AU2013204899B2

AU2013204899B2 - Purine derivatives useful as hsp90 inhibitors

Info

Publication number: AU2013204899B2
Application number: AU2013204899A
Authority: AU
Inventors: Gabriela Chiosis; Weilin Sun; Tony Taldone
Original assignee: Sloan Kettering Institute for Cancer Research
Current assignee: Sloan Kettering Institute for Cancer Research
Priority date: 2009-10-07
Filing date: 2013-04-12
Publication date: 2016-05-12
Anticipated expiration: 2030-10-07
Also published as: AU2013204882A1; AU2013204891A1; AU2013204891B2; AU2013204899A1; AU2013204109B2; AU2013204109A1; AU2013204882B2

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. NH 2 NH 2 X -Y-O ,xa ) -yXa X4 Z2 Nkc x4 R2XNc R X R Xb-Xd 4 z2 N Z1-Z3, Xa-Xc X 2, 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, Hsp 90 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 Hsp90 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 X2 Z1 Z Z Z KY rY Xa

X

4

Z

2 . I Xc R X c R Xb (lA) or R Xb-Xd (1B) wherein Z 1, 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 Z 2 % R Xc Xb (IC) wherein Zi, 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 ECso and IC5 0 being reported in both micromolar and nanomolar ranges.

4 Summary of the Invention The present application provides compounds useful in the inhibition of Hsp90, and hence in the treatment of disease. In a preferred embodiment, the present invention provides a compound of the formula: NH2 X2 Z Z Y X RXb-Xd wherein (a) each of Zi, Z 2 and Z 3 is 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 which is F, Cl, or I, or cyano and R is suitably a primary amino alkyl, a secondary or tertiary alkyl-amino-alkyl, a trialkylammonioalkyl group, 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 7 1 , -S0 2

R

71 , -OR 7 1 , -COOR 7 1 , -CONR 71

R

72 , -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 -R7AN(R7c)OS02R7c, wherein each R 7 1 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, 4a alkylaryl, arylalkyl, alkylheteroaryl, and heteroarylalkyl, each R7A is independently Ci 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 R7C is independently hydrogen, CI to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, or heteroarylalkyl. In this specification, the term 'comprises' and its variants are not intended to exclude the presence of other integers, components or steps. In this specification, references to prior art are not intended to acknowledge or suggest that such prior art is part of the common general knowledge in Australia or that a person skilled in the relevant art could be reasonably expected to have ascertained, understood and regarded it as relevant. Brief Description of the Figures Fig. 1 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-HC1 or with vehicle. Detailed Desciption of the Invention The present invention provides compounds within the scope of Formula 1 A, TB 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 4b 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, "alkyl" 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 carbocyctes. 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. "Alkynyl" 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 X 2 ,

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 NH1 2 , 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 Zi, 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, Thus, the compounds of this embodiment may be represented by the general formula

NH

2 NN N U.A j-Y \/Xa X(N N\_ XNNXb R (2) wherein: one of Xa and Xb is 0 and the other is -CH-; Y is -CH- or -S-, X4 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-(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) propyt. Specific examples of compounds in accordance with this embodiment of the invention are listed in Tables 1A and lB (Compounds lA-i to lA-4, IA-6, IA-11, 1A-18 to lA-28, 1A-30, lA-31, 1A-49, lB-1 to 1B-5, 1B-18, 1B-23 to lB-25, 1B-29 to 1B-32, 1B-34,lB-35, 1B-37, 12-49, 1B-52 1B-56 andlB-57). As shown, in preferred embodiments of formula (2), X4 is H, chlorine or fluorine. In a particular preferred embodiment of formula (2), Y is S, X4 is H, X 2 is . In a particular preferred embodiment of formula (2), Y is CH 2 , X4 is Cl, X 2 is I. In a particular preferred embodiment of formula (2), Y is CH 2 , X4 is F, X 2 is 1. In a particular preferred embodiment of formula (2), Y is S, X4 is F, X 2 is . Tests were run on compounds in accordance with the first embodiment of the invention, and the ECo 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 ECso 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-HZl50 disclosed in US WO 2011/044394 PCT/US2010/051872 9 12/307,063) which has an ECso of 12-14.4 nM and compound lB-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-i -HCl 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 mm3 were treated i.p. (i.p.) using lB-1-HC1 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 lB-i-HCl decreased. Table 2B shows measured values for ECso in JNPL3 brain cell lysates for compounds lB-3, 1B-4 and lB-25 in accordance with this embodiment of the invention which incorporates a fluorine as X 4 and in which Y is -CH 2 -. Desirably low values of ECso were observed. In addition, Table 2B shows measured values for EC 5 o in JNPL3 brain cell lysates for compound lB-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 EC 0 were observed. A-IL. 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-(hydroxyethy, 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: site of 9N-attachrmnt N,xR 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 0 H H i

X-(CH

2 )fr-N-(CH 2 )n-N-S-NH 2 I I 0 0 X-(CH2)n-O-S-NH 2 where m= 2-3 and n= 1-6.

WO 2011/044394 PCT/US2010/051872 11 In embodiments within this group, R has the formula site of 9N-attachrnt H X-(CH)-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, X 2 is a furan, thiophene, pyrazole, imidazole, oxazole or thiazole. In particular embodiments of formula (2), Y is S, X 4 is H, X 2 is 2-, 3-furan or 5 methyl-2-furanyl. In particular embodiments of formula (2), Y is CH2, X4 is Cl, X 2 is 2-, 3- firan or 5 methyl-2-furanyl. 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-furanyl. In particular embodiments of formula (2), Y is 5, X 4 is H, X2 is 2- or 3-thiophene. In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X2 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 CH 2 , X4 is Cl, X2 is 2- or 3- pyrazole. In particular embodiments of formula (2), Y is CH 2 , X4 is F, X2 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.

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, 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, 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 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-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 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 lA and 1B (Compounds IA-5, 1A-7, IA-12, 1A-13, 1A-15 to lA-17, 1A 36, 1A-37, IA-42, IA-45 to 1A-48, IA-50 to lA-52, 1B-6, 1B-8, 1B-12, 1B-14, 1B-15, 1B 17, 1B-26, lB-27, IB-33, 1B-42 to 12-44, 1B-46, 1B-50, 13-51, 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 EC5o in JNPL3 brain cell lysates for compounds 1B-26 and 1B-27 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 EC5 0 were observed.

A-III. 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-(lH-imidazoyl) propyl. In embodiments of formula (2) within this group, R has the formula: site of 9N-attachnrent N'R NR1 X,, ,' N. R 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

X-(CH

2

)-N-(CH

2

)-N--NH

2 0 0

X-(CH

2 )n-O-S-NH 2 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-attachment H X-(CH-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, 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, 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 IA-8, IA-14, lA-29, 1A-32 to 1A-35, IB-10, lB-13, 1B-16, IB-19, IB-28, IB-36, IB-38 to IB-41, lB-45 IB-47 and IB-58). As shown, in preferred embodiments of formula (2) in which X 2 is an alkynyl group, X4 is H, chlorine or fluorine. Table 2D shows a measured value for EC 0 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 ECso was observed. A-IV. In some embodiments of the invention, X 2 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-aniino) 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-(1H-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 , X 4 is Cl, X 2 is CN. In a particular preferred embodiment of formula (2), Y is CH2, X 4 is F, X2 is CN. In a particular preferred embodiment of formula (2), Y is S, X4 is F, X2 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-I1 and 1B-20). A-V. In some embodiments of the invention, X2 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-attachnrnt NR1

-.

R1 xNR 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 00 X-(CH)m-NH 2 -- NH 0 X-(CH2)n-O-S-NH2 where m= 2-3 and n= 1-6. In embodiments within this group, R has the formula site of 9N-attachmnt H x-(CH2)m-N-(CH2)n H 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, X 2 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 , X4 is F, X 2 is dimethylamino. In a particular preferred embodiment of formula (2), Y is S, X4 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 aziridino. In a particular preferred embodiment of formula (2), Y is CH 2 , X4 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 1A-10, 1A-38 to 1A-41, 1A-43, 1A-44, 1B-7, lB-21 and 1B-48). A-VL In some embodiments of the invention, X2 is a cycloalkyl or a cycloalkenyl. In these embodiments, R may be any of the groups disclosed as a substitient 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-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, 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: WO 2011/044394 PCT/US2010/051872 18 site of 9N-affachment N.. 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-attachmert H H 1

X-(CH-N-(CH

2 )n-N-S-NH2 0 0 X-(CH2A-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-attachnrnt H 0 X-(C H2Xyn-N-(CH2)n4 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 CH2, 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 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 IB (Compounds 1 B-9, and I 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

2 , Thus, the compounds of this embodiment may be represented by the general formula

NH

2 NN N X'- \>Xa X4 N N \ Xb R (2) wherein: one of Xa and Xb is S 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 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, methylamino) 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-aitachment N, where R, is selected from COH, COMe, COEt, COnPr, COr~r, 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. 0 H H 1 X-(CHyn-N-(CH 2 )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 21 site of 9N-attachment H X-(C H -N---(CH2)fn HlhOH 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, carbamyl, amido, dialkylamido, alkylamido, alkylsulfonamido, sulfonamide, trihalocarbon, -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, X2 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, 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. 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 (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-(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-(hydroxycthyl, 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-(metbyl, t-butyl- amino) ethyl, 2 7 -(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)-propy, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(metbyl, 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 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 -CH2- or -S-;

X

4 is hydrogen or halogen; and

X

2 and R are in combinations as discussed below. C-. 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 heteroaton 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 H1

X-(CH

2 )n-N-(CH 2 )n-N-S-NH 2 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 site of 9N-attachment H X-(C H2yn-N-(CH2)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 IE-4, 1E-6, 1E-18, 1E-21, lE-23 to 1E-26, 1E 35, 1E-38, 1E-39, IE-42 to IE-48, lE-68 to IE-76). As shown, in preferred embodiments of formula (2), X4 is H, chlorine or fluorine. In a particular preferred embodiment of formula (2), Y is S, X4 is H, X 2 is L In a particular preferred embodiment of formula (2), Y is CH 2 , X4 is Cl, X 2 is I. In a particular preferred embodiment of formula (2), Y is CH 2 , X4 is F,.X 2 is 1. In a particular preferred embodiment of formula (2), Y is S, X4 is F, X 2 is I. Table 2E shows measured values for ECso in JNPL3 brain and SKBr3 cell lysates for compounds IE-2, 1E21 and 1E-23 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. C-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 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, cyclopropylinethyl 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-(JH-imidazoyl) propyl. In embodiments of formula (2) within this group, R has the formula: site of 9N-attachnent xR1NR

N

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

X-(CH

2 )mN-(CH 2 ) -N-S-NH 2 0 0

X-(CHA---S-NH

2 0 where m= 2-3 and n= 1-6. In embodiments within this group, R has the formula site of 9N-attachnrnt H 0 X-(CH2XT -N-(CH2)nHNO H N-OH where m= 2-3 and n= 1-6. In specific embodiments, X2 is an aromatic heterocycle. In specific embodiments, X2 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, X2 is an aromatic heterocycle. In specific embodiments, X 2 is a ftran, thiophene, pyrazole, imidazole, pyrrole, oxazole or thiazole. In specific embodiments, X2 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-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 CH2, X4 is F, X2 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-furan or 5 methyl-2-firanyl. In particular embodiments of formula (2), Y is S, X4 is H, X2 is 2- or 3-thiophene. In particular embodiments of formula (2), Y is CH 2 , X4 is Cl, X2 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, X 4 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 , X4 is F, X2 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 , X4 is Cl, X 2 is 2-thiazolyl, 5 methyl-2-thiazoly, 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 l E (Compounds IE-5, 1E-7, 1E-1I to lE-13, 1E-15 to 1E-17, 1E-27, 1E 29 to lE-33, IE-36, lE-37, 1E-41, IE-59 to lE-76, 1E-84 and 1E-85). As shown, in preferred embodiments of formula (2) in which X2 is an aryl group, X4 is H, chlorine or fluorine. C-I. In some embodiments of the invention, X2 is an alkynyl group. In these embodiments, R may be as described above in Section CII, In specific embodiments, X2 is acetylene. In particular embodiments of formula (2), Y is S, X4 is H, X2 is acetylene. In particular embodiments of formula (2), Y is CH2,. X4 is Cl, X2 is acetylene. In particular embodiments of formula (2), Y is CH 2 , X 4 is F, X2 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. Specific examples of compounds in accordance with this embodiment of the invention are listed in Tables IE (Compounds 1E-8, 1E-14, lE-19. 1E-20, IE-22, 1E-40, IE-49 to IE 58 and 1E-77 to lE-82). As shown, in preferred embodiments of formula (2) in which X2 is an alkynyl group, X4 is H, chlorine or fluorine. Table 2F shows a measured value for EC5 0 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 ECSO 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-Il, 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 CH2, X 4 is C, 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, 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, X2 is an amino group. In these particular embodiments, R may be any one of the types of groups described in Section C-1t In a particular preferred embodiment of formula (2), Y is S, X4 is H, X2 is azetidino. In a particular preferred embodiment of formula (2), Y is CH2, X4 is Cl, X 2 is, azetidino. In a particular preferred embodiment of formula (2), Y is CH2, X 4 is F, X2 is azetidino. In a particular preferred embodiment of formula (2), Y is S, X 4 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, lE-28 and [E-34). C-V. In some embodiments of the invention, X2 is a cycloalkyl or a cycloalkenyl. In these particular embodiments, R may be any one of the types of groups described in Section C-IL In specific embodiments, X2 is a cycloalkyl with one ring. In specific embodiments, X2 is a cyclopropane, cyclobutane or cyclopentane. In particular embodiments of formula (2), Y is S, X 4 is H, X2 is cyclopentyl. In particular embodiments of formula (2), Y is CH2, X 4 is Cl, X2 is cyclopentyl. In particular embodiments of formula (2), Y is CH2, X4 is F, X2, is cyclopentyl. In particular embodiments of formula (2), Y is S, X 4 is F, X2 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 Xh is N In accordance with a fourth embodiment of the invention, the compounds have general formula IA, 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 N N -Q 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 further 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 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-(cyclopenfylamino)-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, 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. 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) WO 2011/044394 PCT/US2010/051872 33 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, X2 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, X2 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.

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-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- WO 2011/044394 PCT/US2010/051872 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 IA in which Xa or Xb is carbonyl or thiocarbonvi 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=0) or thiocarbonyl (C=S), and Xc and the other of Xa and Xb is CH2. Thus, the compounds of this embodiment may be represented by the general formula

NH

2 NN N Y' \/Xa X4 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-, X4 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-(1H-imidazoyl) propyl. In embodiments of formula (2) within this group when X 2 is thiocarbonyl, R may have the formula: site of 9N-attachment NX "1' N R 1 N. 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-att achment H H 9

X-(CH

2 m-N-(CH 2

)-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 within this group, R has the formula WO 2011/044394 PCT/US2010/051872 37 site of 9N-attachnEnt H0 x-(C H2y -N-(CH2)n. 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-(lH-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, cyclopropylnethyl 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 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-(1H-imidazoyl) propyl. In particular embodiments, X2 is 2- or 3-firan 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.

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-(lH-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 (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 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-(IH-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-(1H-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-alkyt, 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 I-H 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 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 C 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-(ethylanino) 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, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylinethyl 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 aryl group. In particular embodiments, X 2 is aryl 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 (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-(IH-imidazoyl) propyl. In particular embodiments, X 2 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 (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 some embodiments of the invention, X2 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-(1H-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, 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 some embodiments of the invention, X2 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, propargy 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 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-(1H-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-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, 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 IA, 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 N -Y \/Xa 4 N N \ - . - Xb R (2) wherein: in which Xa and Xb are O, Y is -CH 2 - or -S-,

X

4 is hydrogen or halogen; and X2 and R are in combinations as discussed below. G-I. In some embodiments of the invention, X2 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 nitrdgen, 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-atachment 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 0 H H i X-(CH2)m-N-(CH2)n-N-S-NH 2

X-(CHA-O-S-NH

2 where m= 2-3 and n= 1-6. In embodiments within this group, R has the formula site of 9N-attachment H X-(C H2 -(CH2)n

HN-OH

WO 2011/044394 PCT/US2010/051872 50 where m= 2-3 and n= 1-6. In specific embodiments, X2 is a heterocycle. In specific embodiments, X 2 is phenyl, furan, thiophene, pyrazole, imidazole, thiazole, oxazole or pyrrole. In specific embodiments of the X 2 is phenyl, furan, metbylfuran, 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 , X 4 is F, X2 is 2-, 3-furan or 5 methyl-2-furany1. In particular embodiments of formula (2), Y is S, X4 is F, X2 is 2-, 3-firan or 5 methyl-2-furanyl. In particular embodiments of formula (2), Y is S, X4 is H, X2 is 2- or 3-thiophene. In particular embodiments of formula (2), Y is CH2, X 4 is Cl, X 2 is 2- or 3- thiophene. In particular embodiments of formula (2), Y is CH2, X 4 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, X2 is 2- or 3-pyrazole. In particular embodiments of formula (2), Y is CH 2 , X4 is Cl, X2 is 2- or 3- pyrazole. In particular embodiments of formula (2), Y. is CH 2 , X4 is F, X2 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, 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 CH2, 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 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, X2 is 2-thiazolyl, 5-methyl 2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl.

WO 2011/044394 PCT/US2010/051872 51 In particular embodiments of formula (2), Y is S, X4 is H, X 2 is optionally substituted phenyl. In particular embodiments of formula (2), Y is CH2, 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, X4 is H, X2 is optionally substituted pyridine. In particular embodiments of formula (2), Y is CH 2 , X4 is Cl, X2 is optionally substituted pyridine. In particular embodiments of formula (2), Y is CH2, X4 is F, X 2 is optionally substituted pyridine. In particular embodiments of formula (2), Y is S, X4 is F, X 2 is optionally substituted pyridine. In particular embodiments of formula.(2), Y is S, X4 is H, X 2 is optionally substituted isooxazole. In particular embodiments of formula (2), Y is CH2, X4 is Cl, X 2 is optionally substituted isooxazole. In particular embodiments of formula (2), Y is CH2, X4 is F, X2 is optionally substituted isooxazole. In particular embodiments of formula (2), Y is S, X4 is F, X 2 is optionally substituted isooxazole. In particular embodiments of formula (2), Y is S, X4 is H, X2 is optionally substituted imidazole. In particular embodiments of formula (2), Y is CH2, X4 is Cl, X2 is optionally substituted imidazole. In particular embodiments of formula (2), Y is CH 2 , X 4 is F, X2 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, X4 is H, chlorine or fluorine. Table 2G shows measured values for EC5 0 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 4H-7 in accordance with this embodiment of the invention which incorporates a hydrogen as X4 and in which Y is S or a fluorine as X4 and in which Y is -- CHI2-. Desirably low values of EC5 0 were observed for several examples. G-IL. 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-(lH-imidazoyl) propyl. In embodiments of formula (2) when X 2 is alkynyl, R has the formula: site of 9N-attachnent xNR1 N,R1 N I 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 X 2 is alkynyl, R has the formula site of 9N-attachment H H 1

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 alkynyl, R has the formula site of 9N-attachnrnt H0 x-(C2y-N-(CH2) H N-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 , 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.

WO 2011/044394 PCT/US2010/051872 54 In these particular embodiments, R maybe 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 ECso 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 -CH 2 -. Desirably low values of ECso were observed. G-If. 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, cyclopropylnethyl 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, 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, X4 is F, X 2 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 0 H H 1

X-(CH

2 -N-(CH2)n-N-S-NH2 0 0 X-(CH2)n-O-S-NHZ 0 where m= 2-3 and n= 1-6, or site of 9N-atiachnent H x-(CH2Yd-N-(CH)n4 HWOH 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 ECso 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 X4 and in which Y is -CH2-. Desirably low values of ECso were observed for several examples. G-IV. In some embodiments of the invention, X2 is a cycloalkyl (saturated carbocyclic) or 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 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 (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: site of 9N-attachment R,~ 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 I

X-(CH

2

)-N-(CH

2 ) -N-S-NH 2 11 0 0

X-(CH

2 )n-O-S-NH 2 where m= 2-3 and n= 1-6. In embodiments when X 2 is aryl, R has the formula sie of 9N-attachrent H X-(CFyr-N-(CH2)n H O 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, X 4 is H, X 2 is cyclopentyl. In particular embodiments of formula (2), Y is CH 2 , X4 is F, X2 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 EC5 0 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 X 4 and in which Y is S. Desirably low values of ECso were observed for several examples. Table 2G shows results for ECs 0 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 EC5o for Hsp9O binding in JNPL3 brain cell lysates. As shown, all of the compounds tested were active, however, those with an acetylene substituent, such as 42-1, 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 ECso 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- 1l, 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- 11). Examples of compounds within this seventh embodiment of the invention, in which X2 is.an aryl group containing a sulfur atom in the aryl ring are shown in Table 4D. Table 2G shows results for EC 5 o 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 Xz= 2-thiazolyl, including both a nitrogen and an oxygen. Examples of compounds within this seventh embodiment of the invention, in which X2 is -CN or cyanoalkyl are shown in Table 4E. Table 21 shows results for ECso for Hsp 90 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 X2 is a 6-membered 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

0 for Esp90 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 X2 groups shown are 3-, 4- and 5-pyrazolyl. Other examples of X2 groups in this category are 4- or 5-imidazolyl. ECo 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 4G-3, 4G-6 and 4G-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

2 is a pyrrolyl group are shown in Table 4H. The specific X 2 groups shown are 2 or 3 pyrrolyl. ECs 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 1B, 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 N N X4 N N R (3) wherein Y is -CH 2 -, -0- or -S-; X4 is hydrogen or halogen; and

X

2 and R are as discussed below. H-. 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 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 X2 is 1, Y is S and X4 is H. Specific examples of compounds within this group are shown in Table 5A. Examples of compounds within this group, in which X2 is a halogen, are shown in Table 5A (5A-1 to 5A-19). Table 2M shows EC 50 values for binding of Hsp9O in JNPL3 brain cells for some of the compounds of Table 5A. All show values of less than 100 nM. H-. In some embodiments of compounds in accordance with formula (3), X2 is aryl. 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 X2 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-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) 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-(11H-imidazoyl)propyl. In embodiments of formula (2) when X 2 is aryl, R has the formula: site of 9N-atachrnt

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 when X 2 is aryl, R has the formula site of 9N-atachment 0 H H "

X-(CH

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

X-(CH

2 )n-O-S-N H 2 0 where m= 2-3 and n= 1-6. In embodiments when X 2 is aryl, R has the formula site of 9N-attachncnt H 0 X-(CH2mN(H) HN-OH where m= 2-3 and n= 1-6. In specific embodiments, X 2 is an aromatic heterocycle. In specific embodiments, X2 is a furan, 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-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-furanyl. 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, 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, X 4 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, X2 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. 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, 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 H, X 2 is 2-thiaiolyl, 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 , 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, X2 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 EC 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 EC5o 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 EC50 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-IL. In some embodiments of the invention, X2 is an alkynyl group. In these embodiments, R may be as described above in Section H-II. In specific embodiments, X2 is acetylene. In particular embodiments of formula (2), Y is S, X4 is H, X2 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 , X 4 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, X4 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, 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 CH2, X4 is F, X2 is CN. In a particular preferred embodiment of formula (2), Y is S, X4 is F, X2 is CN. In other embodiments in which X2 is cyano or cyanoalkyl group, R is site of 9N-attachment 0 H H 1

X-(CH

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

X-(CH

2 )n-O-S-NH 2 0 WO 2011/044394 PCT/US2010/051872 65 where m= 2-3 and n= 1-6, or site of 9N-attachnent H X-(CH2g-N-(CHzn 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 maybe 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 , X4 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 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-V. 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, X2 is cyclopentyl. In particular embodiments of formula (2), Y is CH 2 , X4 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 5H WO 2011/044394 PCT/US2010/051872 66 . 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 I B, 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-. 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-(lH-imidazoyl) propyl. In specific embodiments of the invention, X 2 is L In particular embodiments of the invention X 2 is I, Y is S and X4 is H. I-IL 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-(mcthyl, 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 (cyclopropylinethyl 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-attachnt N.. 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 X 2 is aryl, R has the formula site of 9N-atachment 0 H H r

X-(CH

2

)-N-(CH

2 )n-N-S-NH 2 0 0 11 X-(CH2)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 WO 2011/044394 PCT/US2010/051872 68 site of 9N-attachnent H X-(CH NN-(CH2) 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, 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-furan or 5 methyl-2-furanyl. In particular embodiments of formula (2), Y is CH2, X4 is Cl, X2 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-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-furanyl. 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 , 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, X2 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, X2 is 2- or 3-pyrazole. In particular embodiments of formula (2), Y is CH 2 , X4 is Cl, X2 is 2- or 3- pyrazole. In particular embodiments of formula (2), Y is CH 2 , X4 is F, X2 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 , X 4 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 , 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, 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 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, 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, 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 F, X2 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. I-III. In some embodiments of the invention, X 2 is an alkynyl group. In these embodiments, R may be as described above in Section I-II. In specific embodiments, X2 is acetylene. In particular embodiments of formula (2), Y is S, X4 is H, X2 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, X2 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, 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 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 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, 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 CH2, 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-attachment H H 1

X-(CH

2 )m-N-(CH 2 )n-N-SNH 2 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-(CHI-N-(CH2)n HWNOH where m= 2-3 and n1= 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, X 4 is H, X 2 is aziridino. In a particular preferred embodiment of formula (2), Y is CH 2 , X4 is Cl, X 2 is aziridino WO 2011/044394 PCT/US2010/051872 71 In a particular preferred embodiment of formula (2), Y is CH 2 , X4 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 1 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 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-(1H-imidazoyl) propyl. In embodiments of formula (2) when X 2 is aryl, R has the formula: site of 9N-attachment N,R where Ri is selected from COH, COMe, COEt, COnPr, COiPr, SO 2 Me, CH 2 QX 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-attachment H H 1

X-(CH

2 j-N-(CH 2 )n-NS-NfH 2 00

X-(CH

2 )n-O-S-NH 2

II

0 *where m= 2-3 and n= 1-6. In embodiments when X 2 is aryl, R has the formula site of 9N-attachment H X-(CH2)mN-(CH2)n

H

HN-OH 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 0 in JNPL3 brain cell lysates for compounds 6B-25 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 EC 0 were observed. K. Structures of formula 1C In some embodiments of the present invention having the general formula IC, the compounds of the invention can be represented by the general formula: WO 2011/044394 PCT/US2010/051872 73

NH

2 N? N N R OR 1 (4) in which R1 is alkyl, for example methyl or ethyl, Y is S or CH2,

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-(1H-imidazoyl) propyl. In embodiments of formula (3), R has the formula: WO 2011/044394 PCT/US2010/051872 74 site of 9N-attachment N. NRR 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 formula (3), R has the formula site of 9N-attachment H H 9

X-(CH

2 )r-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 of formula (3) R has the formula site of 9N-attachmnt H 0 X-(CH2yn--N-(CH 2 )n H N-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, dihydrofiuran, furan, dihydrothiophene, thiophene, pyrazole, itnidazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole, 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 ECso 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 ECo were observed, although X 2 = -OCH 3 was observed to be less active than X 2 = -0-CH 2 0- in every shown instance: 4C-5 vs 7C-13 (6.5 nM vs 84nM), 4D-3 vs 7D-3 (18.5nM vs 240nM) and 4G-9 vs 7E-6 (5.5nM vs 32nM). L. Structures in which X2 is alkynvl 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=0, 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, Z1, Z2, and Z3 are all nitrogen. In some embodiments, Z1 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 (1A), (1B) 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 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. In some embodiments, Z 1, 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 1-4: NN N, a,b N"' K j-SH K N N N HN H b 5 or 6 member ring

NH

2 X1 NH 2 X2 c,d N N N NN N ') 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) Cs2CO3, 1,2-dibromoethane or 1,3 dibromopropane; (d) HNR 1

R

2 , OMF, rt (e) X 2 M, Pd (cat.), DMF, 50-100 0C. Scheme 1.

WO 2011/044394 PCT/US2010/051872 77

NH

2

NH

2 HOOC N NH22 a, b N N+ N

H

2 N N NH 2 H 5 or 6 member ring

NH

2

NH

2 c, d,,e FN N rF NN F N N 71 n=1,2 n = 1, 2

NR

1

R

2 NR1R2 (a) triphenyl phosphite, pyridine, microwave; (b) HF-pyridine, NaNO 2 ; (c) NIS, acetonitrile, rt; (d) Cs 2

CO

3 , 1,2-dibromoethane or 1,3-dibromopropane; (e) HNR 1

R

2 , DMF, rt; (f X 2 M, Pd (cat.), DMF, 50-100 cC. Scheme 2. General Methods: 'H and 3 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. 1 3 C chemical shifts are reported in 6 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) H20 + 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 chromatography was performed using 230400 mesh silica gel (EMID). Specific compounds were synthesized as follows; WO 2011/044394 PCT/US2010/051872 78

NH

2 I

NH

2 N N 05 a 0 NH NH PU-H71 Reagents and conditions: (a) RB(OH) 2 , PdCL 2 (PPh 3

)

2 , NaHCO 3 , H20, DMF, 90 0 C. Scheme 3. Suzuki coupling of PU-H71. 9-(3-(isopropylanino)propy)-8-(6-phenylbenzo[d][1,3]dioxel-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 nnol). 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 nL) 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-NH3 (7N), 10:1) to give 19.8 ng (73%) of DZ2-388. 'H NMR (500 MHz, MeOH-d 4 ) 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, 1H), 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); "C NMR (125 MHz, MeOH-d4) S 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 C24H27N6O2S, 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 [DZ2-390]. 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 H20 (0.1 mL) and Pd(PPh 3

)

2 C12 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 904C 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 4 ) 8 8.11 (s, 1H), 7.27 (d, J= 8.4 Hz, 2H), 7.14 (s, 1 H), 7.12 (d, J =8.4 Hz, 2H), 6.86 (s, 1H), 6.06 (s, 2H), 3.93 (t, J= 6.9 Hz, 2H), 2.92 (septet, J=6.5 Hz, 1H); 2.61 (t, J= 7.3 Hz, 2H), 1.86 (m, 2H), 1.28 (s, 9H), 1.12 (d, J= 6.5 Hz, 6H); 13 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 28

H

35

N

6 0 2 S, 519.2542; found 519.2545; HPLC: method A Rt == 7.43, method 13 Rt = 9.45. 8-(6-(3,5-bis(trifluoromethyl)phenyl)benzold [1,3jdioxol-5-ylthio)-9-(3 (isopropylamino)propyl)-9H-purin-6-amine [DZ2-391J. 3,5 Bis(trfluoromethyl)phenylboronic acid (22.6 mg, 0.0877 nmol) 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*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 24.4 mg (70%) of DZ2-391. 'H NMR (500 MHz, CDC1 3 ) 6 8.22 (s, 1H), 7.79 (s, 3H), 7.12 (s, 1H), 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, CDC1 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) m/z [M+H]* called. 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 Rt = 9.38.

WO 2011/044394 PCT/US2010/051872 80 8-(6-(4-(dimethylamino)phenyl)benzo[d [1,3]dioxol-5-ylthio)-9-(3 (isopropylamino)propyl)-9H-purin-6-amine [DZ2-392J. 4-(Dimethylamino)phenylboronic acid (14.5 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 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 904C 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 25.3 mg (85%) of DZ2-392. 'H NMR (500 MHz, CDC13) S 8.24 (s, 1H), 7.13 (d, J= 8.7 Hz, 2H), 6.93 (s, 1H), 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, CDC1 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 2 6 H32N 7 0 2 S, 506.2338; found 506.2330; HPLC: method A Rt = 5.72, method B R 1 = 5.12. 9-(3-(isopropylamino)propyl)-8-(6-(thiophen-2-yl)benzoId][1,3]dioxol-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, 0.175 5 runol). 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(PPh3) 2 C1 2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90"C for 5 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2

C

2 :MeOH-NH 3 (7N), 12.5:1) to give 12.4 mg (45%) of DZ2-395. 'H NMR (500 MHz, CDCl3MeOH-d 4 ) 6 8.17 (s, 1H), 7.33 (dd, J= 1.4,4.9 Hz, 1H), 7.07 (s, 1H), 7.04 (s, 1H), 7.00-7.02 (m, 2H), 6.09 (s, 2H), 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); "C NMR (125 MHz, CDCI 3 /MeOH-d 4 ) 6 154.2, 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) m/z [M+H]* calcd. for C22H25NO 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[d] [1,3]dioxol-5-yltkio)-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

C

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 (CH2Cl 2 :MeOH-NH 3 (7N), 12.5:1) to give 19.1 mg (72%) of DZ3-4. 'H NMR (500 MHz, CDCI 3 /MeOH-d) 6 8.18 (s, 1H), 7.49 (d, J= 1.8 Hz, 1H), 7.25 (s, 1H), 6.96 (s, 1H), 6.71 (d, J= 3.3 Hz, 11), 6.47 (dd, J= 1.8, 3.2 Hz, 1H), 6.06 (s, 2H), 4.20 (t, J= 7.0 Hz, 2H), 2.87 (m, IH), 2.61 (t, J= 6.9 Hz, 2H), 2.00 (m, 2H), 1.14 (d, J= 6.3 Hz, 6H); "C NMR (125 MHz, CDC13/MeOH-d 4 ) 6 154.3, 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]* calcd. for C22H25N 6 0 3 S, 453.1709; found 453.1705; HPLC: method A Rt = 6.23, method B Rt = 6.82. 9-(3-(isopropylamino)propyl)-8-(6-(4-methoxyphenyl)benzojd] [1-,3]dioxol-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 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*C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH2C1 2 :MeOH-NH3 (7N), 12.5:1) to give 20.5 mg (71%) of DZ3-3. 'H NMR (500 MHz, CDC1 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 (m, 2H), 1.07 (d, J= 6.3 Hz, 6H); "C NMR (125 MHz, CDCl 3 ) 3 159.2, 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

2 5

H

2 9

N

6 0 3 S, 493.2022; found 493.2010; HPLC: method A R = 6.57, method B RE = 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 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 3.5 h. 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, CDCl 3 /MeOH-d4) 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, 1H), 6.89 (s, 1H), 6.11 (s, 2H), 4.07 (t, J= 6.8 Hz, 2H), 2.82 (m, 111), 2.51 (t, J= 6.8 Hz, 211), 1.91 (m, 2H), 1.13 (d, J= 6.3 Hz, 6H); "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) m/lz [M+H] t caled. for C23H 2 6

N

7 0 2 S, 464.1869; found 464.1848; HPLC: method A Rt = 5.13, method B Rt= 2.57. 8-(6-(4-bromophenyl)benzo[d] [1,3]dioxoi-5-ylthio)-9-(3-(isopropylamino)propyl)-9H purin-6-amine [DZ3-6]. 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 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), 4:5:2:1) to give 13.9 mg (44%) of DZ3-6. 1H NMR (500 MHz, CDC 3 ) 5 8.23 (s, 1H), 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, 2H), 5.69 (br s, 2H), 4.08 (t, J= 6.0 Hz, 2H), 2.91 (m, 1H), WO 2011/044394 PCT/US2010/051872 83 2.50 (t, J= 5.9 Hz, 2H), 1.98 (m, 2H), 1.20 (d, J= 6.4 Hz, 611); "C NMR (125 MHz, CDC1 3 /MeOH-d 4 ) 8 154.2, 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) z [M+H]f 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 R, = 8.30. 8-(6-(furan-3-yl)henzo[d] [1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-puria-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(PPh3) 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, CDC13/MeOH-d 4 ) 8 8.17 (s, 1H), 7.51 (s, 11), 7.44 (s, 111), 7,07 (s, 1H), 6.97 (s, 1H), 6.49 (s, 1H), 6.08 (s, 211), 4,17 (t, J= 6.9 Hz, 2H), 2.93 (septet, J= 6.4 Hz, 111), 2.64 (t, J= 7.1 Hz, 2H), 2.02 (m, 2H), 1.17 (d, J= 6.4 Hz, 6H); 1 3 C NMR (125 MHz, CDCI,/MeOH-d4) 8 154.1, 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) n/z [M+HJ calcd. for C 2 2

H

2 5

N

6 03S, 453.1709; found 453.1711; HPLC: method A Re = 6.18, method B R = 6.67. 5-(6-(6-amiino-9-(3-(isopropylamino)propyl)-9H-purin-8-ythio)benzo[d][1,31dioxol-5 yl)furan-2-carbaldehyde [DZ3-33]. 2-Formyl-5-furanylboronic 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 H20 (0,1 mL) and Pd(PPh3) 2 Cl 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 (hexane:CH 2

CI

2 :EtOAc:MeOH-NH3 (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, CDCl3/MeOH-d 4 ) 8 9.57 (s, 1H), 8.18 (s, 1H), 7.36 (d, J= 3.8 Hz, 1H), 7.32 (s, 1H), 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, 1fH), 2.93 (t, J= 6.8 Hz, 2H), 2.30 (m, 2H), 1.42 (d, J= 6.6 Hz, 6H); 1 3 C NMR (125 MHz, CDC13/MeOH-d 4 ) 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]* calcd. for C23H25N6O4S, 481.1658; found 481.1657; HPLC: method A R,=5.87, method B Ri= 5.93. 8-(6-(1H-pyrrol-2-yl)benzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H purin-6-amine [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 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 4 h. DMF was removed under reduced pressure and to the resulting residue was added CH 2 C1 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 CI2:EtOAc:MeOH-NH3 (7N), 4:9:2:1) to give 5.8 mg (22%) of DZ3-29. 1H NMR (500 MHz, CDC13/MeOH-d4) 8 8.17 (s, 1H), 7.04 (s, 1H), 7.01 (s, 1H), 6.88 (m, 1H), 6.27 (m, IMH), 6.21 (m, 111), 6.03 (s, 2H), 4.17 (t, J= 6.8 Hz, 21H), 3.29 (septet, J= 6.6 Hz, 1H), 2.80 (t, J= 6.7 Hz, 2H), 2.15 (m, 2H), 1.41 (d, J= 6.6 Hz, 6H); HRMS (ESI) m/z [M+H]+ calcd. for C 2 2 11 2 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[d] [1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H1 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 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 904C for 4 h. Solvent was WO 2011/044394 PCT/US2010/051872 85 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 13.7 mg (53%) of DZ3-30. 'H NMR (500 MHz, CDC1 3 /MeOH-d 4 ) 8 8.17 (s, 1H), 7.58 (s, 2H), 7.10 (s, 1H), 6.95 (s, 1H), 6.06 (s, 2H), 4.08 (t, J= 6.9 Hz, 2H), 2.89 (septet, J= 6.4 Hz, 1H), 2.57 (t, J= 7.2 Hz, 2H), 1.91 (m, 2H), 1.14 (d, J= 6.4 Hz, 6H); "C NMR (125 MHz, CDC13/MeOH-d) 3 154.0, 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]* called. for C 21

H

2 5

N

8 0 2 S, 453.1821; found 453.1819; HPLC: method A R = 5.60, method B Rt = 4.87. 9-(3-(isopropylamino)propyl)-8-(6-(5-methylfuran-2-y)benzo[d] [1,3Jdioxol-5-ylthio) 9Hl-purin-6-amine [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) 2 Cl 2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 904C 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), 4:9:2:1) to give 11.5 mg (42%) of DZ3-35. IH NMR (500 MHz, CD0 3 ) 8 8.25 (s, 1H), 7.19 (s, 1H), 6.84 (s, 1H), 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 (m, 1H), 2.59 (t, J= 6.6 Hz, 2H), 2.34 (s, 3H), 2.05 (m, 2H), 1.20 (d, J= 6.3 Hz, 6H); HRMS (ESI) m/z {M+H]* caled. for C 2 3

H

27

N

6 0 3 S, 467.1865; found 467.1869; HPLC: method A R, = 6.49, method B Re = 7.53. 2-(6-(6-amino-9-(3-(isopropylamino)propyl)-9H-purin-8-ylthio)benzo[d] [1,3Jdioxol-5 yl)acetonitrile [DZ3-39].4-Isoxazoleboronic acid pinacol ester (20.5 mg, 0.1053 mmol) was added to PU-H71 (30 ing, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.175 5 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 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, CDCI 3 /MeOH-d 4 ) 8 8.17 (s, 1H), 7.14 (s, 1H), 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, 1 H), 2.82 (t, J=7.0 Hz, 2H), 2.25 (m, 2H), 1.27 (d, J= 6.5 Hz, 6H); "C NMR (125 MHz, CDC1 3 /MeOH-d 4 ) 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 2 aH 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 [DZ3-41]. 1-Boc-pyrrole-3-boronic acid pinacol ester (30.9 mg, 0.1053 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1.2 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*C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2

C

2 :EtOAc:MeOH-NH 3 (7N), 2:2:1:0.5) to give 7.9 mg (30%) of DZ3-41. 'H NMR (500 MHz, CDCl3/MeOH-d 4 ) 8 8.16 (s, 1H), 7.02 (s, 1H), 6.99 (s, 1H), 6.86 (m, 1H), 6.76 (m, 1H), 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, CDC1J/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 (ESI) mz [M+H]* calcd. for C22H 26

N

7 0 2 S, 452.1869; found 452.1862; HPLC: method A Rt = 6.02, method B Re = 6.27. 9-(3-(isopropylamino)propyl)-8-(6-(1-methyl-1H-pyrazol-5-yl)benzo[d] [1,3]dioxol-5 ylthio)-9H-purin-6-amine IDZ3-44]. 1-Methyl-1-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"C for 2 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 20.1 mg (74%) of DZ3-44. 'H NMR (500 MHz, CDC1 3 ) 6 8.25 (s, 1H), 7.40 (d, J = 1.8 Hz; 1H), 7.05 (s, 1 H), 6.80 (s, IH), 6.08 (s, 21H), 6.06 (d, J= 1.8 Hz, 1H), 5.91 (br s, 2H), 4.10 (t, J= 6.7 Hz, 2H), 3.67 (s, 31H), 2.85 (septet, J= 6.3 Hz, 1H), 2.53 (t, J =6.7 Hz, 2H), 1.97 (m, 2H), 1.13 (d, J= 6.3 Hz, 6H); "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; HUMS (ESI) m/z [M+H]* called. for C22H 2 7 Ng0 2 S, 467.1978; found 467.1985; HPLC: method A R = 5.74, method B 14= 5.20. 8-(6-(1H-pyrazol-3-yI)benzo[d] [1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H purin-6-amine [DZ3-46]. 1 H-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) 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 C]2:EtOAc:MeOH-NH 3 (7N), 2:2:1:0.5) to give 3.7 mg (8%) of DZ346. 'H NMR (500 MHz, CDCI3/MeOH-d 4 ) 6 8.17 (s, 1H), 7.59 (d, J= 2.0 Hz, 1H), 7.10 (s, 1H), 7.07 (s, 1H), 6.38 (d, J= 2.0 Hz, 1H), 6.08 (s, 21), 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 (m, 2H), 1.39 (d, J= 6.6 Hz, 6H); "C NMR (125 MHz, CDCt3/MeOH-d 4 ) S 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 2 1

H

2 5N 8 0 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)benzold] [1,3Jdioxol-5-ylthio)-9H purin-6-amine [DZ3-491. 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 H2O (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*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 CI2:EtOAc:MeOH-NH3 (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, CDCI3/MeOH-d 4 ) 8 8.66 (s, 1H), 8.45 (s, 1 H), 8.17 (s, 1H), 7.18 (s, 1H), 7.01 (s, 1H), 6.13 (s, 2H), 4.37 (t, J= 7.0 Hz, 2H), 3.27 (septet, J= 7.1 Hz, 1H), 2.89 (t, J= 7.1 Hz, 2H), 2.22 (m, 2H), 1.38 (d, J= 6.5 Hz, 6H); MS (ESI) m/z [M+H]+ 454.1; HPLC: method ARt= 5.67 (DZ3-39, 29%) and 5.87 (DZ3-49, 7 1%); method B Rt = 4.58 (DZ3-39, 34%) and 5.57 (DZ3-49, 66%). 4-(6-(6-amino-9-(3-(isopropylanino)propyl)-9H-pnrin-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 nimol) 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:CH2C12:EtOAc:MeOH-NHs (7N), 2:2:1:0.5) to give 18.8 mg (66%) of DZ3-50. 'H NMR (500 MHz, MeOH-d 4 ) 6 10.01 (s, 1H), 8.15 (s, IH), 7.85 (d, J= 8.1 Hz, 2H), 7.47 (d, J =8.1 Hz, 2H), 7.14 (s, 1H), 6.93 (s, 1 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-d4) 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 C2sH27N 6

O

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-amino-8-(6-(3,5-bis(trifluoromethyl)phenyl)benzo[dlll,3]dioxol-5 ylthio)-9H-purin-9-yl)propylamino)hexylearbamate [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 (I 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 (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 C]2:MeOH

NH

3 (7N), 10:1) to give 27.7 mg (63%) of TT-V-43A. 'H NMR (500 MHz, CDC 3 ) S 8.17 (s, 1H), 7.78 (s, 3H), 7.14 (s, 1H), 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 H4F 6

N

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

C

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:CH2Cl2:MeOH-NH3 (7N), 7:1) to give mg (%) of TT-V-47B. 'H NMR (500 MHz, CDC1 3 /MeOH-d4) 8 8.04 (s, 1H), 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, 2H), 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]* calcd. for C 2 9

H

32

FN

7 0 2 5, 656.2242; found 656.2242; HPLC: method A Rt = 6.98, method B Rt = 8.38.

