-9-yl)ethyl)piperidin-1-yl)ethanone; 1-(4-(2-(6 amino-8-((6-(5-(aminomethyl)furan-2-yl)benzo [d] [1,3 ]dioxol-5-yl)thio)-9H-purin-9 yl)ethyl)piperidin-1-yl)ethanone; 2-fluoro-8-((6-(furan-2-yl)benzo[d][1,3]dioxol-5-yl)methyl)

9-(2-(isobutylamino)ethyl)-9H-purin-6-amine; 5-(6-((6-amino-2-fluoro-9-(2 (isobutylamino)ethyl)-9H-purin-8-yl)methyl)benzo[d][1,3]dioxol-5-yl)furan-2-carbaldehyde; 2 fluoro-9-(2-(isobutylamino)ethyl)-8-((6-(5-methylfuran-2-yl)benzo[d][1,3]dioxol-5- yl)methyl) 9H-purin-6-amine; 8-((6-(5-(aminomethyl)furan-2-yl)benzo[d][1,3]dioxol-5- yl)methyl)-2 fluoro-9-(2-(isobutylamino)ethyl)-9H-purin-6-amine; 5-(6-amino-2-fluoro-8-((6- (5 methylfuran-2-yl)benzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-9-yl)pentane-1-sulfonamide; 6-(6 amino-2-fluoro-8-((6-(5-methylfuran-2-yl)benzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-9 yl)hexanamide; 2-fluoro-9-(3-(isopropylamino)propyl)-8-((6-(5-methylfuran-2 yl)benzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-6-amine; 9-(3-(tert-butylamino)propyl)-2 fluoro-8-((6-(5-methylfuran-2-yl)benzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-6-amine; and 9 (3-aminopropyl)-2-fluoro-8-((6-(5-methylfuran-2-yl)benzo[d][1,3]dioxol-5-yl)methyl)-9H purin-6-amine. 7. The compound of claim 4, wherein X 2 is oxazolyl. 8. The compound of claim 7, wherein the compound is selected from the group consisting of: 8-(6-(5-methyloxazol-2-yl)benzo[d][1,3]dioxol-5-ylthio)-9-(2-(neopentylamino)ethyl)-9H purin-6-amine; 6-(6-amino-8-(6-(5-methyloxazol-2-yl)benzo [d] [1,3 ]dioxol-5-ylthio)-9H- purin 9-yl)hexanamide; 1-(3-(2-(6-amino-8-(6-(5-methyloxazol-2-yl)benzo[d][1,3]dioxol-5- ylthio) 9H-purin-9-yl)ethyl)piperidin-1-yl)ethanone; 9-(3-(isopropylamino)propyl)-8-((6- (oxazol-2 yl)benzo[d][1,3]dioxol-5-yl)thio)-9H-purin-6-amine; 9-(3-aminopropyl)-8-(6-(5- methyloxazol 2-yl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine; 9-(3-(tert- butylamino)propyl)-8-((6 (oxazol-2-yl)benzo[d][1,3]dioxol-5-yl)thio)-9H-purin-6-amine; 1-(4 (2-(6-amino-8-((6-(oxazol-2-yl)benzo[d][1,3]dioxol-5-yl)thio)-9H-purin-9-yl)ethyl)piperidin 1-yl)ethanone; 8-((6-(5-methyloxazol-2-yl)benzo[d][1,3]dioxol-5-yl)thio)-9-(2-(1- 213 (methylsulfonyl)piperidin-3-yl)ethyl)-9H-purin-6-amine; 9-(3-(tert-butylamino)propyl)-8-((6 (5-methyloxazol-2-yl)benzo[d][1,3]dioxol-5-yl)thio)-9H-purin-6-amine; 1-(6-amino-8-((6-(5 methyloxazol-2-yl)benzo[d][1,3]dioxol-5-yl)thio)-9H-purin-9-yl)-3-(isopropylamino)propan- 2 ol; 5-(6-amino-8-(6-(5-methyloxazol-2-yl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-9 yl)pentane-1-sulfonamide; 8-(6-(5-methyloxazol-2-yl)benzo[d][1,3]dioxol-5-ylthio)-9-(3-(1 (methylsulfonyl)pyrrolidin-3-yl)propyl)-9H-purin-6-amine; 1-(3-(6-amino-8-(6-(5 methyloxazol-2-yl)benzo [d] [1,3] dioxol-5-ylthio)-9H-purin-9-yl)propyl)pyrrolidin-3-one; 1-(3 (2-(6-amino-2-fluoro-8-((6-(5-methyloxazol-2-yl)benzo[d][1,3]dioxol-5-yl)methyl)-9H-purin- 9 yl)ethyl)piperidin-1-yl)ethanone; 3-(2-(6-amino-2-chloro-8-((6-(5-methyloxazol-2 yl)benzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-9-yl)ethyl)piperidine-1-sulfonamide; 1-(3-(2- (6 amino-8-((6-(5-(aminomethyl)oxazol-2-yl)benzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9H- purin 9-yl)ethyl)piperidin-1-yl)ethanone; 2-fluoro-9-(2-(isobutylamino)ethyl)-8-((6-(oxazol-2 yl)benzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-6-amine; 1-(3-(6-amino-2-fluoro-8-((6-(5 methyloxazol-2-yl)benzo [d] [1,3] dioxol-5-yl)methyl)-9H-purin-9-yl)propyl)pyrrolidin-3 -one; 6 (6-amino-2-fluoro-8-((6-(5-methyloxazol-2-yl)benzo[d][1,3]dioxol-5-yl)methyl)-9H-purin- 9 yl)hexanamide; 5-(6-amino-2-fluoro-8-((6-(5-methyloxazol-2-yl)benzo[d][1,3]dioxol-5 yl)methyl)-9H-purin-9-yl)pentane-1-sulfonamide; 2-fluoro-9-(3-(isopropylamino)propyl)-8 ((6-(5-methyloxazol-2-yl)benzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-6-amine; 9-(3-(tert butylamino)propyl)-2-fluoro-8-((6-(5-methyloxazol-2-yl)benzo[d][1,3]dioxol-5-yl)methyl)- 9H purin-6-amine; 9-(3-(tert-butylamino)propyl)-2-fluoro-8-((6-(oxazol-2- yl)benzo[d][1,3]dioxol 5-yl)methyl)-9H-purin-6-amine; and 9-(3-aminopropyl)-2-fluoro-8-((6- (5-methyloxazol-2 yl)benzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-6-amine. 9. The compound of claim 4, wherein X 2 is pyrazolyl.

