AU2013204109A1

AU2013204109A1 - Purine derivatives useful as hsp90 inhibitors

Info

Publication number: AU2013204109A1
Application number: AU2013204109A
Authority: AU
Inventors: Gabriela Chiosis; Weilin Sun; Tony Taldone
Original assignee: Sloan Kettering Institute for Cancer Research
Current assignee: Memorial Sloan Kettering Cancer Center
Priority date: 2009-10-07
Filing date: 2013-04-11
Publication date: 2013-05-02
Anticipated expiration: 2030-10-07
Also published as: AU2013204882B2; AU2013204891B2; AU2013204899B2; AU2013204109B2; AU2013204891A1; AU2013204882A1; AU2013204899A1

Abstract

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

Description

P/00/001 Regulation 3.2 AUSTRALIA Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Invention title: PURINE DERIVATIVES USEFUL AS HSP90 INHIBITORS The following statement is a full description of this invention, including the best method of performing it known to us: la PURINE DERIVATIVES USEFUL AS HSP90 INHIBITORS Statement of Related Cases This application is a divisional of Australian patent application no. 2010303343, the entire disclosure of which is incorporated herein by reference. Background of the Invention This application relates to compounds that inhibit heat shock protein 90 (Hsp90). The Hsp90 family of proteins has four recognized members in mammalian cells: Hsp90 a and P, Grp94 and Trap-1. Hsp90 a and P exist in the cytosol and the nucleus in association with a number of other proteins. Hsp90 in its various forms is the most abundant cellular chaperone, and has been shown in experimental systems to be required for ATP- dependent refolding of denatured or "unfolded" proteins. It has therefore been proposed to function as part of the cellular defense against stress. When cells are exposed to heat or other environmental stresses, the aggregation of unfolded proteins is prevented by pathways that catalyze their refolding or degradation. This process depends on the association of the unfolded protein in an ordered fashion with multiple chaperones (Hsp 60, 90 and 70 and p23), forming a "refoldosome" and ultimately the ATP-dependent release of the chaperones from the refolded protein. Hsp90 may also play a role in maintaining the stability and function of mutated proteins. It seems to be required for expression of mutated p53 and v-src to a much greater extent than for their wild-type counterparts. It has been suggested that this occurs as a result of Hsp90-mediated suppression of the phenotypes of mutations that lead to protein unfolding. Hsp90 is also necessary to the conformational maturation of several key proteins involved in the growth response of the cell to extracellular factors. These include the steroid receptors as well as certain transmembrane kinases (i.e., Raf serine kinase, v-src and Her2). The mechanism whereby Hsp90 affects these proteins is not fully understood, but appears to be similar to its role in protein refolding. In the case of the progesterone receptor, it has been shown that binding and release of Hsp90 from the receptor occurs in a cyclic fashion in concert with release of other chaperones and immunophilins and is required for high affinity WO 2011/044394 PCT/US2010/051872 2 binding of the steroid to the receptor. Thus, Hsp90 could function as a physiologic regulator of signaling pathways, even in the absence of stress. Hsp90 has been shown to be overexpressed in multiple tumor types and as a function of oncogenic transformation. Whether it plays a necessary role in maintaining transformation is unknown, but it could have at least three functions in this regard. Cancer cells grow in an environment of hypoxia, low pH and low nutrient concentration. They also rapidly adapt to or are selected to become resistant to radiation and cytotoxic chemotherapeutic agents. Thus, the general role of Hsp90 in maintaining the stability of proteins under stress may be necessary for cell viability under these conditions. Secondly, cancer cells harbor mutated oncogenic proteins. Some of these are gain-of-function mutations which are necessary for the transformed phenotype. Hsp90 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 Z, -,

Z

1 " 0 -X 5y XA Z ,Xc

X

4 A Z 2 N ' 2 N 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 ZN z 2 N R Xc Xb (IC) wherein ZI, Z2, 73 are selected from C and N. While these compounds are generally active as inhibitors of Hsp90, the level of activity is extremely variable with measured values for