WO 2011/044394 PCT/US2010/051872 - 90

NH

2

NH

2 F F N HN HN PU-DZ13 Reagents and conditions: (a) RB(OH) 2 , PdCI 2 (PPh 3 )2, NaHCO 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 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*C for 4 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 19.1 mg (72%) of DZ3-25. IH NMR (500 MHz, CDC13/MeOH-d 4 ) 3 7.46 (d, J= 1.4 Hz, 1 H), 7.08 (s, I H), 6.64 (s, 1H), 6.46 (dd, J= 1.4,3.2 Hz, 1H), 6.34 (d, J= 3.2 Hz, 1H), 6.00 (s, 2H), 4.34 (s, 211), 4.08 (t, J= 6.3 Hz, 211), 2.85 (t, J= 6.3 Hz, 211), 2.38 (d, J= 6.8 Hz, 2H), 1.70 (m, iH), 0.88 (d, J= 6.7 Hz, 6H); 13 C NMR (125 MHz, CDCI,/MeOH d4) 8 158.9 (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) m/z [M+H]* caled. for C 23 H2uFN 6 O3, 453.2050; found 453.2041; HPLC: method A Rt = 7.10, method B Rt = 8.52.

WO 2011/044394 PCT/US2010/051872 91 2-fluoro-8-((6-(furan-3-yl)benzold] [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 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 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 23.4 mg (88%) of DZ3-26. 'H NMR (500 MHz, CDC1 3 ) 8 7.49 (m, 1H), 7.46 (m, 1H), 6.82 (s, 1H), 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, 1H), 0.83 (d, J= 6.7 Hz, 6H); "C NMR (125 MHz, CDCl 3 ) 8 158.9 (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]* calcd. for C 23

H

2 6

FN

6 0 3 , 453.2050; found 453.2044; HPLC: method A Rt = 7.10, method B Rt = 8.50. 8-((6-(1H-pyrrol-2-yl)benzo[d][1,3]dioxol-5-yf)methyl)-2-fluoro-9-(2 (isobutylamino)ethyl)-9H-purin-6-amine [DZ3-311. 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 ing, 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 )2C 2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90*C for 4 h. DMF was removed under reduced pressure and to the resulting residue was added CH2C12 (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 Cl 2 :EtOAc:MeOH-NH3 (7N), 4:15:2:1) to give 5.2 ing (20%) of DZ3-31. 'H NMR (500 MHz, CDC 3 /MeOH-d 4 ) S 6.91 (s, 1H), 6.84 (dd, J= 1.4,2.5 Hz, 1H), 6.65 (s, IH), 6.22 (m, 1H), 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 6H); 3 C NMR (125 MHz, CDC1 3 /MeOH-d4) 5 158.8 (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; HRMS (ESI) m/z [M+H]* called. for

C

2 3H27FN,0 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-(isobutylamino)ethyl)-9H-purin-8 yl)methyl)benzo[d][1,3]dioxol-5-yl)furan-2-carbaidehyde [DZ3-34J. 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'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, CDC13/MeOH-d 4 ) 8 9.47 (s, 1H), 7.27 (d, J= 3.7 Hz, 1H), 7.20 (s, 1H), 6.77 (s, 1 H), 6.63 (d, J= 3.7 Hz, 1H), 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 Rt = 7.62. 8-((6-(IH-pyrazol-4-yI)benzo[d] [1,3]dioxol-5-yl)methyl)-2-fluoro-9-(2 (isobutylamino)ethyl)-9H-purin-6-amine [DZ3-32J. I -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'C for 5 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CCH 2 C1 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 4 ) 5 7.50 (s, 2H), 6.83 (s, 1,H), 6.69 (s, IH), WO 2011/044394 PCT/US2010/051872 93 5.98 (s, 2H), 4.18 (s, 2H), 4.01 (t, J= 6.6 Hz, 2H), 2.78 (t, J= 6.6 Hz, 2H), 2.40 (d, J= 7.0 Hz, 2H), 1.71 (m, 1H), 0.88 (d, J= 6.7 Hz, 6H); 3 C NMR (125 MHz, CDC1 3 /MeOH-d 4 ) 6 158.6 (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 22

H

26 FNQ0 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 [DZ3-36]. 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-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 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 CJ2;EtOAc:MeOH-NH 3 (7N), 4:15:2:1) to give 15.6 mg (57%) of DZ3-36. 'H NMR (500 MHz, CDC 3 ) 6 7.04 (s, 1H), 6.53 (s, lH), 6.26 (d, J= 3.1 Hz, 1H), 6.21 (br s, 2H), 6.05 (d, J= 3.1 Hz, iH), 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, lH), 0.83 (d, J= 6.7 Hz, 6H); HRMS (ESI) m/z [M+H]* calcd. for C 24

H

2 gFN 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[d] [1,3]dioxol-5-yl)methyl)-2-fluoro-9-(2 (isobutylamino)ethyl)-9H-purin-6-amine [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 Cl 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*C for 6.5 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), 4:7:2:1) WO 2011/044394 PCT/US2010/051872 94 to give 20.9 mg (79%) of DZ3-38. 'H NMR (500 MHz, CDC 3 ) 8 8.72 (br s, 1H), 6.85 (s, 1H), 6.83 (m, 1H), 6.76 (m, 1H), 6.62 (s, lH), 6.34 (br s, 2H), 6.23 (m, 1 H), 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 (m, 1H), 0.82 (d, J= 6.6 Hz, 6H); "C NMR (125 MHz, CDCJ) S 158.8 (d, J= 208.0 Hz), 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 2 3

H

27

FN

7 0 2 , 452.2210; found 452.2204; HPLC: method A Rj= 6.77, method B R, = 7.93. 2-(6-((6-amino-2-fluoro-9-(2-(isobutylamino)ethyl)-9H-purin-8 yI)methyl)benzojdj [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, 0.175 5 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) 2 Cl 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

C

2 :EtOAc:MeOH-NH 3 (7N), 4:7:2:1) to give 8.3 mg (%) of DZ3-40. 'H NMR (500 MHz, CDC13/MeOH-d 4 ) S 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, 1H), 0.99 (d, J= 6.7 Hz, 6H); 1 3 C NMR (125 MHz, CDC13/ MeOH-d 4 ) 6 158.7 (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) m/z [M+H]* called. for C 2 1H25FN70 2 , 426.2054; found 426.2048; HPLC: method A t = 6.48, method B Rt = 7.10. 8-((6-(1H-pyrazol-3-yl)benzold][1,3]dioxol-5-y1)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 C1 2 (8 mg, 0.0117 nmol) were added and the reaction mixture was heated under nitrogen at 90'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, CDCl3/MeOH-d 4 ) 8 7.63 (d, J= 2.15 Hz, 1H), 6.95 (s, 1H), 6.82 (s, lH), 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); 13 C NMR (125 MHz, CDCIs/ MeOH-d 4 ) 5 158.8 (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]* caled. for C22H26FNB02, 453.2163; found 453.2149; HPLC: method A R, = 6.37, method B Rt = 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 mnmol) 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*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 ) S 7.49 (d, J= 1.5 Hz, 1H), 6.76 (s, IH), 6.74 (s, 1H), 6.28 (br s, 2H), 6.17 (d, J= 1.5 Hz, I H), 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 (i, 1H), 0.84 (d, J= 6.7 Hz, 6H); 1 3 C NMR (125 MHz, CDC1 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 C23H 28

FN

8 O2, 467.2319; found 467.2323; HPLC: method A Rt =6.37, method B R =6.90.

WO 2011/044394 PCT/US2010/051872 96 2-fluoro-9-(2-(isobutylamino)ethyl)-8-((6-(thiophen-2-y1)benzo[d] [1,3] dioxol-5 yl)methyl)-91-purin-6-amine [DZ3-481. 2-Thienylboronic acid (11.2 mg, 0.0877 mmol) was added to PU-DZ13 (30 mg, 0.0585 mmol) and NaHCO 3 (1.4.7 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,20 (0.1 mL) and Pd(PPh) 2

C

2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 90*C for 2 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 18.3 mg (67%) of DZ3-48. 'H NMR (500 MHz, CDC1 3 /MeOH-d 4 ) 8 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, 211), 2.37 (d, J= 6.9 Hz, 2H), 1.70 (m, 1H), 0.88 (d, J= 6.7 Hz, 6H); "C NMR (125 MHz, CDC1 3 /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]+ calcd. for C2 3 H26FN 6 0 2 S, 469.1822; found 469.1830; HPLC: method A RIt = 7.21, method B R= 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) 2 Cl 2 (8 Mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 60*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 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 1 4 =7.08 (DZ3-40, 65%) and 7.52 (DZ3-51, 35%).

WO 2011/044394 PCT/US2010/051872 97

NH

2 NH 2 N S R N NN N HN HN PU-HZ151 Reagents and conditions: (a) RB(OH) 2 , PdC12(PPh 3

)

2 , NaHCO 3 , H20, DMF, 90*C. Scheme 5. Suzuki coupling of PU-HZ151. 8-(6-(furan-2-yl)benzojd] [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 FU-HZ151 (66.4 mg, 0.126 mmol) 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 H 2 0 (0.4 mL) and Pd(PPh 3

)

2

C

2 (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, CDC1 3 ) 5 8.30 (s, 1H), 7.49 (d, J= 1.3 Hz, 111), 7.17 (s, 1H), 6.84 (s, 1H), 6.75 (d, J= 3.3 Hz, 1H), 6.48 (dd, J= 1.8, 3.3 Hz, 1H), 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, 2H), 0.83 (s, 9H); "C NMR (125 MHz, CDCI 3 ) 8 154.6,153.0,151.7,151.1, 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]f called. for C23H 2 7

N

6

O

3 S, 467.1865; found 467.1870; HPLC: method A R, 6.78, method B Rt = 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-amine [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"C for 4.5 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH2C1 2 :MeOH-NH 3 (7N), 15:1) to give 9.3 mg (34%) of DZ3-56. 'H NMR (500 MHz, CDC1/MeOH-d 4 ) 8 8.19 (s, 1H), 7.24 (s, 1H), 6.89 (s, 1H), 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); 1 3 C NMR (125 MHz, CDC 3 /MeOH-d 4 ) & 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 C 2 4 H2 9

N

6 0 3 S, 481.2022; found 481.2002; HPLC: method A K =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'C for 4 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 16.0 mg (58%) of DZ3-58. 'H NMR (500 MHz, CDC13/MeOH-d 4 ) & 8.18 (s, 1H), 7.32 (dd, J= 1.6, 4.7 Hz, 1H), 6.98-7.03 (m, 4H), 6.07 (s, 2H), 4.29 (t, J= 5.4 Hz, 2H), 3.03 (t, J= 5.4 Hz, 2H), 2.48 (s, 2H), 0.97 (s, 9H); ' 3 C NMR (125 MHz, CDC1s/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]* called. for

C

2 3H 2 7

N

6 0 2 S2, 483.1637; found 483.1621; HPLC: method A R,=7.14, method B Rt = 7.73.

WO 2011/044394 PCT/US2010/051872 99 8-(6-(1H-pyrrol-3-yl)benzo[d] [1,3]dioxol-5-ylthio)-9-(2-(neopentylamino)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"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 10.1 mg (38%) of DZ3-59. 'H NMR (500 MHz, CDCI 3 /MeOH-d 4 ) S 8.15 (s, 1H), 7.03 (s, lH), 6.95 (s, 1H), 6.85 (m, 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-d 4 ) 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/z [M+H]* calcd. for C 2 3

H

28

N

7 0 2 S, 466.2025; found 466.2016; HPLC: method A Rt= 6.86, method B Rt = 7.20. 8-(6-(furan-3-y)benzo[dJ [1,3]dioxo-5-ylthio)-9-(2-(neopentylamino)ethyl)-9H-purin-6 amine [DZ3-601. 3-Furanylboronic acid (9.5 mg, 0.0853 nmol) 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"C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CHzC1 2 :MeOH-NH 3 (7N), 20:1) to give 13.8 mg (52%) of DZ3-60. 'H NMR (500 MHz, CDC1/MeOH-d 4 ) 8 8.17 (s, 1H), 7:50 (s, 1H), 7.43 (d, J= 1.5 Hz, 1$), 7.02 (s, 1H), 6.94 (s, 1$), 6.49 (d, J= 1.5 Hz, 1H), 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); "C NMR (125 MHz, CDClJ/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 (ESI) mz [M+H]* called. for C 2 3

H

27

N

6 0 3 S, 467.1865; found 467.1845; HPLC: method A Rt = 6.65, method B Rt 7.09.

WO 2011/044394 PCT/US2010/051872 100 8-(6-(1H-pyrazol-3-yl)benzo [d] [1,3] dioxol-5-ylthio)-9-(2-(neopentylamino)ethyl)-9H purin-6-amine [DZ3-61]. lH-Pyrazole-3-boronic acid (19 mg, 0.1707 mmol) was added to PU-HZI151 (30 mg, 0.0569 mmol) and NaHCO 3 (14.3 mg, 0.1707 mmol). DMF (1.2 m.L) 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 C2 (8 mg, 0.0113 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

C

2 :MeOH-NH3 (7N), 15:1) to give 6.5 mg (25%) of DZ3-61. 'H NMR (500 MHz, CDCl 3 /MeOH-d) 8 8.18 (s, 111), 7.58 (d, J= 2.0 Hz, 1H), 7.05 (s, 211), 6.40 (d, J= 2.0 Hz, 1H), 6.06 (s, 211), 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-d) 8 154.6, 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+Hj caled. for C22H 2 7 NsO 2 S, 467.1978; found 467.1972; HPLC: method A RT =6.50, method B R= 6.61.

WO 2011/044394 PCT/US2010/051872 101

NH

2 r rt a b N NN - c H2N:A : 0 rtSr% H2N a H 0 S6-1 S6-2 S6-3

NH

2 NN - N Nz S6Y H -64 S6-5 d, e d, e

NH

2 N N -NH 2 I SN N N K- N RH n= 1, 2 N N 0 RHN RH n= 1, 2 S6-4 PU-WS4 n= 2, R= isopropyl PU-WS9 n= 1, R= isobutyl PU-W321 n= 1, R= neopentyl Reagents and conditions: (a) NaNO 2 , KI, AcOH/TFA, OC; (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, DMF, rt; (f) DDQ, dioxane, 100*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 OT* for 15 minutes and quenched with H 2 0 (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, CDC1 3 ) 8 7.14 (d, J= 7.6 Hz, 111), 7.11 (s, 1H), 6.89 (d, J= 7,6 Hz, 111), 4.54 (t, J= 8.7 Hz, 2H), 3.14 (t, J= 8.7 Hz, 2H); "C NMR (125 MHz, CDC1 3 ) 6 161.1, 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 86-2 (50 mg, 0.2 mmol) in DMF (2 mL) was added 8-mercaptoadenine (34 ng, 0.2 mmol), Cs 2

CO

3 (99.4 mg, 0.3 mmol) and PdCl 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 C1 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) 5 8.14 (s, 1H), 7.24 (d, J= 7.6 Hz, 1H), 7.07 (d, J=7.3 Hz, 11), 6.97 (s, 1H), 4.62 (t, J= 8.7 Hz, 2H), 3.25 (t, J= 8.7 Hz, 2H); MS (ESJ) m/z 285.8 [M+H]; HRMS (ESI) m/z [M+H]* called. for C 13 Hi 2

N

5 0S, 286.0763; found 286.0768. 8-(5-iodo-2,3-dihydrobenzofuran-6-ylthio)-9H-purin-6-amine (S6-4) To a solution of S6 3 (40 mg, 0.14 nmol) 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. 1 H NMR (500 MHz, CDC1 3 ) 5 8.26 (s, 1H), 7.79 (s, 1H), 7.12 (s, 1H), 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-isopropylamino-propyl)-9H-purin 6-ylamine (PU-WS4). A mixture of 56-4 (54 mg, 0.13 mmol), CS2CO 3 (127 mg, 0.39 mmol) and 1,3-dibromopropane (202 mg, 0.65 mmol) in anhydrous DMIF (2 mL) was stirred at rt for 2 h. Solvent was removed under reduced pressure and the residue purified by chromatography (CH 2

CI

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 A. The reaction afforded PU-WS4 (13 mg, 20%; over two-steps) as a yellow solid after purification. 'H NMR (500 MHz, CDC1 3

/CD

3 0D) 6 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]f; HRMS (ESI) m/z [M+H]* caled. for C1 9

H

2 4IN 6 0S, 511.0777; found 511.0779. 8-(5-iodo-2,3-dihydro-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. 1H NMR (500 MHz,

CDC

3 ) & 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, 2H), 1.99 (m, 1H), 0.97 (d, J=7 Hz, 6H); HRMS (ESI) m/z [M+H]f calod. for C 19

H

24

TN

6 0S, 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 , 8): 7.56 (s, 1H), 6.60 (s, 1 H), 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]

4 calod for C 20

H

2 6INOS 525.0933; found 525.0927.

WO 2011/044394 PCT/US2010/051872 104

NH

2 H 2 N S XD b N~ c

H

2 N H 2 N N N 86-1 87-1 S7-2

NH

2 NH 2 I N -N SO N N - N 80 - _ 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 10*C; (c) NaNO2, KI, AcOH/TFA, 0*C; (d) 1,3-dibromopropane, Cs 2

CO

3 , DMF, rt; (e) isopropylamine, DMF, rt. Scheme 7. Synthesis ofPU-WSIO. 5-iodo-2,3-dihydrobenzofuran-6-amine (S7-1). To a solution of 2,3-dihydrobenzofturan-6 amine (86-1; 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, CDCl 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-dihydrobenzof-uran-5-ylthio)-9H-purin-6-amine (S7-2). The mixture of S7-1 (80 mg, 0.31 mmol), 8-mercaptoadenine (52 mg, 0.3 mmol), neocuproine (7 mg, 0.03 mmol), Cul (7 mg, 0.03 mmol) and sodium t-butoxide (100 mg, 1.04 mmol) 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, CDCl 3 ) 8 8.15 WO 2011/044394 PCT/US2010/051872 105 (s, 1H), 7.33 (s, 11), 6.35 (s, 1H), 4.57 (t, J= 8.5 Hz, 211), 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/1 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"C for 10 minutes and condensed under reduced pressure. The residue was purified by flash chromatography (CH 2

CI

2 :MeOH, 100:0 to 90:10) to yield S7-3 (13 mg, 41%) as a yellow solid. 1H NMR (500 MHz, CD 3 0D) 8 8.13 (s, 1H), 7.57 (s, 1H), 7.44 (s, 1H), 4.66 (t, J= 8.5 Hz, 2H), 3.22 (t, J= 8.6 Hz, 211); 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 pL, 0.16 mmol) and Cs 2 CO3 (20 mg, 0.06 nimol) 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, CDCl 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, 211), 3.42 (t, J= 6.2 Hz, 2H), 3.18 (t, J= 8.9 Hz, 2H), 2.39 (m, 2H); MS (ESI) m/z 531.9/533.9 [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 nL) was stirred for 12 h. Solvent was removed under reduced pressure and the residue purified by preparative thin layer chromatography (CHCl3:MeOH-NH 3 (7N), 20:1) to afford PU-WS1O (4.0 mg, 60%) as a pale yellow solid. 'H NMR (400 MHz, CDCl 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, 211), 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, 211), 1.98 (in, 2H), 1.05 (d, J= 6.5 Hz, 6H); "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 NH2 NH2 N a. b, c N N N -X1 > X I X 3 N N ora,d,c 2 or a, d, e, c =n= 1, 2 RH n=, 2 -RHN PU-DZ8 X,=CH 2 , X 2 =F, n= 2, R= isopropyl PU-WS3 X 1 =CH2, X 2 =F, X 3 =CN, n=2, R= isopropyl PU-H71 X 1 =S, X 2 =H, n= 2, R= isopropyl PU-WS5 X 1 =S, X 2 =H, X3=CN, n= 2, R= isopropyl PU-HZI50 X 1 =S, X 2 =H, n= 1, R= isobutyl PU-WS7 X 1 =S, X 2 =H, X 3 =CCt-Bu, n= 2, R= isopropyl PU-HZ151 X=S, X 2 =H, n= 1, R= neopentyl PU-WS7 X 1 =s, X 2 =H, X=CCPh, n= 2 R= isopropyl PU-DZ13 X 1

=CH

2 , X 2 =F, n= 1, R= isobutyl PU-WSB X 1 =S. X 2 =H, X=CCH, n= 2, R= isopropyl PU-WS16 X,=S, X2=H, X3=CCH, n= 1, R= isobutyl PU-WSI9 X,=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) PdCI 2 (dppf), Zn(CN) 2 , Zn, DMF, 130"C; (c) 10% TFA-CH 2 C1 2 , rt, 2-5h; (d) CuL 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-WSS, PU-WS16, PU-WS19 and PU-WS20. 6-[6-amino-2-fluoro-9-(3-isopropylamino-propyl)-9H-purin-8-ylmethyl] benzo[1,3]dixole-5-carbonitriIe (PU-WS3). A solution of PU-DZ8 (118 mg, 0.231 mmol), (Boc) 2 0 (55 mg, 0.254 mmol) 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-NH3 (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 nL) was added PdC1 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 (CHC 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 C1 2 was added WO 2011/044394 PCT/US2010/051872 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

(CHC

3 :MeOH-NH 3 (7N), 20:1) to yield PU-WS3 as a white solid in quantitative yield (12 mg, 59% for three steps). 1H NMR (500 MHz, CD 3 0D) 6 7.13 (s, 1H), 6.96 (s, 1H), 6.03 (s, 2H), 4.31 (s, 2H), 4.25 (t, J= 7 Hz, 2H), 3.26 (m, 1H), 3.01 (t, J= 7.5 Hz, 2H), 2.14 (m, 2H), 1.23 (d, J= 6.5 Hz, 6H); "C NMR (125 MHz, CD 3 OD) 8 160.4 (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-yIsulfanylbenzo [1,3] dixole-5 carbonitrile (PU-WS5). The procedure for the preparation of PU-WS3 was followed starting from PU-H71. The reaction afforded PT-WS5 (6.5 mg, 32% for three steps) as a white solid. H NMR (500 MHz, CDC1 3

/CD

3 0D) $ 8.21 (s, 1H), 7.22 (s, 1H), 7.19 (s, IH), 6,19 (s, 2H), 4.40 (t, J= 7 Hz, 211), 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 CjH22N70 2 S, 412.1556; found 412.1560. 8-[6-(3,3-dimethyl-but-1-ynyl)-benzo[1,3]dioxol-5-yIsulfanyl]9-(3-isopropylamino propyl)-9H-purin-6-ylamine (PU-WS6). A solution of PU-H71 (70 mag, 0.137 mmol), (Boc)zO (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 (CHCI 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 Cul (4 mg, 0.1 mmol), PdCl 2 (PPh) 2 (14 mg, 0.02 mmol), t-butylacetylene (72 pL, 0.59 mmol) and triethylamine (137 pL) 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 Cl 2 was added TFA (1.5 mL) and stirred at RT for 2 hrs. 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, 1H), 6.99 (s, 1H), 6.97 (s, 1$), 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, CDCl3/CD30D) 6 50.5, 41.3, 40.2, 30.3, 27.8, 25.9, 18.5; MS (ESI) m/z 467.3 [M+H]f; HRMS (ESI) m/z [M+H]* calcd. for C 2 4 H31N 6 0 2 S, 467.2229; found 467.2233. 9-(3-isopropylamino-propyl)-8-(6-phenylethynyl-benzo [1,3]dixool-5-ylsulfanyl)-9H puriu-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) & 8.2 (s, 1H), 7.30-7.40 (m, 5H), 7.08 (s, 1H), 6.96 (s, 1H), 6.06 (s, 2H), 4.27 (m, 2H), 2.69 (m, 1H), 2.51 (m, 2H), 1.97 (m, 2H), 1.01 (d, J= 6.5 Hz, 6H); 1 3 C NMR (125 MHz, CDCts/CD30D) 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., 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]r called. for

C

2 JH27NO 2 S, 487.1903; found 487.1913. 8-(6-ethynyl-benzo[1,3]dioxol-5-ylsulfanyl)-9-(3-isopropylamino-propyl)-9H-purin-6 ylamine (PU-WS8). The procedure for the preparation of PU-WS6 was followed with trimethylsilanylacetylene (82 pL, 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 CI2 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 ) 6 8.32 (s, 1H), 6.99 (s, 1H), 6.84 (s, 1H), 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+HI*; HRMS (ESI) m/z [M+H]*' calcd. for

C

2 oH23N 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, CDCl 3 ) 8 8.24 (s, 1H), 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); 13 C NMR (125 MHz, CDC1 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 oH22N 6

O

2 S, 411.1603; found 411.1606. 8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9-(2-(neopentylamino)ethyl)-9H-purin-6 amine (PU-WS19). Following the procedure to make PU-WS8, PU-WS19 was obtained as a white solid. 1H 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); 13 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]* called. for

C

2 1

H

25

N

6 0 2 S, 425.1760; found 425.1753. 8-((6-ethynylbenzoldl1,3]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) 6: 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 N 2 H2N jy 0 1 0/ 0 b, c -s d 59-1 S9-2 89-3 Oj

NH

2

NH

2 N N N" N N N - NJ X X Br O 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-RKI 1 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 0 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, DMF, rt. Scheme 9. Synthesis of PU-HT165, PU-HT 175, 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 (59-1; 5 g, 33 mmol) was dissolved in 10% HC1 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 the reaction mixture was stirred at O 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/CH2CI2 (1:1) was added. The reaction mixture was stirred overnight at room temperature then extracted with CH 2

CI

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. I H NMR (500 MHz, CDC 3 ) S 7.28 6 (s, 1H), 7.13 (d, J= 8.5 Hz, 1H), 6.63 (d, J= 8.5 Hz, 1H), 4.27-4.24 (m, 4H).

WO 2011/044394 PCT/US2010/051872 111 8-(7-Iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-9H-porin-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), Cul (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) m/z 301.9 [M+H]). To 0.400 g (1.4 mmol) of this and NIS (0.945 g, 4.2 nmol) 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 (CHCl,: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, 500 MHz) 6 8.37 (s, 1H), 8.03 (br s, 2H), 7.47 (s, iH), 7.10 (s, 1H), 4.25-4.27 (m, 4H); MS (ESI) m/z 427.9 [M+H]*. 9-(2-Bromoethyl)-8-(7-iodo-2,3-dihydrobenzo[b] [1,4]dioxini-6ylthio)-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 C0 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) 5 8.29 (s, 1H), 7.36 (s, 1H), 7.00 (s, IH), 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, 2H); 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 59-3 (0.213 g, 0.5 mmol), 1,3-dibromopropane (0.512 g, 2.5 mmol) and Cs 2 CO3 (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 (CHC1 3 :MeOH-NHa (7N), 20:1) to give S9-5 (0.104 g, 38 %). '1H NMR (CDCIs, 500 MHz) S 8.26 (s, IH), 7.32 (s, IH), 6.94 (s, IH), 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 (m, 2H); MS (ESI) m/z 547.9/549.8 [M+H]*.

WO 2011/044394 PCT/US2010/051872 112 8-(7-Iodo-2,3-dihydrobenzob] [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

CI

2 :MeOH) to give 0.040 g, 78%) of PU-H1T165 as a yellow solid. lH NMR (500 MHz, CDCI 3 ) 8 8.24 (s, 1H), 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 (n, 111), 0.92 (d, J= 6.0 Hz, 6H); "C NMR (125 MHz, CDC1 3 ) 5 155.4, 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 (CH 2 Cl 2 :MeOH) to give 0.038 g (73%) of PU-HT175 as a yellow solid, 'H NMR (500 MHz, CDC1 3 ) 5 8.31 (s, 1H), 7.37 (s, 1H), 6.94 (s, 1H), 5.79 (br s, 211), 4.33 (t, J= 6.5 Hz, 2H), 4.20-4.24 (m, 4H), 2.99 (t, J= 6.5 Hz, 2H), 2.34 (s, 2H), 0.84 (s, 9H); 1 3 C NMR (125 MHz, CDC 3 ) a 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 rt. 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, CDCl 3 ) 6 8.30 (s, 1H), 7.38 (s, 1H), 6.95 (s, 1H), 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, 1H), 2.61 (t, J= 6.7 Hz, 2H), 2.07 (m, 2H), 1.11 (d, J =6.7 Hz, 6H); 13C 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) m/z 527.1 [M+H]*.

WO 2011/044394 PCT/US2010/051872 113 9-(3-(LH-imidazol-1-y1)propyl)-8-(7-iodo-2,3-dihydrobenzo[b][1,4]dioxiu-6-ylthio)-9H purin-6-amine (PU-RK1Z). S9-5 (0.045 g, 0.082 mmol) and imidazole (0.056 g, 0.82 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 C1 2 :MeOH) to give 0.029 g (67%) of PU-RK12. 'H NMR (500 MHz, CDC1 3 ) 6 8.34 (s, 1H), 7.62 (s, IH), 7.39 (s, 111), 7.09 (s, 1H), 6.98 (s, 1H), 6.94 (s, 1H), 5.70 (br s, 2H), 4.19-4.28 (m, 6H), 4.00 (t, J= 7.5 Hz, 2H), 2.25 (m, 2H); "C NMR (125 MHz, CDC 3 ) S 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 0 a, ab0 )C i0 C NI-I 2 /\ d NH, C J OH _ " N 0 (\ H H F N 810-1 S10-2 H 2 N N H H 810-3 S10-4 0 0 0 0 NH 2 e NH /\ f NH 2 NN 2 g N F FNN F .ANF N N H He NH S10-5 Br 810- DZ3-73 R= isobutyl DZ4-84 R= t-butyl Reagents and conditions: (a) sulfur, morpholine, 140'C, 14 h; (b) 10% KOH (aq.), reflux, 12 h; (c) 2,4,5,6-tetraminopyrimidine, triphenyl phosphite, pyridine, microwave irradiation at 220"C, 75 min.; (d) HF/pyridine, NaNO 2 , 0 *C to rt, 1 h; (e) NIS, TFA, CH3CN, it overnight; (f) Cs 2

CO

3 , 1,2 dibromoethane, DMF, 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[bJ [14]dioxin-6-y)acetic acid (S10-2). A mixture of 1,4 benzodioxan-6-yl methyl ketone (S10-1; 5.5 g, 30.9 mmol), sulfur (1.98 g, 61.8 mmol) and morpholine (6.73 g, 6.76 mL, 77.3 mmol) was refluxed at 140*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

CI

2 , transferred to a seperatory funnel and washed with 25 mL of ice-cold brine. The aqueous layer was further extracted with C1 2

C

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 CH2C 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 ) 6 6.80-6.82 (m, 2H), 6.74 (dd, J= 2.0, 8.2 Hz, IH), 4.24 (s, 4H), 3.53 (s, 2H); MS (ESI) m/z 195.1 [M+H]*. 8-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-9H-purine-2,6-diamine (S1O-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 nL, 6.19 nunol) 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 Cl 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, CDCls/MeOH-d4) 6 6.75-6.84 (m, 3H), 4.24 (s, 4H), 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-9H1-purin-6-amine (S10-4). To a solution of S10-3 (1.00 g, 3.35 mmol) in HF/pyridine (2.4 mL) at 0 'C, NaNO2 (0.3 g, 4.36 mmol) was slowly added. The reaction was brought-to room temperature and further stirred for 1 h. Following dilution with CH 2 Cl 2 (20 mL), the excess HF was quenched by stirring for 1 h with CaCO 3 (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. 1H NMR (500 MHz, CDCl 3 /MeOH-d4)8 6.75-6.84 (m, 3H), 4.24 (s, 4H), 4.04 (s, 2H); MS (EST) 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 (S1D-5). 510-4 (0.310 g, 1.03 mmol), NIS (0.301 g, 1.34 mmol), CH3CN (20 mL), TFA (2.34 g, 1.56 mL, 20.5 mmol) 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]f) along with diiodinated compound (m/z 554.1 [M+H]t). 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, 1H), 6.82 (s, 1H), 4.25 (s, 4H), 4.18 (s, 2H); MS (ESI) m/z 428.2 [M+H]f. 9-(2-bromoethyl)-2-fluoro-S-((7-iodo-2,3-dihydrobenzo[b] [1,4]dioxin-6-yI)methy)-9H purin-6-amine (S1O-6). S10-5 (0.340 g, 0.796 mmol), 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 C1 2 :MeOH:AcOH, 200:1:0.5 to 120:1:0.5) to give 0.360 g (85%) of a mixture of 510-6 (m/z 534.0/536.2 [M+H]f) along with diiodinated compound (m/z 659.5/661.9 [M+H]f). 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]diosin-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

C

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 mLJmin) to give 0.196 g (58%) of DZ3-73. 'H NMR (500 MHz, CDC 3 ) 6 7.35 (s, 111), 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); 1 3 C NMR (125 MHz, CDCl 3 ) a 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 (ESI) z [M+H]* calcd. for C 2 0

H

25

FIN

6 02, 527.1068; found 527.1066; HPLC: method A Rt =6.91, method B Rt = 8.48. 9-(2-(tert-butylamino)ethyl)-2-fluoro-8-((7-iodo-2,3-dihydrobenzo[b] [1,4]dioxin-6 yI)methyl)-9H-purin-6-amine [DZ4-84]. S 10-6 (8 mg, 0.0 149 mmo) and tert-butylamine (109 mg, 157 g1) 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 C1 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 ) 3 7.36 (s, 1H), 6.55 (s, 1H), 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) m/z 527.1 [M+H]*. SNHH b N S11-1 911-2 S11-3 S11-4 I NH 2 H2N 02 O H2N yNj N >-=\ N~ 02NH S11-5 S11-6 511-7 S11-8 N NH 2

NH

2 U- H N N H 0KN N 0 0K S11-9 Br NHR S11-0 S11-11 Reagents and conditions: (a) NaBHI 4 , AcCH, THF, rt; (b) dibromoethane, acetone, H 2 0, K2CO3, reflux; (c) NBS, DMF, 80*C; (d) KNO3, H 2 S0 4 ; (e) NaI, CuI, N,N'-dimethylethylenediamine, dioxane, 1 10*C; (f) Fe, NH4Cl, isopropanol, reflux; (g) 8-mercaptoadenine, neocuproine, Cu, NaOtBu, DMF, 1150C; (h) NaNO 2 , KI, AcOH, 0"C; (i) Cs 2

CO

3 , 1,2-dibromoethane or 1,3-dibromopropane, DMF, rt; (j)N1H 2 R, DMF, rt.

WO 2011/044394 PCT/US2010/051872 117 Scheme 11. Synthesis of Morpholine-type compounds S 11-11. HI O2N NH2 a 02N N b 0 H2N IN H O $12-1 S12-2 S12-3 S12-4

NH

2

NH

2 I d 1,a e N > \/0 S12-5 S12-6 812-7 / ----- NN 9 -S-N-O (Q)n=1,2 /N? , N (?) n=1,2 / Br NHR S12-8 S12.9 Reagents and conditions: (a) 1,2-dibromoethane, K 2 C0 3 , DMF, 125 0 C; (b) MeI, DMF, (PC then rt; (c) Pd/C, H12, MeOHl, it; (di) NaNO 2 , AcOH, KI, 04C; (e) 8-mercaptoadenine, neocuproine, CuI, Na~tBu, DMF, ii15*C; (f) NIS, CH4 3 CN, rt; (g) Cs 2

CO

3 , 1,3 dibromopropane or 1 ,2..dibromo~ethane, DMF, rt; (h) NH- 2 R, DMF, it.