10. The compound of claim 9, wherein the compound is selected from the group consisting of: 8-((6-(1H-pyrazol-3-yl)benzo[d][1,3]dioxol-5-yl)thio)-9-(3-(isopropylamino)propyl)-9H purin-6-amine; 8-((6-(5-methyl-1H-pyrazol-3-yl)benzo[d][1,3]dioxol-5-yl)thio)-9-(2 (neopentylamino)ethyl)-9H-purin-6-amine; 1-(3-(2-(6-amino-8-(6-(5-methyl-1H-pyrazol-3 yl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-9-yl)ethyl)piperidin-1-yl)ethanone; 8-((6-(1H pyrazol-3-yl)benzo[d][1,3]dioxol-5-yl)thio)-9-(2-(neopentylamino)ethyl)-9H-purin-6-amine; 214 8-(6-(1 H-pyrazol-3-yl)benzo[d] [1,3 ]dioxol-5-ylthio)-9-(2-(1 -(methylsulfonyl)piperidin-3 yl)ethyl)-9H-purin-6-amine; 1-(3-(2-(8-(6-(1H-pyrazol-3-yl)benzo[d][1,3]dioxol-5-ylthio)-6 amino-9H-purin-9-yl)ethyl)piperidin-1-yl)ethanone; 1-(3-(2-(6-amino-8-(6-(5-methyl-1H pyrazol-3-yl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-9-yl)ethyl)piperidin-1-yl)ethanone; 4-(2 (8-((6-(1H-pyrazol-3-yl)benzo[d][1,3]dioxol-5-yl)thio)-6-amino-9H-purin-9 yl)ethyl)piperidine-1-carbaldehyde; N-(2-((2-(8-((6-(1H-pyrazol-3-yl)benzo[d][1,3]dioxol-5 yl)thio)-6-amino-9H-purin-9-yl)ethyl)amino)ethyl) sulfamide; N-(2-((2-(8-((6-(1H-pyrazol-3 yl)benzo[d][1,3]dioxol-5-yl)thio)-6-amino-9H-purin-9-yl)ethyl)amino)ethyl) sulfamide; 3-((2 (8-((6-(1H-pyrazol-3-yl)benzo[d][1,3]dioxol-5-yl)thio)-6-amino-9H-purin-9-yl)ethyl)amino)- N hydroxypropanamide; 8-((6-(1H-pyrazol-3-yl)benzo[d][1,3]dioxol-5-yl)thio)-9-(3 aminopropyl)-9H-purin-6-amine; 8-((6-(1H-pyrazol-3-yl)benzo[d][1,3]dioxol-5-yl)thio)-9-(3 (tert-butylamino)propyl)-9H-purin-6-amine; 1-(8-((6-(1H-pyrazol-3-yl)benzo[d][1,3]dioxol-5 yl)thio)-6-amino-9H-purin-9-yl)-3-(isopropylamino)propan-2-ol; 5-(8-(6-(1H-pyrazol-3 yl)benzo[d][1,3]dioxol-5-ylthio)-6-amino-9H-purin-9-yl)pentane-1-sulfonamide; 6-(8-(6-(1H pyrazol-3-yl)benzo[d][1,3]dioxol-5-ylthio)-6-amino-9H-purin-9-yl)hexanamide; 1-(3-(8-(6 (1H-pyrazol-3-yl)benzo[d][1,3]dioxol-5-ylthio)-6-amino-9H-purin-9-yl)propyl)pyrrolidin-3 one; 8-((6-(1H-pyrazol-3-yl)benzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9-(2 (isobutylamino)ethyl)-9H-purin-6-amine; 2-fluoro-9-(2-(isobutylamino)ethyl)-8-((6-(5- methyl 1H-pyrazol-3-yl)benzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-6-amine; 8-((6-(1H- pyrazol-3 yl)benzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9-(2-(1-(methylsulfonyl)piperidin-3- yl)ethyl)-9H purin-6-amine; 1-(3-(2-(8-((6-(1H-pyrazol-3-yl)benzo[d][1,3]dioxol-5- yl)methyl)-6-amino-2 fluoro-9H-purin-9-yl)ethyl)piperidin-1-yl)ethanone; 4-(2-(8-((6-(1H- pyrazol-3 yl)benzo[d][1,3]dioxol-5-yl)methyl)-6-amino-2-chloro-9H-purin-9- yl)ethyl)piperidine-1 carbaldehyde; 8-((6-(1 H-pyrazol-3-yl)benzo[d][1,3]dioxol-5-yl)methyl)- 9-(2-aminoethyl)-2 fluoro-9H-purin-6-amine; 1-(3-(8-((6-(1H-pyrazol-3- yl)benzo[d][1,3]dioxol-5-yl)methyl)-6 amino-2-fluoro-9H-purin-9-yl)propyl)pyrrolidin-3-one; 5-(8-((6-(1H-pyrazol-3 yl)benzo[d][1,3]dioxol-5-yl)methyl)-6-amino-2-fluoro-9H-purin-9 yl)pentane-1-sulfonamide; 6-(8-((6-(1H-pyrazol-3-yl)benzo[d][1,3]dioxol-5-yl)methyl)-6 amino-2-fluoro-9H-purin-9-yl)hexanamide; and 8-((6-(1H-pyrazol-3-yl)benzo[d][1,3]dioxol 5-yl)methyl)-9-(3-(tert-butylamino)propyl)-2-fluoro-9H-purin-6-amine. 215

11. The compound of claim 4, wherein X 2 is thiazolyl.

12. The compound of claim 11, wherein the compound is selected from the group consisting of: 9-(3 -(isopropylamino)propyl)-8-((6-(thiazol-2-yl)benzo[d][1,3]dioxol-5 yl)thio)-9H-purin-6-amine; 2-fluoro-9-(2-(isobutylamino)ethyl)-8-((6-(thiazol-2 yl)benzo[d][1,3]dioxol-5-yl)methyl)-9H- purin-6-amine; 9-(3-(tert-butylamino)propyl)-8-((6 (thiazol-2-yl)benzo[d][1,3]dioxol-5-yl)thio)-9H-purin-6-amine; 9-(3-(tert-butylamino)propyl) 8-((6-(5-methylthiazol-2-yl)benzo[d][1,3]dioxol-5-yl)thio)-9H-purin-6-amine; 1-(3-(2-(6 amino-8-(6-(5 -methylthiazol-2-yl)benzo [d] [1,3] dioxol-5-ylthio)-9H-purin-9- yl)ethyl)piperidin 1-yl)ethanone; 1-(6-amino-8-((6-(5-methylthiazol-2-yl)benzo[d][1,3]dioxol- 5-yl)thio)-9H purin-9-yl)-3-(isopropylamino)propan-2-ol; 5-(6-amino-8-(6-(5-methylthiazol- 2 yl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-9-yl)pentane-1-sulfonamide; 2-(2-(6-amino-8-(6- (5 methylthiazol-2-yl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-9-yl)ethyl)pyrrolidine-1 carbaldehyde; 2-fluoro-9-(2-(isobutylamino)ethyl)-8-((6-(5-methylthiazol-2 yl)benzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-6-amine; and 8-((6-(5-methylthiazol-2 yl)benzo[d][1,3]dioxol-5-yl)thio)-9-(2-(neopentylamino)ethyl)-9H-purin-6-amine.

13. A compound of the formula: NH 2 Zi c R Xb wherein (a) each of Zi, Z 2 and Z 3 is independently CH or N; (b) Xa-Xc-Xb is CH 2 -CH 2 -CH 2 , CH=CH-CH 2 , or CH 2 -CH=CH; (c) Y is -CH 2 - or -S-; (d) X 4 is hydrogen or halogen; and (e) X 2 and R in combination are selected from the group consisting of: (i) X 2 is halogen and R is a primary amino-alkyl, a secondary alkyl-amino alkyl, a tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl, wherein 216 the amine's nitrogen and the heterocycle's heteroatom are substituted to satisfy valence, with the proviso that R is not a piperidino moiety; or (ii) X 2 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, saturated heterocycle, unsaturated heterocycle, aryloxy, alkoxy, halogenated alkoxy, alkenyloxy, hydroxyalkyl, amino, alkylamino, dialkylamino, acylamino, carbamyl, amido, alkylamido, dialkylamido, sulfonamido, alkylsulfonamido, trihalocarbon, thioalkyl, -SO2-alkyl, -C(=O)O-alkyl, -OH, or alkyl-CN, or is part of a ring formed by joining X 2 and R, and R is: (a) hydrogen; or (b) a straight-chain- or branched- C1 to Cio alkyl, C 2 to C 6 alkenyl, or C 2 to C 6 alkynyl, which is unsubstituted or substituted; or (c) aryl, heteroaryl, heterocyclic, cycloalkyl, alkylaryl, or arylalkyl, which is unsubstituted or substituted; or (d) -SR 71 , -S(O)R 71 , -SO 2 R 7 1 , -OR 71 , -COOR 71 , -CONR 71 R 7 2 , -CN, R7AOR7B, -R7ANR7B, -R7ANR71R7B, -R7ASR7B, -R7AS(O)R7B, -R7ASO2R7B, NR 71 R 72 , -OSO 2 N(R 7 c) 2 , -N(R 7 c)SO 2 OH, -N(R 7 c)SO 2 R 7 c, -R7AOSO2N(R7c)2, or -R 7 AN(R 7 C)OSO 2 R 7 C, wherein each R 71 and R 7 2 is independently selected from the group consisting of hydrogen, COOR7B, CON(R 7 c) 2 , C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, -R7AOR7B, -R7ANR7B, -R7ASR7B, R7AS(O)R7B, -R7ASO2R7B, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, and heteroarylalkyl, each R7A IS independently C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl, and each R7B is independently hydrogen, C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, -SO 2 OH, SO2N(R7A)2, -SO2NHR7A, or -SO 2 NH 2 ; and each R 7 c is independently hydrogen, C1 to C 6 alkyl, C 2 to C 6 220 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, or heteroarylalkyl; or (e) -Mi-M 2 -M 3 -M 4 , wherein: Mi is absent, C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, aryl, or heteroaryl, M 2 is absent, 0, S, S(O), SO 2 , N(Rss), or C(=0), M 3 is absent, C(=O), 0, S, S(O), SO 2 , or N(Rss), and M 4 is hydrogen, halogen, CN, N 3 , hydroxy, amino, substituted amino, CF 3 , C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein Rss is hydrogen, aliphatic, substituted aliphatic, or acyl.