EC

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

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

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

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

X

4 and R is identified as an aryl group, an atom of the aryl ring is bound directly to an atom of the central structure. An aryloxy substituent is an aryl group connected to the central structure through an oxygen atom. The aryl group may include any of the substituents mentioned above for an alkyl group, and in addition an aryl group may include an alkyl, alkenyl or alkynyl group. All references to aryl groups in the specification and claims hereof encompass both substituted and unsubstituted aryl groups unless the context is clearly to the contrary. "Amino" group refers to any group which consists of a nitrogen attached by single bonds to carbon or hydrogen atoms. In certain instances, the nitrogen of the amino group is directly bound to the central structure. In other instances, an amino group may be a subtituent on or within a group, with the nitrogen of the amino group being attached to the central structure through one or more intervening atoms. Examples of amino groups include NI2, alkylamino, alkenylamino groups and N-containing non-aromatic heterocyclic moiety (i.e., cyclic amines). Amino groups may be substituted or unsubstituted. All references to amino groups in the specification and claims hereof encompass substituted and unsubstituted amino groups unless the context is clearly to the contrary. "Halogen " group refers to fluorine, chlorine, bromine or iodine.

WO 2011/044394 PCT/US2010/051872 7 "Heterocyclic" group refers to a moiety containing at least one atom of carbon, and at least one atom of an element other than carbon, such as sulfur, oxygen or nitrogen within a ring structure. These heterocyclic groups may be either aromatic rings or saturated and unsaturated non-aromatic rings. Some examples are given in Fig. 2. Heterocylic groups may be substituted or unsubstituted. All references to heterocyclic groups in the specification and claims encompass substituted and unsubstituted heterocyclic groups unless the context is clearly to the contrary. In the compounds of the invention, all of the atoms have sufficient hydrogen or non hydrogen substituents to satisfy valence, or the compound includes a pharmaceutically acceptable counterion, for example in the case of a quaternary amine. In the structures set forth below examples are provided in which all of Zl, Z2 and Z3 are nitrogen. These examples are intended as exemplary, and are not intended to exclude options in which one or more of Z1, Z2 and Z3 is carbon. In particular, corresponding compositions in which Z2 or Z3 is carbon are considered to be within the scope of this disclosure. A. Structures of formula 1A in which Xa or Xb is 0 In accordance with a first embodiment of the invention, the compounds have general formula 1A, in which one of Xa or Xb is 0, and Xc and the other of Xa and Xb is CH 2 Thus, the compounds of this embodiment may be represented by the general formula