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 mnmol) 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, 1 H NMR (CDCl 3 , 500 MHz) 8 7.55-7.58 (ddl, J= 2.7, 8.9 Hzi, 1H1), 7.48 (d1J 2.6 H~z, 1H1), 6.81 (di, J= 8.9 Hz, WO 2011/044394 PCT/US2010/051872 118 1H), 4.34 (m, 2H), 4.12 (br s, IH), 3.47 (in, 2h); "C NMR (CDC1 3 , 125 MHz) 6 149.4,141.8, 133.8, 115.0,114.8, 110.2, 65.6, 40.0. 4-Methyl-6-nitro-3,4-dihydro-2H-benzo[b]1,4]oxazine [S12-31. To a solution of S12-2 (0.66 g, 3.7 mol) 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 gL, 3.7 nmot) and kept stirring at ft 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 (CDC1 3 , 500 MHz) 6 7.56 (d, J= 8.8 Hz, 1H), 7.45 (s, 1H), 6.76 (d, J= 8.8 Hz, 1H), 4.36 (in, 2H), 3.32 (m, 2H), 2.95 (s, 3H); ' 3 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)". 4- Methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine [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 (CDCl 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); 1 3 C NMR (CDCl 3 , 125 MHz) 6 140.8, 137.4, 137.0,116.2, 104.8, 100.4, 64.6, 49.5, 38.7. 6-lodo-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 rt and stirred for 2 h. The resulting mixture was quenched with 100 mL of water, extracted with ethyl acetate (3 x 150 mL). The organic layer was combined, treated with Na 2

S

2

O

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 (CDC1 3 , 500 MHz) 8 6.64 (d, J= 8.3 Hz, 1H), 6.56 (s, 11H), 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) 8 138.1, 126.6, 120.5, 117.6, 111.9, 83.7, 64.8, 48.7, 36.5. - WO 2011/044394 PCT/US2010/051872 119 OOH aNHBoc

NH

2 S13-1 S13-2 S13-3

NH

2

H

2 N NH 2 . NN N K- >-S N H -N N 813-4 S13-4

NH

2

NH

2 N ~N N NNNN

N

Br HN S13-6 DZ4-52-N9 Reagents or conditions: (a) (C 6 HsO) 2

P(O)N

3 , t-BuOH, Et 3 N, toluene, reflux; (b) t-BuLi, THF, -20*C, then ICH 2 CH2I, -78*C to rt; (c) TFA, CH 2

CI

2 , rt; (d) 8-mercaptoadenine, neocuproine, Cul, NaOtBu, DM3, 115*C; (e) KI, NaNO 2 , HCl, H20, < 5*C; (f) 1,3-dibromopropane, Cs 2

CQ

3 , DMF, rt; (g) isopropylamine, DM3, rt. Scheme 13. Synthesis of DZ4-52-N9. tert-Butyl naphthalen-2-ylcarbamate (S13-2)..2-Naphithoic 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 mmnol), 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 (7 1%) of S13-2. 'H NMR (500 MHz, CDCI,) 6 7.99 (s, WO 2011/044394 PCT/US2010/051872 120 lH), 7.72-7.78 (m, 3H), 7.44 (t, J= 7.8 Hz, iH), 7.31-7.38 (m, 2H), 6.61 (br s, 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 THF under argon at -20'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 -784C, a solution of diiodoethane (2.9 g, 10.27 mmol) in 10 mL dry THF was added dropwise and then allowed to warm to rt for 3 h. A saturated aqueous NH4C1 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 aininonaphthalene, 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, CDCl3) 6 8.25 (s, 1H), 7.59 (d, J= 8.3 Hz, 1H), 7.56 (d, J= 8.3 Hz, 1H), 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); ' 3 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 ng, 0.0185 mmol), CuI (3.5 mg, 0.0185 nimol), 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 I. 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, CDCI3/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 (m, iH), 7.24-7.30 (m, 1H), 7.20 (s, 1H); MS (ESI) m/z 308.95 [M+H].

WO 2011/044394 PCT/US2010/051872 121 8-(3-iodonaphthalen-2-ylthio)-9H-purin-6-amine (S13-5). To a suspension of S13-4 (14 mg, 0.0454 mmol) in water (150 pL) at 5'C was added 6 M HCI (140 gL) 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 gL) 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 (CH2C 2 :MeOH-NH 3 (7N), 8:1) to give 8 mg (42%) of S13-5 as a solid. 'H NMR (500 MHz, CDC3/MeOH-d4) S 8.51 (s, 1H), 8.17 (s, 2H), 7.75-7.80 (m, 2H), 7.52-7.60 (m, 2H); MS (ESI) m/z 420.01 [M+H]. 9-(3-bromopropyl)-8-(3-iodonaphthalen-2-ylthio)-9H-purin-6-amine (513-6). S13-5 (8 mg, 0.0 19 mmol), Cs 2

CO

3 (7.4 mg, 0.0228 mmol), 1,3-dibromopropane (19.2 mg, 9.7 gL, 0.095 mmol) in DMF (0.2 mL) was stirred for 30 min. Then additional Cs2CO3 (7.4 mg, 0.0228 mmol) and 1,3-dibromopropane (19.2 mg, 9.7 IL, 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, CDC13/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 [DZ4 52-N9]. S13-6 (4.6 mg, 0.0085 mmol) and isopropylamine (100 gL) in DMF (100 4L) 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 ) S 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 H2N 0 2 N C 2N c

I-

2 N, HNC 814-1 814-2 S14-3

NH

2

H

2 N

NH

2 H2N N N N N N N 'd N H H S14-4 814-5 S14-6

NH

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

SO

4 , (OC to rt; (c) NaNO 2 , KI, AcOH, 0*C to rt; (d) Fe, NH 4 C1, isopropanol, reflux; (e) 8-mercaptoadenine, Cul, nBu 4 NBr, Naot Bu, mv; (f) NaNO 2 , KJ, AcOH, 0*C; (g) 1,3-dibromopropane or 1,2-dibromoethane, Cs 2

CO

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

WO 2011/044394 PCT/US2010/051872 123 O, 2N) 2 02N 0 2 N

H

2 N S15-1 S15-2 S15-3

NH

2

H

2 N NH 2 H2N ' N NN N N H2H 815-4S15- S15-6

NH

2

NH

2 [NH2 g -S\h NS N N N n= 1,2 RNn=1,2 HN 8r RHN 815-7A 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-W827 Reagents and conditions: (a)Ac 2 O, dioxane, 0*C to rt; (b) KNO 3 , H 2 SO4, 0* to rt; (c) NaNO 2 , KI, AcOH, 04C to rt; (d) Fe, NH4CL, isopropanol reflux; (e) 8-mercaptoadenine, Cul, nBu 4 NBr, NaOt Bu,.mv; (f) NaNO 2 , KI, AcOH, OC; (g) 1,3-dibromopropane or 1,2-dibromoethane, Cs 2

CO

3 , DMF, rt; (h) isopropylamine or isobutylamine or neopentylamine, DMF, rt; (i) Cul, PdC1 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 H2SO4, cooled in ice bath.

KNO

3 in 15 mL of concentrated H 2

SO

4 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, 1H), 6.65 (s, 1H), 6.02 (br, 211), 2.83 (m, 4H), 2.06 (in, 2H); "CNMR (125 MHz, CDC 3 ) 8 154.4, 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 mmol) in acetic acid cooled in ice bath was added NaNO 2 (65 mg, 0.94 mmol). 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

O

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. 'HNMR (500 MHz, CDC 3 ) 8 7.83 (s, 1H), 7.71 (s, 1H), 2.95 (m, 4H), 2.11 (m, 2H). 5-amino-6-iodo-indane (S154). To a solution of 815-3 (1.65 g, 5.7 mmol) in isopropanol (100 mL) and saturated aqueous NH4CI solution (20 mL) was added iron powder (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. 1H NMR (500 MHz, CDC 3 ) 8 7.44 (s, 1H), 6.59 (s, 1H), 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]. 8-((6-amino-2,3-dihydro-1H-inden-5-yl)thio)-9-H-purin-6-aimine (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 nmol) in anhydrous DMF (4 mL) was vortexed and heated at 190 *C under microwave for lh. 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. 1 HNMR (500 MHz, MeOH-d4/CDCI 3 ) 5 8.11 (s, 1H), 7.36 (s, 1H), 6.81 (s, IfH), 2.85 (m, 4H), 2.06 (m, 2H); MS (ESI): m/z 299.02 [M+H]*. 8-((6-iodo-2,3-dihydro-1IH-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 mng, 0.22 mmol) 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/US2010/051872 125 methylene chloride (2 x 20 mL). The organic layer was washed with saturated aqueous Na 2

S

2

O

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, CDC 3 ) 6 8.12 (s, 1H), 7.84 (s, 1H), 7.39 (s, 1H), 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 ) 6 8.36 (s, 1H), 7.75 (a, 1H), 7.18 (s, 1H), 4.62 (t, 2H), 3.68 (t, 2H), 2.88 (t, 2H), 2.81 (t, 2H), 2.06 (m, 2H); ' 3 CNMR (125 MHz, CDC1 3 , 6): 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-1HI-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) 6 8.32 (s, 1H), 7.73 (s, 1H), 7.1 (s, 1H), 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 C 21

H

28 INS, 523.1141; found 523.1140. 8-((6-iodo-2,3-dihydro-lH-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 DIVF (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, CDCI 3 ) 5 8.31 (s, 1H), 7.74 (s, WO 2011/044394 PCT/US2010/051872 126 1H), 7.11 (s; 1H), 573 (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, 2H), 2.49 (d, J= 6.6 Hz, 2H), 2.05 (m, 2H), 1.81 (m, 1H), 0.92 (m, 611); HRMS (m/z): [M+H]* called for C2 0 H2 6 1N 6 S 509.0984; found 509.0990. 9-(3-bromopropy)-8-((6-iodo-2,3-dihydro-1H-inden-5-yl)tkio)-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 gL, 0.86 nmol) and Cs 2

CO

3 (46 mag, 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 ) 6 8.27 (s, 1H), 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, 211); MS (ESI): m/z 530.3, 532.3[M, M+2]. 8-((6-iodo-2,3-dihydro-1H-inden-5-yl)thio)-9-(3-(isopropylamino)propyl)-9H-purin-6 amine (PU-WS29). To a solution of S15-7B (8 mg, 0.0 15 mmol) in DMF (3 inL) was added isopropylamine (100 4L), 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, CDC 3 )8 8.32 (s, 1H), 7.75 (s, 1H), 7.12 (s, 1H), 5.73 (br s, 2H), 4.29 (t, 2H), 2.87 (t, J= 7.4 Hz, 2H), 2.7-2.79 (In, 3H), 2.55 (t, 2H), 2.03-2.09 (m, 4H), 1.05 (d, J= 11.2 Hz, 6H); "C NMR (125 MHz, CDCl 3 ) 8 154.5, 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

26 1N 6 S 509.0984; found 509.1003. 8-((6-ethynyl-2,3-dihydro-1H-inden-5-yI)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. 'H NMR (CDC1 3 , 500 MHz) 8 8.32 (s, 1 H), 7.41 (s, IH), 7.13 (s, IH), 5.67 (br s, 211), 4.42 (m, 2H), 3.48 (s, 1H), 3.02 (m, 211), 2.77-2.91 (m, 4H), 2.39 (s, 2H), 2.06 (m, 2H), 0.89 (s, 9H); HRMS (ESI) m/z [M+H]* calcd. for C2H 2 gN 6 S, 421.2174; found 421.2164.

WO 2011/044394 PCT/US2010/051872 127 COOEt OH HO COOEt a Nb 0 c d O- EtOOC _ HOOC COORt COOEt S13-4 S13-1 513-2 SI13-3 - NH 2 HOOC HOOC HN NH22NH2 H 0 816-S 516 - 16-7

NH

2

NH

2 F F F N H F N N H H H 816-8 516-9

NH

2

NH

2 NN N - ~N F N N N N r RHN 816-IOA n= 2 PU-WSI8 n= 2, R= isopropyl 816-1OB 0= 1 PU-WS17 n= 1,R= isobutyl PU-WS22 n= 1, R= neopentyl Reagents and conditions: (a)EtOH, H2SO4, reflux; (b) 2-bromomethylmalonate, NaH, DMF, 11 0*C; (c) PPA, toluene, reflux; (d) NaOH, MeOH, rt, then HCl; (e) Pd/C, H 2 (2 atm.), MeOH; (f) 2,4,5,6-tetraaminopyrimidine, triphenyl phosphite, pyridine, microwave, 2104C; (g) HF/pyridine, NaNO 2 , 0 0 C 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 neopentylanine, 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, 1H), 7.12 (m, 1H), 6.69-6.78 (m, 3H), 4.12 (m, 2H), 3.53 (s, 211), 1.21 (m, 3H). Diethyl 2-((3-ethoxy-2-oxoethyl)phenox)methyl)malonate (S16-3). To a solution of S16-2 (11.8 g, 65.5 mmol) in 150 mL of DMF cooled in ice bath was added NaH (2.36 g, 98 mmol) and stirred at 0 C under argon for 20 min. To the resulting mixture was added diethyl 2 bromomethylinalonate (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, CDC 3 ) 5 7.19 (t, 1H), 6.80-6.86 (m, 3H), 4.81 (m, 1H), 4.12 (in, 2H), 3.97 (m, 2H), 3.74 (m, 2H), 3.63 (m, 2H), 3.55 (s, 2H), 1.19 (m, 9H); "C NMR (125 MHz, CDC 3 ) 3 171.3, 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-(benzofaran-6-yl) acetate (S16-4). To a solution of S1 6-3 (6 g, 17 nmol) 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, CDC13) 5 7.31-7.42 (m, 3H), 6.95 (m, 1H), 6.51 (s, 1H), 3.94 (m, 2H), 3.51 (s, 2H), 1.02 (m, 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-yl) acetic acid (S13-5). To a solution of S16-4 (3 g, 14.7 mmol) 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 ) S 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, 111), 3.70 (s, 2H); "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 methapol was added Pd/C (10%, 120 mg) and stirred at rt under H2(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. 1H NMR (500 MHz, MeOH-d4) 6 7.12 (d, J= 7.6 Hz, 1H), 6.73 (d, J= 7.9 Hz, 111), 6.71 (s, 1H), 4.55 (in, 2H), 3.56 (s, 2H), 3.16 (in, 2H); "C NMR (125 MIHz, MeOH-d4) 5 177.9, 160.4, 133.3, 126.2, 124.8, 121.5, 110.5, 71.5, 41.1, 29.4. 8-((2,3-dihydrobenzofuran-6-yi)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 mmol) 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-ds) 5 7.16 (m, 111), 6.79 (m, 1H), 6.73 (s, 111), 4.57 (m, 211), 4.12 (s, 2H), 3.18 (in, 211); MS: m/z 283.2 (M+H). 8-((2,3-dihydrobenzofuran-6-yl)methyl)-2-fluoro-9H-purin-6-amine (S 16-8). 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 d 4 ) 8: 7.16 (m, 1H), 6.77 (m, IH), 6.71 (s, 1H), 4.57 (in, 2H), 4.12 (s, 2H), 3.19 (m, 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 mmo) 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 t 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. 1H NMR (500 MHz, MeOH-d 4 ) 8 7.67 (s, 1H), 6.76 (s, 1H), 4.59 (m, 211), 4.28 (s, 2H), 3.21 (m, 2H); 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 DMIF was added 1,3-dibromopropane (150 p) and Cs 2

CO

3 (80 mg, 0.24 mmol). The resulting mixture was stirred at ft for 2 h, evaporated to dryness and purified by preparatory TLC to give S16-10A (23 mg, 36%) as a white solid. 'H NMR (500 MHz, MeOH-d 4 ) 6 7.48 (s, 1H), 6.31 (s, 1H), 4.35 (m, 2H), 4.12 (s, 2H), 3.92 (m, 2h), 3.14 (m, 211), 3.01 (m, 21H), 2.03 (m, 21H); MS: m/z 530, 532 (M, M+2). 2-fluoro-8((5-iodo-2,3-dihydrobenzofuran-6-yl)methyl)-9-(3-(isopropylamino)propyl) 911-purin-6-amine (PU-WS1S). To a solution of S16-1OA (15 mg, 0.03 mmol) in 1 miL 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 ) 6 7.67 (s, 1H), 6.72 (s, 111), 4.63 (m, 211), 4.26 (in, 411), 3.22-3.29 (m, 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]* called. for C 2

H

25

N

6 OF, 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 jL) 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 mmol) in I mL of DMF was added isobutylamine (100 uL), stirred at ft overnight, evaporated to dryness and purified by flash chromatography to give PU-WS17 as a white solid. 'H NMR (MeOH d 4 /CDCI3, 500 MHz) : 7.67 (s, 1H), 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, 211), 2.45 (d, J = 6.9 Hz, 2H), 1.69 (in, IH), 0.88 (d, J = 6.8 Hz, 6H); HRMS (ESI) m/z [M+H]t called. for C2 0 H2 5 FINO, 511.1119; found 511.1113. 2-fluoro-8-((5-iodo-2,3-dihydrobenzofuran-6-yl)methyl)-9-(2-(neopentylamino)ethyl) 91-purin-6-amine [PU-WS22]. To a solution of S16-9 (70 mg, 0.17 mmol) in 2 mL of DMF was added 1,2-dibromoethane (150 gL) and Cs 2 CO3 (110 mg, 0.34 mmol). The resulting WO 2011/044394 PCT/US2010/051872 131 mixture was stirred at it 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 neopentylanine (50 pL), stirred at rt overnight, evaporated to dryness and purified by flash chromatography to give compound PU-WS22 as a white solid. 1 H NMR (CDCl 3 , 500 MHz) 8 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, 211), 2.34(s, 2H), 0.91 (s, 9H); HRMS (ESI) m/z [M+H]* called. for C 21

H

2 7

FIN

6 0, 525.1275; found 525.1249. 02N 0 0 d aB2N b 02N c + H2NI 817-1 S17-2 317-3 817-4 S17-5 S117

NII

2 2N 0 9 e

NH

2 N N N N N N HH S17-5 S17-S

NH

2 H0 N N () n=1,2 n=1,2 NHR Br S17-7 S17-a Reagents and conditions: (a) HNO 3 , H 2 S0 4 ; (b) Nal, Cul, NN'-dimethylethylenediamine, dioxane, 110 0C; (C) Fe, HClI; (d) 8-mercaptoadenine, neocuproine, CuI, NaOtBu, DMF, 1 15*C; (e) KI, NaNO 2 , HCI, <5 0 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 AcH AcHN S18-I 88-2 S18-3 318-4 O 0 NH 2 HN d e N f AI

H

2 N N N AcH H2 S18- 318-6 S18-7

N-

2

NIH

2

NH

2 N .' t iN ; hll rN xsC N NN N N N H O - (n=1,2 \ n=1,2 Br Br 518.8 318-9 S18-10 Reagents and conditions: (a) Ac 2 O, CH 2 C1 2 , rt; (b) Br 2 , AcOH, 10*C; (c) CrO 3 , AcOH/H 2 0, 50-55*C; (d) Nal, CuI, N,N'-dinethylethylenediamine, dioxane, I 0 0 C; (e) 6M HC (aq.), reflux; (f) 8 mercaptoadenine, neocuproine, CuI, NaOt~u, DMF, 115*C; (g) KI, NaNO 2 , HCL <5*C ; (h) Cs 2

CO

3 , 1,3-dibromopropane, DMF, rt; (i) isopropylanine, DMF, it. Scheme 18.

NH

2 NH 2 X N \0, N ell N> o YZ aorb Z X N N X N kN 2 ( n=1,2 ( n=1,2 NHR NHR PU-HJP1B 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-HT16B X= H, Z= S, n= 1, R= isobutyl PU-HJP23 X= H, Z= S, n= 1, R= isobutyl, X= 2-furanlyl DZ3-73 X= F Z= CH 2 , n= i R= isobutyl TT-VI-63A X= F, Z= CH 2 , n= 1, R= isobutyl, X= 2-furanyl TT-VI-54A 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 Reagents or conditions: (a) boronic acid, PdC1 2 (PPh 3 )2, NaHCO 3 , H20, DMF; (b) XSn(Bu) 3 , LiCl, Pd(PPh 3

)

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[bI [1,4ldioxin-6-y1)thio)-9-(3 (isopropylamino)propyl)-9H-purin-6-amine [HJP18]. 2-Furanylboronic acid (8 mg, 0.0712 nunol) was added to PU-RK11 (25 mg, 0.0475 mmol) and NaHCO 3 (12 ig, 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*C for 12 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 10.2 mg (45%) of HJP18. 'H NMR (500 MHz,

CDC

3 /MeOH-d 4 ) 8 8.29 (s,1H), 7.47 (s, 1H), 7.26 (d, J= 3.8 Hz, IH), 6.89 (s, 111), 6.73 (d, J= 3.9 Hz, 1H), 6.46 (m, IH), 4.25 (m, 411), 4.16 (t, J= 6.2 Hz, 211), 2.67 (m, 1H), 2.47 (t, J = 7.1 Hz, 2H), 1.86 (m, 2H), 1.01 (d, J= 6.2 Hz, 6H); 3 C NMR (125 MHz, CDCl 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) m/z467.14 [M+H]*. 8-((7-(1H-pyrazol-3-yI)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9-(3 (isopropylamino)propyl)-9H-purin-6-amine IHJP19]. I H-Pyrazole-3-boronic acid (6.4 mg, 0.057 mmol) was added to PU-RK11 (20 mg, 0.038 mmol) and NaHCO 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 nL) and Pd(PPh 3

)

2

C

2 (5.3 ing, 0.0076 mmol) were 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

(CH

2

CI

2 :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/MeOH-d4) 8 8.18 (s, 111), 7.53 (d, J= 2.4 Hz, 1H), 7.15 (s, 1H), 7.14 (s, 1H), 6.36 (d, J= 2.4 Hz, 11), 4.29 (m, 4H), 4.19 (t, J= 6.6 Hz, 2H), 2.75 (septet, J= 6.1 Hz, 1H), 2.52 (t, J= 6.6 Hz, 211), 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 NaHCO3 (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*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 HJP23. 'H NMR (500 MHz, CDCl 3 ) 8 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, 1H), 6.47 (m, 1H), 5.63 (br s, 2H), 4.20-4.30 (m, 6H), 2.90 (t, J=6.0 Hz, 2H), 2.38 (d, J= 6.8 Hz, 2H), 1.65 (m, 1 H), 0.85 (d, J= 6.9 Hz, 6H); HRMS (ESI) m/z [M+H]* calcd. for C 2 3

H

2 7

N

6 0 3 S, 467.1865; found 467.1884. 2-fluoro-8-((7-(furan-2-y)-2,3-dihydrobenzo [b] [1,4]dioxin-6-yl)methyl)-9-(2 (isobutylamino)ethyl)-9H-purin-6-amine [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 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

C

2 (6.7 mg, 0.0095 mmol) were 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

(CH

2 Cl 2 :MeOH-NH3 (7N), 20:1) to give 20.9 mg (94%) of TT-VI-53A. 'H NMR (500 MHz, CDCl3/MeOH-d4) 5 7.45 (d, J= 1.8 Hz, 1H), 7.13 (s, 1H), 6.60 (s, IH), 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 (m, lH), 0.85 (d, J=6.7 Hz, 6H); "C NMR (125 MHz, CDCI 3 /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) n/iz [M+H]* calcd. for C2H2sFN 6 0 3 , 467.2207; found 467.2203; HPLC: method A Rt = 7.05, method B R = 8.74.

WO 2011/044394 PCT/US2010/051872 135 8-((7-(IH-pyrazol-3-yI)-2,3-dihydrobenzo[b] [1,4]dioxin-6-yl)methyl)-2-fluoro-9-(2 (isobutylamino)ethyl)-9H-purin-6-amine [TT-VI-54A]. 1H-Pyrazole-3-boronic acid (26 mg, 0.228 mmol) was added to DZ3-73 (30 mg, 0.0570 mmol) and NaHCO 3 (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 C12 (8 mg, 0.0114 mmol) were 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

(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) S 7.60 (d, J= 2.1 Hz, IH), 7.02 (s, 1H), 6.82 (s, lH), 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 (m, IH), 0.96 (d, J= 6.7 Hz, 6H); "C NMR (125 MHz, CDCI 3 /MeOH-d 4 ) S 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]* calcd. for C 23

H

2 gFN 8 0 2 , 467.2319; found 467.2323; HPLC: method A Rt= 6.39, method B Rt = 7.03. 9-(3-(isopropylamino)propyl)-8-((7-(oxazol-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6 yl)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 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 4.7 mg (27%) of HJP20. Additionally, 7 mg of unreacted PU-RK1 1 was recovered for an actual yield of 45%. 'H NMR (500 MHz, CDCl 3 ) & 8.32 (s, iH), 7.70 (s, iH), 7.54 (s, iH), 7.26 (s, IH), 6.59 (s, iH), 5.79 (br s, 2H), 4.20-4.34 (in, 6H), 2.67 (in, J= 6.1 Hz, iH), 2.50 (t, J= WO 2011/044394 PCT/US2010/051872 136 6.8 Hz, 2H), 1.93 (m 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 N" N aorb N S N N- N

OCH

3

QCH

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

)

2 , NaHCO 3 , H20, DMF; (b) CuI, PdCl2(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-(neopentylainiio)ethyl)-9H-purin-6-amine [TT-V-138]. 2-Furanylboronic acid (8.2 mg, 0.073 2 mmol) was added to EC102 (25 mg, 0.0488 mmol) and NaHCO 3 (12.3 mg, 0.1464 nmol). 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 (6.8 mg, 0.00976 mmol) were added and the reaction mixture was heated under nitrogen at 90*C for 5 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 20.7 mg (94%) of TT-V-138. 'H NMR (500 MHz, CDCl 3 ) 8 8.31 (s, 1H), 7.62 (d, J= 8.7 Hz, IH), 7.50 (d, J= 1.8 Hz, IH), 6.86 (dd, J= 2.6, 8.7 Hz, 1H), 6.70-6.73 (m, 2H), 6.49 (dd, J= 1.8, 3.3 Hz, 1H), 5.98 (br 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); "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]* caled. for C 2 3

H

2 9

N

6 0 2 S, 453.2073; found 453.2071; HPLC: method A Rt = 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-139J. 2-Thiopheneboronic acid (18.8 mg, 0.147 umol) was added to EC102 (25 mg, 0.0488 mmol) and NaHCO 3 (24.6 mg, 0.293 nunol). 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

)

2 Cl 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 (CH2C1 2 :MeOH-NH 3 (7N), 20:1) to give 16.2 mg (71%) of TT-V-139. 'H NMR (500 MHz, CDCl 3 /MeOH-d 4 ) 5 8.19 (s, 1H), 7.45 (d, J= 8.5 Hz, 1H), 7.30-7.33 (m, 1H), 6.99-7.04 (m, 3H), 6.97 (dd, J= 2.6, 8.5 Hz, 1H), 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, CDC13/MeOH-d 4 ) S 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 C23H 29

N

6

OS

2 , 469.1844; found 469.1830; HPLC: method A R =6.84, method B Re = 7.48. 8-(5-methoxy-2-(1H-pyrazol-3-yl)phenylthio)-9-(2-(neopentylamino)ethyl)-9H-purin-6 amine [TT-V-140J. 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

C

2 (8.2 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 901C for 7 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2 C1 2 :MeOH-NH 3 (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%. 1H NMR (500 MHz, CDC1/MeOH-d 4 ) 8 8.19 (s, 1H), 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, 9H1); 1 3 C NMR (125 MHz, CDC13/MeOH-d 4 ) 6 154.6, 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) mI/z [M+H]* calcd. for CnH29NeOS, 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-aniine (PU-WS31). Following the procedure to make PU-WS8, PU-WS31 was obtained from EC102 as a white solid. 1H NMR (CDC1 3 , 500 MHz) 6: 8.35 (s, 1H), 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, IH), 2.97 (t, J -6.3 Hz, 2H), 2.31 (s, 2H), 0.87 (s, 9H); MS (ES1) m/z 411.3 (M+H).

NH

2 NH 2 R N NH )00 PU-H71 N N a N N FN N FAN HN HN PU-DZ13 Reagents and conditions: (a) RSn(Bu) 3 , LiCl, Pd(PPh 3

)

4 , DMF, 90*C.

WO 2011/044394 PCT/US2010/051872 139 Scheme 21. Stille coupling of PU-H71 and PU-DZ13. 9-(3-(isopropylamino)propyl)-S-(6-(oxazol-2-yl)benzo[d] [1,3]dioxol-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 yl, 0.234 mmol), LiCi (5 mg, 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'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, CDCl 3 /MeOH-d) 6 8.25 (s, 1H), 7.75 (s, 1H), 7.46 (s, 1H), 7.27 (s, 1H), 6.71 (s, 1H), 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 (m, 2H), 1.06 (d, J= 6.3 Hz, 611); HRMS (ESI) m/z [M+HJ1 calcd. for C 21 iH 24

N

7 0 3 S, 454.1661; found 454.1650; HPLC: method A R, = 5.77, method B Rt = 5.28. 9-(3-(isopropylamino)propyl)-S-(6-(thiazol-2-yl)benzo[d][1,3]dioxol-5-ylthio)-9H-purin 6-amine IDZ4-21. A mixture of PU-H71 (30 mg, 0.0585 mmol), 2-(tri-n butylstannyl)thiazole (87.6 mg, 72.4 jil, 0.234 mmol), LiC1 (5 mg, 0.117 inmol) and Pd(PPh 3

)

4 (6.7 mg, 0.005 8 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 901C for 18 h. Then additional 2-(tri-n-butylstannyl)thiazole (21.9 mg, 18 11, 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. 1H NMR (500 MHz, CDCl3/MeOH-d 4 ) 5 8.20 (s, 111), 7.87 (d, J= 3.3 Hz, 1H), 7.45 (s, 1H), 7.44 (d, J= 3.3 Hz, 1H), 6.98 (s, 11), 6.11 (s, 211), 4.21 (t, J= 6.9 Hz, 2H), 2.78 (septet, J= 6.3 Hz, 111), 2.55 (t, J= 6.9 Hz, 211), 1.98 (m, 2H), 1.09 (d, J=6.3 Hz, 611); HRMS (ESI) m/z [M+H]* calcd. for C 2 1H24N 7 0 2 S2, 470.1433; found 470.1438; HPLC: method A Rt = 5.86, method B Rt = 5.66.

WO 2011/044394 PCT/US2010/051872 140 2-fluoro-9-(2-(isobutylamino)ethyl)-8-((6-(oxazol-2-yl)benzo[d] [1,3]dioxol-5-yl)methyl) 9H-purin-6-amine IDZ4-23J. A mixture of PU-DZ13 (20 mg, 0.039 mmol), 2-(tri-n butylstannyl)oxazole (55.9 mg, 32.7 sl, 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 904C for 18 h. Then additional LiCI (3.3 mg, 0.078 mmol) and Pd(PPh) 4 (4.5 mg, 0.0039 mmol) were 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 two times (hexane:CH 2 Cl 2 :EtOAC:MeOH-NH 3 (7N), 2:2:1:0.5 then CH 2 Cl2:MeOH-NH 3 (7N), 20:1) to give 5.5 mg (3 1%) of DZ4-23. 'H NMR (500 MHz, CDCs/MeOH-d) 5 7.68 (s, 1IH), 7.53 (s, 1H), 7.12 (s, iH), 6.84 (s, IH), 6.07 (s, 2H), 4.74 (s, 2H), 4.41 (t, J= 6.4 Hz, 2H), 3.15 (t, J= 6.4 Hz, 2H), 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 03, 454.2003; found 454.1995; HPLC: method A R = 6.61, method B R = 7.58. 2-fluoro-9-(2-(isobutylamino)ethyl)-8-((6-(thiazol-2-yl)benzo[d][1,3]dioxoI-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 nmol) 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-NH 3 (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, CDC3/MeOH-d 4 ) 3 7.77 (d, J= 3.3 Hz, iH), 7.36 (d, J= 3.3 Hz, 1H), 7.17 (s, IH), 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, 2H), 1.64 (m, 1H), 0.86 (d, J= 6.8 Hz, 6H); HRMS (ESI) z [M+HJ' calcd. for

C

2 2H2sFN 7 02S, 470.1774; found 470.1770; HPLC: method A R= 6.68, method B Rt= 7.79.

WO 2011/044394 PCT/US2010/051872 141

NH

2 1

NH

2 R N N N N$ 0 - -o N N0 NH NH PU-H7' Reagents and conditions: (a) alkene (R), Pd(PPh 3

)

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 ing, 21 pL, 0.117 mmol), cyclopentene (80 mg, 103 iL, 1.171 mmol) and Pd(PPh 3

)

4 (6.8 mg, 0.00586 mmol) 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

CI

2 :MeOH, 7:3) to give 9.2 mg (35%) of TT-VI-116. 'H NMR (500 MHz, CDCl 3 /MeOH-d 4 ) 3 8.16 (s, 1H), 6.99 (s, 1H), 6.82 (s, 1H), 6.01 (s, 2H), 5.98 (m, 1H), 5.63 (in, 1H), 4.41 (t, J= 6.4 Hz, 211), 3.39 (m, 1H), 3.34 (septet, J= 6.6 Hz, 1H), 2.95 (t, J= 6.4 Hz, 2H), 2.22-2.52 (m, 5H), 1.50-1.59 (m, iH), 1.44 (d, J= 6.6 Hz, 6H); HRMS (ESI) m/z [M+H] calcd. for C23H 29

N

6 0 2 S, 453.2073; found 453.2064; HPLC: method A Rit = 6.51, method B R = 7.79. 8-(6-(2,5-ihydro-JH-pyrrol-2-yl)benzoId][1,31dioxol-5-ylthio)-9-(3 (isopropylamino)propyl)-9H-purin-6-amine [DZ3-141]. A solution of PU-l71 (30 mg, 0.0585 mmol) and N-Boc-2,3-dihydro- 1 H-pyrrole (19.8 ing, 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 pL, 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 Cl 2 :MeOH-NH 3 (7N), 15:1) and the resulting residue was dissolved into 2 mL of

CH

2 Cl2: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-NH3 (7N), 10:1) to give 6.0 mg (23%) ofDZ3-141. 'H NMR (500 MHz, CDCI3/MeOH-d 4 ) 6 8.19 (s, IH), 6.98 (s, 2H), 6.04 (m, 1H), 6.01 (s; 2H), 574 (m, 1H), 5.62 (d,J= 2.0 Hz, 1H), 4.31 (t, J=6.9 Hz, 2H), 3.81-3.88 (m, 1H), 3.89-3.95 (m, 1H), 2.87 (septet, J= 6.3 Hz, 1H), 2.68 (t, J= 6.7 Hz, 2H), 2.14 (m, 2H), 1.15 (d, J= 6.3 Hz, 6H); HRMS (ESI) m/z [M+H] 4 caled. for

C

22

H

28

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-(isopropylanino)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 pL, 0.117 mmol), 2,3-dihydrofuran (82 mg, 88 IL, 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*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 CI2: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. 'H NMR (500 MHz,

CDC

3 ) 8 8.23 (s, 1H), 7.06 (s, 1H), 6.96 (s, 1H), 6.43 (in, 1H), 6.01 (s, 2H), 5.94 (dd, J= 8.1, 10.8 Hz, 111), 5.72 (br s, 2H), 4.93 (in, IH), 4.35 (t, J= 6.8 Hz, 2H), 2.95-3.55 (in, 211), 2.70 (t, J= 6.5 Hz, 2H), 2.39-2.47 (m, 1H), 2.22 (m, 2H), 1.25 (d, J= 6.2 Hz, 6H); HRMS (ESI) m/z [M+H]* calcd. for C 2 2

H

27

N

6 0 3 S, 455.1865; found 455.1865; HPLC: method A Rt = 6.07, method B Rt = 6.49. 8-(6-(2,3-dihydrofuran-3-yl)benzo[d]l1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl) 9H-purin-6-amine [DZ3-143]. A solution of PU-H71 (30 mg, 0.0585 minol) in NMP (1.5 mL) was evacuated and back filled with nitrogen. This was repeated four times, then DIEA (15.1 ing, 21 L, 0.117 mmol), 2,5-dihydrofuran (82 mg, 88 pAL, 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"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) 6 8.18 (s, 1H), 7.02 (s, 1H), 7.00 (s, 1H), 6.55 (m, 1H), 6.04 (s, 2H), 4.99 (m, 1H), 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) m/z [M+H]* called. for C22H 21

N

6

O

3 S, 455.1865; found 455.1862; HPLC: method A R, = 6.04, method B 1 = 6.32.

NH

2

NH

2 R S aorb,c N N N 0 N N 0 HN HN PU-WS23 R= 2-furanyl PU-WS2 PU-WS24 R= 2-thiophenyl PU-WS28 R= CCH Reagents and conditions: (a) PB(OH) 2 , PdCl 2 (PPh 3

)

2 , NaHCO 3 , H20, DMF, 90'C; (b) CuJ, 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-WS231. 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, I H), 7.49 (s, 2H), 6.68 (d, J= 3.4 Hz, 1H), 6.58 (s, IH), 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]* called for CuH29N602 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. 1 HNMR (500 MHz, CDC 3 ) 3 8.31 (s, I H), 7.32 (m, 1H), 7,27 (s, 1H), 7.03-7.07 (m, 2H), 6.67 (s, 1H), 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]* called for C24H 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. 1 HNMR (500 MHz, CDC 3 , 5): 8.33 (s, 1H), 7.36 (s, 1H), 6.59 (s, 1H), 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]* called for C22H2 7 N6OS 423.1967; found 423.1968. H2 Ac-HN b O 0 H 2 N< o -(CrCo> )XH> 0 S24-1 S24-2 824-3 S244

NH

2 -N NH 2 -N

INI-

2 -N N r 'y5y 0 N N N N N 0 H ( ) = 1, 2n=1, 2 S24-5 824-6 Br RHN 824-7 S24-8 Reagents and conditions: (a) Ac20, AcOH, rt; (b) ICI, CH2C 2 , AcOH, rt; (c) NaOH, EtOH, H 2 0, reflux; (d) paraformaldehyde, NaBH 3 CN, MeOH, 50*C; (e) 8-mercaptoadenine, neocuproine, Cul, NaOtBu, DM1F, 115*C; (f) Cs2C0 3 , 1,3-dibromopropane or 1,2-dibromoethane, DMF, rt; (g) amine, DMF, rt. Scheme 24. Similarly, WO 2011/044394 PCT/US2010/051872 145 H2N H2N I2 H i 0 H N d g NH 2

-N

N N N N H2NHl 2 N RH n= 1,2 5 or 6-membered ring RHN corresponding to 2-lodoamine

H

2 N H2N N Scheme 25. Synthesis of various bromides required for alkylation of the purine skeleton.

NH

2 X2

NH

2 X2 , N N s 2

C

3 ,DMF X4 N R 5or6- r me er membered ring memberedi ring WO 2011/044394 PCI!US2OIO/051872 146 (-J4-Br ND+' I1,2 HC(OEt) 3 H Br Br OH "Br n-1,~2 Ph3P. CBr 4 TWA HCC N 'n=, N~oc NHN0 ~ , NBaC CHaS02CI (-$Br OH H /~ ~nn1,1,2 N Bc 0 rx-Br -S-N04/ 0I\...a WO 2011/044394 PCT/US2010/051872 147 0 i-PBu FPS H H TIPS t-butyl poyber on- 4 NF N H 2 -LiAIH 4 ? n-B___ 10% PdIC Pd(OAc) 2 COOn-SBu COOr-Bu COOri-Bu HO Boc Boo H H-z PjO B N N N HO OO Br Br I CISO2NCO HG(07/ACI ". 2. TPA HC(OEt~h AcCf CHaSO 2 Ci H N- 2 N N N N Br Br Br B Br H 0CB 1) Tscl NHa 2) LiBr N Br HO Br