14. The compound of claim 13, wherein X 2 is not halogen.

15. The compound of claim 14, wherein X 2 is alkynyl.

16. The compound of claim 15, wherein the compound is selected from the group consisting of: 8-((6-ethynyl-2,3-dihydro-1H-inden-5-yl)thio)-9-(3-(isopropylamino)propyl) 9H-purin-6-amine; 1-(3-(2-(6-amino-8-(6-ethynyl-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9 yl)ethyl)piperidin-1-yl)ethanone; 1-(3-(3-(6-amino-8-(6-ethynyl-2,3-dihydro-1H-inden-5 ylthio)-9H-purin-9-yl)propyl)pyrrolidin-1-yl)ethanone; 8-((6-ethynyl-2,3-dihydro-1H-inden-5 yl)thio)-9-(2-(neopentylamino)ethyl)-9H-purin-6-amine; 5-(6-amino-8-(6-ethynyl-2,3-dihydro 1H-inden-5-ylthio)-9H-purin-9-yl)pentane-1-sulfonamide; 1-(4-(3-(6-amino-8-(6-ethynyl-2,3 dihydro-1H-inden-5-ylthio)-9H-purin-9-yl)propyl)piperidin-1-yl)ethanone; 9-(3-(tert butylamino)propyl)-8-(6-ethynyl-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-6-amine; 1-acetyl 3-(3-(6-amino-8-(6-ethynyl-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9- yl)propyl)imidazolidin 2-one; 8-((6-ethynyl-2,3-dihydro-1H-inden-5-yl)thio)-9-(2-(1- methylpiperidin-2-yl)ethyl)-9H purin-6-amine; 8-((6-ethynyl-2,3-dihydro-1H-inden-5- yl)thio)-9-(2-(1-methylpiperidin-3 yl)ethyl)-9H-purin-6-amine; 8-((6-ethynyl-2,3-dihydro-1H- inden-5-yl)thio)-9-(2-(1 (methylsulfonyl)piperidin-3-yl)ethyl)-9H-purin-6-amine; 1-(3-(2-(6- amino-8-((6-ethynyl-2,3 dihydro- 1 H-inden-5-yl)methyl)-2-fluoro-9H-purin-9- 221 yl)ethyl)piperidin-1-yl)ethanone; 9-(3-(tert-butylamino)propyl)-8-((6-ethynyl-2,3-dihydro-1H inden-5-yl)methyl)-2-fluoro-9H-purin-6-amine; 6-(6-amino-8-((6-ethynyl-2,3-dihydro-1H inden-5-yl)methyl)-2-fluoro-9H-purin-9-yl)hexanamide; 1-(3 -(6-amino-8-((6-ethynyl-2,3 dihydro- 1 H-inden-5-yl)methyl)-2-fluoro-9H-purin-9-yl)propyl)pyrrolidin-3-one; 4-(6-amino 8-((6-ethynyl-2,3-dihydro-1H-inden-5-yl)methyl)-2-fluoro-9H-purin-9-yl)butane-1 sulfonamide; 8-((6-ethynyl-2,3-dihydro-1H-inden-5-yl)methyl)-2-fluoro-9-(3 (isopropylamino)propyl)-9H-purin-6-amine; 8-((6-ethynyl-2,3-dihydro-1H-inden-5 yl)methyl)-2-fluoro-9-(2-(neopentylamino)ethyl)-9H-purin-6-amine; 3-(2-(6-amino-8-((6 ethynyl-2,3-dihydro-1H-inden-5-yl)methyl)-2-fluoro-9H-purin-9-yl)ethyl)piperidine-1 sulfonamide; 8-((6-ethynyl-2,3-dihydro-1H-inden-5-yl)methyl)-2-fluoro-9-(2-(1 methylpiperidin-2-yl)ethyl)-9H-purin-6-amine; and 8-((6-ethynyl-2,3-dihydro-1H-inden-5 yl)methyl)-2-fluoro-9-(2-(1-methylpiperidin-3-yl)ethyl)-9H-purin-6-amine.

17. The compound of claim 14, wherein X 2 is heteroaryl.

18. The compound of claim 17, wherein the compound is selected from the group consisting of: 8-((6-(furan-2-yl)-2,3-dihydro-1H-inden-5-yl)thio)-9-(3 (isopropylamino)propyl)-9H-purin-6-amine; 9-(3-(isopropylamino)propyl)-8-((6-(oxazol-2 yl)-2,3-dihydro-1H-inden-5-yl)thio)-9H-purin-6-amine; 1-(3-(2-(6-amino-8-(6-(oxazol-2-yl) 2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9-yl)ethyl)piperidin-1-yl)ethanone; 3-(2-(8-(6-(1H pyrazol-3-yl)-2,3-dihydro-1H-inden-5-ylthio)-6-amino-9H-purin-9-yl)ethyl)piperidine-1 carbaldehyde; N-(2-((2-(6-amino-8-((6-(oxazol-2-yl)-2,3-dihydro-1H-inden-5-yl)thio)-9H purin-9-yl)ethyl)amino)ethyl)sulfamide; 3 -(2-(6-amino-8-(6-(oxazol-2-yl)-2,3 -dihydro- 1 H inden-5-ylthio)-9H-purin-9-yl)ethylamino)-N-hydroxypropanamide; 9-(3 (isopropylamino)propyl)-8-((6-(5-methyloxazol-2-yl)-2,3-dihydro-1H-inden-5-yl)thio)-9H purin-6-amine; 8-((6-(5-methyloxazol-2-yl)-2,3-dihydro-1H-inden-5-yl)thio)-9-(2-(1 (methylsulfonyl)piperidin-3-yl)ethyl)-9H-purin-6-amine; 9-(3-aminopropyl)-8-((6-(5 methyloxazol-2-yl)-2,3-dihydro-1H-inden-5-yl)thio)-9H-purin-6-amine; 9-(3-(tert butylamino)propyl)-8-(6-(4-methylthiazol-2-yl)-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-6 amine; 8-((6-(5-methyloxazol-2-yl)-2,3-dihydro-1H-inden-5-yl)thio)-9-(2 (neopentylamino)ethyl)-9H-purin-6-amine; 1-(6-amino-8-((6-(5-methyloxazol-2-yl)-2,3- 222 dihydro-1H-inden-5-yl)thio)-9H-purin-9-yl)-3-(isopropylamino)propan-2-ol; 1-(2-(4-(6 amino-8-(6-(5-methylfuran-2-yl)-2,3 -dihydro- 1 H-inden-5-ylthio)-9H-purin-9 yl)butyl)pyrrolidin-1-yl)ethanone; 1-(3-(2-(6-amino-8-(6-(5-methyloxazol-2-yl)-2,3-dihydro 1H-inden-5-ylthio)-9H-purin-9-yl)ethyl)piperidin-1-yl)ethanone; 6-(6-amino-8-(6-(oxazol-2 yl)-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9-yl)hexanamide; 1-(3-(6-amino-8-(6-(4 methyloxazol-2-yl)-2,3 -dihydro- 1 H-inden-5 -ylthio)-9H-purin-9-yl)propyl)pyrrolidin-3 -one; 2 fluoro-9-(3-(1-(methylsulfonyl)pyrrolidin-3-yl)propyl)-8-((6-(oxazol-2-yl)-2,3-dihydro-1H inden-5-yl)methyl)-9H-purin-6-amine; 1-(3-(2-(6-amino-2-fluoro-8-((6-(4-methylthiazol-2- yl) 2,3-dihydro-1H-inden-5-yl)methyl)-9H-purin-9-yl)ethyl)piperidin-1-yl)ethanone; 9-(3- (tert butylamino)propyl)-2-fluoro-8-((6-(4-methylthiazol-2-yl)-2,3-dihydro-1H-inden-5- yl)methyl) 9H-purin-6-amine; 8-((6-(1H-pyrazol-3-yl)-2,3-dihydro-1H-inden-5-yl)methyl)-9- (3-(tert butylamino)propyl)-2-fluoro-9H-purin-6-amine; 6-(6-amino-2-fluoro-8-((6-(oxazol-2- yl)-2,3 dihydro-1H-inden-5-yl)methyl)-9H-purin-9-yl)hexanamide; 1-(3-(6-amino-2-fluoro-8- ((6 (oxazol-2-yl)-2,3 -dihydro- 1 H-inden-5-yl)methyl)-9H-purin-9-yl)propyl)pyrrolidin-3 -one; 5-(6 amino-2-fluoro-8-((6-(oxazol-2-yl)-2,3-dihydro-1H-inden-5-yl)methyl)-9H-purin-9- yl)pentane 1-sulfonamide; 2-fluoro-9-(2-(1-methylpiperidin-2-yl)ethyl)-8-((6-(oxazol-2-yl)- 2,3-dihydro 1H-inden-5-yl)methyl)-9H-purin-6-amine; and 2-fluoro-9-(2-(1-methylpiperidin- 3-yl)ethyl)-8 ((6-(oxazol-2-yl)-2,3-dihydro-1H-inden-5-yl)methyl)-9H-purin-6-amine.