NH

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

X

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

X

2 and R are in combinations as discussed below. A-I. In some embodiments of the invention, X 2 is halogen. In these embodiments, R is suitably a primary aminoalkyl, a secondary or tertiary alkyl-anino-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-(1H-imidazoyl) propyl. Specific examples of compounds in accordance with this embodiment of the invention are listed in Tables 1A and 1B (Compounds lA-I to 1A-4, 1A-6, 1A-I1, 1A-18 to 1A-28, 1A-30, 1A-31, IA-49, lB-1 to 1B-5, 1B-18, 1B-23 to 1B-25, IB-29 to 1B-32, 1B-34,1B-35, 1B-37, 1B-49, 1B-52 1B-56 and1B-57). As shown, in prefered embodiments of formula (2), X 4 is H, chlorine or fluorine. In a particular prefered embodiment of formula (2), Y is S, X 4 is H, X 2 is I. In a particular prefered embodiment of formula (2), Y is CH 2 , X 4 is Cl, X 2 is I. In a particular preferred embodiment of formula (2), Y is CH 2 , X 4 is F, X 2 is I. In a particular prefered embodiment of formula (2), Y is S, X 4 is F, X 2 is I. Tests were nn on compounds in accordance with the first embodiment of the invention, and the EC50 for Hsp90 binding in JNPL3 brain cell lysate and SKBr3 cell lysate was assessed. The results are summarized in Table 2A. While all of the compounds had desirable low EC 50 values, both compounds tested in which Xb is 0 were superior to the related compound in which Xa is 0. In addition, compound 1B-1 was superior to an otherwise identical compound in which both Xa and Xb are 0 (PU-HZ150 disclosed in US WO 2011/044394 PCT/US2010/051872 9 12/307,063) which has an EC5o of 12-14.4 nM and compound 1B-2 was superior to an otherwise identical molecule in which both Xa and Xb are 0 (PU-H71 disclosed in US 11/814,506) which has an EC 50 of 30.8-54 nM in the same experimental system. Animal Studies. Four- to 6-week-old nu/nu athymic female mice were obtained from Taconic Farms. Experiments were carried out under an Institutional Animal Care and Use Committee approved protocol, and institutional guidelines for the proper and humane use of animals in research were followed. Before administration, a solution of I B-1-HCI was formulated in PBS (pH 7.4). All mice received Augmentin (amoxicillin/clavulanate potassium; SmithKline Beecham) in their drinking water while on therapy. Mice were killed by CO 2 euthanasia. Mice bearing MDA-MB-468 tumors (n=5) reaching a volume of 100-150 mmn3 were treated i.p. (i.p.) using 1B-1-HCI at 50 mg/kg 3 x week or vehicle. Tumor volume was determined by measurement with Vernier calipers, and tumor volume was calculated as the product of its length x width 2 xO.4. Tumor volume was expressed on indicated days as the median tumor volume ± SD indicated for groups of mice. The average tumor volumes are summarized in Fig. 3. As shown, in the 35 days of the experiment the average tumor volume in the control mice increased by about a factor of 3X, while the tumor size in the mice treated with 1B-1-HC1 decreased. Table 2B shows measured values for EC 50 in JNPL3 brain cell lysates for compounds 1B-3, 1B4 and 1B-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 50 in JNPL3 brain cell lysates for compound 1B-24 in accordance with this embodiment of the invention which incorporates a hydrogen as X 4 and in which Y is S. Desirably low values of ECso were observed. A-II. In some embodiments of the invention, X 2 is an aryl group. In these embodiments, R may be any of the groups disclosed as a substituent at the 9-position nitrogen in this application, or in the various patents and patent applications cited herein. Table 8 provides a summary of the R groups from these patents and applications.

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

X-(CH

2

-N-(CH

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

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

WO 2011/044394 PCT/US2010/051872 12 In particular embodiments of formula (2), Y is CH 2 , 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 , 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, X4 is H, X 2 is 2-thiazolyl, 5-methyl 2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is CH 2 , X4 is Cl, X 2 is 2-thiazolyl, 5 methyl-2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is CH 2 , X4 is F, 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 we listed in Tables 1A and lB (Compounds IA-5, 1A-7, IA-12, 1A-13, lA-15 to 1A-17, 1A 36, 1A-37, IA-42, 1A-45 to 1A-48, IA-50 to IA-52, 1B-6, IB-8, 1B-12, IB-14, lB-15, 1B 17, 1B-26, 1B-27, 1B-33, 1B-42 to 1B44, IB-46, lB-50, IB-51, 1B-53 to 1B-55). As shown, in preferred embodiments of formula (2) in which X 2 is an aryl group, X4 is H, chlorine or fluorine. Table 2C shows measured values for EC 50 in JNPL3 brain cell lysates for compounds 1B-26 and 1B-27 in accordance with this embodiment of the invention which incorporates a hydrogen as X4 and in which Y is S. Desirably low values of 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-(1IH-imidazoyl) propyl. In embodiments of formula (2) within this group, R has the formula: site of 9N-atachnent N'R1NRI 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 1 X-(CH2)r-N-(CH2)-N-S-NH 2 It 0 0 x-I(CH2)n-O-S-NH2 0 where m= 2-3 and n= 1-6. In embodiments within this group, R has the formula WO 2011/044394 PCT/US2010/051872 14 site of 9N-attachnent H 0 X-(CH2-N-(CH2)n 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 1B (Compounds 1A-8, IA-14, IA-29, 1A-32 to 1A-35, 1B-10, 1B-13, 1B-16, 1B-19, 1B-28, 1B-36, 1B-38 to 1B-41, 1B-45 IB-47 and 1B-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 EC5o in JNPL3 brain cell lysates for compound 1B-28 in accordance with this embodiment of the invention which incorporates a hydrogen as