NH

2 0 NH 3 O0 Br- -~N OH Br--Cr 0 -0 0 MeNH 2 BrS NH-- N 0 0 PPh 3

CH

3

SO

2 CI MOr~-- ~ 4 0 WO 2011/044394 PCI!US2OIO/051872 148 Table IA No. Name lA-i PU-WSiO 8 -((6-iodo-2,3 -dihydrobenzofhran-5-yl)tbio)-9-(3 (isopropylamino)propyl)-9H-purin-6-amine lA-2 8-((6-iodo-2,3 -dihydrobenzofuran-5-yl)thio)-9-(2-(isobutylamino)ethyl) 9H--purin-6-amine lA-3 1 -(6-amino-S-(6-iodo-2,3-dihydrobenzofiiran-5-ylthio)-9H-purin-9-yl)-3 (ten-butylamino)propan-2-ol lA-4 2-fluoro-8-((6-iodo-2,3-dihydrobenzofuan-5-yl)methyl)-9-(2 (isobutylamino)ethyl)-911-purin-6-amime lA-S 2-chloro-8-((6-(furan-2-yl)-2,3-dihydrobenzoiaran-5-yl)methyl)-9-(3 (isopropylamfio)propyl)-911-purin-6-amine lA-6 2-fluoro-8-((6-iodo-2,3-dihydrobenzofura-5-yl)methyl)-9-(3 JA-7 8-((6-(fbran-2-yl)-2,3-dihydrobenzofuamn-5-yl)thio)-9-(3 (isopropylamino)propyl)-9H-pu-rin-6-andne lA-S 8-((6-ethynyl-2,3-dihydrobenzofuran-5-yl)thio)-9-(3 (isopropylaina)propyl)-9H-purin-6-andne, JA-9 5-((6-amino-9-(3-(isopropylamino)propyl)-9H-putrin-8-yl)thio)-2,3 diliydrobenzofuran-6-carbonitrile lA-1U 8-((6-(azirdin-1I-yl)-2,3-diliydrobenzofurn-5-yl)methyl)-2-fluoro-9-(2 (neopentylainino)ethyl)-9H-purin-6-ainine lA-il 8-((6-iado-2,3-dihydrobenzofur-an-5-yl)thio)-9-(2-(isobutylamino)ethyl) ________9H-purin-6-amine lA-12 3-(2-(6-amino-8-(6-(5 -metliylfuran-2-yl)-2,3-dibydrobenzofuran-5 _________ lthio)-9H-purin-9-yI)ethyl)piperidine-1-sulfonantde lA-13 I -(3-(2-(8-(6-(1H-pyrazol-3-yl)-2, 3-dihydrobenzofuran-5-ylthio)-6 _________amino-9H-purin-9-yi)ethyl)piperidin- 1 -yl)ethanone 1A-14 4-(3-(6-amino-8-(6-ethynyl-23 -dihydrobenzofuran-5-yltbio)-9H-puriu-9 yl)propyl)piperidine-1I -carbaldehyde lA-i5 1-(3-(2-(6-amino-2-fluoro-8-((6-(furan-2-yl)-2,3 -dihydroberizofuran-5 yl~ey)-9-purin-9-y)ethy)piperidin-1I -yl)ethanone lA-16 N-(2-((2-(6-arnino-8-((6-(fuian-2-y)-2,3-dihydrobenzofuran-5-yl)thio) 9W-puri-9-y)ethyl)amino)ethy1 sulfamide 1A-17 3-((2-(6-amino-8-((6-(furan-2-yl)-2,3-dihydrobenzofiara-5-yl)tlio)-9H purin-9-yl)ethyl)amino)-N-hydroxypropananide lA-i8 2-fluoro-8-((6-iodo-2,3 -dihydrobenzofuran-5-yl)thio)-9-(3 _________ poylno)propy)-9H-purin-6-anine WO 2011/044394 PCI!US2OIO/051872 149 IA-19 2-chloro-8-((6-iodo-2,3 -dihydrobenzofuran-5-yl)methyl)-9-(2 (isobutylamino)ethyl)-9H-purin-6-amine IA-20- 9-(2-aminoetliyl)-2-fluoro-8-((6-iodo-2,3 -dihydrobenzofu~an-5 yl)methyl)-9H-punin-6-amnine IA-21 9-(3-arninopropyl)-8-((6-iodo-2 ,3-diliydobenzofuran-5-yl)thio)-9H purin-6-amine IA-22 9-(2-aminoetliyl)-S-((6-iodo-2,3-dihydrobenzoftiran-5 -yl)thio)-9H-purin _________6-amine IA-23 9-(3-(tert-butylamino)propyl)-8-((6-iodo-2,3 -dihydrobenzofiiran-5 yl)thio)-9H-purin-6-anine IA-24 i.-(6-am-Lino-S-((6-iodo-2,3-dihydrobenzofbran-5-y)thio)-9H-purin-9-yl) _________3-(isqpcqyamino propan-2-ol 1A-25 1-(3-(6-amino-2-fluoro-8-((6-iodo-2,3-dihydrobenzoftran-5-yl)methyl) _________9H-purin-9-yl)propyl)pyrrolidin-3-one IA-26 1 -(3-(6-amino-S-(6-iodo-2,3-dihydrobenzofuiran-5-yltiio)-9H-purin-9 yl)propyl)pyrrolidin-3 -one IA-27 5-(6-amnino-8-(6-iodo-2,3-dihydrobenzofhiran-5-ylthio)-9H-purin-9 yl)pentane- I -sulfonamide IA-28 I -(6-amino-2-fluoro-8-((6-iodo-2,3-dihydrobenzofiiran-5-yl)methyl)-9H purin-9-yl)-3-(isopropylaminao)propan-2-ol IA-29 8-((6-ethynyl-2,3-di'hydrobenzofhran-5-yl)methyl)-2-fluoro-9-(5 IA-30 2-fluoro-S-((6-iodo-2,3 -dihydrobenzof'unn-5-yl)methyl)-9-(2-(1 (methylsulfonyl)pyrrolidin-3-yl)ethyl)-9H-purin-6-ammne JA-31 N-(4-(6-amnino-2-fluoro-8-((6-iodo-2,,3-dihydrobenzofuran-5-yl)methyl) 9H-purin-9-yl)butyl)methanesulfonamide lA-32 1-(6-amino-8-((6-ethynyl-2,3-dihydrobenzofuran-5-yl)methyl)-2-flnoro 9H-purin-9j4l)--soroyamino)propan-2-o lA-33 6-(6-amino-8-((6-ethynyl-2,3-dihydrobenzofuran-5-yl)methyl)-2-luoro 9H-purin-9-yl)liexanamide lA-34 1 -(4-(2-(6-ainoe-8-((6-ethynyl-2,3-dihydrobenzofuran-5-yl)metbyl)-2 fluoro-9H-pur 9-yl)ctyl)p~peridin-l -yl)ethaone IA-35 S-((6-ethyny1-2,3-dihydrobe-nzofuran-5-y)metby) 2-fluoro-9-(2-fI -(methylsulfonyl)piperidin-3 yl)ethyl)-9H-purin-6-ammne 9-(3-(isopropylamino)propyl)-S-((6-(5 methylfhra-2-yl)-2,3 -dihydrobenzofuran-5 yl)thio)-9H-purin-6-amine 9-(3 -(tert-butylamino)propyl)-8-((6-(5-methylfbxan 2-yl)-2,3-dihydrobenzofuwan-5-yl)thio)-9H-purin-6 amine __________9-(3-(tert-butylamino)propyl)-8-((6- WO 2011/044394 PCI!US2OIO/051872 150 (diinethylaxnino)-2,3-dihydrobeazofura-5-yl)thio) 9H-purin-6-wnine WO 2011/044394 PCI!US2OIO/051872 151 I -(4-(2-(6-amino-8-((6-(dimethylaxnino)-2,3 dihydrobenzofuran-5-yl)thio)-9H-purin-9 yl)ethyl)piperidin-1 -yl)ethaone IA-40 8-((6-(dincthylamino)-2,3-dihydrqbeizofhmn-5-ylftbio)-9-(2-(I1 __________(iethylsufonyl)piperidin-3-yI)ethyl)-9H-purin-6-amine 1A-41 4-(3-(6-amnino-8-(6-(aziridin-1 -yl)-2,3-dihydrobenzofizran-5-ylthio)-9H purin-9-yl)propyl)piperidine-1I -carbaldehyde 1A-42 8-((6-Qburan-2-yl)-2,3 -diliydrobenzofhran-5-yl)thio)-9-(2-( 1 (methylsulfonyl)piperidin- 3-yI)ethyl)-9H-purin-6-ainine 1A-43 8-((6-(dimnetliylamino)-2,3-dihydrobenzofura-5-yl)rnethyl)-2-fluoro-9-(2 ______b ~~yamino)ethyl)-9H-purin-6-amine 1A-44 8-((6-(dimethylami~no)-2,3-dihydrobenzofuran-5-yI)thio)-9-(2 __________(neopentylamino)ethyl)-9H-purin-6-ainine XA-45 9-{3 -(tert-butylamino)propyl)-B-{(6-(oxazol-2-yl-2,3 -dihydrobenzofuran-5 __________yl)ihio)-9H-purin-6-amine 1A-46 1-(3-(2-(6-amino-8-(6-(oxazol-2-yl)-2,3-dihydrobenzottirn-5-ylthio)-9H-purin 9-yl)ethyl)piperidin- 1 -yl)edbaione 1A-47 4-(3 -(6-amino-S-(6-(oxazol-2-yl)-2,3-diliydrobenzofuran-5-ylthio)-9H-purin-9 1A-48 9-(2-(1-(methylsulfcnyl)piperidin-3-yl)ethyl)-8-((6-(oxazol-2-yl)-2,3 JA-49 1-(2-(-6-aiino-8-(6-iodo-2,3-dihydrobenzofurin-5-ylt'hio)-9H-purin-9 IA-5O 9-(3-(tert-butylamino)propyl)-8-((6-(5-methyloxazol-2-yl)-2,3 diydrobenzofua-5-y)thio)-9H-purin-6-aine 1A-51 9-(3-(tert-butylami no)propyl)48-((6-(thiazol-2-yl)-2,3 -dihydrobenzofuran-5 yl)thio)-9H-purin-6-amine 1A-52 9-(3-(tert-butylam-ino)propyl)-S-((6-{5-methyltbiazol-2-yl)-2,3 dihyrbezfumrn-5-yl)thio)-QHF-purin-6-amine Table lB No. Name lB-i PU-WS9 8-((5-iodo-2,3-dihydrobenzofuran-6-yl)thio)-9(2-(isobutylamin)ethyl)-91-purin 6-amine 1B-2 PIJ-WS4 S-((5-iodo-2,3-dihydrobenzofuran-6-yl)tbio)-9-(3-{isopropylamino)prpyl)-9H __________purin-6-amine WO 2011/044394 PCI!US2OIO/051872 152 1B-3 PU-WS17 2-fl-uoro-8-((5-iodo-2,3-dihydrobenzofuran-6-yl)methyl)-9-(2 __________(isobutylamino)ethyl)-9H-purin-6-amine 1BA4 PU-WS18 2-fluoro-S-((5-iodo-2,3-dihydrobenzoftiran-6-yl)methyl)-9-(3 (iso to ylamino tropy1-911-purin-6-amine lB-S 2-cbhloro-3-((5-iodo-2,3-dihydrobenzoffLran-6-ylpnetbyl)-9-(3 1B-6 8-((5-(fira-2-yi)-2,3 -dihydrobenzofuran-6-yl)thio)-9-(3-(isopropylaxnino)propyl) 1B-7 8-((5-(dimethylamnino)-2,3-dihydrobenzofuran-6-yI)methyl)-2-fluoro-9-(2 lB-S 8-((5-(1 H-pyrazol-3-yl)-2,3-dihydrobenzofiuan-6-yl)thio)-9-(2 __________(isobutylamino)ethyl)-9H-purin-6-aniine 1B-9 8-((5-cyclopentyi-2,3-dihydrobenzofuran-6-yl)thio)-9-(3-(isopropylam:ino)propyl) _________9H-purin-6-amine lB-I0 S-((5-ethynyl-2,3-dihyclrobenzofuran-6-yl)methyl)-2-fluoro-9-{2 __________(isobutyianino)ethyl)-9H-purin-6-amine lB-li 6-((6-amnino-2-fluoro-9-(3-(isopropylamino)propyl)-9H-purin-8-yl)methyl)-2,3 __________dihydrobenzofixran-5-carbonittile lB-12 2-chloro-9-(3 -(isopropylamnino)propyl)-8-((5-(5-mnethylfumn-2-yl)-2,3 lB-13 4-(2-(6-amino-8-((5-ethynyl-2,3-dihydrobenzofuran-6-yl)thio)-9H-purin-9 IB-14 1 -(4-(2-(6-amino-2-fluoro-8-((5-(furart-2-yl)-2,3-dihydrobergzofuran-6-yl)mthyl) 1B-1S N-(2-((2-(6-ain:ino-8-((5-(fixran-2-yl)-2,3-dihydrobenzofiuran-6-yI)rbio)-9H-purin 9-yl)erhyl)amino)ethyl)sulfamide 1B-16 3-((2-(6-amino-8-((5-ethynyl-2,3-dihydrobenzofuran-6-yl)thio)-9H-purin-9 yl)ethyl)amino)-N-hydroxypropanarnide 1B-17 9-(2-(isobulylamino)etbyl)-8-((5-(thiophen-2-yl)-23-dihydrobenzofaran-6-yl)thio) 9H-purin-6-anine lB-iS 3-(3-(6-ainino-8-(5-iodo-2,3-dihydrobenzofuran-6-yrhio)-9H-purin-9-,yl)propyl)-2 _________oxointidazolidinc- 1-carbaldehyde iB-i9- 2-chloro-8-((5-ethynyl-2,3-dihydrobenzofuran-6-yl)methyl)-9-(2 __________ isobutylamino)ethy1)-9H-purin-6-amine IB-20 6-((6-amino-2-chloro-9-(3-(isopropylannino)propyl)-9H-purii-8-yl)metbyl)-2,3 _______dihydrobenzofuran-5-cartonitrile lB-21 2-chloro-8-((5-(dimethylamino)-2,3-dihydrobenzofiiran-6-yl)methyl)-9-(2 (neopentylam-ino)ethyl)-9H-purin-6-amine lB-22 8-((5-cyclopentyl-2,3-dihydrobenzofivran-6-yi)tbio)-2-fl-uoro-9-(3 (isopropylamino)propyl)-9H-purin-6-amaine 1B-23 1-(3-(6-amino-8-(5-iodo-2,3-dihydrobenzofuran-6-ylthio)-9Hf-purin-9 yl)ptopyl)pyrrolidin-3 -one IB-24 PU-WS2L 8-((5-iodo-2,3-dihydrobenzof'uran-6-yl)thio)-9-(2-(neopentylamino)et'hyl)-9H purin-6-ainine IB-25 PU-WS22 2-fluoro-8-((5-iodo-2,3-dihydrobenzofuran-6-yl)methyl)-9-(2 ________neopetlamino ethy1 -9H-purin-6-amnine WO 2011/044394 PCT/US2010/051872 153 1B-26 PU-WS23 8-((54furan-2-yl)-2,3-dihydrobenzofuran-6-yl)thio)-9-(2-(neopentylamino)ethyl) 9H-purin-6-amine 1B-27 PU-WS24 . 9-(2-(neopentylamino)ethyl)-8-((5-(thiophen-2-y)-2,3-dihydrobenzofuran-6 yl)thio)-9H-purin-6-amine 1B-28 PU-WS28 8-((5-ethynyl-2,3-dihydrobenzofuran-6-yl)thio)-9-(2-(neopentylamino)ethyl)-9H purin-6-amine 11-29 9-(3-aminopropyl)-8-((5-iodo-2,3-dihydrobenzofuran-6-yl)thio)-9H-purin-6-amine 1B-30 9-(2-aminoethyl)-2-fluoro-8-((5-iodo-2,3-dihydrobenzofuran-6-yl)methyl)-9H purin-6-amine 1B-31 9-(2-aminoethyl)-8-((5-iodo-2,3-dihydrobenzofuran-6-yl)thio)-9H-purin-6-amine lB-32 9-(3-(tert-butylanino)propyl)-8-((5-iodo-2,3-dihydrobenzofuran-6-yl)thio)-9H purin-6-amine 1B-33 2-fluoro-8-((5-(5-methylfuran-2-yl)-2,3-dihydrobenzofuran-6-yl)methyl)-9-(2-(1 (methylsulfonyl)piperidin-3-yl)ethyl)-9H-purin-6-amine 1B-34 1-(3-(6-amino-8-(5-iodo-2,3-dihydrobenzofuran-6-ylthio)-9H-purin-9-yl)propyl)-4 hydroxypyrrolidin-2-one IB-35 N-(3-(6-amino-8-((5-iodo-2,3-dihydrobenzofuran-6-yl)thin)-9H-purin-9 yl)propyl)methanesulfonamide 1B-36 1-(3-(6-amino-8-(5-ethynyl-2,3-dihydrobenzofuran-6-ylthio)-9H-purin-9 yl)propyl)pyrrolidin-3-one 1B-37 8-(5-iodo-2,3-dihydrobenzofuran-6-ylthio)-9-(2-(1 -(methylsulfonyl)pyrrolidin-3 yl)ethyl)-9H-purin-6-amine 1B-38 N-(3-(6-amino-8-((5-ethynyl-2,3-dihydrobenzofuran-6-yl)thio)-9H-purin-9 yl)propyl)methanesulfonamide IB-39 1-(4-(2-(6-amino-8-((5-ethynyl-2,3-dihydrobenzofuran-6-yl)thio)-9H-purin-9 yl)ethyl)piperidin-I -yl)ethanone WO 2011/044394 PCI!US2OIO/051872 154 IB-40 8-((5-ethynyl-2,3-dihydrobenzofuran-6-yl)thio)-9-(2-(1 -(mcthylsulfonyl)pipcridin 3-yl)ethyfl-9H-pufin-6-amine 11341 5-(6-amino-8-(5-ethyny1-2,3-dihydrobenzofuran-6-ylthio)-9H-purin-9-y)pentane 1-sulfonamide IB42l I-(4-(2-(6-amnino-8-((5-(fiwan-2-yl)-2,3-dihydrobenzofuran-6-yl)thio)-9H-purin-9 yl)ethyl)piperidin-1-yl)ethanone IB-43 8-(5-(5-methylfhran-2-yl)-2,3-dihydrobenzofhran-6-ylthio)-9-(2-( 1 (methylsulfonyl~piperidin-3-yl)ethyl)-PH-purin-&-antne 110-44 2-(3-(6-amina-S-(5-(5-methylffiran-2-yI)-2,3-dihydrobenzoftiran-6-ylthio)-911 purin-9-y1)propylpyrrolidine- I -carbaldehyde 1B045 N-(2-(6-amnino-S-((5-ethynyl-2,3 -dihydrobenzoftnan-6-yl)thio)-9H-purin-9 yl)ethyl) N t -metbyl-sulfiiric diamide 11B46 9-(3-(tert-butylamino)propyl)-8-((5-(oxazol-2-yl)-2,3-dihhydrobenzofbran-5 _________yl)thio)-9H-purin-6-amine 1B-47 9-{3-(tert-buyiaiino)propyl)-4(5-ethynyl-2,3-dihydrbenzofuran-6-yl)thio)-9H _________purin-6-amine 11B48 9-(3-(tert-butylarnino)propyl)-8-((5-(dimethylamino)-2,3-dihydrobenzfun-6 yl)tbio)-9H-purin-6-aniine 1IB49 l-(6-amino-8-((5 -iodo-2,3-dihydrobenzofrran-6-yl)tbio)-9H-purin-9-yl)-3 (isopropylamino)propan-2-ol 113-50 1-(4-(2-(6-amnino-8-((5-(oxazol-2-yl)-2,3-dihydrobenzfuran-6-yl)thio)-9H-purin 9-yl)ethyl)piperidin- 1 -yl)ethanone lB-Si 9-(2-( 1-(methylsulfouyl)piperidin-3-yl)ethyl)-8-((5-(oxazol-2-y)-2,3 dihydrobenzofuran-6-yl)thio)-9H-purin-6-amxine 1IB-52 3-(3-(6-amino-S-(5-iodo-2,3-dihydrobenoffiran-6-yltbio)-9H-purin-9 yl)propyl)pyrrolidine- 1 -sulfonamide IB-53 9-(3 -(tert-butylainino)propyl)-8-((5-(5-methyloxazol-2-yl)-2,3 -dihydrobenzofuran 6-yl)thio)-9H-purin-6-atnine IB-54 9-(3-(tert-b-utylanlino)propyl)-8-{(5-(thiazol-2-yl)-2,3-dihydrobenzofuiran-6 -yl)thio)-9H-purin-6 -amine 1IB-55 9-(3-{tert-butylamino)propyl)-S-((5-(5-inethyltbiazol-2-yl)-2,3-dihydrobenzofuran 6-yl)thio)-9H-purin-6-amine 1B-56 6-(6-amino-8-(5-iodo-2,3-dihydrobenzofixra-6-ylthio)-9H-purin-9-yl)hexanamide 1B-57 5-(6-amnino-S-(5-iodo-2,3-dihydrobenzofixra-6-ylthio)-9H-purin-9-yl)pentane-I sulfonamide 1B58 3-(6-amino-8-(5 -ethynyl-2,3-dlihydrobenzofuran-6-ylthio)-9H-purin-9-yl)propy __________sufamate Table IC NO. Name ic-i 8-((6-iodo-2,3-dihydrobenzo[blthiophen-5-yl)thio)-9-(3 (isopropylanuiip)propyl-9H-purin-6-amine 1 C-2 E-((6-iodo-2,3--dihydrobenizo[blthiophen-5-yl)thio)-9-(2-(isobutylamino)etyl) 9H-purin-6-antne 1C-3 8-((6-iodo-2,3-diliydrobenzo[b]thiophen-5-yflthio)-9-(3 ____________(isopropylainino)propyl)-911-purin-6 -armine 1C-4 2-fluoro-8-((6-iodo-2,3-dihydrobenzorblthiophen-5-yl)methyl)-9-(2- WO 2011/044394 PCI!US2OIO/051872 155 (isobutylanmino)ethyl)-9H-purin-6-amine ic-s 2-chloro-S-((6-(fuan-2-yl)-2,3-dihydrobenzo[bjthiophen-5-yl)methyl)-9-(3 (isopropylamino)propyl)-911-purin-6-amine 1 C-6 R-((6-( 1H-imidazo1-4-y1)-2,3-dihydrobenzo[bltbiophen-5-y1)methy1)-2-fluoro-9 (3-(isopropylamino)prppy -911-purin-6-amine 1(2-7 8-((6-(frra-2-yI)-2,3-dihydrobenzo[bjthiophen-5-yl)thio)-9-(3 (isopropylamino)propyl)-9H-purin-6-amine 1(2-8 8-((6-cthynyl-2,3 -dibydrobenzo[b]thicphen-5-yl)thio)-9-(3 (isopropylarmino)pxopyl)-9H-putin-6axnine 1(2-9 5-((6-amino-9-(3-(isopropylamino)propyl)-9H-purin-S-yl)tbic)-2,3 diliydrobenzo[blthiaphene-6-carbonirile IC(-10 S-((6-(aziridiu- 1 -yI)-2,3-dihydrobenzo[b]thiophen-5-yl)metbyl)-2-fluoro-9-(2 (neopentylami no)ethyl)-914-purin-6-amine ic-li 8-((6-iodo-2,3-dihydrobenzo[blthiophen-5-yl)thio)-9-(2-(isobuylanina)ethyl) 9H-purin-6-amine iC-12 1 -(4-(2-(6-anTino-8-((6-(furan-2 -yl)-2,3-dihydrobenzo~bllthiophen-5-yl)thio)-9H purin-9-yl)ethyl)piperfidin- 1-yl)ethanone.