19. The compound of claim 13, wherein X 2 is iodine.

20. The compound of claim 19, wherein the compound is selected from the group consisting of: 1-(6-amino-8-(6-iodo-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9-yl)-3-(tert butylamino)propan-2-ol; 8-((6-iodo-2,3-dihydro-1H-inden-5-yl)thio)-9-(2 (isobutylamino)ethyl)-9H-purin-6-amine; 1-(3 -(6-amino-8-(6-iodo-2,3 -dihydro- 1 H-inden-5 ylthio)-9H-purin-9-yl)propyl)pyrrolidin-3 -one; 1-(3-(3-(6-amino-8-(6-iodo-2,3-dihydro-1H inden-5-ylthio)-9H-purin-9-yl)propyl)pyrrolidin-1-yl)ethanone; 8-((6-iodo-2,3-dihydro-1H inden-5-yl)thio)-9-(2-(neopentylamino)ethyl)-9H-purin-6-amine; 8-((6-iodo-2,3-dihydro-1H inden-5-yl)thio)-9-(3-(isopropylamino)propyl)-9H-purin-6-amine; 9-(3-aminopropyl)-8-((6 iodo-2,3-dihydro-1H-inden-5-yl)thio)-9H-purin-6-amine; 9-(2-aminoethyl)-8-((6-iodo-2,3 dihydro-1H-inden-5-yl)thio)-9H-purin-6-amine; 9-(3-(tert-butylamino)propyl)-8-((6-iodo-2,3- 223 dihydro-1H-inden-5-yl)thio)-9H-purin-6-amine; 5-(6-amino-8-(6-iodo-2,3-dihydro-1H-inden 5-ylthio)-9H-purin-9-yl)-N-methylpentane-1-sulfonamide; 5-(6-amino-8-(6-iodo-2,3-dihydro 1 H-inden-5-ylthio)-9H-purin-9-yl)pentane- 1-sulfonamide; 1-(3-(6-amino-8-(6-iodo-2,3 dihydro-1H-inden-5-ylthio)-9H-purin-9-yl)propyl)pyrrolidin-3-ol; 6-(6-amino-8-(6-iodo-2,3 dihydro-1H-inden-5-ylthio)-9H-purin-9-yl)hexanamide; 8-((6-iodo-2,3-dihydro-1H-inden-5 yl)thio)-9-(2-(1-methylpiperidin-2-yl)ethyl)-9H-purin-6-amine; 8-((6-iodo-2,3-dihydro-1H inden-5-yl)thio)-9-(2-(1-methylpiperidin-3-yl)ethyl)-9H-purin-6-amine; 8-((6-iodo-2,3 dihydro-1H-inden-5-yl)thio)-9-(2-(1-(methylsulfonyl)piperidin-3-yl)ethyl)-9H-purin-6-amine; 3 (2-(6-amino-8-((6-iodo-2,3-dihydro-1H-inden-5-yl)thio)-9H-purin-9-yl)ethyl)piperidine-1 sulfonamide; 2-fluoro-8-((6-iodo-2,3-dihydro-1H-inden-5-yl)methyl)-9-(2 (isobutylamino)ethyl)-9H-purin-6-amine; 2-fluoro-8-((6-iodo-2,3-dihydro-1H-inden-5 yl)methyl)-9-(3-(isopropylamino)propyl)-9H-purin-6-amine; 1-(3-(6-amino-2-fluoro-8-((6 iodo-2,3 -dihydro- 1 H-inden-5-yl)methyl)-9H-purin-9-yl)propyl)pyrrolidin-3 -one; 1-(3-(3-(6 amino-2-fluoro-8-((6-iodo-2,3-dihydro-1H-inden-5-yl)methyl)-9H-purin-9- yl)propyl)pyrrolidin 1-yl)ethanone; 9-(3-(tert-butylamino)propyl)-2-fluoro-8-((6-iodo-2,3- dihydro-1H-inden-5 yl)methyl)-9H-purin-6-amine; 5-(6-amino-2-fluoro-8-((6-iodo-2,3- dihydro-1H-inden-5 yl)methyl)-9H-purin-9-yl)-N-methylpentane-1-sulfonamide; 5-(6-amino- 2-fluoro-8-((6-iodo 2,3-dihydro-1H-inden-5-yl)methyl)-9H-purin-9-yl)pentane-1-sulfonamide; 2-fluoro-8-((6-iodo 2,3-dihydro-1H-inden-5-yl)methyl)-9-(2-(1-methylpiperidin-2-yl)ethyl)- 9H-purin-6-amine; 2 fluoro-8-((6-iodo-2,3-dihydro-1H-inden-5-yl)methyl)-9-(2-(1- methylpiperidin-3-yl)ethyl)-9H purin-6-amine; 2-fluoro-8-((6-iodo-2,3-dihydro-1H-inden-5- yl)methyl)-9-(2-(1 (methylsulfonyl)piperidin-3-yl)ethyl)-9H-purin-6-amine; 3-(2-(6-amino-2- fluoro-8-((6-iodo 2,3-dihydro-1H-inden-5-yl)methyl)-9H-purin-9-yl)ethyl)piperidine-1- sulfonamide; and 9-(3 (tert-butylamino)propyl)-2-fluoro-8-((6-iodo-2,3-dihydro-1H-inden-5- yl)methyl)-9H-purin-6 amine.

21. A compound of the formula: NH 2 Z cb R Xb 224 wherein (a) each of Zi, Z 2 and Z 3 is independently CH or N; (b) one of Xa and Xb is 0 and Xc and the other of Xa and Xb are -CH 2 -; (c) Y is -CH 2 - or -S-; (d) X 4 is hydrogen or halogen; and (e) X 2 and R in combination are selected from the group consisting of: (i) X 2 is halogen and R is a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl, with the proviso that R does not include a piperidino moiety; or (ii) X 2 is an aryl, an alkynyl, an amino, a cycloalkyl, or a cycloalkenyl and R is: (a) hydrogen; or (b) a straight-chain- or branched- C1 to Cio alkyl, C 2 to C 6 alkenyl, or C 2 to C 6 alkynyl, which is unsubstituted or substituted; or (c) aryl, heteroaryl, heterocyclic, cycloalkyl, alkylaryl, or arylalkyl, which is unsubstituted or substituted; or (d) -SR 71 , -S(O)R 71 , -S0 2 R 7 1 , -OR 71 , -COOR 71 , -CONR 71 R 7 2 , -CN, R7AOR7B, -R7ANR7B, -R7ANR71R7B, -R7ASR7B, -R7AS(O)R7B, -R7ASO2R7B, NR 71 R 72 , -OSO 2 N(R 7 c) 2 , -N(R 7 c)SO 2 OH, -N(R 7 c)SO 2 R 7 c, -R7AOSO2N(R7c)2, or -R 7 AN(R 7 C)OS0 2 R 7 C, wherein each R 71 and R 7 2 is independently selected from the group consisting of hydrogen, COOR7B, CON(R 7 c) 2 , C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, -R7AOR7B, -R7ANR7B, -R7ASR7B, R7AS(O)R7B, -R7ASO2R7B, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, and heteroarylalkyl, each R7A IS independently C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl, and each R7B is independently hydrogen, C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, -SO 2 OH, - 225 SO2N(R7A)2, -SO2NHR7A, or -SO 2 NH 2 ; and each R 7 c is independently hydrogen, C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, or heteroarylalkyl; or (e) -Mi-M 2 -M 3 -M 4 , wherein Mi is absent, C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, aryl, or heteroaryl, M 2 is absent, 0, S, S(O), SO 2 , N(Rss), or C(=0), M 3 is absent, C(=O), 0, S, S(O), SO 2 , or N(Rss), and M 4 is hydrogen, halogen, CN, N 3 , hydroxy, amino, substituted amino, CF 3 , C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein Rss is hydrogen, aliphatic, substituted aliphatic, or acyl.