X

4 and in which Y is S. A desirably low value of EC5o 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-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, WO 2011/044394 PCT/US2010/051872 15 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl, and 3-(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, X 4 is F, X 2 is CN. Specific examples of compounds in accordance with this embodiment of the invention are listed in Table IA and 1B (Compounds 1A-9, 1B-11 and 1B-20). A-V. In some embodiments of the invention, X 2 is an amino group. In these embodiments, R may be any of the groups disclosed as a substituent at the 9-position nitrogen in this application, or in the various patents and patent applications cited herein. See Table 8. In some embodiments within this group, R includes a heteroatom, such as nitrogen, oxygen or sulfur. In some embodiments, the heteroatom is nitrogen. In some of these embodiments, R is a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl . Specific R groups include without limitation 2-(methyl, t butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2 (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl, and 3-(IH-imidazoyl) propyl. In embodiments of formula (2) within this group, R has the formula: WO 2011/044394 PCT/US2010/051872 16 site of 9N-attachnrent NR1 NR 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 0 X--(CH2)mr-N-(CH2)-N-S-NH2 0 0 X-(CH2)n-O-S-NH 2 0 where m= 2-3 and n= 1-6. In embodiments within this group, R has the formula site of 9N-attachnrent H 0 X-(CH2)my-N-(CH2)n H O HN-OH. where m 2-3 and n= 1-6. In a particular preferred embodiment of formula (2), Y is S, X 4 is H, 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 , X 4 is F, X2 is dimethylamino In a particular preferred embodiment of formula (2), Y is S, X 4 is F, X 2 is dimethylamino.

WO 2011/044394 PCT/US2010/051872 17 In a particular preferred embodiment of formula (2), Y is S, X 4 is H, X 2 is aziridino. In a particular preferred embodiment of formula (2), Y is CH 2 , X 4 is Cl, X2 is aziridino. In a particular preferred embodiment of formula (2), Y is CH 2 , X 4 is F, X 2 is aziridino. In a particular preferred embodiment of formula (2), Y is S, X 4 is F, X 2 is aziridino. Specific examples of compounds in accordance with this embodiment of the invention are listed in Tables IA and lB (Compounds lA-10, 1A-38 to 1A-41, 1A-43, IA-44, 1B-7, 1B-21 and 1B-48). A-VI. In some embodiments of the invention, X 2 is a cycloalkyl or a cycloalkenyl. In these embodiments, R may be any of the groups disclosed as a substituent at the 9-position nitrogen in this application, or in the various patents and patent applications cited herein. See Table 8. In some embodiments within this group, R includes a heteroatom, such as nitrogen, oxygen or sulfur. In some embodiments, the heteroatom is nitrogen, In some of these embodiments, R is a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2 (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl, and 3-(lfH-imidazoyl) propyl. In embodiments of formula (2) within this group, R has the formula: WO 2011/044394 PCT/US2010/051872 18 site of 9N-aftachnmnt X "'N , R 1 N ,,, OR 1 where R, is selected from COH, COMe, COEt, COnPr, COiPr, SO 2 Me, CH 2 OX where X can be H or oxygen, nitrogen, sulphur or halogen containing alkyl of linear, branched or cyclic nature. In embodiments of the invention within this group, R has the formula site of 9N-attachment H H 0 X-(CH2m-N-(CH 2 )n-N-S-NH 2 0 0 X-(CH2)n-O-S-NH 2 0 where m= 2-3 and n= 1-6. In embodiments within this group, R has the formula site of 9N-atiachnent H 0 X-(CH2X9-N-(CH2)n HN-OH where m= 2-3 and n= 1-6. In specific embodiments, X 2 is a cycloalkyl with one ring. In specific embodiments, X 2 is a cyclopropane, a cyclobutane or a cyclopentane. In particular embodiments of formula (2), Y is S, X 4 is H, X 2 is cyclopentyl. In particular embodiments of formula (2), Y is CH 2 , X4 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 1B (Compounds IB-9, and 1 B-22) although the embodiment is not limited to the option in which Xb is 0, and includes compounds in which Xa is 0. B. Structures of formula 1A in which Xa or Xb is S In accordance with a second embodiment of the invention, the compounds have general formula IA, in which one of Xa or Xb is S, and Xc and the other of Xa and Xb is