1(2-13 4-(2-(8-((6-(1H-pyrazol-3-yl)-2,3-dihydrobenzo[blthiopben-5-y)thio)-6-amino 9H-purin-9-yl)ethyl)piperidire- 1-carbaldehyde 1IC-14 4-(2-(6-amino-8-((6-ethynyl-2,3-diiydrobenzo[bjthiophen-5-yl)thio)-9H-purin-9 ylethy~pperidine- I1-carbaldehyde IC-is i -(4-(2-(6-anino-2-fluoro-8-((6-Qbmrn-2-yI)-2,3-dihydrobenzo[bjthiapben-5 yl)mehl-9H-purin-9-yt)ethyl)piperidin- 1-yI)ethanone 1IC-16 N-(2-((2-(6-amino-8-((6-Qiira-2-yl)-2,3-dihydrobenzofblthiopben-5-y)thio) 9H-puriin-9-y1)ethy1)amino)ety)sulfamide iC-i17 3-((2-(6-amino-84(6-(furan-2-yI)-2,3-dihydrobenzo[bjthiophen-5-y)tio)-9H purin-9-yl)ethyl)amino)-N-hydroxypropanamide iC4S 9-(3-aminopropyl)-8-((6-ioda-2,3-diiydrobenzo[bJtiophen-5 -yl)thio)-9H-purin 6-amine 1(2-19 9-(2-amninoethyl)-2-fluoro-8-((6-iodo-2,3-dihydrobenzolb]thiophen-5-yl)nethyl) 9H-purin-6-amine 1IC-20 9-{2-aniuoethyl)-8-((6-iodo-2,3-dihydrobenzo[b]thiophen-5-yl)thio)-9H-purin-6 amine 1C-21 9-(3-(tert-butylamino)propyl)-S-((6-iodo-2,3-dihydrobenza[btiophen-5-yl)thio) _________9H-purin-6-amine Table ID No. Name 1D-1 8-{(5-iodo-2,3-dihydrobenzc~bjthiophen-6-yl)rhio)-9-(2-(isobutylamino)ethyl) _____________9H-purin-6-amine 1fl-2 -(5-iodo-2,3-dihydrobenzo[b~thophen-6-yl)thio)-9-(3 _____________(isopropylarmino)propyl)-9H-purin-6-amine 113-3 2-fluoro-8-((5-iodo-2,3-dihydrobenkzo[b]tbiophen-6-yl)methyl)-9-(2 _____________(isobu~ylaino)etbyl)-9H-purin-6-amine 113-4 2-fluoro-S-((5-iodo-2,3-clihydrobenzo[bjtbiophen-6-yl)methyl)-9-(3 _____________(isoypropylanino)propyl)-9H-purin-6-anmine ID-5 8-((5-iodo-2,3-dihydrobenzo[bjthiophen-6-y])thio)-9-(2-(isobutylamino)ethyl) ___________9H-purin-6-amine ID-6 8-{(5-(furan-2-yl)-2,3-dihydrobenzc~blthiorpjen-6-yl thia -9-(3- WO 2011/044394 PCI!US2OIO/051872 156 ______________(isopropylamnio)propyl)-9H-purin-6-aniine 111-7 8-((5 -(dimethylamino)-2,3-dihydrobenzob]thiophen-6-y)methyl)-2-fluoo-9 (2-(neopentylamino)ethyl)-9H-purin-6-amine 1D-8 8-((5-(I H-pyrazol-3-yl)-2,3-dihydrobenzo[b]thiophen-6-yl)thic)-9-(2 (isobutylamino)ethyl)-9H-purin-6-amiine 1D-9 S-((5-cyclopentyl-2,3-dihydrobenzo[bjrhiophen-6-yl)tbic)-9-(3 (isopropylarmino)propyl)-9H-purin-6-amine I10J S-((5-erhyny1-2,3-dihydrobenzo[bltbiophcn-6-y1)methyl)-2-fluoro-9-(2 (isobutylamino)ethyl)-9H-purin-6-amine ID-1 1 6-((6-amaino-2-fluoro- 9-(3-(isopropylamino)propyl)-9H-purin-8-yl)mnethyl)-2,3 dihydrobenzo[blthiophene-5-carbonitrile 1D-12 2-chloro-8-((5-(furan-2-y1)-2,3-dihydrobenzo[b]tbiophen-6-y)methy)-9-(3 (isopropylamin)paoyl)-9H-purin-6-anine 1D-13 4-(2-(6-anino-8-((5-ethynyl-2,3-dihydrobenzo[bltbiophen-6-yl)thio)-9Hf-purin 1D1-14 1 -4-(2-(6-amino-2-fluoro-8-((5-(ffran-2-yl)-2,3-dihydrobenzo[b]thiophen-6 y$)methyD)-9H-pudn-9-y)ethy)pAperidin-1 -yl)erhanone 1D-15 N-(2-((2-(6-amino-8-((5-(furan-2-yl)-2,3-dihydrobenzo[blthiophen-6-yl)thio) 9H-purin-9-yl)ethyl)amino)ethyl)sulfamide 1D-16 3-((2-(6-axnino-8-((5-ethynyl-2,3-dihydrobenzo*]thiophen-6-yl)thio)-9H ______________puin-9-yl)ethyl)amiino)-N-hydroxypropanamide WO 2011/044394 PCI!US2OIO/051872 157 ID-17 2-chloro-S-((5-iodo-2,3-dihydrobenzo[b]thiophen-6-yl)metiyl)-97(3 _____________(isopropylaminop)propyl)-9H-purin-6-mine ID-i8 9-(3-aminopropyl)-S-((5-ioclo-2,3-dibydrobenzo~b]thiopben-6-yl)thio)-9H __________ purin-6 -amine ID-19 9-(2-amiinoethyl)-2-fluoro-8-{(5-iodo-2,3-dihydrobenzo[bjtbiopben-6 yl)methyl)-914-purin-6-ainine ID-20 9-(2-am-inoethyl)-8-((5-iodo-2,3-dihydrobenzo[bjthiophen-6-yl)thio)-9H-purm 6-amine 1D-21 9-(3 -(teii-butylamino)propyl)-8-((5-iodo-2,3-dihydrobenzo[b]thiophen-6 ______________yl)thid)-9H-purin-6-amine Table 1E No. Name 1E-1 1-(6-amiino-8-(6-iodo-2,3-dihydro-1 H-inden-5-ylthic)-9H-purin-9-yl)-3-(tert _______butylamina)prnpan-2-nl 1E-2 PU-WS26 8-((6-iodo-2,3-dihydro-IH-inden-5-yl)tbia)-9-(2-(isobutylamino)ethyl)-9E-purin-6 _______amidne iE-3 1-(3-(6-anaino-B-(6-iodo-2,3-diycrc- 1H-inden-5-ylthio)-9H-purin-9 ________yflpropyl)pyrrolidin-3 -one lEA 2-fluoro-S-((6-iodo-2,3-dihydro-1H-inden-5-yl)methyl)-9-(2-(isobutylamino)ethyl)-9H _______purin-6-amine 1E-5 2-chlcro-8-((6-(fhra-2-yl)-2,3-dihydro-IH-inden-5-yl)mnethyl)-9-(3 _______(isopropylamno)propyl)-9H-purin-6-amine 112-6 2-fluoro-8-((6-iodo-2,3-dilhydro- 1H-inden-5-yl)methyl)-9-(3-(isopropylamino)propyl) 9H-purin-6-aniine 1E-7 8-((6-(fhran-2-yl)-2,3-dihydro-1H-inden-5-yl)thio)-9-(3-(isopropylamino)propyl)-9H ypurin-6-amine 1E2-8 8-((6-ethynyl-2,3-dhydro-1H-inden-5-ylfthio)-9-(3-(isopropylamino)propyl)-9H-purin 6-amine 112-9 6-((6-amino-9-(3-ijsopropylami no)propyfl-9H-purin-8-yl)thio)-2,3-dihydro-1 H-inclene 5-carbonitrile 1IE-10 8-((6-(azetidin-1I-yl)-2,3-clihydro-1H-inden-5-yl)methyl)-2-fluoro-9-(2 (neop entylamino)ethyl)-9H-purin-6-amine 11E-11 9-(3-(isopropylami~no)propyl)-8-((6-(oxazol-2-yl)-2,3-dihydro-1H-inden-5-yl)thio)-9H purin-6-amine 1E2-12 1-(3-(2-(6-anon-8-(6-(oxazol-2-y9)-2,3-dihydro-1 H-inden-5-ylthio)-9H-purin-9 _______yl)ethyl)piperidin-1I -yl)ethanane WO 2011/044394 PCI!US2OIO/051872 158 1E-13 3-(2-(8-(6-(1H-pyrazol-3-yl)-2,3-dihydro-1H-inden-5-ylthio)-6-amino-9H-purin-9 _______yl)ethyl pieri dine- 1-carbaldehyde 1E-14 1 -(3-(2-(6-antino-8-(6-ethynyl-2,3-dihydro- 1H-inden-5-ylthio)-9H-purin-9 yl)ethyl)piperidin-1 -yl)etbanone iL-iS 2-fluoro-9-(-(-ethylsulfanyl)pyrrolidin-3-yl)propyl)-8-((6-(oxazol-2-yl)-2,3 dihydro- 1H-inden-5-yl)niethyl)-9H-purin-6-amine 1E-16 N-(2-((2-(6-am-ino-S-(6-(oxazol-2-yl)-2,3-dihydro-1 H-inden-5-yl)tbio)-9H-purin-9 yl)ethyl) mno)ethyl)sulfaniide 1E-17 3-(2-(6-amino-8-(6-(cxazol-2-yl)-2,3-dibydro-1H-inden-5-ythio)-9H-purin-9 vlehlmn)Nhdoyrpnnid IE-i8 1 -(3(3 -(6-amino-8-(6-iodo-2,3 -dihydro- 1H-inden-5-ylthio)-9H-purin-9 yl)propyl)pyrrolidin- 1-yl)ethanone IE-19 1 -(3-(3-(6-amino-S-(6-ethynyl-2,3-dihydro-1H-inden-5-ythio)-9H-purin-9 yl)propyl)pyrrolidin-1 -yl)ethaone 1E-20 2-chloro-8-((6-etbynyl-2,3-diliydro-1H-inden-5-yI)methyl)-9-(3 _______(iscopropylainino)propyl)-9H-purin-6-amine IE-21 PIJ-WS25 8-((6-iodo-2,3-dfihydro-1 H-indn-5-yl)thio)-9-(2-(neopenylamino)ethyl)-9H-purin-6 aie IE-22 PIJ-WS27 8-((6-ethynyl-2,3-dihydro- 1H-inden-5-yI)tbio)-9-(2-(neopentylaniino)ethyl)-9H-purin 6-amine IE-23 PU-WS29 8-((6-ioclo-2,3-dibydro-1 H-inden-5-yl)thio)-9-(3-(isopropylaxnino)propyl)-9H-purin-6 amidne 1E-24 9- 3-aminop~qpy1)-84 6-iodo-2,3-dihydro-1H-inden-5-yl)thio)-9H-purin-6-amine 1E-25_ 9-(2-amninoethyl)-S-((6-iodo-2,3-dihydro-1H-inden-5-yl)thio)-9H-purin-6-ami ne 1E-26 9-(3-(tert-butylamino)propyl)-8-((6-ioda-2,3-dihydro-IH-inden-5-yl)tio)-9H-purii-6 ami ne 1E-27 9-(3-(isaprcpylaninc)propyl)-8-((6-(5-mnethyloxazal-2-y)-2,3-dihydro-1H-inden-5 yl)thio)-9H-purin-6-amine IE-28 1 -(4-(3-(6-amino-8-(6-(dimerhylamino)-2,3-dihydrc- 1H-inden-5-yl thio)-9H-purin-9 yl)propyl)piperidin-1 -yl)ethanone IE-29 1 -(3-(2-(6-aniinc-2-fluoro-8-((6-(4-maetbythiazol-2-yl)-2,3-dihydro-1 H-inden-5 yl)mety)-9H-purn-9-y)ethy)piperidin- 1-yl)ethanone IE-30 8-((6-(5-znethyloxazol-2-yI)-2,3-dihydro- 1H-inxlen-5 -yI)tbio)-9-(2-(1 (methyls-ulfny1)piperidin-3-y1)ethyI)-9H-purin-6-anline IE-3 1 9-(3-am-inoprcpyl)-S-((6-(5-maethyloxazol-2-yl)-2,3-diydro-1H-inden-5-yl)thio)-9H 1E-.32 9-(3-(tert-b-utylawino)propyl)-2-tluoro-8-((6-(4-methylthiazol-2-yl)-2,3-dihydro-l11 inden-5- yl~mthy1)-9H-purin-6-amine 1E-33 8-((6-(1 H-pyrazol-3-yl)-2,3-dihydro-1 H-inden-5-yl)methyl)-9-(3-{tert butylamnopropyl)-2-fluoro-9H-purin-6-amine IE-34 8-(6-(aziridin-1-yI)-2,3-dihydro- 1H-inde-5 -ylthio)-9-(3-(1 -(methylsulfonyl)pyrrolidin 3-YI)PropY1)9H-purin-6amie 1E-35 1 -(3-(6-arnino-2-fluoro-8-((6-ioda-2,3-dlihydro- 1H-inden-5-yl)methyl)-9H-purin-9 yl)propyl)pyrrolidin-3-one IE-36 8-((6-(5-methyloxazol-2-yl)-2,3-dihydro-IH-inden-5-yl)tbio)9-(2 (neopentylaino±th I-911- urin-6-amnine i-7 1 -(6-amino-8-((6-(5-methyloxazol-2-yl)-2,3-clihydro- 1H-inden-5-yl)thio)-9H-purin-9- WO 2011/044394 PCI!US2OIO/051872 159 yl)-3-(isoprcopylamino)propan-2-ol 1E-38 5-(6-amino-8-(6-iodo-2,3-diliydro-1H-inden-5-ylthio)-9H-purin-9-yl)-N-methylpentane 1-sulfonan-ide 1E-39 5-(6-amino-8-(6-iodo-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9-yl)pentane- I sulfonamide IE-40 5-(6-amino-8-(6-ethynyl-2,3-dibydro- 1H-inden-5-yltbio)-9H-purin-9-yl)pentane- 1 sulfonamide 1E-41 1-(2-(4-(6-amino-8-(6-(5-methylfuran-2-y)-2,3-dihydro- lH-inden-5-ylthio)-9H-purin 9-yl)butyl pyrroli din- 1-yl)ethaone IE-42 14-3 -(6-axnino-8-(6-iodo-2,3-dihydro- lH-inden-5-ylthio)-9H-purin-9 yl)propyl)pyrrolidin-3-ol IE-43 6-(6-amino-.S-(6-iodo-2,3-dihydro-1 H-inden-5-ylthio)-9H-purin-9-yl)hexanamide 1E-44 1-(3 -(3-(6-amrino-2-fluoro-S-((6-iodo-2,3 -dihydro- lH-inden-5-yl)inethyl)-9H-purin-9 Syl)propyflpyrrolidin-l -yl)ethanone IE-45 5-(6-amino-2-fluoro-8-((6-io-do-2,3-dihydro-1H-inden-5-yl)methyl)-9H-purin-9-yl)-N methylpentane- 1 -sulfonamide 1E-46 5-(6-aiio-2-fluoro-8-((6-iodo-2,3-dihydro-IH-inden-5-yl)methyl)-9H-purin-9 yl)pentane-1 -sulfonamide IE-47 9-(3-(tert-butylamino)propyl)-2-fluoro-8-((6-iodo-2,3-dihydro-1 H-inden-5-yl)niethyl) 9H-purin-6-amine 1E-48 2-fluoro-8-((6-iodo-2,3-dihydro-1H-inden-5-yl)methyl)-9-(2-(neopentylamino)ethyl) 9H-purin-6-amine IE-49 I -(4-(3-(6-amino-8-(6-ethynyl-2,3-dibydro-IH-inden-5-yltbio)-9H-purin-9 yl)propyl)piperidin- l-y1)ethanone 1E-50 1-(3-(2-(6-aiano-S-((6-ethynyl-2,3-dihydro-1 H-inden-5-yI)methyl)-2-fluoro-QH-purin 9-yl)ethyl)piperidin-1-yl)etbanone 1E-51 9-(3-(tert-butylamino)propyl)-8-(6-ethynyl-2,3 -dihydro-IH-inden-5-ylthio)-9H-purin-6 amine IE-52 9-(3-(tert-butylamnino)propyl)-8-((6-ethynyl-2,3-dihydro- 1H-inden-5 -yI)methyl)-2 1____ fluoro-9H-purin-6 -amine IE-53 '6-(6-amino-8-((6-ethynyl-2,3-dihydro-1 H-inden-5-yl)methy])-2-tluoro-9H-purin-9 yl)hexanamide 1E-54 1-(3-(6-amino-S-((6-ethynyl-2,3 -dihydro- 1H-inden-5-yI)methyl)-2-fluoro-9H-purin-9 yl)propyl)pyrrolidin-3-one 1E-55 4-(6-amino-8-((6-ethynyl-2,3-dihydro-1H-inden-5-yl)methyl)-2-fluoro-9H-purin-9 yl)butane-1-sulfonamide 1E-56 8-((6-ethynyl-2,3-dihydro-1H-i-nden-5-yl)methyl)-2-fluoro-9-(3 (isopropylamino)propyl)-9H-purin-6-amine IE-57 8-((6-ethynyl-2,3-dihydro-1 H-inden-5-yl)methyl)-2-fluoro-9-(2 (neopentylamino)ethyl)-9H-purin-6-amine IE-58 1-acetyl-3-(3-(6-amina-8-(6-ethynyl-2,3-dihydro-lIi-inden-5-ylthio)-9H-purin-9 yI)propyl)inidazolidin-2-one IE-59 9-(3-(tert-butylamino)propyl)-8-(6-(oxazol-2-yl)-2,3-dihydro- lH-inden-5-ylthio)-9H purin-6-amine 1E-60 9-(3-(tert-butylamino)propyl)-8-(6-(5-methyloxazol-2-yl)-2,3-dihydro-JH-inden-5 1E-61 8-(6-( 1H-pyrazol-3-yl)-2,3-dihydro-1 H-inden-5-ylthio)-9-(3-(tett-butylamino)propyl) _______ 9-purin-6-amine IE-62 1-(3-(2-(6-aniino-8-(6-(5-methyloxazol-2-yl)-2,3-dihydro- H-inden-5-ylthio)-9H-purin ____9-yl)ethyl)piperidin- I1-yl)ethanone WO 2011/044394 PCI!US2OIO/051872 160 IE-63 6-(6-ami no-8-(6-(oxazol-2-yl)-2,3-diliydro-1H-inden-5-ylthio)-9H-purin-9 _______yl)hexanamide IE-64 I -(3-(6-amino-8-(6-(4-methyloxazol-2-yl)-2,3-dihydro-1H-inden-5-yltbio)-9H-purin-9 _______yl)prapyl pyrrolidin-3-ane 1E-65 6-(6-aminao-2-fl-uoro-S-((6-(oxazol-2-yl)-2,3-dihydo- 1H-inden-5-yl)methyl)-9H-purin _______9-yl)hexanamide 1E-66 14-3-(6-amino-2-fluoro-8-((6-(oxazol-2-yl)-2,3-dihydro-l H-inden-5-yl)methyl)-9H purin-9-yI propyl)pyrrolidin-3-one IE-67 5-(6-amino-2-fluoro-S-((6-(oxazol-2-yI)-2,3-dihydro- 1H-inden-5-yl)methyl)-9H-purin 9-yl)pentane-1 -sulfonamide 1E-68 S-((6-iodo-2,3-dihydro-l H-inden-5-yl)thio)-9-(2-(1-methylpiperidin-2-yl)etbyl)-9H _______purmn-6-amine IE-69 8-((6-iodo-2,3-dibydro-1H-inden-5-yl)thio)-9-(2-( I -methylpiperidin-3-yl)ethyl)-9H _______purin-6-aimne IE-70 8-((6-iodo-2,3-dibydro-1I1-inden-5-yl)thio)-9-(2-( I-(naethylsulfonyl)piperidin-3 _______yl)ethyl)-9H-purin-6-amine 1E-71 3-(2-(6-amino-8-((6-iado-2,3-dihyclro-IH-inden-5-yl)thio)-91-purin-9 _______yl)ethyl)pi eridine-1-sulfonamide 1E-72 2-fluoro-8-((6-iodo-2,3-dihydro- lR-inden-5-yl)metbyl)-9-(24(1 -methylpiperidin-2 ______ Iethy1 -9--urin-6-amine 1E-73 2-fluoro-S-((6-iodo-2,3-dihydro-l H-inden-5-yl)methyl)-9-(2-( I-methylpiperidin-3 _______yI)erhyl)-9H-purin-6-amnine 1E-74 2-fluoro-8-((6-iodo-2,3-dibydro-1 H-inden-5-yl)metbyl)-9-(2-(1 _______(methylsulfonyl)piperidin-3-yl)ethl)-9H-purin-6-amine IE-75 3-(2-6-amino-2-fluoro-8-((6-iodo-2,3-dihydro-lH-inden-5-y)methyl)-9H-purin-9 _______yI)ethyl)piperidine- 1 -sulfonamaide i.E-76 9-(3-tert-butylamino)propyl)-2-fluoro-S-((6-iodo-2,3 -dihydro- lH-inden-5-yl)methlyl) ____ 911-purin-6-amine IE-77 S-{(6-ethynyl-2,3-diliydro- IH-inden-5-yl)thio)-9-(2-(1 -methylpiperidin-2-yl)ethyl)-9H _______punin-6-amne IE-78 8-((6-ethynyl-2,3-dihydro- IH-inden-5-yl)thio)-9-(2-(1 -methylpiperidin-3-yI)ethyl)-9H purin-6-aminne 1E-79 3-(2-(6-amino-8-((6-ethynyl-2,3-diiydro-1 H-inden-5-yI)methyl)-2-fluoro-911-purin-9 yI)ethyl)piperidine-1-sulfonarnide l.E-SO 8-((6-ethynyl-2,3-diliydro- IH-inden-5-yI)thio)-9-(2-(l -(metbylsulfonyl)piperidin-3 _______yl)ethyl)-9H-purin-6-amine IE-81 8-((6-ethynyl-2,3-dihydro-liH-inden-5-yl)methyl)-2-fluoro-9-(2-(l -methylpiperidin-2 _______ I ethyI -911- urin-6-amine IE-82 8-((6-ethynyl-2,3 -dihydro- 1F-inden-5-yl)methyl)-2-fluorc-9-(2-(I -methylpiperidin-3 _______yl)edhyl)-9H-purin-6-anaine 1E-83 9-{3-(trt-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-(I -methylpiperidin-2-yl)erhyl)-8-((6-(oxazol-2-yl)-2,3-dihydro- 11-inden _______5-yIl ty)-9H-purin-6-amine IF-85 2-fluoro-9-(2-(1 -methylpiperidin-3-yI)ethyl)-8-((6-(oxazol-2-y)-2,3-clihydro-1H-inden _______5-yl)mehy)-9H-purin-6-anxine Table iF No. Name WO 2011/044394 PCI!US2OIO/051872 161 IF-i 8-ff6-iodoinidolin-5-yl)thio)-9-(2-(isobutylamino)ethyl)-9H-purin-6-amine iF-2 2-fluoro-S-((6-iodoindolin-5-yl)methyl)-9-(2-(isobutylaaino)ethyl)-9H-purin-6-anine JF-3 8-((6-( 1H-pyrazol-3-yI)indolin-5-ylflhio)-94-(sobutylamino)ethyl)-9Hpurin-6-amine iF4I 8-((6-ethynylindolin-5-yl)thio)-9-(2-(isobutylaniino)ethyl)-9H-purin-6-amine iF-S S-((6-( 1H-pyrrol-3-yl)indolin-5-yl)methyl)-2-fluoro-.9-(2-(isobutylamino)ethyl)-9H purin-6-amine 1F-6 5-((6-amino-9-(3-(isopropylamino)propyl)-9H-purin-8-yl)bio)indoline-6-carboitl WO 2011/044394 PCI!US2OIO/051872 162 1F-7 8-((6-(fiiran-2-yl)-1 -metbyiindolin-5-yl)tbio)-9-(3-(isoprapylamino)propyl)-9H-purin 6-ami~ne IF-S 8-((6-cyclobutyl-1 -methylindolin-5-yl)methyl)-2-fluoro-9-(2-Qsobutylamino)ethyl) ~9H-purin- -amine IF-9 1 -(5 -ff6-amino-2-fluoro-9-(2-(eopentylamino)ethy)-9H-purin-8-y)metby)-6 (aziridin-i -yl)indolin-i -y1}Sthanone IF-10 I -(4-(2-{6-am-ino-8-((6-(furan-2-yi)indolin-5-yl)thio)-9H-pnrin-9-y)ethyl)piperidin-I yl)ethanone I.F-il 4-(2 -(S-((6-(1H-pyrazoi-3 -yl)indolin-5-yl)tbio)-6-awino-9H-purin-9 yl)etl)piperi dine- I -carbaidehyde IF-12 4-(2-(6-ami~no-8-((6-e.thynyl-i -metlhylindolin-5-yl)thio)-9H-puxin-9 I thyI pipridinc-1I -carba!Ldh de i.F-13 I -(4-(2-(6-amino-2-fluoro -S-((6-(fbran-2-yi)indolin-5-yl)methyl)-9H-purin-9 ylethyi)piperidin- 1 -yi)ethanone IF-14 N-(2-((2-(6-amino-8-((6-(furan-2-yi)indolin-5-yl)tbio)-9H-purin-9 yi)ethyl)anaino)ethyl)sulfamide IF-i5 3-((2-(6-arnino-8-((6-(furan-2-yi)indolin-5-yl)tbio)-9H-purin-9-yl)ethyl)amino)-N bydoxyropanamide IF-16 2-cbloro-S-if6-iodoindolin-5-yl)methy)-9-(2-(isobutylamino)ethyl)-91-purin-6-anine i.F-17 9-(3-aminopropyl)-S-((6-iodoindolin-5-yl)thio)-9H-purin-6-aniine iF-iS 9-(2-amioethyi)-8-((6-iodoindoiin-5-yl)thio)-9H-purin-6-amne iF7-19 9-(3 -(tert-butylatnino)propyl)-S-((6-iodoindolin-5-yl)thio)-9H-purin-6-aniine I F-20 S-((6-iodoindolin-5-yI)thio)-9-(3-(isopropyiamino)prgpyl)-9H-purin-6-amine _E Table I G No. Name 1 G-1 I -(6-(6-amino-9-(3-(isopropylanino)propyl)-9H-purin-8-ylthio)-5-iodoindolin- 1 yI)ethanone 1G-2 2-fluorn-8-((5-icdoindoiin-6-yl)methyl)-9-(2-isob-utylimino)ethyl)-9H-purin-6-amine 1G3-3 S-if5-(1H-pyrazoi-3-yI indolin-6-yI thick -9- 2-isobutylamino ethy1)-9H-purin-6-amnine 104 8-if 5-ethynylindolin-6-yl)thio)-9-(2-(isobutylamidno)ethy)-9H-puin-6-anaine 105 8-((5-(1H-pyrrol-3-yI)indoiin-6-yi)methyl)-2-fluoro-9-(2-(isobutylamino)ethy)-9H _____purin-6-anine WO 2011/044394 PCI!US2OIO/051872 163 16-6 6-if 6-axnino-9--(-isopropylamino)propy9)-9H4-purin-X-yl)thio)indoline-5-carbcnitrile 16-7 S-((5-(furan-2-yl)-I -methylindolin-6-yl)vhio)-9-{3-(isopropylamino)propyl)-9H-punin-I _______6-amine 1G-8 8-((5-cyclobutyl- 1-methylindolin-6-yl)methyl)-2-fluoro-9-(2-{isobutylamino)ethyl) _____9H-purin-6-amnine 10-9 I -(6-((6-aniino-2-fluoro-9-(2-(neopentylamino)ethyl)-9H-purin-R-yl)metbyl)-5 (aziridin-1 -yl)mndolin- I -yl)ethanone 1G-10 1-(4-(2-(6-amino-8-((5-(fiiran-2-yI)indolin-6-yl)thio)-9H-purin-9-yflethyl)piperidin- 1 yl)ethanone 1G-11 8-(5-(1H-pyrazol-3-yl)indolin-6-ylthio)-9-(2-(1 -(methylsulfonyl)piperidin-3-yl)ethyl) 9H-purin-6-amine 1G-12 3-(2-(6-ainino-8-(I -ethyl-5 -ethynylindolin-6-ylthio)-9H-purin-9-yl)ethyl)pipeiidine- 1 carbaldehyde 1G-13 1-(3-(2-(6-arnino-2-fluoro-S.-(( 1 -methyl-5-($-methylfflran-2-yl)indolin-6-yI)methyl) 9H-purin-9-y1)ethylpiperidin-I -yIethanone 1G-14 N-(2-(f2-(6-amino-S-((5-(Thran-2-yl)indolin-6-yl)tbio)-9H-purin-9 yl)ethyl)amino)ethyl)sulfarnide 1G-15 3-(2-(6-amnino-8-(5-(5 -methylfuran-2-yl)indolin-6-ylthio)-9H-purin-9-yI)ethylamino) N-hydroxypropananmide 16-16 1-(3-(4-(6-amnino-8-(5-iodo-1-methylindohin-6-ylthio)-98-purin-9-y)buty)pyrrolidin 1-yI)ethanone 1G-17 9-(3-amnopropyl)-8-if5-iodoindolin-6-yl)thio)-9H-purin-6-amine 1G-18 9-(2-aminoethyl)-8-((5-iodoindolin-6-yl)tbio)-9H-purin-6-ane 1G-19 9-(3-(tert-butylamnino)propyl)-8-( 1-ethyl-5-iodoindolin-6-ylthio)-9H-purin-6-amine 16-20 8- 5-iodo- 1 -mietlindolin-6-ylthio)-9-(3-(iso MIaniino trop1)-9H-purin-6-amine 16-21 1-(3-(6-am-ino-8-(5-iodo-1 -methylindolin-6-ylthio)-9H-purin-9-yl)propyl)pyrrolidin-3 one Table 1H No. Name 1H-1 6-((6-amino-9-(2-(isobutylanaino)ethyl)-9H-purin-8-yl)thio)-5-iodo-2,3-dihydo- H ____inden-1 -one 1H-2 6-((6-aniino-9-(3-(isopropylamino)propyl)-9H-purin-8-yl)thio)-5-iodo-2,3-dihydro ____1H-inden-1 -one 1H-3 6-((6-amino-2-fluoro-9-(2-(isobutylanino)ethyl)-9H-purin-8-yl)methyl)-5-iodo-2,3 dihydro- I H-inden- I -one LH-4 6-((6-aniino-2-fluoro-9-(3-(isoprapylamino)propyl)-9H-purin-8-yl)mehyl)-5-iodo 2,3-dhyr-1H-inden-I-one 1H-5 6-(6-amino-9-(2-hydroxy-3-(isopropylamino)propyl)-9H-p-urin-8-yltbio)-5-iodo-2,3 diiidro-1H-inden-1-one 1H-6 6-((6-amino-9-(3-(isopropylaniino)propyl)-9H-purin-8-y)tbio)-5-(fnran-2-yl)-2,3 dihydro-JH-inden-1 -one 111-7 6-((6-amino-2-fiuoro-9-(2-(neopentylanino)ethyl)-9H-puin-8-yl)metyl-5 111-8 6-((6-aniino-9-(2-(isobutylamiino)ethyl)-9H-purin-8-y)thio)-5-( H-pyraol-3-yl) _____2,3-Jilt d-IH-inden-I-one 1H-9 6-f 6-am-ino-9-(3- isopropylamino)propyl)-9H-purin-8-y1)thio)-5-cyclopropyI-2,3- WO 2011/044394 PCT/US2010/051872 164 dihydro-iH-inden- 1-one 1H-10 6-((6-amino-2-fluoro-9-(2-(isobutylamino)ethyl)-9H-purin-8-yl)methyl)-5-ethynyl 2,3-dihyd-1H-inden-1-one 1H-11 6-((6-amnino-2-fluoro-9-(3-(isopropylamino)propyl)-9H-purin-8-yl)methyl)-1 -oxo 2,3-dihydro-1 H-indene-5-carbonifrile IH-12 6-((6-amino-2-chloro-9-(3-(isopropylamino)propyl)-9H-purin-8-yl)methyl)-5 (furan-2-yl)-2,3-dihydro-1H-inden- -one 1H-13 4-(2-(6-amino-8-((6-ethynyl-3-oxo-2,3-dihydro-1H-inden-5-yl)thio)-9H-purin-9 yl)ethyl)piperidine-1-carbaldehyde 1H-14 6-((9-(2-(1 -acetylpiperidin-3-yl)ethyl)-6-amino-2-fluoro-9H-purin-8-yl)methyl)-5 (5-methylfuran-2-yl)-2,3 -dihydro- 1H-inden-1 -one 1H-15 N-(2-((2-(6-amino-8-((6-(fran-2-yl)-3-oxo-2,3-dihydro-1H-inden-5-yl)thio)-9H purin-9-yl)ethyl)amino)ethyl)sulfamide 1H-16 3-((2-(6-amino-8-((6-ethynyl-3-oxo-2,3-dihydro-IH-inden-5-yl)thio)-9H-purin-9 yl)ethyl)amino)-N-hydroxypropanamide 1H-17 6-((6-amino-9-(2-(isobutylamino)ethyl)-9H-purin-8-yl)thio)-5-iodo-2,3-dihydro-1H indene-1-thione 1H-18 6-((6-amino-2-fluoro-9-(3-(isopropylamino)propyl)-9H-purin-8-yl)methyl)-5-iodo 2,3-dihydro-1H-indene-l-thione 1H-19 6-((6-amino-9-3-aminopropyl)-9H-purin-8-yl)thio)-5-iodo-2,3-dihydro-1H-inden 1-one 1H-20 6-((6-amino-9-(2-aminoethyl)-2-fluoro-9H-purin-8-yl)methyl)-5-iodo-2,3-dihydro I1H-inden-1-one 1H-21 6-((6-anino-9-(2-aminoethyl)-9H-purin-8-yl)thio)-5-iodo-2,3-dihydro-IH-inden-1 one IH-22 6-((6-anino-9-(3-(tert-butylamino)propyl)-9H-purin-8-yl)thio)-5-iodo-2,3-dihydro 1 H-inden-1 -one 1H-23 3-(2-(6-amino-8-(6-iodo-3-oxo-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9-. yl)ethyl)pyrrolidine-1-carbaldehyde 1H-24 6-(6-amino-9-(2-(1-(methylsulfonyl)pyrrolidin-3-yl)ethyl)-9H-purin-8-ylthio)-5 iodo-2,3-dihydro-1 H-inden-1 -one 1H-25 N-(3-(6-amino-2-fluoro-8-((6-iodo-3-oxo-2,3-dihydro-IH-inden-5-yl)methyl)-9H purin-9-yl)propyl)methanesulfonanide 1H-26 6-((6-amino-9-(2-(1-(methylsulfonyl)piperidin-3-yl)ethyl)-9H-purin-8-y)thio)-5 (1 -pyrazol-3-yl)-2,3-dihydro-1 H-inden-1 -one 1H-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-yl)thio)-5-(5-methylthiazol 2-yl)-2,3-dihydro-1H-inden-1 -one 1H-29 6-((6-amino-9-(3-(tert-butylamino)propyl)-9H-purin-8-yl)thio)-5-(thiophen-2-yI) 2,3-dihydro- 1H-inden- 1-one 1H-30 2-(3-(6-amino-8-(6-iodo-3-oxo-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9 yl)propyl )azetidine-1-carbaldehyde 1H1-31 6-((6-amino-9-(3-(tert-butylamino)propyl)-2-fluoro-9H-purin-8-yl)methyl)-5 ethynyl-2,3 -dihydro- 1H-inden-1 -one 1H-32 6-((6-amino-9-(2-(1-(methylsulfonyl)piperidin-3-yl)ethyl)-9H-purin-8-y)thio)-5 (dimethylamino)-2,3-dihydro-1H-inden-1 -one IH-33 6-((6-amino-9-(3-(tert-butylamino)propyl)-2-fluoro-9H-purin-8-yl)methyl)-5-(5 methyloxazol-2-yl)-2,3-dihydro-1H-inden-1 -one IH-34 6-((9-(2-(] -acetylpiperidin-4-yl)ethyl)-6-amino-2-fluoro-9H-purin-8-yl)methyl)-5- WO 2011/044394 PCT/US2010/051872 165 (5-methylthiazol-2-yl)-2,3-dihydro- 1H-inden- I -one 11-35 N-(3-(6-amino-2-fluoro-8-((6-(5-methyloxazol-2-yl)-3-oxo-2,3-dihydro-IH-inden 5-yl)methyl)-9H-purin-9-yl)propyl)methanesulfonamide 1H-36 1-(3-(6-amino-8-(6-iodo-3-oxo-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9 yl)propyl)pyrrolidin-3-one 1H-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 ECg 0 ; binding to EC 5 o; binding JNPL3 brain to SKBr3 cell Hsp90(nM) Hsp9W(nM) 1B-1 PU-WS9 5.5 ND 1B-2 PU-WS4 8.0-14 ND 1A-1 PU-WSIO 132.9-346 ND Table 2B Compound # Name EC 50 ; binding to EC 50 ; binding JNPL3 brain to SKBr3 cell Hsp9O (nM) Hsp90 (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 EC5o; binding JNPL3 brain to SKBr3 cell Hsp90 (nM) Hsp9O (nM) 1B-26 PU-WS23 12.2 ND 1B-27 PU-WS24 25.4 ND Table 2D Compound # Name ECwo; binding to EC5 0 ; binding JNPL3 brain to SKBr3 cell Hsp90 (nM) Hsp90 (nM) 1B-28 PU-WS28 8.1 ND Table 2E Compound # Name ECso; binding to EC 50 ; binding JNPL3 brain to SKBr3 cell Hsp90 (nM) Hsp90 (nM) 1E-2 PU-WS26 3.6 ND IE-21 PU-WS25 7.2 ND 1E-23 PU-WS29 4.5 ND Table 2F Compound # Name EC 0 ; binding to EC 50 ; binding JNPL3 brain to SKBr3 cell Hsp90 (nM) Hsp9O (nM) IE-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 Hsp9 (nM) Hsp90(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 -Hsp9O (nM) Hsp9O (nM) 4B-1 PU-WS8 19.1 ND 4B-2 PU-WS6 403 ND 4B-3 PU-WS7 731 ND 4B4 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 ECU,; binding to EC 5 o; binding JNPL3 brain to SKBr3 cell Hsp9 (nM) Hsp9O(nM) 41-12 TT-VI-116 ND 394 WO 2011/044394 PCT/US2010/051872 169 Table 2K Compound # Name EC.o; binding to EC 0 ; binding JNPL3 brain to SKBr3 cell Hsp90 (nM) Hsp9O (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 EC5,; binding JNPL3 brain to SKBr3 cell Hsp9O (nM) Hsp90 (nM) 4H-1 DZ3-29 309 740 4H-2 DZ3-31 89 121 4H-3 DZ3-41 57 161 4H-4 DZ3-59 ND 24.6 4H-6 DZ3-38 23 47 4H-7 DZ3-141 ND 26,653 Table 2M Compound # Name ECo; binding to EC 5 o; binding JNPL3 brain to SKBr3 cell Hsp9 (nM) Hsp9O(nM) 5A-1 PU-RK11 ND 34.5 SA-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 ECo; binding to EC 0 ; binding JNPL3 brain to SKBr3 cell Hsp90 (nM) Hsp9O (nM) 5B-1 HJPI8 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 ECso; binding to EC 50 ; binding JNPL3 brain to SKBr3 cell Hsp90(nM) Hsp9 (nM) 5D-2 | HJP19 | ND 11.2 513-4 TT-VI-54A ND 7.7 Table 2P Compound # Name ECso; binding to ECso; binding JNPL3 brain to SKBr3 cell Hsp9O (nM) Hsp9O (nM) 6B-25 DZ4-52-N9 ND 97.0 Table 2Q Compound # Name ECso; binding to ECsc; 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 PCI!US2OIO/051872 171 Table 3A No. Name 3A-1 2-fluoro-8-((5-(furan-2-yI)benzofirn-6-yl)methyl)-9-(2 (neopentylamino~ethyjjj-9H-purin--6-amiine 3A-2 2-fluoro-8-((5-iodo-IH-indol-6-yl)methyl)-9-(2-(neopentylamino)ethyl) 9H-purin-6-amine 3A-3 N-(2-((2-(6-amino-8-((5-(furan-2-yl)benzo[b]thiophen-6-y)thio)-9H ______________purin-9-yl)ethyl)amino)ethyl)sulfanuide 3A-4 3-((2-(8-((1 -acetyl-5 -(fhran-2-yl)-1 H-indol-6-ylfthio)-6-amino-9H purin-9-yl)ethyl)amino)-N-hydroxypropananiide 3A-5 8-((5-(azetidin- 1 -yl)benzofuran-6-yl)thio)-9-{2-(isobutylamino)ethyl) QH-purin-6-anume 3A-6 8-((5-iodobenzo[b]thiophen-6-yl)thio)-9-(2-(isobutylamino)ethyl)-9H ______________purin-6-amine 3A-7 8-((5-( I H-pyrazol-3-yl)-IH-indol-6-yl)thio)-9-(3 (isopropylamino~propyl)-9H-purin-6-amine 3A-8 8-((5-ethynyl-1H-indol-6-yl)thio)-Q-(2-(isohutylamino)ethyl)-9H-purin 6-amine 3A-9 6-((6-amino-9-(2-(isobutylami-nc~ethyl)-9H-purin-8-ylftbio)-I -methyl lH-indole-5-carbonitrile 3A-10 9-(3-aminopropy])-8-((5-iodobenzofaran-6-yl)tbo)-9H-purin-6-amine 3A-1 1 9-(2-aminoethyl)-8-((5-iodobenzofinan-6-yl)thio)-9H-purin-6-amine 3A-12 9-(3-(tert-butylaino)propyl)-8-((5-iodobenzofuran-6-yl~thio)-9H-purin 6-amine 3A-13 2-tluoro-8-((5-iodobenzotbran-6-y)methyl.)-9-(2 (neopentylarnino)ethyl)-9H-purin-6-amnine 3A-14 1 -(4-(2-(6-amino-2-fluoro-8-((5-(5-methylfuran-2-yl)benzofuran-6 ___________ _ yl)methyl)-9H-purin-9-yl)ethyl)piperidin-1 -yI ethanone 3A-15 9-{3-(tert-butylarnino)propyl)-8-((5-ethynylbenzofuran-6-yl)thio)-9H ______________purin-6-amine 3A-16 2-fluoro-8-((5-(5-znethyloxazol-2-yl)benzofuran-6-yI)methyl)-9-(2 (neapentylarmino)ethyl)-9H-purin-6-amine 3A-17 9-(3-(tert-butylamino))propyl)-8-((5-(dimetbylaniino)benzofuran-6 yl)thio)-9H-purin-6-amine 3A-18 8-((5-iodobenzofiwan-6-yl)thio)-9-(2-(1 -(metbylsulfonyl)piperidin-3 yl)ethyl)-9H-purin-6-ainine 3A-19 8-((5-(1 H-pyrazol-3 -yl)benzofuran-6-yI)rhio)-9-(2 (neopentylamaino)ethyl)-9H-p-urin-6-amine 3A-20 N-(3-(6-ainino-8-((5 -(aziridin-l-yl)benzofim-6-ylfthio)-9H-purin-9 ______________yl)propylinethanesulfonamide 3A-21 3-(6-anino-8-((5-iodobenzoftiran-6-yl)thio)-98-purin-9-yl)propy sulfamate 3A-22 9-(3-(tert-butylamino)propyl)-8-((5-(oxazol-2-yl)benzofuran-6-y)tbio) 9H-purin-6-amine 3A-23 8-((5-ethynylbenzofuran-6-yI)thio)-9-(2-(neopentylamino)ethyl)-9H ______________purin-6-amine 3A-24 1 -(6-ainino-8-((5-iodobenzofuran--6-yI)thio)-9H-purin-9-yl)-3-(tert- WO 2011/044394 PCI!US2OIO/051872 172 ____________butylamino)propan-2-ol 3A-25 j8-((5-iodobenzofiiran-6-yl)tbio)-9-(3-(isopropylamino)propyl)-9H ____________purin-6-aniine 3A-26 9-(3 -(tert-hutylamino)propyl)-8-((5-(5-naethyltbiazol-2-yl)benzoibran-6 yl)thio)-9H-purin-6-amine Table 3B ____________________________ No. Name 3E-I 5-((6-amino-9-(2-(isobutylamino)ethyl)-9H-purin-8-yl)thio)benzofumn ____________6-carbonitrile 3B1-2 8-((6-iadobenzofhrn-5-yl)thin)-9-(2-(isobutylaminn)ethyl)-9H-purin-6 amine 3B0-3 8-((6-(furan-2-yI)benzofuran-5-yl)thio)-9-(2-(isobutylainino)ethyl)-9H purmn-6-amine 3B04 N-(2-{(2-(6-amino-8-((6-(fiiran-2-yl)benzofbran-5-yl)thio)-9H-purin-9 yl)ethyl~amnino)te-etb)slfaride 3R-5 3-((2-(6-ainino-8-((6-(fhran-2-yl)benzofixran-5-yl)thio)-9H-purin-9 yl)ethyl)amino)-N-hydroxypropanamide 313-6 2-fluoro-8-((6-(ftzran-2-yl)-1 H-indol-5 -yl)methyi)-9-{2 __________(neop yamino)etyl)-9H-purin-6-amine 313-7 8-((6-(azetidin- I -yI)-IH-indol-5-yl)thio)-9-(2-(isobutylamino)ethy])-9H ___________purin-6-amne 31B-8 9-(2-(isobutylamino)ethyI)-8-((6-(pyrrolidin- 1 -yl)- 1H-indol-5-yI)thio) ____________9H-purin-6-amaine 3B0-9 8-((6-(fbran-2-yI)-1 -methyl-IH-indol-5-yl)thio)-9-(3 ___________ (sopropylamino)propyl)-911-purin-6-amilne 311-10 2-fluoro-8-((6-iodo- 1-isopropyl-1H-indol-5-yl)methyl)-9-(2 ________(isobutylarnino)ethyl)-9H-purin-6-amin .e SB1-il 2-fluoro-8-((6-(furan-2-yI)benzo[b]tbiophen-5-yI)methyl)-9-(3 ____________(isopropylamino)propyl)-9H-purin-6-anmine 313-12 2-fluoro-8-((6-iodobenzo[bjtbiophen-5-yI)methyl)-9-(2 (neopentylaniino)ethyl)-9H-purin-6-amine 31B-iS 8-((6-( IH-pyrrol-3-yI)benz[b]thiophen-5-yl)metbyl)-2-fiuoro-9-(2 (isobutylamino)9thy1)-9H-purin-6-amine 313-14 S-((6-ethynylbenzo[b]tbiophen-5-yl)methyl)-2-fluoro-9-(2 (isobutylaznino)ethyl)-9H-purin-6-amine 3B0-15 2--chloro-8-((6-ethynylbenzo[b]thiophen-5-yl)merhyl)-9-(2 (isobutyl mno)ethyl)-9H-purin-6-anujne 3B3-16 8-((6-(azetidin-1 -yi)-1H-indol-5-ylflhio)-9-(2-(isobutylanino)ethy)-9H puflfr-6-amine 3B0-17 8-((6-(aziridin- l-yl)- 1H-indol-5-yl)thio)-9-(2-(isob-utylamino)ethyl)-9H punin-6-amme 31B-i8 9-(3-aminopropyl)-8-((6-iodobenzofuran-5-yl)thio)-9H4-purin-6-mine 31B-19 9-(2-aninoethyl)}8 6-iodobenzofiuan-5-yI)thio)-9H-puuin-6-amiine 313-20 9-(3-(tert-butylamino)propyl)-8-((6-iodobenzofiran-5-yl)thio)-9H purin-6-almne 3B0-21 1 -(4-(2-(6-amino-2-fluoro-S-((6-(5-methylfiiran-2-yl)benzofua-5 ___________yl)methyl)-9H-purin-9-yl)erhyl)piperidin- 1-yflethanone 31B-22 9-(3-(tert-butylamino)propyl)-8-((6-ethynylbenzofizran-5-yI thio)-H WO 2011/044394 PCI!US2OIO/051872 173 ___________purina-6-atnine 31B-23 2-fluoro-8-((6-(5-methyloxazol-2-yl)benzofixran-5-yl)methyl)-9-(2 (epnlamino)ethyl)-9H-purin-6-amine 3E-24 9-(3-(tert-butylamino)propyl)-8-((6-(dimethylamino)benzofitran-5 ylfthio)-911-puuin-6-arnine 3B-25 8-((6-iodobenofuiran-5-yI)thio)-9-(2-( 1 -(methylsulfonyl)piperidin-3 yl)ethyl)-9-purin-6-amine 3B3-26 8-((6-(1H-pyrazol-3-yl)benzoffiran-5-yl)thio)-9-(2 (n-eopenyamaino)ethyl)-9H-purin-6-amine 3B-27 N-(3-(6-amino-8-((6-(aziridin-] -yl)benzolbm-5-yl)thio)-9H-purin-9 yl~propyl inethanesulfonamide 3B3-28 3-(6-arnino-8-((6-iodobenzofitran-5-yl)thio)-9H-purin-9-yl)propyl sulfsmate 3B-29 9-(3-(tert-butylamino)propyl)-8-((6-(oxazo-2-yl)benzofiiran-5-yl)thio) 9H-purin-6-amine 3B-30 8-((6-ethynylbenzaffiran-5-yl)thio)-9-(2-(neopentylamino)ethyl)-9H ___________purin-6-ami ne 3B3-31 1 -(6-smiino-8-((6-iodobenzoftran-5-yl)thio)hOH-purin-9-yl)-3-(tert utlmn)propan-2-ol 3B-32 8-((6-iadobenzoffiran-5-yI)thio)-9-(3-Qisopropylamino)propyl)-9H puriu-6-ainine 3B3-33 9-(3-(tert-butylamino)propyl)-8-((6-(5-rnethyltbiazol-2-yl)benzofuran-5 jj)thio)-91{- Urin-6-amine 3B-34 1 -(3 -(6-aniino-8-(6-iodobenzofhran-5-ylthio)-9H-purin-9 yl)propyl)pyrrolidin-3-ol 3B-35 I -(3-(6-amaino-8-(6-iodobenzofuran-5-ylt'hio)-9H-purin-9 ___________yl)propyl)pygrolidin-3-one Table 3C No. Name 3C-1 6-((6-aniino-9-(2-(isobutylaanino)ethyl)-9H-purin-8-yl)thio)benzo[doxazole-5 carbonitrile 3C-2 8-((5-(ffiran-2-yl)benzo[dJthiazol-6-yl)thio)-9-(2-(neopentylan-ino)ethyl)-9H purin-6-amine 3C-3 2-fluoro-S-((5-(furan-2-yl)benzoldoxazol-6-yl)methyl)-9-(2 (neotcintylaniino)etbyl)-9H-purin-6-arnine 3C-4 8-((5-(azetidin-1 -yl)benzo[djoxazol-6-yl)thio)-9-(2-(isobutylamino)ethyl)-9H purin-6-amme 3C-5 9-(2-(isobuylaniino)ethy)-8-((5-(pyrrolidin- 1 -yl)benzc~d]thiazol-6-yi-)thio)-9H purin-6-amine 3C-6 8-((5-ethynylbenzo[dltbiazol-6-yl)methyl)-2-fluomo-9-(2-(isobutylamino)ethyl) 9H-purin-6-an-ine 3C-7 N-{2-((2-(6-amino-8-((5-iodobenzoloxazol-6-yl)thio)-9H-purin-9 _yl~ethyl)amino)4thyI sulfamide 3C-8 3-((2-(6-amino-8-((5-(furan-2-yl)benzodjoxazol-6-yl)tbio)-9H-purin-9 yl)ethyl)aniino)-N-hydroxypropanamide WO 2011/044394 PCI!US2OIO/051872 174 Table 3D No. Name 3D-1 5-((6-amino-9-(2-(isobutylamino)ethyb)-9H-purin-8-y)Pliio)- lH _____ ______benzo[dlimidazole-6-carbonitrile 3D-2 8-((6-(furan-2 -yI)- 1H-benzc~d]imidazol-5 -yl)thio)-9-(2 (j -ppentyamino)ehfl-9Hpurn-6-amine _ __ ------------- (neopentylamino)ethyl)-9H-purin-6-amine 3D-4 S-((6-(azetidin-1 -yl)- 1H-benzo[d] imidazol-5-yl)tbio)-9-(2 3D-S 9-(2-(isobutylamino)etyl)-B-((6-(pyrr&I idin-1 -yl)-l H-benzo[dlimidazoi- -] ____________ lflhio)-91H-purin-6-armine 3D- 6 8-((6-ethynyl- I-inethyl-iLH-benzo[dlirnidazol-5-yI)methiyl)-2-f-iuoro-9-(2 _____________(isob-utylamaino)ethyl)-9H-purin-6-arnine ___________9lr-purin-9-vl)ethy)amino)erhyi)mrethanesuifonanide 3D-8 3-1j2-(6-amaino-8-((6-(furan-24-yi)-i 1I-benzo[d]imidazol-5-y)tio-91- 3D-9 ii. 2Lflz n-9-D'tflY IsroVbyla&ioxetypOl9-mLdeii8 __________yIthio)benxzo [d]o--azole-6-carbo itrile I 3D-I10 18-((6-iodobenzo~d]oxazol-5-y)thio)-9-(2--(neopentylamino)ethyl)-9- ____________purin-6-anix 3D-Il 5-((6-amino-9(2(isobuty1aino)et y1)-9H-pui~ yl)thio)benzofdlthiazole-6-carbonitrile 3D- 12 8-((6-(furan-2-yl)benzo[djthiazoi-5-yI)thio)-9-(2-(neopentylami no)ethyl) 91--purin-6-amine 3D-i13 2-fluoro-S-((6-(furan-2-yl)benzo[cl]oxazol-5-yl)mnetbyl)-9-(2 (neopentylamino)ethyl)-9H-purin-6-amiiie 3D- 14 8-((6-(azetidini -yi)benzo~d]oxazol-5 -yl)thio)-9-(2-(isobutylaniTno)ethyi) ___________91-i-purin-6-arnine 3D-15 9-(2-(isobutylamino)ethyl)-S-((6-(pyrroiidin-l -yI)benzoldjthiazol-5 3D-I16 3-((6-ethynylbeazo~djthiazol-5-yl)methyl)-2-fluoro-9-(2 ___________(isobutylamnino)ethyl)-9H-purin-6-amine Table 3E No. IName 3E-1 I6-((6-ami no-9-(2-(isobur-.ylamrino)erhyl)-9H-pmti-S-y)thio)benzo[d] [ 1,2,3]1oxadiazole-5 ___________ arb-onitrile 3E-2 984((5-(fiuan-2-yl)benzo[d][1I,2,3 :]thiadiazol-6-ylI)thi<)9-(2-(nvopenutdamino)ethyl)-9H-purin 6-amine 3E-3 2-fl-uoro-S--((5 -(furai-2 -yi)benzo[d] [1 ,2,3]oxadilazol-6-yI)rnethvl)-9-(2 __________(neiopentylarino)ethyl)-9H-purin-6-aminre 3E-4 S-((5-(azetidin-1 -yl)benizo[d] [1 ,2,3]oxadiazol-6-yi)thio)-9-(2-(isobcitylamino)ethyl)-9 __________purin-6-aniine 31>5 j~7~sobuy~anino~thy1-S{( -(yrrldi- 1 )ybenzo[d] [1 ,2,3]thiadiazol-6-yl)thio)-911- WO 2011/044394 PCT/US2010/051872 175 purin-6-amine 3E-6 8-( (5-ethynylbenzo[d] [1,2,3]thiadiazol-6-ys)methyl)-2-fluoro-9-(2-(isobutylanino)ethyl)-9H purin-6-amine 3E-7 N -(2-((2-(6-amino-8-{(5-iodobenzo[d] [ 1,2,3]oxadiazol-6-yl)thio)-9H-purin-9 yl)ethyl)amino)ethyl)sulfamide 3E-8 3-((2-(6-amino-8-((5-(furan-2-yl)benzo[d][1,2,3]oxadiazol-6-y1)thio)-9H-purin-9 y_ )ethy)amino)-N-hydroxypropanamide 3E-9 5-((6-amino-9-(2-(isobutylamino)ethyl)-9H-purin-8-yl)thio)-3H-indazole-6-carbonitrile 3E-10 84(6-(furan-2-yl)-3H-indazol-5-yl)thio)-9-(2-(neopentylamino)ethyl)-9H-purin-6-anine 3E-11 2 -fluoro-8-((6-(furan-2-yl)-3H-indazol-5-yl)methyl)-9-(2-(neopentylamino)ethyl)-9H-purin 6-amine 3E-12 8-(6-(azetidin-1-yl)-3H-indazol-5-ylthio)-9-(2-(isobutylamino)ethyl)-9H-purin-6-anine Table 3F No. Name 3F-1 5-((6-amino-9-(2-(sobutylamino)ethy)-9H-purin-8 y )thio)bczo[d][1,2,3]oxadiazole-6-carbonitrile 3F-2 8-((6-(IH-pyrazol-3-yl)berzo[d] [1.2,3]oxadiazol.-5-yl)thio)-9-(2 (neopentyamino)ety)-9H-purin-6-amine 3F-3 2-fluoro-8-(6-(furan-2-yl)-IH-benzo(d][1,2,3]iriazoi-5-y1)methy)-9-(2 (neopentylamino)ethyl)-9H-purin-6-anine 3F-4 8-((6-(azetidin-1 -yl)benzo.[d][.,]hdiz-5yti)9(2 (isobutylamino)ethyl)-9H-purin-6-amine 3F-5 9-(2-(isobutylamino)ethyl)-8-((5-(pyrrolidin-1-yl)-3H-indazol-6-yl)thio)-9H purin-6-amine 3F-6 8-((6-ethynyl-1-methyl-IH-benzo[d][1,2,3]triazol-5-yl)methyl)-2-fluoro-9 (2-( sobuytlamino)ethyl)-9H-purin-6-amine 3F-7 N-(2-((2-(6-amino-S-((6-iodobenzo[d][1,2,3]oxadiazol-5-yl)thio)-9H-purm 9-yl)ethyl)amino)ethyl)sulfarnide 3F-8 3-((2-(6-amino-8-((5-(furan-2-yl)-3H-indazol-6-yl)thio)-9H-purin-9 yl)ethyl)amino)-N-hydroxypropana.mde __...... 3F-9 6-((6-amino-9-(2-(isobutylamino)ethyl)-91-1-purin-8-yl)thio)-3H-indazole-5 carbonitrile 3F-10 8-((6-iodobenza[d]l,2,3]oxadiazol-5-vl)thio)-9-(2-(neopentylarnino)ethyl) 9H-purin-6-amine 3F-1 5-((6-amino-9-(2-(isobutylamino)ethyl)-9H-purin-8 yl)thiorbenzotyd1,2,31thiadiazole-6-carbonitrile 3F-12 8-((6-(fn -2-yl)benzo[ diazol-5-y])hio- (n~eopentylamino)ethy)-9H-p urin-6-amine 3F-13 . -fluoro-8-((6-(furan-2-yl)benzo[d][1,2,3]oxadiazol-5-yl)mrethyl)-9-42 (neopentlaminoety)9-ui6amn 3F-14 8-((6-(azetidin-1-yl)benzo[d] [1,2,3]oxadiazol-5-yi)thio)-9-(2 (isoburvlanino)ethy l)-9H-purin-6-amine 3F-15 9 (2-(isobutylamino~ethyl)-8-((6-pyrrolidin-1-yl)benzo[d][ i,2,3]thiadiazol 5-yl)thio)-9H-purin-6-amine 3F-16 8-((5-ethynyl-3H-indazol-6-yl)methyl)-2-fluoro-9-(2-(isobutylamino)ethyl) 9H-purin-6-amine WO 2011/044394 PCI!US2OIO/051872 176 Table 4A No~ Name 4A-1 D72-388 9-(3 -(isopropylami no)propvl)-S-(6-phenylbenzo[d][ 1,3]dioxoi-5-ylthio) _______________9H--pnin-6-amine 4A-2 DZZ-390 - _J(isoropylamino tropy1-9W utrin-6-amine 4A-3 DZ2-391. S-(6-(3,5-bis(rrifluorornethyl)phenyl)benzo[djf 1 ,Sjdioxol-5-ylthio)-9-(3 - .............. (isoppropylamino)propyl)-9H-purin-6-ani~ne 4A-4 TT-V-47B NI -(3-(6-amaino-S-(6-(3 ,5-bis(trifl1uoromethyl)phenvl)benzo[dJ [1 ,3]dioxol 5-vltho ~9~ui~:I)propyi)hexane- I .6-diarnine 4A-5 D12-392 8-(6-(4-(dirnetlivlarrii'no)phenyl)benizo[d] [ Jjdioxol-5-ylthio)-9-3 4A-6 DZJ-3 9-(3J-(isopropylarn io)propy)-B-(6-Q4-methoxypheny1)b-enzo[dj[ [1,3jjdioxoI _____________5-yirhia -9W-pu-an.%--6-amnine 4A-7 DZ3-6 8-(6-(4-bromophienyl)benzo[dj [I ,3],dioxoi-5-ylthio)-9-(3 _____________(isopropyiamino)propyl -PH-purm-6-ie 4A-8 DZ3-5O 4-(6-(6-amino-9-(3-{isopropylamino)propyl )-9H-purin3-S yltbio)benzo[d][ I ,3jdioxol-5-yl)benzaldehyde 4A-9 4-(2-(6-arnino-8-(6-phenylbenzo[d] [I,3]dioxol-5-ylthio)-9H-purin-9 - §LethDpiprdn1 -cabadehde 4A-1O I -(4-(2-(6-amino-2-fl-uoro-S-((6-pheniyibenrzo[d)[1I,3]dioxol-5 -yI)metbyl) 9H-purin-9-y)ethyl)pipeidin-]1-ylethanone 4A-11 N-(2-((2-(6-arnino-8-((6-phenyibenizofd) [1,3]dioxo1-5-y1)tbio)-9H-puriLn-9 __________ ____yi~thyl) min)ety)sulfamide 4A-12 3-(2-(6-amino--(6-phenvbenzo~d][ 1,3]dioxo-5 -ylthio)-911-purin-9 4A-13 y! tY !mqpoy)- (-proxyropanand[1 5 3]dioxol-5 -ylthiio)-9H-pur-in-6 Table 4B No. -Name 4$-I PIJ-WS8 t (6-eth-ynylbenzo[d][ 1,3 ]dioxol-5-ylLhi o)-9-(3-(isopropylamino)propy) 91{-purin--6-arnine 4B3-2 PIJ-WS.6 S (6(3 ,3-di-met~hyibut- 1-yriyl)benzo[d)rI,3]dioxol-5 -ylthio)-9-(3 gsopopy~nunopropj~9f-pun-6-amine 4B3-3 PU-WS7 9-(3-(isopropylamino~propyl)-8-(6-(phenylethynyl)benzo[d] [1,3] dioxol-5 -ylthio)9fl-purin-6-amife - WO 2011/044394 PCT/US2010/051872 177 4B-4 PU-WS16 8-(6-ethynylbenzo[d] [1,3]dioxol-5-ylthio)-9-(2-(isobutylarnino)ethyl)-9H purin-6-amine 4B-5 1-(3-(2-(6-amino-8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9H-purin-9 yl)ethyl)piperidin-I -yl)ethanone 4B-6 8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9-(2-( 1 (methylsulfonyl)piperidin-3-yl)ethyl)-9H-purin-6-amine 6B-7 1-(3-(4-(6-anino-8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro 9H-purin-9-yl)butyl)pyrrolidin-1-yl)ethanone 4B-8 5-(6-amino-S-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9H purin-9-yl)pentane--sulfonamide 4B-9 3-(2-(6-amino-2-chloro-8-((6-ethynylbenzo[d][1 ,3]dioxol-5-yl)methyl) 9H-purin-9-yl)ethyl)piperidine-1-carbaldehyde 4B-10 3-(2-(6-amino-8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro 9H-purin-9-yl)ethyl)piperidine-I -sulfonamde 4B3-11 N-(2-((2-(6-amiino-8-((6-ethynylbenzo~d][1, 3]dioxol-5-yI)thio)-9H-purin 9-yl)ethyl)amino)ethyl)sulfaide 4B-12 3-(2-(6-amino-8-(6-ethynylbenzo[d] 1,3]dioxol-5-ylthio)-9H-purin-9 yl)ethylamino)-N-lydroxypropanamide 4B-13 PU-WS19 8-(6-ethynylbenzo[d][1 ,3]dioxol-5-ylthio)-9-(2-(neopentyiamino)ethyl) 9H-purin-6-amine 4B-14 PU-WS20 8-((6-ethy n pylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9-2 (isobuitylaminio)ethyl)-9H-purin-6-amnine 4B-15 9-(3-aminopropyl)-8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9H-purin-6 amine 4B-16 9-(2-amninoethyl)-8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9H1-purin-6 ammne 4B-17 9-(3-(tert-butylamino)propyl)-8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio) 9H-purin-6-amine 4B-18 1-(3-(6-amino-8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9H-purin-9 yl)propyl)pyrroli din-3-one 4B-19 3-(2-(6-amino-8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)thio)-91-1-purin-9 yl)ethyl)piperidine-1 -sulfonamide 4B-20 6-(6-amino-8-(6-ethvnylbenzo[d][1,3]dioxoi-5-ylthio)-9H-purin-9 yl)Ihexanamide 4B-21 i-(6-amino-8-(6-ethynyibenzo[d][I 3]dioxol-5-ylthio)-9H-purin-9-y)-3 (tert-butylamiino)propan-2-ol 4B-22 6-(6-amino-8-((6-ethynylbenzo [d][ 1,3] dioxol-5-yl)methyl)-2-fluoro-9H puri-9-yl)hexanamide 4B-23 1-(2-((2-(6-amino-S-(6-ethynybenzo[d][ 1,3] dioxol-5-ylthio)-911-purin-9 yl)ethylamino)methyl)pyrrolidin-I-yl)ethanone 4B-24 5-(6-amino-S-(6-ethynylbenzo[d.][1,3]dioxol-5-ylthio)-.9H-purin-9 yI)pentane-1 -sulfonamide 4B-25 1-(3-(2-(6-anino-8-((6-ethynylbenzo[d] [1,3]dioxol-5-yl)methyl)-2 -fluoro 9H-purin-9-yl)ethyl)piperidin-1-yl)ethanone 4B-26 8-((6-ethynylbenzotd][ 13]dioxol-5-yl)methy)-2-fluoro-9-(2- WO 2011/044394 PCI!US2OIO/051872 1.78 4B-27 84&ebniez .][ 3]dioxol-5-yI)niethyl)-2-tluoro-?-{3 _____________(isopropylamino)propyl)-9H-puirin-6-amine 4B-28 9-(3-(tert-bulylarnino)propyl)-8-((6-ethynyibenio[d][] ,3]dioxol-5 yl)methyl)-2-fluoro-9H-purini-6-arnine 4B-29 8-if 6--elhynylbenzo~d][1 ,3]dioxol-5-yl~rnethyl)-2-fluoro-9-(2-( 1 meth 1su lfony j~p peridin-3-y1 ethy1 -9H-purin-6-arrine 4B-30 1 -(3-(6-amino-8-((6-ethynylbenizo[d]f I,3Jdioxol-5-yl])metbyl)-2-fluoro 9H-purini-9-yj1 ro I pyrolidin-3-one 4B-31 8-((6-ethynylbenzo[d]Ll ,3jdioxol-5-yI)methyl)-2-fluoro-9-(2-( 1 _________________methyI iperidin-3- I orb 1)-91--urin-6--amine 4B-32 8-(6-ethynylbenizo[d'1[ I,3]dioxol-5 -ylthio)-9-(2-( 1-methylpiperidin-2 ______________ Iorb )I-uvt-6-anine 4B-33 1 -(2-((2-(6=amino-8-((6-ethynyibenzo[d [1 ,3]di ol-5-yI)mnethyl)-2 _____________ luoo-9-purn-9yi~thyamin~mehylpyrriidn- -vltbanone 4B-34 8-(6-ethynylberizo[d][1I,3]dioxot-5 -ylthtio)-9-(2-( I -rnethylpiperidio-3 4 yl)ethy)-9H-purin-6-amine 4W-35 j 8-((6-ethynylbenzo,"d] 13]ix-5yfnhl}2iur9(-(1 Table 4C No. Name 4C-1 DZ3-4 8-((6-Q.ftrana-2-yl)benzo[dj[1I,3]dioxol-5 -yI)thio)-9-(3-(isopropylamino)propyl)-9H 8-if6-(fIuran-3-yljibenzo[d][1,3]dioxol-5-yI)tbio)-9-(3-(isopropylarnino)propyfl-9H -purin-6-amiae 4C-3 DZ3-25 2-fluoro-8-((6-(furan-2-yl)benzo~d][7 ,3]dioxol-5-yI)methiyl)-9-(2-(isobutylaminolethyl) I9H-Ipmuin6-aminec 4C-4 DZ3-26 2-fluoro-8-if6.-(furan-3 -yl)benzo[d] [1 ,3]dioxol-5-yl)methyl}-9-(2-(isobutylamino)ethyl) 9H-purin-6-armne 4C-5 TTS-53A 8-if 6-(furan-2 -yI)benzo[d)[1 3]dioxol-5 -yl)thio)--9-(2-(neopentylamidno)erbylfr9H-p-urin 6-amine 4C-6 IDZ3-33 5 -(6-((6-ainino-9-(3 -(isopropyiami-no)propy1)-9H-purin-8-y)thioybenzo[d] [1 ,3]dioxol-5 '1 fhran--arbaldeh de 4C-7 DZJ3-34 5-(6-((6-amninoD-2-fluoro-9-(2-(isobuv-ylamino)crhyl)-9H-purn"8 4C-8 )Z3-35 9-(3-(i sopropylaniino)propyl)-8-((6-(5-methylfkaan-2-yi)benzo[d]'[1 ,3]dioxo]i-5-yl)tbio) __________9H-purin-6-ane 4C-9 DZ3-36 .f (6(-[1vlua--l~ezLL ,3]dioxol-5- WO 2011/044394 PCI!US2OIO/051872 179 I ehyl)-9W- urin-6-arnine 9-(3-(isopropylamrrinc)propy-)-3-((6-(isoxazo1-4-yi)beno[d][1I,3ldiD,oob5-y)hioi)-9F1 _______ _p 2WPamine 4C-11 DZ3-51 2-fl uoro-9-(2-(isobutylamino)erhyi)-8-((6-(isaxazol-4-yl)benzo[d] [1 ,3]dioxol-5 __________yl)mnethyfl-9H-purin-6-amine 4C-12 S-((6-(5-(amninomethyl)ftiran-2-yi)benz-o[d][ 1 ,3]doxol-5-yl)thio)-9-(3 __________ - { pyamino)propy)-9Hpri-antne 4C13 S-((6-(5-(aminomethyl)fnaran-2-yl)henzo[d]r 1,3]dioxol-5-yI)methyl)-2-fluoro-9-(2 IC1 (1sobuvamino)ethy1)-9H.-purn-6-arnine 4C-14 DZ3-60 24((6-(fiwan-3-yI)benzo[d][ 1,3]dioxo1-5-y)thio)-9-(2-(neopentyIarnino)ethyl)-9H-purin _________6-ami ne 4C-15 X-(6-(5-methyloxazo-2 -yl)benzo[d][ I,3]diosol-5-yhthio)-9-(2-(eopentylanmino)ethy)-; __________9H-purin-6-am-ine 4C-16 025 8-((6-(5-metbylftran-2 -yl)benzo[d][ 1,3 ]dioxol-3-yl)thio)-9-(2-(neopenlyl.-ari-no)ethyh _________9-H__urin-6-amine 4C-17 1 -(3-(6-amiino-2-fluoro-S-((6-(5-mietliyioxazo-2-yl)benzodL I,3ldioxoi-5-yl)rnethyl) ________9H-pun-9-Djlipyl)2y1olidin-3-one 4C-18 1 8-((6-(5 -(,aninornethyl)furan-2-yl)benzo(dli 1,3] dioxol-5-yI)thiio)-9-{2 4C-19 I-(3 -(2=(6-a-ino-8-(6-(5-methqylftwa-:2-yl)benzoF~d][1,]ix--lt 4C-20 8-(6-(5-methyifutran-2-y1)benzo[d] [.1,3]diaoxol-5 -yltbio)-9-(2-( 1 4C021 1 -(3-(2-(6-anino-2-fluoro-8-((6-(5-methylfuran-2-yl)benzo~d] [1 ,3]ldoxol-5-yl)methyl) 4C-2 i en r Wtbcanone 4C-224-(2-(6-amino-2-fluoro-8-((6-(furan-2-yljbenofd] [1 ,3]dioxol-5-yl)methyl)-9.H-purin-9 ___________yI)ethyl)piperidine-1 -carbaldehyde 4C-231-(3-QI-aniino-S-(6-(oxazol-2-yl)benzo[d][1I,3]dioxol-5-ylthio)-9H-purin-9 _______________ yj~poyjpyrroldin-3-one 4C-24 6(-mno-8-(6-(5-methyloxazol-2-yI)ben~zo[djt 1,3]dioxol-5-ylthio)-YH-purin-9 F 4C-25 6-(6-arino-2-fuoro-8-((6-(5-rethvloxazol-2 -yl)benzo[d[ 1,3doxo-5 -yl)methyl)-9Hf~ _______ purin-9-yi)hexa-nawide 4C-2 I -4-(2-(6.-anmino-2-fluoro-8-((6-(5-mefhylfaran-2 yl)benzo[d] [1 ,3]dioxol-5-yl)methyl) __________ 9Hpurin- -j1pjpcr din- I-yljethanone 4C-27 1 -(4-(2-(-amino-2 -chloro-8-((6-(5-m!ethyflwhan-2-yl)benzofd[ I,3]dioxol-5-yI)mnethyl) _________9H-pYuin-yIethypteridin-lgil)ethanone 4 C 2 i.-3-(2(6-aino-S-(6-(5-methyvloxazoi-2-vl)benzo[dJ [I ,3]dioxol-5-ylthi.o)-9H-puri-9 ____________________________ I ct I N iadin-1-yl ethanone 4C-29 1 -(3-(2-(6-ami no-2,-fluoro.S-((6-( 5=methylioxazol-2-yI)benzo[d] [1. ,3iidioxoI-5 ________ -n~hy) -yljeffianon 4C 30 -(-6ain--ho-86(5mtyoal--lbno][1,]oo-yimhyl) __________9Hpurin-9-lethyl4pipedidine- -sulfontamide 4C-31 1-(4-(2-(6-amino-S-((6-(5-(,am-inomethyl)ffiran-2-yl)benzo[d] [1,3] dioxo1-5-ylthio)-9- __punn:.2) &1pjeridnn1-)ethatoue [::4C-32 1[ 1dioxol-5-yI mety1 - WO 2011/044394 PCI!US2OIO/051872 _________ f2-fuoro-9H-prirv-yj)qehv1 i eridin-1 - heithanone 4C-33 S-(6-ar-nino-2-fluoro.-8-(1(6-(S-methyloxazoI-2-y1)benzo[d][ I,3jdioxoI-5-yi)rnetwl)-QH 2-fluoro-9-(3-( isopropyiamnino)propyl)-8-((6-(5-methiyloxazol 2-yl)benizo~d]t I,3ldioxol-5-yl)rnethyl)-9H-purin-6-amine t 9-(3 -(tert-b-utylaniino)propyl)-2-fluoro-8-((6-(5-methyloxazol-2 yI)benzo[d)i l43]dioxol-5-yl)rnethyl)-9H-purin-6-amine yl)ber.zo[d][1,3]dioxol-5$yi)tbio)-9H-puini-9 yl)ethyi)arnino)ethyl) suifamide -3--(-246-ami no -=Q5.(5-rnethylfuann-2 -y)henzot[dl[ 1,3--dioxol -5' ylthio)-911-purin-9-yl)ethyiamino)-N-hvdroxypropanatude DZ4-20 9-(3-(isopropylamino)propyl)-8-((6-(oxazol-2 y])benzo[d3[ I ,3]dioxol-5 -yI)thio)-91-I-pui-in-6-amine DZA-23 2-fluoro-9-(2 -(isobutylamino)ethyl)-8-((6-(oxazol-2 yl)beinzo[dJ LI 3jdioxoI-5-y])rnethyi)-9H-purin-6-arnine DZ3-142 S-((6-(2,3-dihydrofuran-2-yl)henzo [d][ 1,3]dioxol.-5-yI)thio)-9 (3-(isoprop-ylaniino,)prcpyl)-911-purin-6-amine DZ3-143 3-((&(2,3 -cihydrofhr-an-3!-yI)ben2o[dj[I ,3jdoxol-5-yI)thio)-9 (3-(isopropylamino)propyl)r9H-purin-6-amine yl)benzo[d] [1,3]di'oxol-5-ylthio)-9H-purin-6-amine 9-(2-anoethyl)-2-fluoro-84((6-(5-methylfbran-2 .... _ ...... .... .. _ _ y ylh no [ ?3) ioxol-5y methy)-91-purn -6-amine WO 2011/044394 PCT/US2010/051872 181 9-(3-(tert-butylamino)propyl)-8-(6-(5-methylfuran-2 yl)benzo[d][1,3]dioxol-5-ylihio)-9H-purin-6-amine 9-(3-(tert-butylamino)propyl)-8-((6-(oxazol-2 yI)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)ethyi)piperidin- I -yl)ethanone 8-((6-(5-methyloxazol-2-yi)benzo[d] [1,3]dioxol-5-y)thio)-9-(2 (1-(methylsulfonyl)piperidin-3 -y)ethyl)-9H-purin-6-amine 9-(3-(tert-butylamino)propyl)-8-((6-(5-methyloxazol-2 yl)benzo~d][,3doo--1ti)9-un6ame 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-oI 1-(6-amino-8-((6-(5-methyloxazol-2-yl)benzo[d][1,3)dioxol-5 yl)thio)-9H-purin-9-yl)-3-(isopropyamino)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-carbaidehyde 5-(6-amino-8-(6-(5-methylfrran-2-y)benzo[d][1,3]dioxol-5 ylthio)-9H-purin-9-y1)pentane- I -sulfonamide 5-(6-amino-8-(6-(5-methyloxazol-2-yl)benzo[d][ 1,3]dioxol-5 ylthio)-9H-purin-9-yl)pentane-1-sulfonamide WO 2011/044394 PCI!US2OIO/051872 8-(6-(5-metbyloxazol-2-yl)benzo[df ] ,3Jdioxol-5-ylthio)-9-(3 (1 -(methylsulfony)pyrrolidin-3-yi)propyl)-9H-purin-6-amine I -(3-(6-amino-8-(6-(5-methyloxazol-2-yl)benizo[d[1 ,3jdioxol 5-yhthio)-9-H-purin -9-yl)propyi)pyrrolidin-3-one 9-(3-(tert-butylamino)propyl)-2-fluoro-8-((6-(oxazol-2 yl.)hertz[d][1I,3]dioxol-5-yl)-rnethyl)-9H--purin-6-amine y1)benzo[d][ I ,3]dioxoi-5--yl)nxtthyil)-9H-puriu-9-yl)pentane-1 sulfonamide 6-(6-arnino-2-Jluoro-8-((6-(5-methyLflzr-2 vI~bcnzo[d)[ I 3] dioxol-5-vI)methyl)-9F1-puriri-9-yl)hexanarnide 2-fluoro-9-(3-(isopropylanmio)propyl)-8-((6-(5-miethyifuran-2 yi)benza[d] [I ,3]dioxol-5-yl)methyl)-9H-purin-6-amine 9-(3-(tert-butylamino)propyl)-2-fluoro-8-((6-(5-methylfran-2 yI)benzo[d] [ 1,3]dioxol-5 -yl)methyl)-9H-purin-6-ami ne 9-{3 -aminoprepyl)-2-fluoro-8 -((6=(5..methyifixran-2 x'i)benzod][ 1,3]dioxal-5-yi)rnethyl)-9H-puin-6-amine 9-(3 -amiinoprop yi)-2-fluoro-S-((6-(5-methiyloxazo]-2 vi)benzo[d][ 1 ,3]dioxol-5-yl)rethyl)-9H-pyurin-6--amine Table 4D) WO 2011/044394 PC'F!US2OIO/051872 183 No. iName 4D-1 IDZ2-395 9-(3-(i sopropylamino)propyt)-8-((6-(thiophen-2 -yl)bienzc~d)[ 1,3 )dioxol-5-yl)thio)-9H __________purin-6-ame 4D-2 f Z3-48 2-fluLoro-9-(2-(isolmtylarnino)ethyl)-8-((6-(thiophen-2-yl)bnzo[d[1 ,3lldioxol-5 4D-3 DZ3-58 9-(2-(neopenrylamino)ethyl)-8-((6-(thiophien-2L-yl)benzo[d] [1 ,3]dioxol-5-yl)thio)-9H purin-6-amine 4D-5 2-fluoro-9-(2-(i'sobutylamino)ethyl)-8 -((6&(thiophen-3-yl)benzo[d] [1 .3]dioxol-5 _________1 yl)methy1)j9H-purin-6-atrilne 40-6 9-(2(neopentyiamino)ethyi)-8-((6-(thiophen-3-y)benz7o[d] [1 ,3]dioxl 1-5-yl)thio)9H _________ l rin-6 -amine * 4D-7 1 -(4-(2-{6-arnino-3-((6-(thopenm2-y1)be-nzo[dI [1 ,3jdoxol-5-yI)thic9-9H-purin-9 ____________ yl)piperidin-l-irlethne * 4D-8 ]-4-(2-(6-aino--(-(thirop--y- i,)e bezoz [1 ,3]diool5-I xho-H-purin-9 ___________ * lety)ierhiie-ri -lehde 40-9 1--(2-(6-anino-2-fluoro--if6-(thiopen-2-yl)benzo[d][ ,3dioxo-5-y)mehyl)-9H 40-10 4-(2-4&amino-2-fluoro-8-((6-(thiophen2-yi( 1brioxJ[ I ,3]dio- -umthyl-9H puin9-leh 'I' I ecride-aldeye * 4D-il 4-(2-(6-amino-8-lo--((6-( hiophe '-yl)benzo[d] ]daxl--ydioo-9-purinhv-9 puinethy)ierh1idine-1 c- -carbaldehyde 4D13 4-(2-(6-aniino-2-tloro-8-((6-(thiophe-3-yl)benzo[dj [I,3]dioxol-5 -yl)miethyl)-9purin-9-yl)ethyi)pipcr-idine-1 -carbaldehyde 4D3-14 N-(2-((2-Qi-amino-8-(-3tliiopheri-2-yl)benzo[d] [1 ,3jdioxol-5-yl)thio)-9H--purin-9 yl)ethyl)amino)ethyi) sulfanxide 40-15 3-((2-(6-arnino-S-((6-(thiophen-2-yl)benzo[dj[ I ,3]dioxol-5-yl)thio)-9I-1-purin-9 -yIjerhylIamrino)-N-yroxyropannide 4D-16 DZ4-21 9-(3-(iso~propyiamino .propyi)-S-((6 -(thiazoi-2-yi)benzo[d[1I,3]dioxoi-5-.yl)thic9-9H -purin-6-amine 40-17 DZA-24 yj ineth '1 -94-2urin-6-amine 4D3-18 9-(3-amiinopropyl)-8-((6-(thicpben-2-yl)benz'd [1 3]dioxli-5 -yI)thio)-9H-pr'in-6 purin-6amn * 4D3-20 943-4tert-butyiamino)propyl)-8-((6-(fbiazoi,-2-y)benzo[d] [I,3]diloxol-5-yI)thio)-911 purin-6-amnine ___________________ 40-21 9-(3-{tert-butylaininio)propyl)-8-((6-(5-methylthiophen-2-yl)benzc[d [1 ,3]dioxol-5 __________ yIthio)-9H-purin-6-amine * 40-22 9-_3-(tr-uy nn~rpy1)-8-((6-(5-ethythiazo-2-y)benzo[d[ I,3]dioxol-5- WO 2011/044394 PC'F!US2OIO/051872 184 ___________yl)thio)-9H--purin-6-amine ________________j 4D-23 I 14 3