22. A compound of the formula: NH 2 X2 Z1 Z3 -Y-Q X X A Z2 I R Xb wherein (a) each of Zi, Z 2 and Z 3 is independently CH or N; (b) one of Xa and Xb is S, C(=0), C(=S), NH or substituted N, and Xc and the other of Xa and Xb are -CH 2 -; (c) Y is -CH 2 - or -S-; (d) X 4 is hydrogen or halogen; (e) X 2 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, saturated heterocycle, unsaturated heterocycle, halogen, aryloxy, alkoxy, halogenated alkoxy, alkenyloxy, hydroxyalkyl, amino, alkylamino, dialkylamino, acylamino, carbamyl, amido, alkylamido, dialkylamido, sulfonamido, alkylsulfonamido, 226 trihalocarbon, -thioalkyl, -S02-alkyl, -C(=O)O-alkyl, -C(=O)-alkyl, -OH, -NO 2 , -CN or alkyl CN, or is part of a ring formed by joining X 2 and R; and (f) R is: (a) hydrogen; or (b) a straight-chain- or branched- C1 to Cio alkyl, C 2 to C 6 alkenyl, or C 2 to C 6 alkynyl, which is unsubstituted or substituted; or (c) aryl, heteroaryl, heterocyclic, cycloalkyl, alkylaryl, or arylalkyl, which is unsubstituted or substituted; or (d) -SR 71 , -S(O)R 71 , -S0 2 R 7 1 , -OR 71 , -COOR 71 , -CONR 71 R 7 2 , -CN, R7AOR7B, -R7ANR7B, -R7ANR71R7B, -R7ASR7B, -R7AS(O)R7B, -R7ASO2R7B, NR 71 R 72 , -OSO 2 N(R 7 c) 2 , -N(R 7 c)SO 2 OH, -N(R 7 c)SO 2 R 7 c, -R7AOSO2N(R7c)2, or -R 7 AN(R 7 )OS0 2 R 7 C, wherein each R 71 and R 7 2 is independently selected from the group consisting of hydrogen, COOR7B, CON(R 7 c) 2 , C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, -R7AOR7B, -R7ANR7B, -R7ASR7B, R7AS(O)R7B, -R7ASO2R7B, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, and heteroarylalkyl, each R7A IS independently C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl, and each R7B is independently hydrogen, C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, -SO 2 OH, SO2N(R7A)2, -SO2NHR7A, or -SO 2 NH 2 ; and each R 7 c is independently hydrogen, C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, or heteroarylalkyl; or (e) -Mi-M 2 -M 3 -M 4 , wherein: Mi is absent, C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, aryl, or heteroaryl, M 2 is absent, 0, S, S(O), SO 2 , N(Rss), or C(=0), 227 M 3 is absent, C(=O), 0, S, S(O), SO 2 , or N(Rss), and M 4 is hydrogen, halogen, CN, N 3 , hydroxy, amino, substituted amino, CF 3 , C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein Rss is hydrogen, aliphatic, substituted aliphatic, or acyl.

23. A compound of the formula: NH 2 X2 Z Xc R Xb wherein (a) each of Zi, Z 2 and Z 3 is independently CH or N; (b) Xa-Xc-Xb is CH=CH-0, CH=CH-NH, CH=CH-S, O-CH=CH, NH-CH=CH, S CH=CH, N=CH-0, N=CH-S, NH-CH=N, O-CH=N, S-CH=N, N=N-O, N=N-S, N=N-CH 2 , 0 N=N, NH-N=N, S-N=N, or CH 2 -N=N; (c) Y is -CH 2 - or -S-; (d) X 4 is hydrogen or halogen; (e) X 2 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, saturated or unsaturated heterocycle, halogen, aryloxy, alkoxy, halogenated alkoxy, alkenyloxy, hydroxyalkyl, amino, alkylamino, dialkylamino, acylamino, carbamyl, amido, alkylamido, dialkylamido, sulfonamido, alkylsulfonamido, trihalocarbon, thioalkyl, -SO2-alkyl, -C(=O)O-alkyl, -C(O)-alkyl, -OH, -NO 2 , -CN and alkyl-CN, or is part of a ring formed by joining X 2 and R; and (f) R is: (a) hydrogen; or (b) a straight-chain- or branched- C1 to Cio alkyl, C 2 to C 6 alkenyl, or C 2 to C 6 alkynyl, which is unsubstituted or substituted; or (c) aryl, heteroaryl, heterocyclic, cycloalkyl, alkylaryl, or arylalkyl, which is unsubstituted or substituted; or 228 (d) -SR 71 , -S(O)R 71 , -S0 2 R 7 1 , -OR 71 , -COOR 71 , -CONR 71 R 7 2 , -CN, R7AOR7B, -R7ANR7B, -R7ANR71R7B, -R7ASR7B, -R7AS(O)R7B, -R7ASO2R7B, NR 71 R 72 , -OSO 2 N(R 7 c) 2 , -N(R 7 c)SO 2 OH, -N(R 7 c)SO 2 R 7 c, -R7AOSO2N(R7c)2, or -R 7 AN(R 7 C)OS0 2 R 7 C, wherein each R 71 and R 7 2 is independently selected from the group consisting of hydrogen, COOR7B, CON(R 7 c) 2 , C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, -R7AOR7B, -R7ANR7B, -R7ASR7B, R7AS(O)R7B, -R7ASO2R7B, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, and heteroarylalkyl, each R7A IS independently C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl, and each R7B is independently hydrogen, C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, -SO 2 OH, SO2N(R7A)2, -SO2NHR7A, or -SO 2 NH 2 ; and each R 7 c is independently hydrogen, C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, or heteroarylalkyl; or (e) -Mi-M 2 -M 3 -M 4 , wherein: Mi is absent, C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, aryl, or heteroaryl, M 2 is absent, 0, S, S(O), SO 2 , N(Rss), or C(=0), M 3 is absent, C(=O), 0, S, S(O), SO 2 , or N(Rss), and M 4 is hydrogen, halogen, CN, N 3 , hydroxy, amino, substituted amino, CF 3 , C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein Rss is hydrogen, aliphatic, substituted aliphatic, or acyl. 229

24. A compound of the formula: NH 2 X2 Y X~c R Xb-Xd wherein (a) each of Zi, Z 2 and Z 3 is independently CH or N; (b) Xa and Xb are 0, and Xc and Xd are CH 2 ; (c) Y is -CH 2 -, -0- or -S-; (d) X 4 is hydrogen or halogen; and (e) X 2 and R are a combination selected from: (i) X 2 is halogen or cyano and R is suitably a primary amino alkyl, a secondary or tertiary alkyl-amino-alkyl, a trialkylammonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl, with the proviso that R does not include a piperidino moiety; or (ii) X 2 is selected from the group consisting of an aryl, an alkynyl, a cycloalkyl and an cycloalkenyl and R is: (a) hydrogen; or (b) a straight-chain- or branched- C 1 to Cio alkyl, C 2 to C 6 alkenyl, or C 2 to C 6 alkynyl, which is unsubstituted or substituted; or (c) aryl, heteroaryl, heterocyclic, cycloalkyl, alkylaryl, or arylalkyl, which is unsubstituted or substituted; or (d) -SR 71 , -S(O)R 71 , -S0 2 R 7 1 , -OR 7 1 , -COOR 71 , -CONR 7 1 R 72 , -CN, R7AOR7B, -R7ANR7B, -R7ANR71R7B, -R7ASR7B, -R7AS(O)R7B, -R7ASO2R7B, NR7 1 R 72 , -OSO 2 N(R 7 c) 2 , -N(R 7 c)SO 2 OH, -N(R 7 c)SO 2 R 7 c, -R 7 AOSO2N(R 7 c)2, or -R7AN(R7c)OS02R7c, wherein each R 71 and R 7 2 is independently selected from the group consisting of hydrogen, COOR7B, CON(R 7 c) 2 , C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, -R7AOR7B, -R7ANR7B, -R7ASR7B, R7AS(O)R7B, -R7ASO2R7B, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, and heteroarylalkyl, 230 each R7A IS independently C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl, and each R7B is independently hydrogen, C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, -SO 2 OH, SO2N(R7A)2, -SO2NHR7A, or -SO 2 NH 2 ; and each R 7 c is independently hydrogen, C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, or heteroarylalkyl; or (e) -Mi-M 2 -M 3 -M 4 , wherein: Mi is absent, C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, aryl, or heteroaryl, M 2 is absent, 0, S, S(O), SO 2 , N(Rss), or C(=0), M 3 is absent, C(=O), 0, S, S(O), SO 2 , or N(Rss), and M 4 is hydrogen, halogen, CN, N 3 , hydroxy, amino, substituted amino, CF 3 , C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein Rss is hydrogen, aliphatic, substituted aliphatic, or acyl.