-(

2 .-(&5amino-S-(64(5-me-ithylthiao.yIbod I ,3doo--lho-1-urin-9 Iyl)~iejdin-lyehnn 4D-24 1 -( 6 -aininio-8-((6-(5-methylthiophen-2-yI)benzof ci][1 ,3idioxol-5-yI)thio)-9H-purin-9 40-25 )I ) l(ioroyamno)ropan-2-o 4D-25 ]-( 6 -antno-8-((-(S-metbylthiazo-2-y1)benzo[dJ [1 ,3jdioxol-5-yiflhio)-911.purin-9.vl) __________3 -isoproplamino)propan-2-ol 4D-26 6 -(E-amino-S-(6-(5-methyithiophen-2-yl)benzo[d] [I,3ldioxol-5-yhthio)-9H--purin-9- 2 -~ yI)hexanamide i 40-27 5-(6-aminao-8-(6-(5-methylthiazot.-2-yljjbenzo[dj I ,3]dioxol-S-ylthio)-91-purin-9 yIpntre- -sulfonamide ! 40'-28 9-(3-(1 -(metbylsulfonyl)pvrrol idin-3-y1)propy1)- S-(6-(5-niethylthiophen-2 yflpbnz~j[1,3oo -~bp-9H-purin-6-amine ______ 4D-29 .2-(2-(6-arin-8-(6-(5-methylthiazoL2',-y1)benzo)[d] [1 .3dioxo--5-ythi)-91-purin--9 1___ yi)ethiyi)pyrroiidin-I -carbalede 4D-30 2 .- fluoro--9-(2 (isobutylarno)eh1--(-5reh~hohn2y)ciod[I3tixl 4D-31 8-((6%'5-methylrhiophen.-2.yI)benzoldj 1,3]dioxoi-5-yi)ltbio)-9-(2 I Leopenvlawino)e-hyl)-9H-pa in-6-wmme 4D - 2 .-fluoro-9-(2Kkiobut-amino)ehy)-S-((6-(5-roetbylthiazo-2-y1)he-nzoidl[ I,'3]cioxoi-5 ___________ ethyl)-9-purin-6-aminie 4D33 -((6-(5-niethylthiaxoi-2-yl)benzo~dl] [i x -5 Table 4E 6-((6-amino-2-fluoro-9-(3-(isopropylamino)propyl)-9H-purin-8 I y4metyt~enzofdl 1,3] dioxole-5 -carbonitrile 6-((6amin9(3(spropyalino)propy)9H-purin-&yl)thi)belzo(d[ I,3]dioxole-5 carbonitrile __________________ 4E-3 D33 I2-(6-((6-amino-9-(3 -(isopropylamino)prnpy1)-9H-purin-3-y1)thio)benzo~d] [1,3)dioxol-5 4E-4 4 acetollitrile 2-(6-((6-amnin-2'-fluoro-9-(2-(isobutylamino)eth y!)-9N-parin-8 ____________yi)rnezhyi)benzotdj I 3doo-5-ylacetonitrile GE-S N-{2-((2-(6 -amino-S-((6-(caoehlbnod ,}ixi5y~ho-Hprn 4E-6 {3 -((2-(6-amino-8-((6-eyanoboenzc~dl [1 ,3]dioxol-5 -yflthio)-9H-purin-9-yl)ethyl)aniino)-N 4 E 7 h yd r ox vp ro p a na rnid e _ _ _ _ _ _ -YI)methiobeqzof dif 131diooe-5--arbonitr1e Table 4F No. 35Name WO 2011/044394 PCT/US2010/051872 185 9-(3[-(isopropylaino)propyl)-8-(6-(pyridin-4-yl)benzo[d][ ,3]dioxol-5 yithio)-9H-purin-6-amine Table SA No. Name 5A-1 PU-RK1I 8-((7-iodo-2.3-dihvdrobenzo[b][],4]dioxin-6-yl)thio)-9-(3 (isopropylamino)propyl)-9H-purin-6-amine 5A-2 PU-HT165 8-((7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9 (2-(isobutylamino)ethyl)-9H-purin-6-amine PU-HTJ.75 8-((7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9 (2-(neopentyiamino)ethy)-9HI-purin-6-amine PU-RK12 9-(3 -(1 H-imidazol-1 -yl)propyl)-8 -((7-iodo-2,3 dihvdrobenzo[b][1,4]dioxin-6-yl)thio)-9H-purin-6-amine PU-DZ3-73 2-fluoro-8-((7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6 yl)methyi)-9-(2-(isobutylanino)ethyl)-9H-purin-6-amine FU-DZ4-84 9-(2-(tert-butylamino)ethyl)-2-fluoro-8-((7-iodo-2,3 dihydrobenzo[b][ 1,4]dioxin-6 -yl)methyl)-9H-purin-6 amine 9-(3-aminopropyl)-S-((7-iodo-2,3 dihydrobenzo[b][ I ,4]dioxin-6-yl)thio)-9H-purin-6-amrine 9-(2-aminoethyl)-8-((7-iodo-2,3 dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9H-purin-6-amine 943-(tert-butylamino)propyl)-8-((7-iodo-23 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)Lhio)-9H-purin-9-yl)-3-(isopropyiamino)propan-2-ol 5-(6-amino-8-(7-iodo-2,3-dihydrobenzo[b][1I ,4]dioxin-6 ylthio)-9H-purin-9-yl)pentane- I-sulfonamide WO 2011/044394 PCI!US2OIO/051872 186 dihydrTobenzo[b] [1 ,4]dioxin-6-ylthio)-9H-purin-9 yl)propyllpynolidiin-3-oue ylthio)-91{-purirt-9-yi)bexanarnide 9-(3-(tert-buTyiami~no)propyl)-2-ftluoro-8-((7-iod6-2,3- I dihydrob-enzo[b] [1 ,4]dioxin-6-yl)methvl)-9R-purin-6 anmine I I-QI-(4-(6-amnino-8-(7-iodo-2,3 dihydrobe:nzo[b] [1 ,4]dioxin-6--ylthio)-9H-purin-9 yl)hutyl)pyrrolidii-1 -yi)ethanonei 2-fl-uro-8-((7-iodo-2,3-chhydrobenzo~b]j 1A]dioxin-6 yl)methyl)-9-(3-(isopropylamioo)propyl)-9H-purin-6 amnine i-(3-(6-amino-2-fluoio-8-((7-iodo-2,3 dihydrobeuzo Ibi [1 ,4]dioxini-6-y)metbyl)-9H--purinQ-9 yl)propyl)pynrolidia-3-one 6-(6-amiino"2Z-fluoro-8{(7-iodo-2,3- -__ dihydrobeaizolb (1,4] 'dioxin-6-y)mety)-9--puriG-9 yl)hexanamide 5-(6-amino-2-fluoro-8-((7-iodo-2 ,3 dihyclrobenzo[h] [1,4]doxin-6-yl)methyl)-91-purin-9 yt~pe-n taute-i-sulfonamide Table 5B No. Name SB-I HJPIS h-((7 -(firran-2-yI)- ,3-dihydrobenzobi,4]dioxin-6-yl)thio)-9-(3-iqsopropylamino)propyl)-9H parin-6-amine SB-2 1 (3-(6-amrinio.8-(7-(oxazol-2-y)-21,3-d hydrobenzo[b)[1I,4]dioxin-6-ylthio)-9H-purin-9 ___________ l)p~ropyli rolidin.-3-one ______________ 5B3-3 - j%-L3-C sopopp ammp )-g-f-(-meth~fran- -yI-2,3-diyr o bzolbfJdioxinQ- I WO 2011/044394 PCI!US2OIO/051872 187 _________ -~yl)thio)-9H-purin-6-arniine 5p4 6-(6-amino-2-fluoro-8-((7-(5-inethyloxazol-2-y)-2,3-dhydrobenzo[b] [1,4] dioxin-6-yl)methyl) __________9H-p-urin-9-yl)hexanamide 513-5 6-(-amnin o-8-(7-(5-rnelhyloxazol-2-yI)-2,3-dihiydrobenzo[b][ 1,4]dioxin-6-ylthio)-911-purin-9 ___________yi hexananice 511-6 2-fluoro-8-((7 .{5-methylftiran-2-yl)-2,3 -d.ihydrobenzc~bj[ [1,4]dioxin-6-yl~naethyl)-9-(2-(1 - .... ,..K (rothyisulfinryl)pipcridin-3-yl)dthyf)-9H-ptidin-6&am-ine SB-7 j TT--VI-53A I2-fluoro-8-((7-(farani-2-yi)-2,3-dihydrobenzo[bj[1I,4jdioxini-6-y)nethyl)-9-(2 I(isobutylaininc~ty)9prn6aii 5BM t I-(3-(2-{6-arnino-2-fluoro-8-((7-(5-methyiftaani-2-yI)-2,3-dihydrobenzo[i [1,4jdioxiu-6 __________I yi)methyl)-91--purin-9-vl)etbyl)pip2eidin-1I -yl)ethanone 58-9 81 847-5-mnethyLfuran-2-y)-,-dihydro benzo [b] [ 1 ,4] diox in-6-ylth io) -9-(1--(1 51B 10 2-fluoro-9-(isoburylanino)ethyl)-8-((7I-(5-meth-ylfrxan-2-yI)-2,3 _____ciiwdrobenzo[b][f 1 ,4]dioin-6-yI)me thylI)-9H -purin -6-ainine SB-1i 1-(3 -(6-amino-2-fluoro- 8-((7-(5$-methyloxazol -2 -yl) -2,3 -dih ydrobenzoF~b][ 1,4] diox irn6 _Uy~metbvI-9H-p-urin-9-yb~propyI)pynoiidina-3 -oQne 5B-12 8-((7-(5-(amninomethvl)furan.-2-y1)-2,3-dihydrobeno[b][ ,4_dioxin-6-vl)metlhyl)-2-fluoro-9-(2 I(isobutlaniioethyl)-9H-puri-6-amine 51B-13 8-((7-(5-methyloxazo-2-y)-2,3-diytroben-zo[b]( 1,4]ioxin-6 -ylthio)-9-(2 _________ neopentvlanmino)ethyl)-9H-puirin-6-ai-ne 58- 14 I(3 -(2-6-anino--(7- (5-nehyltxa-2-y)-2,3 -di hydobezob] [1, 4]dixn-6-ylhio)-9H pri'n-yl tlpridn -yl)ethancone SBS 1 8((-(-nhylfla -2 yl) - 2,3-diby drobenz[I ]io dio-xtio--) o-9-(2 __________(neopenvyiamino~ethy)-911-purin-G-arnine 58 16 8 (-(74aioxao8-4-m-23-hyronzoyl-23-bJ( bnzf~1,4]dioxin-6-yIihc--(-noetyiio)e-pthyl) 5B-20 [ (3(-(6-amino-8-(7-(5-metyoxazol-2-yI)-2,3-dihydrobenzo[b] [1 4]dioxin-6-ykhio)-91-i-9 ____________ prn9- lfylnipidnI-lehne 5B-21 8-(4(-(-aminoaethlor-fb -frani-2-i -3hydrobenzo[b] ,]doxn--ydtio)-9-(2-ntyl-9 ______ I neoenylamoefthy1)9-ui- SB-22 I5-4-(6-afio-7-(- ethylfuran-2-y)-2,3 -diiydrobe[b 4)doxi-- vthio)-9H-n _______ ylupnt--ulfonarnppiden1y~ehnn 5B-23 j 5 4-(6-a-n-fro-S-((7-(5-ao--I)-,dhyroberzo-2,-d-bJ [1 ,4j ][,dioxin-6-ylho-Hprn9 ______yI~ene! l- 1-uonmidyjety)ieiiilyehm 58-241 1-(4-(-(6-anino--chr-85-((7(~ffa-2-y)-,3-diydrobenzo[b][ 4]dioxin-6-yio)methyl)ri-9 I~~~~ _________ prn-yiy)pperidin3-Iethn 5B1-22 1 1-(4-(2e-bu aniino-((7-(5 -yfu--ty-2,3 -idroben ob ],4]dioxin-6-)-H I ____________ ioun-9-petrvi) -ainei1-Ithne 5B1-26 I I--2-(6a o2-loro- 8--((7 45-men, thylf iwan-2-yI)-2,3-dihydrobenzo[b][I,4]dioxin-6 ymeh)-94-. _________ Iytmethyl)-9H-ylprriin-)tyl)pieridi-1 -yarnoane 511-4 j1- (3- -(6-ario-8-(7-(5 -ainethylfuran-2-yl)-2,3-dihydranzo[b][ 1,44] dioxin-6-ylthio)-Hprn9 I j yl ! propyl) tylrniidin-3- n I-Iehnn WO 2011/044394 PCI!US2OIO/051872 5B3-28 - I-(3-(2 -(6-ami~no-8-((7-(5-(ainiinamethyl)fiaa-2-yl)-2,3-dihydro-benzo[b][1,4]dioxin-6 ___________ ImethyI -2-fl9uoro-9H- urin-9- I ct Dieii--Iehn SB-29 5-(6-arno-2-fluoro-8-((7(-methvIfran2y}-2,3-dihydrobenzob(.i,4]dioxin-6-yi)methyl)-I SB-3 ,3Lydoe I b]J,4jdio Lin-6-ylmehyI)-9HI __________)Uri n-9-yletylpipeidine- L-carbaldehyde SB3-31 N -(2-((2-(6-amino-8-(Q1-(fiirani-2-yl)-2,3-dihydrobenz.o[bJ[i ,4]dioxin--&yLthi0-9H -puirin-9 513-32 34((2-(6arnoSI-('l-furan-2-yl-2,3lydobeazob] Lii,4]dioxin-6-yl~ihio)-911-purin-9 5M-33 HJP23 8-((7--(itran-2-yi.)-2,3-dihydrobenizo[b][ 1 4]dioxin-6-yI)thio)-9-(2-(isobutylamino)ethyl)-9H __________purin-&6amine 5B-34 HJPZO 9-(3-{isopropyiainno)propy)-8-((7(oxazoi-2-y)-3-dihydobenzo[b [1 ,4]dioxin-6-yl)tiiio> 911-purin-6-arnine 5B-35 9.{3-amiinopropyl)-2-fluoro-8-((7-(5-methyifttran-2-y)-2,3-dihydrobenzo[b] [II,4] dioxin-6 Iyiftyl)-9H-p-unn-6-aniine 5B3-36 19-(3-ami~nopropyl)-8-(7-(5-methylfliraa-2-yI)-2,3-dhydrobenzoIbj[ IAjdioxin-6-ylthicj)-9fl ________putnn-6-armine SB-37 19-(3-{tert-buiylaiao)propyl)-8-{7-(5-mnetyifran-2-yl)-2,3-dihydrobenzo[b][1 ,4]dioxin-6 yltliio)-9H-puriu-6-amine 5B3-38 9-(3-aminopropyl)-8-{(7-(oxazoi-2-yI)-2,3-dihy-drobenzo[b][ ,4dioxin-6-vl)thio)-91{-purin-6 -amine 5B3-39 9-(3-(tert-buitylamdio)propyl)-8'-(7-(oxazol-2-yl)-2 ,3-dihydrchenzo[b][ i 4]dioxin-6-y1)ihio) 5i340 2 !3-ttbtPlao)propyl)8-7(5methyoxazo 2-yT)-2,3-dihydrobenzo[b] [I,4jdiox.in-6 __________ 1 hio)-9H-purin-6 -aznine 5B-41 1-(4-(2-(6-anio-8-((7-(5-methyloxazol-2-yI)-2,3-dihydrobenzo[b][ 1 ,4jdioxin-6-yi)thio)-9H1 __________purin-9-yI)ethylpiperidin- 1-yl)etbano-ne 5B-42 - -((7-(5 -rneathylcxazol-2-yl)-2 ,3-dibydroben u-o[b][ I ,4]dioxin-6-yI)thio)-9-(2-(1 5B-43 1 -(6-amino-S-((7-(5-methylfhran-2-yI)-2,3-dihydrobenzof bI [I 4]dioxin-6-y1)thio)-9H-purin-9 _________yI)3(sop-opylarrnotropa-2-o 513-44 1 -(6-aminio-b-((7 -(5-rnethyloxazol-2-yl)-23 -dihydrobenizc~b][1 ,4]dioxin-6-yl)thio)-911-purin-9 ____________y1)-3-(isoPropyla nipropan-2-ol 5B3-45 6-(6-aminio-2-fluoro-8-(7 -(5-methyl furar-2-yI)-2,3-dihydrobenzollblrl,4jdioxi-n-6-y)methyl) _____________~~ ~ ~ ~9 _______________purin9-ylhcxaraxide 5B3-46 N-(3-(6-amino-8-((7-(5-methyioxazol-2-yI)-2,3-dibydrobeaizolblll,4jdioxin-6-yl)thio)-9H ____________purn-9-yI)propyimethanesulfonamide 5B-471-(2-(4..(6-amninn-8-(7 45-methyloxazcil-2-yl)-2,3-dihydr-obenzo[b][1I,4]dioxin-6-yltbio)-9H ___________purin-9-yl~buty)pyrrolidin-I -yflethanone SB-48 9-(-amininopropyfl-2-tlhoro-8-((7-(5-methyloxazo-2-yl)-2,3-dihydrobnzo[b[ 1 ,4]dioxin-6 _____________ yE~Imethyi)-9H-prn6ann 5B-50 2 fluorG-9(3-.(isopropyiarnlno)propyl)-8-((7-(5-mrethiyloxazoI-2-y)-2,3 ________dihydrobenzo[b](14jdiuxiu ymnethyl)9H-purin-6-an~ne SB- 1 9-(3-Qtertbutylamnino)propyQ-2 -fluoro-&-((7-(exazol-2-yI)-2,3-diydrohenzob[ -1 Adoxin6 __________- -yI)methvl)-9H-purin-6-arnine WO 2011/044394 PCI!US2OIO/051872 189 _______dihydrobeuzo [bajJ4 ixn-6-yj)meth1l-9H- urin-6-amine ....... 7 -SR53 16-(6-aino-2-fluoro-S-((7-(5-methyloxazol-2-yl)J2,3-dihyvdrobenzo[b][1 ,4]dioxin-6-yl)methyl) ____________91-purin-9-yl~hexanamide 5B-54 5-(6-arnin o-2-fiuoro-8-(f7-(5-rnethyloxazol-2-yl)-2,3-dihydrbenzo(b] [I ,4jdioxin-6-yl)methyl) 511-55 9purin-9-yI)penlane- 1-sulfonami-de 5B-55 ]-(3-(6-amino-2-fl-uoro-S-ff7-(5-Tmethyloxazo1-2-yl)-,3-dihydrobenzo~b[ 1,4jIdioxin-6 _________ viineh 1-9H ujrn-9-yi propylF cdiqdin-3 -one 5B1-56 1-(33-(6-amno-2-fJ uoro-S-((7-{oxazoal -2 -y1)-2,3 -dihydrobenri-ofbl[ 1,4jdioxin-6-yl.)methy])-9H _________ _______________ purin-9-yl)propyl)pyrrolidin-3 -one Table SC No. IName 5C-I 9-(3-isopropylarn-ino)propyi)-8-((7/-(thiophen-2-yl)-2,3-dihydrobenz.o[b[1I,4]di'oxin-6 ____________yl)thio)-911-purin-6-arnine SC-2 I2-fluoro-9-(2-(isobuatyla-w-iao)erl)-S-((7-(thioplien-2-yI)-2,3 __________dihdroenzobj[ ,4dioin--yl)rnethyi)-911-purin-&arnine 5C-3 I9-(2-(neopentylamino)ethyl)-8-((7-(thiophen-:2-yl)-2,3-dihydrobenzo[b][ 1,4]dioxin-6 SC-4 9-{3-(isopropylaxnino)propyl)-8-((7-(thiophen-3-y1)-2,3-dihvdrobenzo[b[ l4dioxn-6 5C-5 2-flu.oro-9-E2-(isobutylamino)etliyI)-S-((7-(thioplien-3 -yl)-2,3 __________ dihydrobenzo~b][ 1,4]dioxin-6-yl)methyi)-911-pu -r-6-aniine SC6 9-(2-(neopentlamio)ethy)-8-((7-(tbiophen-3-y1)-2 ,3-dihydrobenzo*]I I A]dioxin-6 yi~thio)-911-puxinl-6-amine SC7 i-(4-(2-(6-ampino-8-((Q-thiophen-2-yD-23-dihvdrobenzo[b[1 ,4]dioxini-6-yi)thio)-9H SC-8 4-(2-(6-amino-3g-((7-Qhiophen-2-yj-2,3-dihydrobenzolb] [1 ,4]dioxin-6-yl)thiio)-9H p-urin-9jyl)ethyl)vpiperidine- 1-carbaieb de SC-9 I -(4-(2-(6-amno-.-fluoro-R-((7-(thiophen-2--yI)-2,13 -dihydrobenzofb] [I,4]ldioxin-6 ylmtyl9E-purin-9-yl)ethyl)piperidin-1I-yl)ethanone 5C-11 4-(2-(6-amino-8-((T-thiophen-3-y>-2,3-ihydrobenzo~b [1 ,4]dioxiiv-,6yl)thio)-PH SC-13 4-(2-(6-ainino-2-chloro-8-((7-(thiophen-3)-y9)-2,3 -dihydrobenzo[bj ~I1,4jdioxin-6 {y])me-thyI)-9H-purin-9-l)ethyl~piperidine- 1-carbaldehyde 5C2-14 N-(2-((2-(6-amnino-8-((7-(thiophen-2-yl)-2,3-dihydrobenizo[b][1I,4]dioxin-6-yl)thio)-9H ___________ Ipurin-9-yflethy1)anon))thyl)sulfamiide SC-is 3-((2-(6-arninotg-((7-(thiophew-2-yl)-2,3-dihydrobenzn[b][1I,4]dioxin-6-ylthio)-9H piuin-9-yl)ethyl)amino)-N-hydoxypropanam-ide SC-I 6 9-(3 -anminopr-opyI)-S-((7-(thiophen-2-yl-2,3 -dihydx-obeiao[b] [] ,4]dioxin-6 yLMhio)-911-pnn-6-amine SC2-17 9-(3 -(isopropylamino)propyl)-8-((7-(5 -methylthiophen-2-yl)-2,3 dihydrobenzcojb][ 1,4]dioxin-6-ylthio)-,9H-purin-6-aminc * cl 1-(6arino-#(T(methythiophen-2-yi)-2,3 -dihydrobenzo~b][ I,4jd ,ioxin-6-yl)thio) 5C19 1-2-(3-(6-auxino-S-(7-(S-rnethylthiazol-2-y])-2,3-dihydrobenzob [1, m7 ixi--Ii) SII. 94lpun.A9y)propyl)p yrrolidin- I -yI)ethanone _don6yt') WO 2011/044394 PCI!US2OIO/051872 190 5C-20 9-(2-Ql -(rethyisulfony)i~eridin-3-yI)ethyi)4- 2i3 SC-21 I -( 6 -aaino-8_((7-(5-rmethiylthiazoI-2.-y12,-dilhydrohenizr I [14]dioxin-6-yI)thio ).9H pirin-9-yl)-opy(isio)rp lrin~rp q_______ SC-23 9-(3-(tert butylarwtlo)propyi)-8-(J?-(5-rneffiylthiiophen-2-y1>2.3 Table 5D No. _________ Name 511-1 S-((7-(i 1--pyrazoi-4-y)-2,3-dihydrobenzo[b]l I,4ldioxin-6-y1)thio)-9-3 _____ __4 Qs oroyiaraino)p~ropyifr9H-purin-6-armne S-((7-( IH-pyrazol-3-yl)-2,3-dihydrobtnzo[b][1I,4]dioxin-6-yI)thio)-9-(3 's QlOYaaiprp]-9H-purin-6-anne ___________ SD-3 8-((7-(IH-pyrazol-4-yI)-2,3-dihydrobeizofb[ I,4jdioxin-6-yI)methyl)-2-fl-uoro-9-(2 __________(isobutylamino erhy)-91-purin-6-amne~n I -((7 -(1 H-pyrazol-3-yI)-2,3-dihydrobenzo[bJ[ I,4]dioxin-6-yI)methyl)-2-fi-uoro-9-(2 __________("sobut5 1amino ethyl)-9H-prw6 -amnine SD-S I ((3 (7 (1H-pyrazol-3-yl)-2,3 -dihydrobenzofb] 1,4]dioxin-6-ylthio)-6-alnino-9H _____ pin 9v)p opylpyg3idn-3-one ________ -S 5D6 8 ((7 (10 pyrazoi-3-yI)-2,3-dihydrobenzoljb][1,4]dioxini-6-yl)thio)-9{2 5D-7 1-( 2-(8-((-(1 H-pyrazci -3-yl)-2,3-dibydrobcnzo[bj[I,4dioxin-6-yl)hio)-6-an-ino,-9H ___________purmn-9-ybethfyl)piperidin- l-yI)ethiarone SD-8 S-((7-(11-pyrazol-3-yl)-2,3-dihydrobenzorb[ 1,4]dioxin-6-yi)rnethvl)-9{2-aninc'ethyl) 511.9' 1-(4-(2-(8-((7-(i H-pyrazol-3-yl)-2,3-dihydrobernzoit][1I 4]dioxin-6-yl)merhiy1)-6-arnino __________2-fluoro-9H-purin-9-y!Iethyl)piperidin-lI -yl)ethanone 51D-10 1-(3-(2--(S-((7-(1 H-pyrazoi-3-yI)-2,3-dihydrobenzoLb][I4]ixn-y)ey1-arn _______ 2floo-1--pfn-- )th J)p iedn- Ietaone __ 5v-]1 8-(7-I H-pyrazol-3-yi)-2,3-dihydrohenzo[b][1I 4]dioxin-6-y1)xnethyl)-2-fluioro-9-(2-(1 SD12 - 1-(3-(8-((7-(iH-pvrazoi-3-yi)-2,3-dihydrnbenzo[b][1,4dioxin-6-yi)methyl)-6-andino-2 ___________iuoro-9H-puiin-9-y )propyl)pyrroiidin-3 -one SD1-13 I8-(7-( lH-pyrazoi-3-y1)72,3-dihydrobezob][ 1 ,4Jdioxin-6-ylrhio)-9-(241l 1 (mt isulfonvi ni eriin-3- J.et 1 -913-purin-6-amine _____ SD1-14 N-2((-S-(- H-pyr azol-3-yI)-2 ,3-dihydroibenzo~bj[1 ,4Nioxiu-6-yl)thic4-6-aiino ________ 9Hpuin9-y ~tjmn~tb s)lfanide _ _ _- --- 5D-15 7 ((14-((7-(1IT-pyazo-3-y)-2,3-dihydrabenzcjb][ ,4]dioxi-n-6-yI)thio)-6-amnino-9H 511-16 8((7-(l H-imidazol-4-yI}-2,3-dihydrobenzo[b]t 1,4jdioxiri-6-yl)thio)-9-Q, __________(isnpropylasnino)propyl-9H-purin-6-amine 5D1-17 8-((7-( I H-pyrazcl-3-yi)- 2,3 -dihydrobenz-o[bj[ ( 1,4]dioxin-6-yl)thio)-9-(3-aminopropyl) _________9H-purin-6-amine 5D-18 8-((7-(i1 H- nyrazol-3-yQ)-2,3-dihydrobenzofb][ 1 2 4]dioxin-6-y1)tbio)-9-(3-Qert _________ Ibutylarninao)propyl)-9-purin-6-antine WO 2011/044394 PC'F!US2OIO/051872 191 51D-19 1, 8 -((7-(1 H-pyrazol-3-yl)-2,3-dihydrobenzo[b][1I,4]diexin-6-yi)methvl)-9-(3-(tert ___________ ylanino)rol-2-fuojq-fp m6a ne 5D3-20 9-(3-(isopropyl aanino)propyl)-S-((7-(5-metbiy1-1H-pyrazo1-3-y1)-2,3 __________dih 'dro-benzor[ 1,4]dioxin-6-y1)thio)-9iL-purin-6&arnne 5 I-2 8-((7-(5-methyl- iH-pyrazc]-3 -yi)-2,3 -dihydxoberizc[b]f [,4]dioxi-6-yi)tbio)-9-(2 ___________(neopentylanhino)ethvl)-91-i-purin-6-amine 513-22 9-(tent-butylarnino)propy1)-2-fluero-S-((7-(5-rnecthyi-iH-pyrazo1&3y)-2,3 ___________dihydrobenzcjb][ [1,4]dioxini-6-yI)methy1)-9H--purin-6-aminej 5D3-23 1 -(8-((74(iitpyrazol-3-yl)-2,3-dihvdrobenzorb] [1,4]dioxin-6-yl)thio)-6-arnino-9H.

5D3-24 1 -(X-((7-(iH-pyrazol-3-yi)-21,3-dihydrobenzo[b[1 ,4]dioxin-6&yl~neth yl)-6-aminio-2 __________ luoro-911-purin-9- 1)-34 tert-tutylarnino)proan-2-oI 5D-25 5 (8 ((7 (1 H-py-razoi-3-y1)-2,3-dihydrobe-nzo~b][1. ,4]dioxin--6-yl)methyl)-6-arnino-2 __________ flao H- ntm9-y 9entare-l-sulfonamide 5SD-26 6 (S-Q(7 (1H-pyrazol-3-yl)-2,3-dihydrobenzo[b][1I 4]dioxiu-6-yI)mertiy1)-6-andneo-2 ___________ luoro-911 purin-9-:yijhexauamide 5D3-27 5 (8 (7 (lf1-pyrazob-3-y)-2,3-dihydrobenzo[b] [I ,4]dioxin-6-ylthio)-6-anino-9H~pudin __________ 9 1 ~enfane-2 -suifonamide 513-28 6 (8 (7 (11--yrazo-3-yl)-2,3-dihydrobenzo[b] [I ,4]dioxin-6.-ylthib)-6-arni no-9H-purin __________9 vl)hexanalluide Table 5F No. Name 5E-i S-((7-ethyny1-2,^3-dihydxobenzo[b] [1 ,4]dioxin-6-yI)thio)-9-(3 (isoprop'vlamiino)propyl)-911-purin-6-awme 5E-2 3 -(3-(6-amino-8-(7-ethynyl-2,.3-dihydrobenzo[b] [1. ,4jdioxin-6-ylthio)-9 purin9-yIpropl~pyrol....- .ca..a.d..y.. 5E-3 8-{{7-ethynyl-2,3-dihydrobenzofb][ I ,4]dioxin-6-yl)rnethiyl)-2-fluoro-9-(2 _________(isbutlamno~thy-9liniin--amine SE-4 94(2-aminoethyi)-8-(7-ethyny-2,3-dihiydrobenzo[b] i ,4]doxin-6-ylthio)-9H-purin--6 SE-S 84((7-ethyrviy-2,3 -dihydrobenizofb] [ 1,4]dioxiu-6-yl)thio)-9-(2 S(neope-ntylarmno)ethyl)r9fl-purin-6-anine i sE-6 9-(2-aininoethyi)-8-((7-etlnrnyi-2,3-dihydrctenzo~b][ l,4pdoxin-6-yi)thio)-9H-purin 6-amie----- SE-7 1 -(3-(2-(6-anrina-8-(7-ethynyl-2,3-dihvcobenzo~bhi[l Aldioxin-6-ylthio)-9H-purin-9 __________yI)ethyl)piperidin- 1-yflethianone I SE-8 8-(7-ethynyi--2,3-dihydroberizo[b]{ 1,4]dioxin-6-ylthio)-9-(2-(i. (mretylsuifony ~ieii-3-yI)ethyl)-9H-puri-6-amine 5E-9 8-((7-cthyniyl-2 ,3-dihydrobenzo[bl[ [1,4l]dioxin-6-yI)methyl)-2-fluioro-9-(2-( 1 fmeTthyjsuttonyp i _ridn -y ) -9JjPudnr-6-amtne _ _______ 10-i 1 -(3-2-(6-andino-8-((7-ethynvl-2,3-dihydrobenzolb]1[IA]dioxin-6-yl)methyl)-2 SE-il 3-(2-Q5-ainino-S-((7-ethynyl-2,3 -dihydrobenzo[bJ [I,4]dioxin-6 -y])retbyl)-2-fluoro 9f1-purin-9-yi)ethyijperiline-1 -carbaldehyde SE-12 1 .(3-(6-arriuo-8-((7--ethynyl-2,3 -cihydrobenzo[b] [I 4]dioxin-6-yi)metbyl)-2-fluoro 9H-purin-9-yljpropyl)pyrrolidin-3 -onie SE-13 6-(6-amnino-8-((7-cthyniyi-2,3 -dihiydrobenzc~b] [1,4] dioxin-6-yijrnethyl)-2-fl uoro-9 __________ptujn-9-yl)hexanamide WO 2011/044394 PCI!US2OIO/051872 192. SE-14 N-(-2-(6-aminc-8-((7-ethynvl-2,3-dihydrobenzojbj[ 1,4]dioxin-6-yl)thio)-9H _______ p-urin-9-yl)ethyl)amino)ethyl)sulfarnide 5E-1S 3-((2-(6-amaiao-S-((7-ethynyl-2,3 -dihydrobenzo[b] [1 ,4]dioxin-6-yl)thio)-9H-purin-9 _________ y)ethyl)amino)-N-hydroxypropanamide SE- 16 9-(3 -ami nopropyi)-8-({7 -effiynyl-2,3-dihydrobenzo [b][ 1 ,4jdioxin-6 -yl)thio)-91 _________puxi-6-amine 611 i-(6-a mino-8-(7-e-thyny-2,3 -dihydobenzo [b] [I ,41dioxin-6-yltio) -QH-purin-9 _________yflhexanamide _______________________ 51E-18 5-(6 -aniino-8-(7-etbynyl-2,3 -d ihydxobenzo [b] 1 1.4]dioxin-6-yl thio)-9H-purin -9 ________ 1yl)pen-tane.- 1 -sulfonamide 519 1-(6-amino-8-((7 -eihynyi-2.3-dihvdrobenzo[b] [ i,4]dioxin-6-yi)methyl)-2-fiuoro-9H _________ yin-9-yi)-3-(tert-butyiarnino pmpan-2-o 520 1-(6-arnino-S-((7 -ethynyl-2,3-dihydrobenzo[b]f (i,4]doxin-6-yl)thio)-9H-putrini-9-y) _________ 34isopropylanmino)propan-2-ol SE-21 5-6aio-8-((7-eothynyl-2,3-dihydrobenzo[b]([ 1,4]dioxLn-6-yl)mnethyl)-2-fluowo-9H _________ in-9-yl~entane- 1 -sulfonamide 5E-22 8-((7-ethynyl-2-,3-dihydr-obenzo~b][I ,4]dioxin-6-yl)methyi)-2-fluoro-9-(3 ______ ......... _(Jsopr~pylaimino~pyi)-9H-purin-6-amine 5F-23 9-(3-(tert-'butylami no)propyl)-S-((7-etbyny -2,3-dihydrobenzo~b] [ 1,4] dioxin-6 _________yl~ethl)--floro911yurn-6-amino 5E-24 9-(3-a-ninopropyl)-S-((7-ethynyl-2,3-dibydrobenzo[b[ 1,4]dioxin-6-yI)rnethiyl)-2 __________fluoro-9H--purin-6-amine 5E-25 119-43-(ter-butylamino)propyl)-8-(7-ethynyl-2 ,3-d'iydrobenzo[b[1 ,4]dioxin-6-ylthio) I9H-purin-6-axnine 5E.-26 S-(7-etliynyl-2,3-dihydrobenzo[b][i ,4]ldioxin-6-yilio)-9-(2-( 1-methylpiperfdin-2 iyi)ethyl)-9Hl-purin-6-anine 5E-7 j -7-ethynyl1-2,3-dihydrobenzo[b]il ,4]dioxin-6-yitho--(I -methylpiperidin-3 :yletliyl)-9H-purin-6-aninle 5E-28 8-((7-ezhynyi-2,3-dihydrobenzo[bj( 1,4]dixin-6-yI)methyi)-2-tluoro-9-(2-(1 51-9 ethyipipedidin-2-yl)ethyl)-9H-purin-6-amine SE2 -((7- etbyny1-2,3-dihydtrobenzo[b,][i,4]dioxin-6-y)metyi)-2-fioro-9-(2-( __________ - ethyipiperidin-3-yl)ethyl)-9H-purin-6-amine Table ST No. 7-6aiName 5F-. 7-(-mno-9-(3-(isopropylaminojnropyl)-911I-purin-S-yI)tho)-2,3 5F2 7-((6-amnino-9-(3-(isopropylamino)propyit)-9H-purin-8-yi)thio)-2,3 ____-dihydrobenzo-.b][ I ,4]dioxine-6-carbanitrile -SF 3 7-((6-aino--fl-uoro-9-(2-(isobutylamino)ethyl)-9H-puLri-8-yi)meth.yl)-2,3 _________dihydrobeuo~hj[ 1,4]dioxine-6-carbontile 5F-4 1 74((6-arnmro-2-fluoro-9-(2-(isobutyiamino)etbyl)-98-pun-R--y )rnethyl)-2,3 Idibydrobenzo[b][1 ,4],dicxine-6-carbonitrile 5F-5 i7-((6-armno-9-(2-(neopentylamrino)ethyl)-9H-purin-8-y)tbio)-2,3 7-((6 '-nino--2aopb[,]i~enylari tyi-Hpr ylti>23 SF-6 -6--m-,9-2-.epnyaioey)9-ui--lho)23 1 dihydrobenzo[bjj 1 ,4jdioxine-6-carbonitrile SF 7 2-(7-((6-amino-2-fluoro-9-(2-(isobutylanaino)ethy1)-9H-putin-8-y1)mety-2 _________dibvdrobenzo[bI[ I ,4jdoxin-6yLI)acetonitrile WO 2011/044394 PCI!US2OIO/051872 193 SF-S N-(2-((2-(6-arnino-8-((7-(cyanomeothyl)-2,3-dihydobenzo[]j [1 ,4]dioxin-6-yl)thio) - L91-Lpurin-9%y1)ethyI)ami~no)ethly1)sulfamide] SF-9 3-((2-(6-arnino-S-((7-(cyanomethyl)-2,3- dihydrobenzo[b [ I ,4]dioxin-6-yl)thio)-9.H-I ____ ___ puri-9-l~e-hv1 amino)-N-li dro anamido 5F-10 7-((6-arnino-2-chloro-9-(2-(isobutylamino)ethyl)-9H-prin--yl)methyl-,3 _________dihvdrobenzo[b] [1 ,4]dioxine-6-carbooitrile WO 2011/044394 PC'F!US2OIO/051872 194 Table 5G No. ________ Name I_________ 50-I S-((7-(aziridin- 1-yl)-2,3-dihydroberazo[b][I.,ioxn6y)h)-(2 50-2 8-((7-(azetidin-1-yl)-2,3-dihydrobenzo[b][1 ,4]dioxim-6-yl)tbio)-9-(2 (isobautylamino)ethiyl)=9H-p-urin-6-arnine 50-3 19-(2-Qisobutylami~no)ethyl)-8-((7-jpyrroiidin- i -yi)-2,3 -dihydrobcnzo jb] [1,4]dioxin-6 50-4 8-Q(7-(aziridin-1I -yl)-2,3-dihydroberizcb][ I ,4]dioxin-6-yI)rnethyl)-2-tluoro-9-(2 .5G-5 8-((7-(azetidin- I1-yvi>2,3A-ihydrobenzo [b] [ 1,4]dioxiui-6-yl)methyl)Y2-fluoro -9-(2 (isobutulamino eth 1 l-9-1-purin-6-am-ine 5G-6 2-fluoro-9-(2 -(isobutylimno)ethy) -8-((7-(pyrrolidin- 1

-])-

2

.

3 -- ____ 1 d--hydrobenzo~bjji 1,4ldioxin-6=yl)methyi)-9.H-puria-6-anmine 5C-7 2-chloro-9-(2-(isobutylamino)ethyl)-R-((7-{pyrrolidin-1 -yI)- 2