25. The compound of claim 24, wherein X 2 is halogen.

26. The compound of claim 25, wherein X 2 is iodine.

27. The compound of claim 26, wherein the compound is selected from the group consisting of: 8-((7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9-(3 (isopropylamino)propyl)-9H-purin-6-amine; 8-((7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6 yl)thio)-9-(2-(isobutylamino)ethyl)-9H-purin-6-amine; 8-((7-iodo-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9-(2-(neopentylamino)ethyl)-9H-purin-6-amine; 9-(3 (1H-imidazol-1-yl)propyl)-8-((7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9H-purin-6 amine; 9-(3-aminopropyl)-8-((7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9H-purin-6- 231 amine; 9-(2-aminoethyl)-8-((7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9H-purin-6 amine; 9-(3-(tert-butylamino)propyl)-8-((7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio) 9H-purin-6-amine; 1-(6-amino-8-((7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9H purin-9-yl)-3-(isopropylamino)propan-2-ol; 5-(6-amino-8-(7-iodo-2,3 dihydrobenzo[b][1,4]dioxin-6-ylthio)-9H-purin-9-yl)pentane-1-sulfonamide; 1-(3-(6-amino-8 (7-iodo-2,3 -dihydrobenzo [b] [1,4] dioxin-6-ylthio)-9H-purin-9-yl)propyl)pyrrolidin-3 -one; 6 (6-amino-8-(7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-9H-purin-9-yl)hexanamide; 1- (3 (4-(6-amino-8-(7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-9H-purin-9- yl)butyl)pyrrolidin 1-yl)ethanone; and 8-(7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-9- (3 (isobutylamino)propyl)-9H-purin-6-amine.

28. The compound of claim 24, wherein X 2 is heteroaryl.

29. The compound of claim 28, wherein X 2 is pyrazolyl.

30. The compound of claim 29, wherein the compound is selected from the group consisting of: 8-((7-(1H-pyrazol-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9-(3 (isopropylamino)propyl)-9H-purin-6-amine; 8-((7-(1H-pyrazol-3-yl)-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9-(2-(neopentylamino)ethyl)-9H-purin-6-amine; 1-(4 (2-(8-((7-(1H-pyrazol-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-6-amino-9H-purin-9 yl)ethyl)piperidin-1-yl)ethanone; 8-(7-(1H-pyrazol-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6 ylthio)-9-(2-(1-(methylsulfonyl)piperidin-3-yl)ethyl)-9H-purin-6-amine; N-(2-((2-(8-((7-(1H pyrazol-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-6-amino-9H-purin-9 yl)ethyl)amino)ethyl)sulfamide; 8-((7-(1H-pyrazol-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6 yl)thio)-9-(3-aminopropyl)-9H-purin-6-amine; 8-((7-(1H-pyrazol-3-yl)-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9-(3-(tert-butylamino)propyl)-9H-purin-6-amine; 9-(3 (isopropylamino)propyl)-8-((7-(5-methyl-1H-pyrazol-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6 yl)thio)-9H-purin-6-amine; 8-((7-(5-methyl- 1 H-pyrazol-3 -yl)-2,3 -dihydrobenzo [b] [1,4] dioxin 6-yl)thio)-9-(2-(neopentylamino)ethyl)-9H-purin-6-amine; 1-(8-((7-(1H-pyrazol-3-yl)-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)thio)-6-amino-9H-purin-9-yl)-3-(isopropylamino)propan-2- ol; 5-(8-(7-(1H-pyrazol-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-6-amino-9H-purin-9- 232 yl)pentane-1-sulfonamide; 6-(8-(7-(1H-pyrazol-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6 ylthio)-6-amino-9H-purin-9-yl)hexanamide; 1-(3-(8-(7-(1H-pyrazol-3-yl)-2,3 dihydrobenzo [b] [1,4]dioxin-6-ylthio)-6-amino-9H-purin-9-yl)propyl)pyrrolidin-3 -one; 8-((7 (1H-pyrazol-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2-fluoro-9-(2 (isobutylamino)ethyl)-9H-purin-6-amine; 1-(4-(2-(8-((7-(1H-pyrazol-3-yl)-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-6-amino-2-fluoro-9H-purin-9-yl)ethyl)piperidin-1 yl)ethanone; 1-(3-(2-(8-((7-(1H-pyrazol-3-yl)-2,3- dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-6 amino-2-fluoro-9H-purin-9-yl)ethyl)piperidin-1-yl)ethanone; 8-((7-(1H-pyrazol-3-yl)-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2-fluoro-9-(2-(1-(methylsulfonyl)piperidin-3 yl)ethyl)-9H-purin-6-amine; 1-(3-(8-((7-(1H-pyrazol-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6 yl)methyl)-6-amino-2-fluoro-9H-purin-9-yl)propyl)pyrrolidin-3 -one; 8-((7-(1H-pyrazol-3-yl) 2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-9-(3-(tert-butylamino)propyl)-2-fluoro-9H- purin 6-amine; 1-(8-((7-(1H-pyrazol-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-6 amino-2-fluoro-9H-purin-9-yl)-3-(tert-butylamino)propan-2-ol; 5-(8-((7-(1H-pyrazol-3-yl) 2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-6-amino-2-fluoro-9H-purin-9-yl)pentane-1 sulfonamide; 6-(8-((7-(1H-pyrazol-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-6 amino-2-fluoro-9H-purin-9-yl)hexanamide; and 8-((7-(1H-pyrazol-3-yl)-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-9-(2-aminoethyl)-2-fluoro-9H-purin-6-amine.

31. The compound of claim 28, wherein X 2 is furanyl.

32. The compound of claim 31, wherein the compound is selected from the group consisting of: 8-((7-(furan-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9-(3 (isopropylamino)propyl)-9H-purin-6-amine; 9-(3-(isopropylamino)propyl)-8-((7-(5 methylfuran-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9H-purin-6-amine; 8-((7-(5 methylfuran-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9-(2-(neopentylamino)ethyl)-9H purin-6-amine; 8-((7-(5-(aminomethyl)furan-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio) 9-(2-(neopentylamino)ethyl)-9H-purin-6-amine; 8-(7-(5-methylfuran-2-yl)-2,3 dihydrobenzo[b][1,4]dioxin-6-ylthio)-9-(2-(1-(methylsulfonyl)piperidin-3-yl)ethyl)-9H-purin- 6 amine; 1-(3-(2-(6-amino-8-(7-(5-methylfuran-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6- ylthio) 9H-purin-9-yl)ethyl)piperidin-1-yl)ethanone; 1-(4-(2-(6-amino-8-((7-(5-methylfuran-2- 233 yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9H-purin-9-yl)ethyl)piperidin-1-yl)ethanone; 1 (3-(2-(6-amino-8-(7-(5-(aminomethyl)furan-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio) 9H-purin-9-yl)ethyl)piperidin-1-yl)ethanone; 5-(6-amino-8-(7-(5-methylfuran-2-yl)-2,3 dihydrobenzo[b][1,4]dioxin-6-ylthio)-9H-purin-9-yl)pentane-1-sulfonamide; 1-(3-(6-amino-8 (7-(5-methylfuran-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-9H-purin-9 yl)propyl)pyrrolidin-3 -one; 1-(6-amino-8-((7-(5-methylfuran-2-yl)-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9H-purin-9-yl)-3-(isopropylamino)propan-2-ol; 9-(3 aminopropyl)-8-(7-(5-methylfuran-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-9H-purin- 6 amine; N-(2-((2-(6-amino-8-((7-(furan-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9H purin-9-yl)ethyl)amino)ethyl)sulfamide; 3-((2-(6-amino-8-((7-(furan-2-yl)-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9H-purin-9-yl)ethyl)amino)-N-hydroxypropanamide; 9 (3-(tert-butylamino)propyl)-8-(7-(5-methylfuran-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6 ylthio)-9H-purin-6-amine; 6-(6-amino-2-fluoro-8-((7-(5-methyloxazol-2-yl)-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-9H-purin-9-yl)hexanamide; 2-fluoro-8-((7-(5 methylfuran-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-9-(2-(1 (methylsulfonyl)piperidin-3-yl)ethyl)-9H-purin-6-amine; 1-(3-(2-(6-amino-2-fluoro-8-((7-(5 methylfuran-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-9H-purin-9- yl)ethyl)piperidin 1-yl)ethanone; 1-(4-(2-(6-amino-2-fluoro-8-((7-(5-methylfuran-2-yl)-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-9H-purin-9-yl)ethyl)piperidin-1-yl)ethanone; 1-(3 (2-(6-amino-8-((7-(5-(aminomethyl)furan-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)- 2 fluoro-9H-purin-9-yl)ethyl)piperidin-1-yl)ethanone; 2-fluoro-8-((7-(furan-2-yl)-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-9-(2-(isobutylamino)ethyl)-9H-purin-6-amine; 2 fluoro-9-(2-(isobutylamino)ethyl)-8-((7-(5 -methylfuran-2-yl)-2,3 -dihydrobenzo [b] [1,4]dioxin 6-yl)methyl)-9H-purin-6-amine; 8-((7-(5-(aminomethyl)furan-2-yl)-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2-fluoro-9-(2-(isobutylamino)ethyl)-9H-purin-6 amine; 1-(3-(6-amino-2-fluoro-8-((7-(5-methyloxazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6 yl)methyl)-9H-purin-9-yl)propyl)pyrrolidin-3-one; 2-chloro-8-((7-(5-methylfuran-2-yl)-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-9-(2-(1-(methylsulfonyl)pyrrolidin-3-yl)ethyl)-9H purin-6-amine; 9-(3-aminopropyl)-2-fluoro-8-((7-(5-methylfuran-2-yl)-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-9H-purin-6-amine; 5-(6-amino-2-fluoro-8-((7-(5 methylfuran-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-9H-purin-9-yl)pentane-1- 234 sulfonamide; and 6-(6-amino-2-fluoro-8-((7-(5-methylfuran-2-yl)-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-9H-purin-9-yl)hexanamide.