,

3 4 diydrben~bf 1,jdiiv--y1netyl)9H-urin-6-anine 5G-8 1 1 -(4-(2-(6-amnino-8-((7-(sziridin-l -yi)-2,3-dihydrobenzo jb][L,4]dioxin-6-yi)thio)-98 I puin9yehyiprii-I___tann 5G-9 1 1-(3 -(2-(6-aininio-S-(7-(azetidin-1 -yl)-2,3-dihydrobenz-7o[b] [ 1,4]dioxin-6-ylthio)-9Hu _______ jpurin-9-yl)etbyl)piperidin-1 -yl)ethanone 5G-10 4-(2-(6-arnino-2-chloro-8-((7-!(pyrmlidin- 1-yl)-2,3-dibvdrobenzo[b] LI,4]dioxin-6 _______ y th4)-9H- urin-9- '1ethy I iperidine- I -carhaldeb ----- de------- 5-11 8-((7-(dimethylamino)-2,3-dihydrobenzo[b][i,4]dioxin-6-yi)thio)-9-(2 0-l (iscbutylainino thyl-91j-purin-6-arnine 5G1 S-((7-(dhniethylamiino)-2,3-dihydrobenzo[b][l,4]dioxn-6-y~mehyl)-2 -fluorc0-9-(2 ________ isobutyIarnio)evbyl)-9H1-purin-6-amine 50-13 1-(3-(2-(6-awmino-8-(7-(diinethyiarnino)-2,3-dihydrobenz-o[bft I. ,4]dicxin-6-ylbio)-9H yrin-9-yi)ethiyl)piperidiut-1 -yj)ethanone 50S-14 l-(3-(2-(6-arinn-S-((7-(dimethylanwinc)-2,3 -dihydrobenzo~bj [1 ,4dioxin-6-yil)methyl) ________2-florc9H-prin--ylethy~pijeriin-I- I etbiarone 50-15 8-(7-(dimethylarimno)-2,3-dihydroberzorb] [1,4] dioxin-6-ylthiio)-9-(2-( I _______(rnethvlsulfonvl)piperidin-3 -yl)etlhylj-9H-purin-6-arnine *50-16 i8-((7-(dinietbylamino)-2,3-dihydrobenzo[bfi ,4]dioxin-6-yi)methyl)-2-fluoro-9-(2-(1 I metysa oy)ierdn3ykty)-H~rn6ain 5C,17 8-(17-(ethylamino)-2,3-dihydrobenzo[b)[ 1 ,4]dioxirn-6-yl)tbio)-9-(2 *50-18 1-(3 -(2-(6-ainiio-S4-(-elylarnino)-2,3-dihiydrobenzo[bJ 11,4] dioxin-6-ylthio)-9H * purin-9-yi)ethy1)piperidiu-1 -yl)erhanone 5 50-1 9 8-(7 -(et hyl arnino)-2,3 -dihydro benizo[b][ 1,4]dioxin-6-ylth io)-9-(2-(1 5G-20 2-fluorc-9-(2-(isobutylamino)etbyl)-8-((7-(isopropylaniino)-2,3 521 dihydrobenzofbhki,4]divxin-6-yl)methy)-PH-puirin-6-amine 521 8-(7--(isopropylatnino)-2,3-dihydrobenzo~b] III,4]dioxin-6-ylthio)-9-{2-( 1 ________(metbylsuilfonyl)pipedidin-3-yl)ethylt-9H-puri-6-amne 5G-22 l-(3-(2-(6-auiino-2-fluoro-8-((7-{isopropylan'iao)-2,3-dihydrobeizo-"bJ[1 ,4]diox-in-6 5G-23 8-((7-(diinethylamaino)-2,3-d-.ibydrobenzo[bi[ 1,4jdioxi-6-yl)thi.o)-9-(3 _______ I isopropylamino)propylj -9I{-nin-6-amna ________ WO 2011/044394 PCI!US2OIO/051872 195 5G3-24 18-{(7-{dimethyianino)-2,3-dibydrobenzolj)[1I,4]dioxin-6-yI)thiio)-9-(2-(I 1 _________mathyIsulfcrn I iperidin-3-yI eth I -911- urin-6-amine 5G-25 5-(6-arnilno-8-(7-(dimethylamiuo)-2,3 -dihydrobenzo~jb],[i,4jdioxin-6-ylthio)-YH-purrn 9-yljpentni I-sulfonamide 54G-26 6-(6-amnino-8-(7-(diir.ethiylamino)-2,3 -di hydrobenzorhff I ,4jdioxin-6-ylthio)-911-purin 9-yi)bexa.amide 5G3-27 9-(3-Qcrt-butylamino)propyl)-8-((7-(dimethylam~ino)-2,3-d'hydrobeizofb][ I ,4]dioxin 5G-28 1-(-(6-amino-S -{7-(dimethylamino)-2,3-dihydrobenzo[hj[ I ,4]dioxin-6-ylo)-911 ________pauri-9-yflprmpyl)pyr.roli.din-3-one Table 511 No. ___________________Name 5H-i 8-((7-cyclooropyl-2,3-dihydrobenlzo[b] 1 .4]dioxin-6yl)thio)-R{2neopentylamino)ehyl)> 9H-purin-6-amine 511-2 &-((7-cyclobutyl-2,3-dihydrobenizo~b][1 ,4]dtioxinr -6-yI)thi o)-9-(2-(i sobutylaimino)ethy)-9-H purin-6-amine W1-3 8-((7-cyclopentyl-2,3-dihydrobe-nzo(b] [1 ,4]dioxin-6-yl)thio)-9(2-(sobuylaniino)thyl)-911 _____purin- -anii 5H1-4 8-((7-cyclopropyl-2,3-dihydrobenzofbt [1 ,4]dioxini-6-yl)methyl)-2-fluoro-9-(2 51-1-5 8-((7-cyclobutyl-2,3-dihydrohenzo[b] [1 ,4]dioxia-6-yI)methyl)-2-fluoro-9-(2 I(isohuitylamino)ethyl)-9H-purin-6-ainine 511-6 f-((7-cyclopentyl-2,3-dibydrobenzo[b][ 1 ,4]dioxin-6-yl)methyb)-2-fluoro-9-(2 _____ isobuitylanidno)ethiyl)-9H-purin-6-amine 511-7 I-(4-(2-(6-amino-8-((7-cyclopropyl-2,3-dibhydrobenizo~b]1[ I,4]dioxin-6-yl)thio)-9H-purin-9 511-8 I 1-(4-(2-(6-ainvo-8-((7-cyclopropy]-2,3-dihydrobenzo[b[ 1,4]dioxin-6-yI)meth-vl)-2-fluoro _____I91--purin-9-yI)ethyl piperidina- I -yi)eshanone 5H:-9 1 -(4-(2-{6-amirto-2-chioro-8-((7-cyciobutyl-2,3-dihydrobezo [b][1I,4jdioxin-6-yI)methyi-911 purin-9-yI)ethyl)piperidin-i.-yI)ethano-ne 5H1-1 0 4-(2 -(6-arrdno-8 -((7-cycilobutyl-2,3 -dihydrobenzo [b] [ 1,4)]di oxin-6-yl)thio)-9H-purin-9 yl)ethyV)piperidine- I -carbalidehyde SR-il1 4-(2/-(6-ami~no-8-((7-cyclopentyl-2,3-dihyvdrobenzolb] [1,4]dioxiui-6-yl)methyh)-2-fiuoro-9H ----- ------ purin- J-yI)ethvl)piperidine-1 -carbaldehyde 511-12 34(6-amnino-8-((7I-cyclopropy.2,3 -dihydrobenzo(b] [1 ,4)dioxi'n-6-ylfthio})-9H-purin-9 ylpropy] silfamate 5H1-13 8-((7-cyclopropyI-2,3-dihydrobenzoh[I [,4]di.oxin-6-yl)rhio)-9-(2-(I 511-14 9-(3-(tert-butylanino)propyl)-8-((7t-cyclopropyl-2,3 -dihydrobenzo[b] [1,4]dioxin-6-y)thio) _____911purin-6-amine 5H1-15 2**(3-(6-arnino-8 -f7-cyclfobutyI**2,3-dihydxoberzo(b,] [1,4]dioxin-6-ylth ia}-9H-purin9 yI)pxopyl)pyrrolidine-l-sulfonami de 51H-16 3-( -(6-ami-no-8-(7-cyclopentyl-2,3-dihydrobenzo~b][1,4]dioxini-6-yhthio)-9H-purio-9 yI)e~hy1)pyrroine-1 -sulfoinamide 5H1-17 8-(7-cyclopentyi-2,3-dibydrobenzo[b][ 1,4]dioxin-6-ylthio)-9-(2-(i -(rnethylsuifony])piperidin 5-1 93 -ert-ylam -uino6-iroi--74perI2,dhyrbnobj4jion6-ri)-- WO 2011/044394 PC'F!US2OIO/051872 196 purin-6-amine S- H-19 I -(6-aruino-&-(7-cyclopentyi-2,3-dihydrobeno[b] [1,4] dioxin-6-yitbio)-9H.-purin-9-yfl-3 (iso ionlamino propan-2-ol Table 6A 6.A-1 8-((7-iodo-223-dihydrobenizotbj [1 f4joxthiin-6-yl)thio)-9-(3 -(isopropylamnino)propyl) I 9H-purin-6-armne 6A-2 8-((7-(fuxan-2-yl)-2,3-dikydrobenzo[b]j I,4]oxathiiln-6-yl)thio)-9(3 _____(i.sopropvlamino9)prqpyi)-9H-purin-6-amine 6A 3 8-((7-etbynyi-2,3-dihyclrobenzo[b[1 ,43oxathiin-6-y1)thio)-9-3 6A-4 4-(2-(6-amino-8-((7-(fhmrn -- yi)-2,3-dihydrobenzob] [1,4] oxatbiin-6-yl)ttio)-911-purin _____9-yi)erhyl)pipcaidine- .-carhaidehyde 6A-5 2-fluoro -9-(2-(isobutylairdino)ethyl)-84-(7-{pynolidiI- l-yi)-2,3 I____ dihydrob hobj ,]xthiin-6-yl) methyl)-9H-purin-6-anine 6A-6 S-((7-(azi ridin-1 -yl)-2,3-dihydrobenzc~bl[1 ,4joxathiin-6-yl)thio)-9-(2 6A7 I8-((6-(ttran-2-yl)-2,3I-dLihydrobenzo[bJ[ I ,4joxarhiin-7-yI)thio)-9-(3 I____ (isopropylarnino)propyl)-9H-purin-6-arnine 4-( soryamopopyD-9H-purin-6-amine I A9 -6-mn--(6(uan2y)2.-iyroe~ob[1 ,4]oiathiin-7-y)thio)-91-purii 10 9y)ety)piperidine- I -carbaidehvde 6A-1 2-fluoro-9-{2-(isobuty, lamio'o)ethyl)-&{((6-(pynrolidin- 1-yi)-2,3 *_____ dihydrobenzo[b][1 ,4]oxathiini-7--yl)rnethyl)-9H-purin-6-amine 6 A- I 8-(6-Xaziridin- I -yI)-2,3 -dihydrobenzo[bj [I ,4]oxarhiin-7-yl)thio)-9-(2 ______ nopentylamino)e-th 1 -9H-purin-6-arnine 6A-12 S-((7-(furan.-2 -yI)-r-nethyl-3,4-di hydro-2H-b:enzo[b]' 1,4]oxazin-6-yi)thio)-9-(2- _____(neopentyianiino)ethyl)-9JT-purin-6-amine 6A 13 8-((4-rnethyl-7-( lltprzo-3-y)-3,4-dihdro-H-benizo[hJ[1,4oxazin-6-yl)thio)-9-42 6A 14 8-((7-etbynyl-4-methyl-3,4-dibydro-2H-beno[b] [1 ,4joxazin-6-yI)thio)-9-(2 A15 (isobutylamino)ethyl)-911-pnrin-6-aanine 6-lur-8{7-15rn2-l-4rettyl-3.4-dihydro-2Hi-be-rzo[b][ 1,4]oxazin-6-yJ.)methyl) _____9-(2-(neopeptyia antoehy)-9H-purin-6-arnine 616I4-(2--(6-amnino-S-((7-(furar-2-y)-4-methy-,4-diydro-21--enzo[b] [1 ,4jthiazin-6 _____yJ.Ahg) prfl9Y-thIi9iifeI-aradhd 6A-17 18-((6-(Ibran-2-yl)-4-iethyl-3,4-dihydro-24-benzo15J[1 ,4]oxazin-7-yl)thio)-9-(3 * i (iso ci mmmci r 1y)-9H-purin-6-amine 6A-18 943'-(i.sooropylamidno)propyl)-S-(f4-medliyl-6-thiophen-2-yl)-3,4-dibhydro-2H ____ I_ henzc~b][ 1.4ioxazin-7-ylI)thio)-9H-puin-6-amie 6A-19 I 4-(2-(6-amino-A-((6-(fura-n-2-y)-4-methyl-3,4-lihydro-2H--eizb][ 1,4]oxa2in-7 ___ _yi)thio)-9Hf-puri n:9y)ethyl)piperidine-1 -carbaldebyde 6A-20 4-(2-(6-amino-8-(( 6-ethynyl-4-rnethyl-3,4-dihydro-2lkbenzo[b] [1 ,4]oxazin-7-yI)thio) ________~~ - 2! m .th2y ty pp d in ±ah d h s 6 A-2l S-((6-(azetidin-LI -yI)-4-methyi-3,4-dihydro-2H-benzo[b] [~ 1,4]oxazini-7-yl)thio)-9-(2 (____isot ______hl-1ipri--ann WO 2011/044394 PCT/US2010/051872 197 6A-22 I 8-((64ffuran-2-yi)-4-methyl-3,4-dihydro-2H-benzo[b][1 ,4]thiazin-7-yi)thio)-9-(3 (isopropylamino)propyl)-9H-purin-6-amine 6A-23 8-((6-iodochroman-7-yl)thio)-9-(3-(isopropylamino)propyl)-9H-purn-6-amine 6A-24 8-((6-(furan-2-yl)chroman.7-yl)thio)-9-(3-(isopropylamino)propyl)-9H-purin-6-anine 6A-25 8A(6-ethynylthiochroman-7-y)thio)-9-(3-(isopropylanino)propyl)-9H-purin-6-amine 6-426 4-(2-(6-anino-8-((6-(fuTan-2-y1)thiochroman-7-yl)thio)-9H-purin-9-yl)ethyl)piperidine S1-carbaldehyde 6A-27 2-fluoro-9-(2-(isobutylamino)ethyl)-8-((1-methyl-6-(pyrrolidin-1 -yl)-1.2,3,4 tetrahydroquinolin-7-yi)methyl)-9H-purin-6-amine 6A-28 4-(24-6-amino-8-((6-(furan-2-yl)-1,2,3.,4-tetrahydroquinoin-7-vl)thio)-9H-purin-9 yl)ethvl)piperidine- 1-carbaldehyde 6A-29 8-((7-iodochroman-6-yl)thio)-9-(3-(isopropylamino)propyl)-9H-puri-6-amine 6A-30 8-((7-(furan-2-yl)chroman-6-yl)thio)-9-(3-(isopropylamino)propyl)-9H-purin-6-amine 6A 31 8-((7-ethynylthiochroman-6-ylthio)-9-(3-(isopropylamino)propyl-9H-purin-6-adne 6A-32 4-(2-(6-amino-8-((7-(fu-ran-2-yl)thiochroman-6-yl)thio)-9H-purin-9-yl)ethyl)piperidine __ _ I -carbaldehyde 6A-33 2-fluoro-9-(2-(isobutylamino)ethyl)-8-((7-(pyrrolidin-1-yl)-1I,2,3,4-tetrahydroquinolin-6 yl)methyl)-9H-purin-6-amine 6A-34 4-(2-(6-amino-8-((7-(furan-2-vl)- 1 -methyl- 1,2,3.4-tetrahydroquinolin-6-yl)thio)-9H purin-9-yl)ethyl)piperidine-1-carbaldehyde 1 6A-35 2-chloro-8-((7-iodo-2,3-dihydrobenzo[b][1,4]oxathiin-6-yi)nethyl)-9-(2 (isobutylamino)ethyl)-9H-purin-6-amine 6A-36 2-chloro-8-((6-iodo-2,3-dihydrobenzo[b][1,4]oxathiin-7-y)niethyl)-9-(2 (isobutylaminto)ethy )-9H-purin-6-amine 6A-37 2-chloro-8-((6-iodochroman-7-y)metbyl)-9-(2-(isobutylamino)ethyl)-9H-purin-6-amine 6A-38 9-(3 tert-bu tylamino)propyl)-8-((6-iodochroman-7-yl)tIio)-9H-purin-6-anine 6A-39 N-(3-(6-amino-8-((6-ioduchroiman-7-yi)thio)-9H-purin-9-y)propyl)methanesulfonamide 6A-40 3-(6-amino-8-((6-iodochroman-7-yflthio)-9H-purin-9-yl)propy sulfamate 6A-41 1-(6-amino-8-((6-iodochroman-7-yl)thio)-9H-purin-9-y)-3-(isopropylamino)propan-2 ol 6A-42 9-(3-(tert-butylanino)propyl)-8-((6-ethynychroman-7- thi)-9H-purin-6-amime 6A-43 N-(3-(6-amino-8-((6-ethynylchroman-7-ylfthio)-9H-purin-9 _ yl)propyl)methanesulfonamide 6A-44 3-(6-amino-8- (6-(furan-2-yl)chroman-7-yl)thio)-9H-purin-9-y) o pyl sulfamate 6A-45 1.-(6-amino-8-((6-(5-methyloxazol-2-yl)chroman-7-yl)thio)-9H-purin-9-yl)-3 I (isopropylamino)propan-2-ol 6A-46 9-(3-(tert-butylamino)propyl)-8-((6-iodo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin 7-yl)thio)-9H-purin-6-amaine 6A-47 'N-{3-(6-amino-8-((6-iodo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)thio)-911 purin-9-yl)propyl)methanesulfonamide 6A-48 i 3-(6-amino-8-((6-iodo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-y)thio)-9 A purin-9-yl)propyl sulfamate 6A-49 -(6-amino-8(6-iodo-4-methyl-3,4-dihydo-2H-benzo[b][1,4]oxazin-7-yl)thio)-9H purin-9-yl)-3-(isopropyanino)propan-2-ol I 6A-50 9-(3-(tertt-butylamino)propyl)-84(6-ethynyl-4-methyl-3,4-dihydro-2H benzo[b][ 1.,4]oxazin-7-yI)tbio)-91H-purin-6-amine 6A-51 N-(3-(6-amino-8-((6-ethynyl-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yt)thio) A 9H-purin-9-yl)propyl)methanesulfonamide 6A-52 | 3-(6-amino-8-(6-(fuTran-2-yl)-4-miethyl-3,4-dihydro-2H-beinzo[b][1,4]oxazin-7-y)hio) WO 2011/044394 PCI!US2OIO/051872 198 19H-puin-9- I ro I suilfaniate 6A-53 1 -(6-amino--((4-me-thyl-6-(5-me-iyloxazol-2-yD)-3,4-dhydo-21-benz[J[1 ,4]oivtzin i7-y1)thio)-9HWurn-9-y)-3-(isopropylamaino)propant-2-oI 6A-554 9-(3-(ter-i-bnlylarnino)propyl)-8-((4-methyl-6-(5-nethyloxaol-2-yl)-3,4-dihydro-211 jben zofb] [I,4]oxazin-7-yIl)thio)-9H-parin-6-arnine Table 6B1 No. IName F 6B1-1 I8 -((3-iodo-5,,6,7,8-tetrahydronaphthalen-2-yl~thio)-9-(3-(isopropyanino)propyl)-9H _____purin-6-amnine amine 6B-3 8-((3-iodo-5,6,?,8-reu'rabydronaphtbhaien'2-yl)thio)-9-(2-(neopentyiamino)ethiyl)-9H-purin 6-amine 6B1-4 2-fluoro-8-ff3-iodo-5 ,6,7,8-tetrahydronaphthalen-2.-yl)mc-thyl)-9-(2-(isobutyla-mno)ethyl) _____911-purin-6-am-ine 611-S 2--chloro-8-((3-$r~an-2-yl-5,6,,8-tetTahydronaphthaen-2-l)methyl)-9-(3 6B-6 2-fluoro-8-((3-iodo-5 ,6,7,8-tetrahydronaphthalen-2-vl)methyl)-9-(3 (isopropylamno)propyl)-9H-purin-6-amine 6B1-7 8-((3-(furui-2-yl)-5 1 6,7,S-teliahvdxonaphthalen-2-ylfthio)-9-(3-(Lsopropylamiino)propyl) _______ 1--urin-6-axnine 6B1-8 8-((3-ethynyl-5 ,6,7,S-rerrahtydron-aphthalen-2-yI)thIo)-9-(3-(isopropylarntno)propy1)-9H 68-9 3 -(6-amnino-9-(3-(isopropylaniino)propyl)-9H-purin-8-yl)thio)-5 ,6,7,8 ________tetrahydron~apht haiene-2-carbonitrie4 6B1-10 C)-((3-(azevidin-I -yl)-5,6,7,8-tetrabydronaphthalen-2-yl)methy])-2-fluoro-9-(2 ________(neopentylan-iino)ethyl)-9fl-purini-6-amine 611-11 8-((3-iodo-5,6,7,8-tetrahydroniaphthaien-2-yl)thio)-9-(2-{isobutylamino)ethyl)-9H-purin-6- 1 amine 6B-=12 6-(6-a3mino-8-(3-(oxazol-2-yl)-5 ,6,'7,8-r-errahydronaphthalen-2-vthi)-9--purin-9 ________yi)hexanamide 6B1-13 1-(3-(2-{8-(3-( lH-pyrazol-3-yi)-5,6,7,8-tetrahydronaphthakn-2-yltic)-6-aTnino-9H-purn- ________9-y1)th cipridin-I -yI)ethanone 6B1-14 1 -(3-(2-(6-amino-8-(3-ethynlyl-5,6,7, S-tetrahyclronaphthalen-2-ylthio)-911-purin-9 yl)ethyI)piperidin-1 "yl)ethanone 611-15 1 -(3 -(2-(6-arninio-2-fluoro-R-((3-(5-metbylfi-iran-2-yl)-5, A7,S-tetrahydronaphhalen-2 _______yl)inethyl)-9H-purin-9-yl)ethyl piperidin-1 -yl ethanone 6B1-16 N-(2-((2-(6-amidno-8-((3-(fflran-2-yl)-5 ,6,7,8-tetrahydronaphLhalen-2-y])thioi)-9H-pu rin-9 ________ylethy1)amijjo)etyjj)methanesulfonamide 6B1-17 3 -((2-(6-arnino-8-((3 -(fizrn-2-yI)-5,6.7 1 8-tetrahvdronaphthalen-2-yl)thio)-91I1-purin-9 611-18 943 -aminouropyl)-8-((3-iodoP-5,6,7 ,8-tetrahvdronaphthaen-2yi)thi}-91-purin-6-amine 611=19 9-(3 -(isopropylam.ino)propyl)-8-((3-(oxazol-2-yl)-5,6.7,8-tetrahvdronaphthalen-2-yl)thio) _______9H-purin-6-antne 6B1-20 9-(3 -(tert-butylamiino)propyl)-8-((3-iodo-5,6,7,8-etrahydronaphthalen-2-yl)thio)-911 ________purin-6-amine 6B1-21 _I -(%-(6-amino-S-(3-(5 -methylfiiran-2-yi)-5,6,7,8-tetraydronaphthalen-2-llhio-9 11- WO 2011/044394 PCI!US2OIO/051872 199 g urna-9-vI)ethyipeaid in-i -yi)ethanone 6B1-22 1-(3-(2-(6-amino-8-(3-(oxaz.oi-2 -yi-5,6,7.8-tetrahydronaphthalen-2-ylthioi)-9H-purin-9 [y1)ethylpiperidin- .-ylfrthanone 6B1-23 8-(Q3 (dimetli-ylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)thio)-9-(2 _____ (iieopentyiaminio)etbyl)-911-purin-6-arnine retrahydronaphrhalen-2-*ylfthio)-9H-purin-6-amine 6B3-25 DZ4-52-N9 8-Q(3-iodonaphthalen-2-yl~thio)-9-(-(i.opropylamino)prpl)-91-puim-6-amine 6P,-26 R-((3-(dim-etbylam ino)naphithalen-2-yl)thio)-9-(2-(neopentylarnio)ethyl)-9H-puin-6 ami~ne 631-27 1 -(3-(2-(6-arnino-8-(3-(5-rnethylfizran-2-yl)naphthalen-2-yltliio)-9H-purin-9 yI)ethyl)piperidi-, 1-Y1 ethanone 6B-28 9-(2-{ 1-(mrethylifo~nyl)piperidin-3-yI)ethyl)-3-((3-(5-methylthiazol-2--yl)naphthalen-2 yI)tbio)-9H-puxin-6-arnine 6B-29 _S-((3<thynylnaphtlialen-2y)thi)9(34isoPTo!pylaminotpropyl)V9Hpurn4n-6 ine 63-3D 8-((3-(1H-pyrazob-3-yl)naphthalen-2-yl)thio)-9-(3-(isopropylamino)propyl)-9H-_pur-in-6 amine B1-31 1 -(6-aminn-8-((3-iodonaplithalen-2-yl)thiio)-9H-purin-9-yi)-3-(isopropylamino)propan-2 ol 61-32 5-(6-amino)-S-(3-ethyniyl-naphhalen-2-ylthio)-91{-prin-9-yIpnae-lI-sulfonamide 611-33 93(ethtltiopoy)8(3-ooa~tae--lli)9-ui--mn 6B3-34 8-{(3-(5-methyloxazoi'-2-yI)naphthale-2'-yl)thio)-9-(2.( I-(methylsulfonyl)piperidin-3 _____ yl)echyl)-9H-puri-6-ami ne] 6B1-35 2-fluoro-8-.Q3-iodonaphthalen-2-vl)methyl)-9-(2(iobutylanino)ethyl)91-puri-6-anine 611 36 .1 -(3-(2-(6-am-irot-8-(3-(aziridini-1 -yI[)naphthalen-2-yi.thio)-9H-,purin-9-yi:)ethy])piperidin-1 ____ )etbanone 63-37 6-(6-awino-S-(3-(5-methyloxazol-2-yl)-5 ,6,7I,8-tetrahydronaphthaleni-2-ylthio)-PH-purin +9-yl)hexanamide .63381 6-,-nno93-oo567-tiayrln-: e amd 6B- 39 '5 -(6-ainino-S-{3-iodo-5,6,7 ,8-tetratydironaphthal;eo,-2-ylthio)-9H-purin-9-yl)pentane- 1 __sulfonamide 611 40 1 -(3-Q-aminn-8-(3-iodo-5,6,7 ,8-tetrahydrnnaphthalen-2-yltrhio)-9H4-purin-9 _____yl)propyi)pMroldin-3-one Table 7A No. IName 7A-. S-(2-ethynyl-5-methoxyphenylthio)-9-(3-(isopr-opylanino)popyl)-9H-purin-6-amine I 7A-2 J9-(3-(isopropyiamiino)propyl)-S-(5-methoxy-2-(prop-1-ynyl)phenylthio)-9H-purin-6-atnie I 7A-4 8-(2-ethyn -5-methoxyphenylthio)-9 2-(isobutylai-nino)ethyi)-QH-purin-6-amine S yi)ethanone 7A-6 I4-(24(6-ami-no-8-(2-ethynyl-5-methoxyphenylthio)-9H-purin-9-yl)ethyl)pip-ridine- 1 ________ arbaldehyde WO 2011/044394 PCI!US2OIO/051872 200 7A-7 1 -4-(2-(t3-anino-8-(2-ethyriyi-5-methoxybenzyi)-2-ftuaoro-9H-purin-9-yl)ethyl)piperidin ________ -yl)ethanona 7A-8 4-(2-(6-axnino-8-(2-ethy-nyl-5-methoxybenzyl)-2-fluoro-91{-purin-9-yl)ethyl)piperidine-1 carbaldehyde 7A-9 I-(4-(2-(6-arino-2-chioro-8-(2-ethyniyl-5-methioxybenzyl)-9H-purin-9-yl)ethiyl)pipendin 1-y])elhanone 7A-10t 4-(2-(6-arniino-2-ohIoro-8-(2-ethyniyI-5-methoxybenzy)-9H-purin-9-y)el)piperidine- carbaideliyde 7A-1 1 N-(2-(2-(6-aniino-8-(2-ethvnyl-5-methoxyphenylthio)-98-p-urini-9 yl)eth.ylarnino)ethyl.)sulfaniide 7A-12 3-(2-(6-amnino-8-(2-ethynyl-5 -methoxyphenylhi o)-9H-purin-9-yl)ethylamino)-N hydroxyprOpanamidQ 7A-13 8--ehx--tr heiti--3-ior imnor 1-9-ur--aie 7A-14 I -(6-amino-8-(2 -ethvuyl-5-methioxyphenylhio)-9H-purin-9-yl)-3-(isopropylamino)propani 2-ol 7A-15 8-(-ethynyl-5-methoxyphenylt-hio)-9-(2-(1 -(methylsulfonyl)piperidin-3-yl)ethyl)-9purin-6-amine 7A1 N-(3-(6-amino-8-(2-ethynyl-5-mretboxypheniyithio)-9H-purin-9 yl)propyl)methanesulfonamide 7A-17 2-(3-(6-a,,if.o-8-(2-ethynyl-5-rnethoxyph eny.ithio)-9HJ-purin-9-ylpropylpyTrolidine"c I carbaid e e 7A-18 8-(2-etynyl-5-mnethoxybervi)-2-fluoro)-9-(3-(isopropylani-no)prapyl)-9H-purin-6-arnine 7A-19 1-(3-(6-antao-8-(2-ethyy1-5-.nthoxyphenythio)-YH-purin-9-yl)propy1)pyrrolidin-3-onc 7 A-209 UW3 _______8-(2ethy-5-nerohoxyphny)thi)-9-(2-(nopnylamino)ethyl)-91-purin-6-aniine_ Table 7B No. Name l7B-1 2-((6-amino-2-fluoro-9-(3-(isopropylamino)propyl)-91-purin-8-y)methy)4 mcthoxybenzonirrie 7B-2 2- 6-amino-9 (3-(isopq rpinpoy:H u Sylthio)4metoybnzonitrile 7B-3 2-(2-(6-aminn-9-(3-(isopropylarnn)propyl)-9H-purin-8-ylthio)-4 7R84 2-(2-ffE-amnino-2-fluoro-R-(2-(isobutyla-:nety)9pur-8ymthl-4 mtix henylacetonitrile lB-S -(9-2-(l-acetypjperidim.4-yI ethyI -6-ami no-9H-purin-8-yIthin -4-methox eaznitil 7B8-6 2-({6-arnitio-2-fluoro-9-(2-(i -f(=nnyipper dinA--yI)ethyl)-9H--purin-B-yI)methyl)-4 7B-7 2-((9-42-(l -acetylpiperidin-4-yi)ethyl)-6-amino-2-chloro-9H-pulin-8-yt)aiethyl)-4 meathoxybenzonirnle 7B8-8 2-(2-(,6-axnino-9-(2-(I -forrnylpiperidin-4-yI)ethyl)-9H-porin-8-ylthio)-4 methoxyhenyl)acetonitrile 7B8-9 2-(2-((9-(2-( I-acetyipiperidin--4-yI)ethyl)-6-am~xino-2-fluoro-9H-porin,-8 -yI)methyl)-4 rnqethoxyphenI)acetonin-ile 7B1-0 2-((6-aniinn-24fluoro-9-(3-(isopropylamno)propyl)-9H-purin-8-yl)mety)- WO 2011/044394 PCI!US2OIO/051872 201 713-11 N4(2-2-(&aro-8-(2-cyano-5rnethoxvphe.vlthio)-9H-puri-9 712yflethylamino)ethv-y imethanesulfonamide 712 3-(2-(6-amino-$-2-cyanao--5-methoxyphen.ylthio)-9H-purin-9-yl)ethylamino)-N hydrp~ropanamide Table 7C 7C-1 -8-(2-(fUran2-yl)-5 -rnethoxyphen ylthio)-9-(3 -(itsopropylamino)propyi)-9Hpui-G-amine 7C-2 9-(3 -(isopropylamino)propyl)-8-(5-inethoxy-2-(5-methylfuran-2-yl)phenylthio)-9H--puin * ______ -ane 7C-3 9-<3-(isopropylamiino)propyl)-8-(2-(isoxazol-4-yl)-5 -methoxyphienylthio)-9H-purin-6 * ___ ____ mifle r 7C-4 - -(2 -(5-(arninomnethyi)fiiran-2-yI)-5-inethoxyphienvthio)-9-(3-(isopropyl amino)propyl) _______9H:-purin-6-amnine 7C-5 2-loo8(-fzn2-l--~e xrw.,)9(-iouyamino)ethyi)-9H-purin-6 amine * ______armne r7C-7 L2-fluoro-9-(2-(isobutylamiino)-ethyl)-8 41%rnethoxy-2-(5 -m-ethylfluan-2&-yl)ben-zyl)-9H _______purin-6-amine4 7C8 2-fluoro-942-}isobutylaniino)ethyI)-8-(2-(isoxazo'i-4-yl)-5-methoxyben27.)-9H-puhm-6 amine 7C-10 1 -(3 -(6-amino-8-(5-methoxy-2-(5-methylfbran-2-yl)plienylthio)-93-purin-9 yl)propyL)pyrrolidin-3-one 7C-11 S-(5 -methoxy-2-(5-rnerhylffran-2-yl)phenyltbio)-9-(2-( t-(methylsulfonyl)piperidin-3 yl~ethyl)-9H-purin-6-amine 7C-1 2 5-(6-ainino-8-(5-methoxy-2-(oxazol-2-ybphenylthio)-9H-purin-9-y)pentane- ________sulfonamide 7C-13 TF-V-138 7C4-8-(2 -(ftirani-2-yl)-5-rnethoxyphenylthio)-9-(2-(neopentylamnan)ethyl)-9H-purin-6-ammne :7C-14 8-(2-(ftzran-3-yl)-5-metioxyphenyithio)-9-(2-(neopen 1Tylaino)ethy)-9 H-puri-6-ami.e 715 8-(5-methoxy-2-(5-methylfuran-2-yl)phenylthio)-9-(2-(neopentyamino)ethyl)-9H-purin-6 amine 7-7 6-(G-antino-8-(5-methox y-2-(5-methylfj'u-2--l jjeny~ii)9-ui--ihxnmd 7C-1S 8-(2'-(5-(.aininom ethyl)ftiran-2-y)-5-me-tboxyphenylthio)-9-(2-(neopentylarniuno)ehyl)-9H ________purin-6-arnine 7C-19 I -(3-('2-(6-ami~no-S&{5-methloxy-2-(oxazol-2-yl)phenylthi. o)-9H-purin-9-yl)ethiylpiperid4n _______I -yI)ethanone 7C-20 1-3{-6ain--ioo8( mtoy2(xzi2y~eny)9-wn9 ________yl)etlwl)piperi din-i -yl)ethanone 7C-21 3-(2-(6-amino-2-chloro-8-(5-meth oxy-2-(5-rnethyifuran-2-yi)benzyl)-9H-purin-9 7-2 y1)efbyl)piperidine-I -carbaldfehyde 7C2 13-2(-rnog5-methoxy-2-(5-merhylfhran-2-y)phenylthio)-9H-puin-9 _________ etb~VY IpieiinI-Iehne WO 2011/044394 PCI!US2OIO/051872 202 7C-23 1-(4-(2-(6-auiino-2-luara-8-(5-methoxy-2-(5-methyfuran-2-yl)benzyl)-Q14pudni-9 ________yI)ethyl)piperidin-1 -yI)ethanone 7C-24 143 -(6-arnino-8-(5 -methoxy-2-(thiazol-2-yl)phenylrhio)-9H-pudin-9-yI)propyl1)pyrroiidmi 3-one 7C-25 9-(3 -aminopropylD-&-(5-methoxy-2-(5-mnethyffuran-2-y Ieythio)-9H-Tufin-6-anine 7C-26 9-(3 -(isopropylarnino)pr-opyl)--845-methoxy-2-(oxazol -2-yl)phenylthio)-914-puri-6-amine 7C-2'7 1 -(4-(2-(6-amino-8-(2-(5-(am-in-omethyl)fir.an-2-ylj-5-methoxyphenylthiio)-9H-purin-9 _______yI)ethyjpipedidin-Imyl~ethanone 7C-28 i -(4-(2-(6-arnioo-8-(2-(5-(aminomnethyl)ftiran-2-yil)-5-methoxybenzyl)-2-fluoro-9H-purin 7C-29 11 4-(2-(6 -armino-S -(2-(isoxazoi-4-yD)-5-methox-ypheniyhhlio)-9H-puiii-9-y)ethyl)pperidine 1____ I1-carbaldefhyde II 7(2-31 1N-(242-(6-amioo-S-(2-}furan-2-y}-5 ,-methoxyphenyhthio)-9H--purin-9 _______ Iyl)ethylaminc)ehyl)sulfhmide 7C2-32 31-(2-(6-amino-S-(2-(f uran-2-yI)-5-mnetlioxyphenylthio,)-9H-purin-9-y)eh-ylznino)-N I____ hydroxypropanarnide I7C2-33 8-(5-ethoxy-2 -(ftiran-2-y )phenylthiuo)9-(3-(isopropylamiino)poropyl)-9H-purin-6-amine 2 : E 3 - sp .- UR ail 7C2-35 9-(3-(tcrt-butylanmino)propyl)-S-(2-(ftira-2-yi)-5-rnethoxyphenylthio)-9H-pun -6-aine tPable 7D No. Name '7D-1 9-(3-(isopropylamino proyl-S-5-methoxy-2-(ti.gphen-2-yi)phen ilthia -9Ff--urin-6-amine 7D1-2 2-fi-uoro-9-(2-(isobulamino)ethyl)-8-(5-methoxy-2-thiophen-2 -yl)benzyl)-9H-purin-6-amine 70-3l TT-VI-139 ______ 8-S-ethxy- -{hiphe-2-~phnythio)-9-(2-(neopentyaioeh1-9-H-purin-6-amine 7D-4 94-iorp~mn~rp~8( mtoy2Qipe--lpenvlho- -urio-6-aroie '7D-5 N-(3-(6-anidno-8-(5-metlioxy-2-(thiazol-Z-yl)phlenylthio)-9H-purin-9-yl)propyl)methanesulfonamide 7D-6 j-5rehx--hohn3ypeyti)9(4epnyam noJety1)-9Hprn--m 7D1-7 1 -(4-(2-(6ami'no-S -{5-mneboxy-2-4tbiophen-2-v1)phenylthio)-9Hpurin--y)ethy)pipelidin- _______ y)ethanorie 7D- 8 4-(2-(6-ai-nino-8-(5-methoxcy-2-(thiophen-2-yl)phenylthio)-9H-purin-9-yl)ethy)pipeidine- _____carbaldehyde 7D- 9 1 (4-(2-(6-amnino-2-fluoro-S-(5-methoxy-2-(thiophen-2-y])henzyl)-9H1-purin-9-yl)ethyl)piperidin-1 _____yi)Cthanone 7D-10 1 (6-amnino-8-(5-methcixy-2-(thiophen-2-yl)phenylhi)-9--puarin-9-yl)-3-(isopropylamino)propani-2 7D-11 I S-(5-methoxy-24-5-methylthi:ophen-2-ylphenylthio)-9-(2-(1 -(m-eth-yisulfonyl)piperidin-3 -yl)etkl _____9H-1purin-6-amine----- 70-12 N-(2-(2-(6-axnino-8-(5 -iethoxy-2-(tiopheri-2-yI)pheniylthio)-9H-purin-9 _____yl)etlauiino)ethyl)sulfamide 7D1-13 3-(2-(6-amino-g-(5-methoxy-2'-(thlophen-2-y1)phenvlthio)-9H-purin-9-yi)ethyamiono)-N _____hydroxypropanamnide 7D-14 2-$eiijhoen21hi--ioo--2j obaamio)ethy)-9H-puin-6-amiie 70-15 9-(3-arninopropyl)-S-(-methoxy-2-(thiophen.-2-yl)phenylthio)-914-pnrin-6-amine 7D-16 9-(3-{isopropylanio propyjj-8- 5 -rethoxy--(hiazo1-2-yjjphe~py.thio ~jj--mn WO 2011/044394 PCI!US2OIO/051872 203 Table 7E NO. Name 7E-1 9-(3-(isopropylamrino)propy9)-8-(5-methoxy-2-(1 H-pyrazol-4--yl)phenvlthio)-9H-puxin-6 amine Y7E-2 9-(3-(isopropylamino)propyi)-S}(5-methoxy-2-( iH-pyrazai-3 -yl)phenylthio)-911.-purin-6 ________amine 7E-3 2for-(2-(isobutylarnino)ethyl)-S-(5-mefloxy-2-(1Hl-pyrazol-4-yl)benzy)-9H--prin 7E-4 j2-tiuoro-9-(2-(isobuatylarino)ethyl)-S-(5-methoxy-2-(1H-pyrazol-3-ylbenzyl)-9H-purin 7E-5 l-(3-42-(6-amino-8-(5-methoxy-24(lHpyrazol-3-yl)phenylthio)-9H-purin-9 ________ ivi)erhyl~pyrolidin -I-yl)ethanone 7E-6 ITT-V4-40 I -(5-metboxy-241 H-pyrazob-3-yI)phienyfthio)-9-(2-(necp-env.ylainin-o)ethyl)-9H-purini-6 1am-ine 7E S 4-(2-(6-amino=8-(5-rnethoxy-2-{ iH-pyrazol-3=-yI)phenylhio)-9H-pourin-9 _______I yI)eth 1) i eridine-1 -carbaldeh de ______I yI)ethvl~pipecridin-1 -vbecthanone 7E-10 j 4-(2-6-amino-2 -flnoro-8-(5-methoxy-2-( 1 H-pyrazol-3-y i)benzy])-911-purin-9 ________ vl-thliperi dine-' -carbaIlehyd 7F-11I 1-(4-(2-(6-am ino-2-chloro-S-(5 -melhoxy-2 -( 1H-pyrazol-3-yI)benzyl)-9H-purin-9 ________ l~ehy~pieriin-. yl)ethanone 7E-1 2 4-(2-(6-aniino-8-(5-metboxy-2-(IH-pyrazol-4-y)phenylthio)-9H-purini-9 yI)ethyl)piperidine-] -zarbaldehyde 7E-13 I -(6-amino-8-(5-methoxy-2-( IH-pyrazol -3-yI)phenyi thio)-9-H-purin-9-yl)-3 (isopropylaminTpopan-2-ol 7E-14 N-(2-(2-(6-amino-S-(5 -methioxy-2-( 1H-pyraz&I-3-yphenylthio)-9H-purin-9 yl)ethylamino)ethyl)sulfamide 7E-1 5 3-(2-46-aniino-S-(5-methoxy-2-(1 H-pyrazol-3-yi)phenylthio)-9H-purin-9-yl)ethylamino) N-hydroxypropanamide 7E-16 S-(5-ethoxy-2-( IH-pyrazol-3-vI)phenylthio)-9-(3-(isopropylamino)propyl)-9H-piui-6 amine 7E-17 8-(5-ethoxy-2-( H-pyrazol-3-yl)benzyi)-2'C-fluoro-9-(2-(isobuyianino)ethyl)-9H-puin-6 almne 718 I 9-(3-(tert-hurylanilno)propvlI)-S-(5-methoxy-2-(iH-pyrazo-3-yiphentyliio)-9H-pmiin-6 amine 7E-19 9-(3-arninopropyl)-S-(5-r-nethoxyv-2-(1 H-pyrazol-3-yl)phenvh.-hio)-9H-purin-6-an-Ii nc 7E-20 I 8(5-mrethoxy-2-(1 H-pyrazol-3 -yl)phenylthilo)-9-(2-(l -(methylsuifonyl)piperidin-i vety-9-n-urin-&aminc 7M-21 N (3 -(6-arrina-3-(5-rnethax;v-2-('i H-pyrazoi-3-yI)phenylrhio)-91{-purin-9 ylprnpyl~methanesulfonaraide _______________________ --- FE-22 1 9-(3-(isopropylamnino)propyl)-3-(5 -merhoxy-2-(5-m ethyl-IH-pyrazol-3-yI)phenylthio> _______9H-purio-6-amiae Table V1 WO 2011/044394 PCI!US2OIO/051872 204 No. Name 7F-1 9-(3-(isoptopylain,-o)propyi.)-8-(5 -mreth-oxy-2-(1H-pyrrol-3 -yl)phenylthic9-9H ................ p..unn-6-ainen 7F-2 9-(3-(isopropylamnino)propyl)-8-(5 -methoxy-2-(1H-pyrrol-2-yl)pbeiylthio)-911 ______________purin-6-amine 7F-3 2-fluoro-9-(2-(isobutylamino)ethyl)-8-(5-oethoxy-2-(1 H-pyrrol-3-yl)benzyl) _____________9H-purin--arnine 7F-4 8-(5-methoxy-2-(i li-pyrrol-3-yl)phenylthio)-9-(2-(1 -(metbyisulfonyl)pyrrolidin ______________ -yl)ethyl)-9H-pur'in-6-amine 717-5 8-(5-metboxy-2-(1 TI-pyrroi-3-yl)pbenylihi'o)-9-(2-(neopentylamino)etyl)-91 ________purin-6-amine 7F-6 94-(isopropylamino)propyl)-8-(5-rnethoxy-2-(5 -methyl-I H-pyrrol-3 ______________yl)phenlylffiio) -9H-purin-6-amine 7F-7 i4-(3-(6-amnino--(5-methoxy-2-(iH-pyrrol-3 -yl)phenyithio)-9H-purin-9 _______________ i) to '1 ieridine- I-cabadhde 7F-9 4 2(-mno8(-ohoy2(I -pyrrol-3-yl)phenzylthio-9H-p'ain-9 1 y1)e hyi piperidin- l-yl)ethanone 717-10 I-(4=(3-(6-aniino-2'-fluoro-8-(5-methoxy-24l H-pyrroi3-.)benzylfr9H-purin-9 ______________yl)propyl)piperidin- Ilj'i)ethanone 717-11 l-(4-(2-(6-arnino-2-ch14oro-8-(5inethLoxy-2 -(I H-pynvdl-3-yl)benzyl)-9H1-pmin-9 ________________ )ethyl)piperidin- I -yi)ethanone 77-12 -N-(3-(6-antno-S-(5-methoxy-2-Q H-pyrroi-3 -yl)phenylthio)-9H-purin-9 I propyI)metbanesulfonamide 7F7-13 8-(5 -methoxy-2-(1 H-pyrrol-3 -yl)phenylthio)-9-(24-(-methylsuffonyl)piperidin _____________3-vl ethyl)%91-I-pudn-6-arnine * 7F-14 NT-(2-(2-(6-amnino-8-(5 -rnethoxy-2-( IH-pyrrol-3 -yI)phenylthio)-9H-purin-9 yl)ethylaniino)ethyl)sulfamide -7F-1.5 3-(2-(6-amnino-3-(5-methoxy-2-(IH.-pyrrol -3-yl)phenylthio)-9Hl-puxrin-9 * 7F-16 8-(5-ethoxy-2-( lH-pyrrol-3-yl)phenyltliio)-9 .{3-(isopropylamrino)propyl)-9H __________________purin-6-aini * 717-17 8-(S -ethoxy-2-( 1 H-py-rrol-3 -yl)benzyl)-2-fl.uoro-9-(2-(isobutylamino)ethyl)-9H1 ____________ prn-6-amine 7F-18 9-(3 -(terL-ht-xlamilno)proipyl) 8-(5-rnethoxy-2-(I E-pyrrol-3-yi)phonylthio)-9H ______________ pan-6-armne 7F149 9-(3-ami'nopropyl)-S-(5-methoxy-2-(i H-pyrro1-'3-yI)pher.ylthiio)-9H.purin-6= 717-20 {1-(6-amino-S-( S -rethoxy-2-( IH-pyrrol-3 -yI)phenylthio)-9H-puLrin-9-vi)-3 ___________ 0 (soporopylamino)proan-2-oI WO 2011/044394 PCT/US2010/051872 205 Table 8 Options for R. I, R is hydrogen, a C, to C. alkyl, alkenyl, alkynyl, or an alkoxyalkyl group, optionally including heteroatorns 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(O), S02, N{R 21 m), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic; substituted or unsubstituted cycloalkyl; or -B Y M1-M2-M3-M4 R m B is a linker; R 2 1 , is selected from the group consisting of hydrogen, N(R 2 )COR4,

N(R

2

)CON(R

3

)R

4 , N(R 2 )COOR, N(R2)S(O)nR, N(Rj)S(0)nN(R 3

)R

4 ; where R 2 and R 2 are independently selected from hydrogen, aliphatic or substituted aliphatic; R 4 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 -Cl-C 6 alkyl, -C 2

-C

6 alkenyl, or -Cr C6 alkynyl each containing 0, 1, 2, or3 heteroatoms selected from 0, S or N; n is 1 or 2; Mi is absent or selected from substituted or unsubstituted -Ci-C 6 alkyl, -Cr C 6 alkeny, or -CrC alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;

M

2 is absent, 0, 5, 50, 507, N(R 2 ) or CO; M. is absent, 0, 5, 50, SO2 N(Rz), CO, Cl-C 6 alkyl, C-C6 alkeny, C 2

-C

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

M

4 is hydrogen, NR 5

R

6 , CF 3 , 0114, halogen, substituted or unsubstituted -Cr C 6 alkyl, -C 2

-C

6 alkenyl, or -C Csalkynyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl or substituted heteroaryl; where Rs and R 6 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-M 2 Mr

M

4 cannot be both hydrogen.

WO 2011/044394 PCT/US2010/051872 206 Table 8 cont'd 3 R is N 32 R wherein R3' is (a) hydro; (b) CrGq 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 3 3 wherein R 3 is amino; (c) -C(=)R, wherein R 3 is selected from the group consisting of: (1) hydro, (2) C-CIO (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, (8) hydroxyl, (C) thiol, (D) cyano, (E) CrC, haloalkyl (e.g., trifluoromethyl), (F) C, Cs aikoxy (e.g., methoxy) optionally substituted with CrCS alkoxy (e.g., methoxy), (G) C-amido, (H) N-amido, (I) sulfonyl, (J) -N(R )(R ) wherein R" and R" are independently hydro, C- 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 C;-C6 haloalkyl (e.g., trifluoromethyl), and (4) C-CG alkoxy optionally substituted with 1, 2, 3, 4, or 5 substituents each independently chosen from halo, hydroxyl, amino, cyano, and CrCs haloalkyl (e.g., trifluoromethyl), (f) heterocycle or heterocyclylalkyl, optionally substituted with 1, 2, 3, 4, or 5 substituents independently chosen from halo, hydroxyl, amino, cyano, trihalomethyl, and CrC 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 CrC alkyl); (g) sulfonyl; and (h) optionally substituted heteroa ryl Table 8, cont'd 4. R is -R 4 -R 5 , wherein WO 2011/044394 PCT/US2010/051872 207 RF is -(CH4,- wherein n=0-3, -C{O), -C(S), -SO2 or -SO 2 N-; and R 5 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 alkenyl, lower alkynyl, lower aryl, lower alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyI, perhaloalkyl, perhaloalkyloxy, perhaloacyl, -NJ, -SRa, -o R -CN, -C0 2 R NQ 2 , or -N Rs 8 Rs'

R

5 5 is hydrogen, lower alky], lower aryl, or -C(0) R t Re is lower alkyl, lower aryl, lower heteroaryl, -N R5o R5 1 0 or -OR5;

R

51 0 is independently hydrogen or lower alkyl; and R 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 ailkoxyalkyl, alkylaminoalkyl, alkykarbonylainnoalkyi, alkylcarbonyoxylalkyl, optionally substituted heterocyclic, hydroxyalkyl, haloalkyl, perhaloalkyl, C(O)R , S(O) 2 R 2 , C(O)NHR6 2 , and C(O)OR ; where R" is 6. R is H, SR-, SO SOR :, OR- 1 , COOR, 1 , CONR-,R 2 , -CN, C1.6 alkyl, C2, alkenyl, C2 alkynyl, -R7AORi-, -R~ANRah, -PR N y, -RSRm, --RmSO~e or -RASO2R , cycloalkyl, heteroalkyl, heterocycioalky, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl. heteroarylaikyl, NR 71

R

2 ,

--OSO

2 N(R7c)2, --N(Rc)SO2OH, -N(Rjc)S0R7c, --R7AOSO 2 N(R7c)2, or -R-AN(c)OSOc;

R

1 and R 2 are independently selected from the group consisting of H, COORM, CON(R 7 c)2 CA alkyl, C6 alkenyl, C 2

.

6 alkynyl, --RAOR7B--, --RINRa, --R7ANR71R-Ra, --RfSR, -R 7 ASORI or -R7ASO2Rm cycloalkyl, beteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryi, arylalkyl, alkylheteroaryl, and heteroarylalkyl; each R7A is independently C 16 alkyl, C2- alkenyl, C 2

-

6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, alkylheteroarytalkyl, or heteroarylalkyl; and each Rma is independently H4, CIA alkyl, C2.6 alkenyl, C2.6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, --SO 2 OH, --SO2N(R7A)2, --SO2NHRA or -SO 2 NH2; and each R.sub.C is independently H, C1.6 alkyl, C2e alkenyl, C2.. alkynyl, 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), SO, N(Rs)., C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic; substituted or unsubstituted cycloalkyl; where Rg8 is hydrogen, acyl, aliphatic or substituted aliphatic. 7B. R is -Ml -M2-M3-M4, wherein Mi is absent, Cr-CE alkyl. C-C6 alkenyl, O_-C6 alkynyl, aryl or heteroaryl;

M

2 is absent, 0, S, SO, S02, N(R 8 ), or C=0;

M

3 is absent, C=0, 0, S, SO, 802 or N(Rs); and M4 is hydrogen, halogen, CN, N, hydroxy, substituted hydroxy, amino, substituted amino, CF 3 , C-C alkyl, Cr-C alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl.

Claims

1. A compound of the formula: NR wherein (a) each of Zi, Z 2 and Z 3 is 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 which is F, Cl, or I, or cyano and R is suitably a primary amino alkyl, a secondary or tertiary alkyl-amino-alkyl, a trialkylammonioalkyl group, 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 7 1, -S(O)R 7 i, -SO 2 R 7 1, -OR 7 1, -COOR 7 i, -CONR 7 1R 72 , -CN, R7AOR7B, -R7ANR7B, -R7ANR71R7B, -R7ASR7B, -R7AS(O)R7B, -R7ASO2R7B, NR 7 1R 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 -R7AN(R7c)OS02R7c, wherein each R 7 i 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, - 209 R7AS(O)R7B, -R7ASO2R7B, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, and heteroarylalkyl, each R7A is independently Ci 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.

2. A compound according to claim 1, wherein X 2 is halogen which is F, Cl, or I,.

3. A compound according to claim 2, wherein X 2 is iodine.

4. A compound according to claim 3, 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 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- 210

6-amine. 5. A compound according to claim 1, wherein X 2 is heteroaryl. 6. A compound according to claim 5, wherein X 2 is pyrazolyl.

7. A compound according to claim 6, 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-(lH-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-(lH-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-(lH-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-iH-pyrazol-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6 yl)thio)-9H-purin-6-amine; 8-((7-(5-methyl-iH-pyrazol-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin- 6 yl)thio)-9-(2-(neopentylamino)ethyl)-9H-purin-6-amine; 1-(8-((7-(lH-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 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-(lH-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-(lH-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-(lH-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-(lH-pyrazol-3-yl)- 2,3- 211 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.

8. A compound according to claim 5, wherein X 2 is furanyl.

9. A compound according to claim 8, 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-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- 212 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 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.

10. A compound according to claim 5, wherein X 2 is oxazolyl.

11. A compound according to claim 10, 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- 213 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)-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.

12. A compound according to claim 1, wherein X 2 is alkynyl.

13. A compound according to claim 12, 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- 214 (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 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- 215 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.

14. A compound according to claim 1, wherein the compound is 8-((7-(furan-2-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-(3-(isopropylamino)propyl)-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, 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, 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, or 9-(3-(isopropylamino )propyl)-8-((7-(oxazol-2-yl)-2,3-dihydrobenzo [b] [1,4] dioxin-6 yl)thio)-9H-purin-6-amine.

15. A compound according to claim 9, wherein the compound is 8-(2-(furan-2-yl)-5 methoxyphenylthio)-9-(2-(neopentylamino)ethyl)-9H-purin-6-amine, 8-(5-methoxy-2-(thiophen 2-yl)phenylthio)-9-(2-(neopentylamino)ethyl)-9H-purin-6-amine, 8-(5-methoxy-2-(1H-pyrazol-3 yl)phenylthio)-9-(2-(neopentylamino)ethyl)-9H-purin-6-amine, or 8-((2-ethynyl-5 methoxyphenyl)thio)-9-(2-(neopentylamino)ethyl)-9H-purin-6-amine.

16. A compound according to any one of claims 1-3, 5-6, 8, 10, and 12, wherein R is secondary or tertiary alkyl-amino-alkyl.

17. A compound according to any one of claims 1-3, 5-6, 8, 10, and 12, 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. 216

18. A compound according to claim 17, wherein R is 3-(isopropyl-amino)propyl, 2 (isobutyl-amino)ethyl, or 2-(neopentyl-amino)ethyl.

19. A compound according to claim 17 or 18, wherein Y is S, X4 is H, and X2 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.

20. A compound according to claim 17 or 18, wherein Y is S, X4 is H, and X2 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.

21. Use of a compound in accordance with any one of claims 1-20 in formulating a pharmaceutical composition for the inhibition of Hsp90.

22. Use of a compound in accordance with any one of claims 1-20 in formulating a pharmaceutical composition for the treatment of cancer or neurodegenerative disease.

23. A method of treating cancer or neurodegenerative disease comprising administering a therapeutically effective amount of a compound in accordance with any one of claims 1-20.

24. A pharmaceutical composition comprising a compound according to any one of claims 1-20.

25. A compound according to claim 1, substantially as hereinbefore described, with reference to any one of the examples.