33. The compound of claim 28, wherein X 2 is oxazolyl.

34. The compound of claim 33, wherein the compound is selected from the group consisting of: 1-(3-(6-amino-8-(7-(oxazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-9H purin-9-yl)propyl)pyrrolidin-3 -one; 6-(6-amino-8-(7-(5-methyloxazol-2-yl)-2,3 dihydrobenzo[b][1,4]dioxin-6-ylthio)-9H-purin-9-yl)hexanamide; 8-(7-(5-methyloxazol-2-yl) 2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-9-(2-(neopentylamino)ethyl)-9H-purin-6-amine; 1 (3-(2-(6-amino-8-(7-(5-methyloxazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-9H purin-9-yl)ethyl)piperidin-1-yl)ethanone; 1-(4-(2-(6-amino-8-((7-(5-methyloxazol-2-yl)-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9H-purin-9-yl)ethyl)piperidin-1-yl)ethanone; 8-((7-(5 methyloxazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9-(2-(1- (methylsulfonyl)piperidin 3-yl)ethyl)-9H-purin-6-amine; 5-(6-amino-8-(7-(5-methyloxazol-2- yl)-2,3 dihydrobenzo[b][1,4]dioxin-6-ylthio)-9H-purin-9-yl)pentane-1-sulfonamide; N-(3-(6- amino-8 ((7-(5-methyloxazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9H-purin-9 yl)propyl)methanesulfonamide; 1-(2-(4-(6-amino-8-(7-(5-methyloxazol-2-yl)-2,3 dihydrobenzo[b][1,4]dioxin-6-ylthio)-9H-purin-9-yl)butyl)pyrrolidin-1-yl)ethanone; 1-(6 amino-8-((7-(5-methyloxazol-2-yl)-2,3 -dihydrobenzo [b] [1,4] dioxin-6-yl)thio)-9H-purin-9-yl)- 3 (isopropylamino)propan-2-ol; 9-(3-(tert-butylamino)propyl)-8-((7-(oxazol-2-yl)-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9H-purin-6-amine; 9-(3-aminopropyl)-8-((7-(oxazol-2 yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9H-purin-6-amine; 8-((7-(furan-2-yl)-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9-(2-(isobutylamino)ethyl)-9H-purin-6-amine; 9-(3 (isopropylamino)propyl)-8-((7-(oxazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9H purin-6-amine; 1-(2-(4-(6-amino-8-(7-(5-methyloxazol-2-yl)-2,3 -dihydrobenzo[b] [1,4] dioxin 6-ylthio)-9H-purin-9-yl)butyl)pyrrolidin-1-yl)ethanone; 1-(4-(2-(6-amino-8-((7-(5 methyloxazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9H-purin-9-yl)ethyl)piperidin- 1 yl)ethanone; 8-((7-(5-methyloxazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9-(2-(1 (methylsulfonyl)piperidin-3-yl)ethyl)-9H-purin-6-amine; 2-fluoro-9-(3 (isopropylamino)propyl)-8-((7-(oxazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)- 235 9H-purin-6-amine; 2-fluoro-9-(3-(isopropylamino)propyl)-8-((7-(5-methyloxazol-2-yl)-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-9H-purin-6-amine; 9-(3-(tert-butylamino)propyl)-2 fluoro-8-((7-(oxazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-9H-purin-6-amine; 9 (3-(tert-butylamino)propyl)-2-fluoro-8-((7-(5-methyloxazol-2-yl)-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-9H-purin-6-amine; 6-(6-amino-2-fluoro-8-((7-(5 methyloxazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-9H-purin-9-yl)hexanamide; 5-(6-amino-2-fluoro-8-((7-(5-methyloxazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6 yl)methyl)-9H-purin-9-yl)pentane-1-sulfonamide; 1-(3-(6-amino-2-fluoro-8-((7-(5 methyloxazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-9H-purin-9 yl)propyl)pyrrolidin-3 -one; 1-(3-(6-amino-2-fluoro-8-((7-(oxazol-2-yl)-2,3 dihydrobenzo [b] [1,4]dioxin-6-yl)methyl)-9H-purin-9-yl)propyl)pyrrolidin-3 -one; and 9-(3 aminopropyl)-2-fluoro-8-((7-(5-methyloxazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6 yl)methyl)-9H-purin-6-amine.

35. The compound of claim 24, wherein X 2 is alkynyl.

36. The compound of claim 35, wherein the compound is selected from the group consisting of: 8-((7-ethynyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9-(3 (isopropylamino)propyl)-9H-purin-6-amine; 3-(3-(6-amino-8-(7-ethynyl-2,3 dihydrobenzo[b][1,4]dioxin-6-ylthio)-9H-purin-9-yl)propyl)pyrrolidine-1-carbaldehyde; 8-((7 ethynyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9-(2-(neopentylamino)ethyl)-9H-purin-6 amine; 9-(2-aminoethyl)-8-((7-ethynyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9H-purin-6 amine; 1-(3-(2-(6-amino-8-(7-ethynyl-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-9H-purin-9 yl)ethyl)piperidin-1-yl)ethanone; 8-(7-ethynyl-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-9-(2 (1-(methylsulfonyl)piperidin-3-yl)ethyl)-9H-purin-6-amine; N-(2-((2-(6-amino-8-((7-ethynyl 2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9H-purin-9-yl)ethyl)amino)ethyl)sulfamide; 9-(3 aminopropyl)-8-((7-ethynyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9H-purin-6-amine; 6 (6-amino-8-(7-ethynyl-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-9H-purin-9-yl)hexanamide; 5 (6-amino-8-(7-ethynyl-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-9H-purin-9-yl)pentane-1 sulfonamide; 1-(6-amino-8-((7-ethynyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9H-purin-9 yl)-3-(isopropylamino)propan-2-ol; 9-(3-(tert-butylamino)propyl)-8-(7-ethynyl-2,3- 236 dihydrobenzo[b][1,4]dioxin-6-ylthio)-9H-purin-6-amine; 8-(7-ethynyl-2,3 dihydrobenzo[b][1,4]dioxin-6-ylthio)-9-(2-(1-methylpiperidin-2-yl)ethyl)-9H-purin-6-amine; 8 (7-ethynyl-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-9-(2-(1-methylpiperidin-3-yl)ethyl)- 9H purin-6-amine; 9-(2-aminoethyl)-8-(7-ethynyl-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)- 9H purin-6-amine; 8-((7-ethynyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2-fluoro-9-(2 (isobutylamino)ethyl)-9H-purin-6-amine; 8-((7-ethynyl-2,3-dihydrobenzo[b][1,4]dioxin-6 yl)methyl)-2-fluoro-9-(2-(1-(methylsulfonyl)piperidin-3-yl)ethyl)-9H-purin-6-amine; 1-(3-(2 (6-amino-8-((7-ethynyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2-fluoro-9H-purin-9 yl)ethyl)piperidin-1-yl)ethanone; 3-(2-(6-amino-8-((7-ethynyl-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2-fluoro-9H-purin-9-yl)ethyl)piperidine-1 carbaldehyde; 1-(3-(6-amino-8-((7-ethynyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2 fluoro-9H-purin-9-yl)propyl)pyrrolidin-3 -one; 6-(6-amino-8-((7-ethynyl-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2-fluoro-9H-purin-9-yl)hexanamide; 1-(6-amino-8 ((7-ethynyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2-fluoro-9H-purin-9-yl)-3-(tert butylamino)propan-2-ol; 5-(6-amino-8-((7-ethynyl-2,3-dihydrobenzo[b][1,4]dioxin-6 yl)methyl)-2-fluoro-9H-purin-9-yl)pentane-1-sulfonamide; 8-((7-ethynyl-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2-fluoro-9-(3-(isopropylamino)propyl)-9H-purin-6 amine; 9-(3-(tert-butylamino)propyl)-8-((7-ethynyl-2,3-dihydrobenzo[b][1,4]dioxin-6 yl)methyl)-2-fluoro-9H-purin-6-amine; 9-(3-aminopropyl)-8-((7-ethynyl-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2-fluoro-9H-purin-6-amine; 8-((7-ethynyl-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2-fluoro-9-(2-(1-methylpiperidin-2-yl)ethyl)-9H purin-6-amine; and 8-((7-ethynyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2-fluoro-9-(2 (1-methylpiperidin-3-yl)ethyl)-9H-purin-6-amine.

37. A compound of the formula: NH 2 X2 Z 1 N. Z 3 -Y X~c X 4 Z 2 NIX R Xb-Xd wherein (a) each of Z 1 , Z 2 and Z 3 is independently CH or N; 237 (b) Xa, Xc, Xd and Xb are all carbon connected by single or double bonds; (c) Y is -CH 2 -, -0- or -S-; (d) X 4 is hydrogen or halogen; (e) X 2 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, saturated heterocycle, unsaturated heterocycle, halogen, aryloxy, alkoxy, halogenated alkoxy, alkenyloxy, hydroxyalkyl, amino, alkylamino, dialkylamino, acylamino, carbamyl, amido, alkylamido, dialkylamido, sulfonamido, alkylsulfonamido, trihalocarbon, -thioalkyl, -SO2-alkyl, -C(=O)O-alkyl, -C(=O)-alkyl, -OH, -NO 2 , -CN or alkyl CN; and (f) R is: (a) hydrogen; or (b) a straight-chain- or branched- C1 to Cio alkyl, C 2 to C 6 alkenyl, or C 2 to C 6 alkynyl, which is unsubstituted or substituted; or (c) aryl, heteroaryl, heterocyclic, cycloalkyl, alkylaryl, or arylalkyl, which is unsubstituted or substituted; or (d) -SR 71 , -S(O)R 71 , -S0 2 R 7 1 , -OR 71 , -COOR 71 , -CONR 71 R 7 2 , -CN, R7AOR7B, -R7ANR7B, -R7ANR71R7B, -R7ASR7B, -R7AS(O)R7B, -R7ASO2R7B, NR 71 R 72 , -OSO 2 N(R 7 c) 2 , -N(R 7 c)SO 2 OH, -N(R 7 c)SO 2 R 7 c, -R7AOSO2N(R7c)2, or -R 7 AN(R 7 )OS0 2 R 7 C, wherein each R 71 and R 7 2 is independently selected from the group consisting of hydrogen, COOR7B, CON(R 7 c) 2 , C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, -R7AOR7B, -R7ANR7B, -R7ASR7B, R7AS(O)R7B, -R7ASO2R7B, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, and heteroarylalkyl, each R7A IS independently C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl, and each R7B is independently hydrogen, C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, -SO 2 OH, SO2N(R7A)2, -SO2NHR7A, or -SO 2 NH 2 ; and 238 each R 7 c is independently hydrogen, C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, or heteroarylalkyl; or (e) -M 1 -M 2 -M 3 -M 4 , wherein: Mi is absent, C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, aryl, or heteroaryl, M 2 is absent, 0, S, S(O), SO 2 , N(Rss), or C=0), M 3 is absent, C(=O), 0, S, S(O), SO 2 , or N(Rss), and M 4 is hydrogen, halogen, CN, N 3 , hydroxy, amino, substituted amino, CF 3 , C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein Rss is hydrogen, aliphatic, substituted aliphatic, or acyl.

38. A compound of the formula NH 2 X x N N X 4 R OR 1 wherein (a) R 1 is alkyl; (b) Y is -CH 2 - or -S-; (c) X 4 is H or halogen; (d) X 2 is a saturated non-aromatic carbocycle, an unsaturated non-aromatic carbocycle, a saturated heterocycle, an unsaturated heterocycle, an aryl, an alkylamino, a dialkylamino, an alkynyl, or is part of a ring formed by joining X 2 and R; and (e) R is hydrogen or linear, branched, or cyclic alkyl, alkenyl, or alkynyl, optionally including N, S, or 0, and optionally part of an 8 to 10 member ring formed by joining the 2'-position X 2 and R. (Support: PCT claim 39) 239

39. The compound of any one of claims 1, 2, 4, 5, 7, 9, 11, 13, 14, 15, 17, 21-26, 28, 29, 31, 33, 35, and 37, wherein Z 1 , Z 2 , and Z 3 are each N.

40. The compound of any one of claims 1, 2, 4, 5, 7, 9, 11, 13, 14, 15, 17, 21-26, 28, 29, 31, 33, 35, and 37, wherein Z 2 or Z 3 is CH.

41. The compound of claim 40, wherein Z 3 is CH.

42. The compound of any one of claims 1, 2, 4, 5, 7, 9, 11, 13, 14, 15, 17, 21-26, 28, 29, 31, 33, 35, and 37, wherein Zi and Z 3 are N and Z 2 is CH.

43. The compound of any one of claims 39-42, wherein R is 2-(methyl, t-butyl amino)ethyl, 2-(methyl, isopropyl-amino)ethyl, 3-(neopentyl-amino)propyl, 2-(isobutyl amino)ethyl, 2-(ethyl, isopropyl-amino)ethyl, 3-(isopropyl-amino)propyl, 3-(t-butyl amino)propyl, 2-(isopropyl-amino)ethyl, 2-(hydroxyethyl, isopropyl-amino)ethyl, 3 (cyclopentylamino)propyl, 3-(cyclopentyl, methyl-amino)propyl, 3-(ethylamino)propyl, 3 (ethyl, methyl-amino)propyl, 2-(neopentyl-amino)ethyl, 3-(methyl, isopropyl-amino)propyl, 3 (ethyl, isopropyl-amino)propyl, 3-(hydroxyethyl, isopropyl-amino)propyl, 3-(methyl, propargyl-amino)propyl, 2-(methyl, propargyl-amino)ethyl, 3-(allyl, methyl-amino)propyl, 3 (propyl, cyclopropylmethyl-amino)propyl, 3-(hydroxyethyl, cyclohexyl-amino)propyl, 2 (cyclopropylmethyl-amino)ethyl, and 2-(methyl, isobutyl-amino)ethyl.

44. The compound of claim 43, wherein R is 3-(isopropyl-amino)propyl.

45. The compound of claim 43 or 44, wherein Y is S, X 4 is H, and X 2 is acetylenyl, 2 furanyl, 3-furanyl, 5-methyl-2-furanyl, 2-thiophene, 3-thiophene, 2-pyrazolyl, 3-pyrazolyl, 2 thiazolyl, 5-methyl-2-thiazolyl, 2-oxazolyl, 5-methyl-2-oxazolyl, or optionally substituted imidazole. 240

46. The compound of claim 43 or 44, wherein Y is S, X 4 is H, and X 2 is acetylenyl, 2 furanyl, 3-furanyl, 5-methyl-2-furanyl, 2-pyrazolyl, 3-pyrazolyl, 2-thiazolyl, 5-methyl-2 thiazolyl, 2-oxazolyl, or 5-methyl-2-oxazolyl.

47. Use of a compound in accordance with any preceding claim in formulating a pharmaceutical composition for the inhibition of Hsp90.

48. Use of a compound in accordance with any one of claims 1-46 in formulating a pharmaceutical composition for the treatment of cancer or neurodegenerative disease.

49. A method of treating cancer or neurodegenerative disease comprising administering a therapeutically effective amount of a compound in accordance with any one of claims 1-46.