CH

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

NH

2 NN N \Xa Xb R (2) wherein: one of Xa and Xb is S and the other is -CH 2 -; Y is -CH 2 - or -S-, X4 is hydrogen or halogen; and

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, 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-(IH-imidazoyl) propyl. In embodiments of formula (2) within this group, R has the formula: site of 9N-attachNent where R, is selected from COH, COMe, COEt, COnPr, COi~r, SO2Me, CH2OX where X can be H or oxygen, nitrogen, sulphur or halogen containing alkyl of linear, branched or cyclic nature. In embodiments of the invention within this group, R has the formula site of 9N-attachment H H0 X-(CH2r-N-(CH-N-S NH 2 0 0

X-(CH

2 )n-O-S-NH 2 0 where m2-3 and n= 1-6. In embodiments within this group, R has the formula WO 2011/044394 PCT/US2010/051872 21 site of 9N-attachnent H0 X-(CF O-N(CH2)n HN-OH where m= 2-3 and n= 1-6. In embodiments of formula (2) in which Xa or Xb is S, X 2 may be any group shown to be attached to the same position as X 2 in any of the compounds disclosed herein or in the various patents and patent applications cited above. Specifically, X 2 may be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, saturated or unsaturated heterocycle, aryl, halogen, aryloxy, alkoxy, halogenated alkoxy, alkenyloxy, hydroxyalkyl, amino, alkylamino, dialkylamino, acylamino, carbamyl, amido, dialkylamido, alkylamido, alkylsulfonamido, sulfonamido, tribalocarbon, -thioalkyl, S0 2 -alkyl, -COO-alkyl,- COalkyl, OH, NO 2 , CN or alkyl-CN, or part of a ring formed by R; In particular embodiments of the invention, X 2 is halogen, and R is an (alkylamino) alkyl or (dialkylamino) alkyl. In particular embodiments, X 2 is halogen and R is 2-(methyl, t-butyl- amino) ethyl, 2 (methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2 (ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2 (isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino) propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl, or 3-(hydroxyethyl, isopropyl amino) propyl. In some embodiments of the invention, X 2 is an aryl group. In particular embodiments, X 2 is aryl and R is 2-(methyl, t-butyl- amino) ethyl, 2 (methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2 (ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2 (isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino) propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl, or 3-(hydroxyethyl, isopropyl amino) propyl.

WO 2011/044394 PCT/US2010/051872 22 -4 In some embodiments of the invention, X 2 is a heteroaryl group. In some embodiments, X 2 is a heteroaryl group and R is 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl, or 3-(hydroxyethyl, isopropyl amino) propyl. In particular embodiments, X 2 is 2- or 3-furan and R is 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl, or 3-(hydroxyethyl, isopropyl amino) propyl. In particular embodiments, X 2 is 2- or 3-thiophene and R is 2-(methyl, t-butyl amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl, or 3-(hydroxyethyl, isopropyl amino) propyl. In particular embodiments, X 2 is 3-pyrazolyl and R is 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, WO 2011/044394 PCT/US2010/051872 23 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl, or 3-(hydroxyethyl, isopropyl amino) propyl. In some embodiments of the invention, X 2 is an alkynyl group. In some embodiments of the invention, X2 is an alkynyl group, and R is 2-(methyl, t butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2 (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl, or 3-(hydroxyethyl, isopropyl amino) propyl. In particular embodiments of the invention, X 2 is acetylene, and R is 2-(methyl, t butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2 (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl, or 3-(hydroxyethyl, isopropyl amino) propyl. In some embodiments of the invention, X 2 is CN. In particular embodiments of the invention, X 2 is CN, and R is 2-(methyl, t-butyl amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (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- WO 2011/044394 PCTIUS2010/051872 24 amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3- (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl, or 3-(hydroxyethyl, isopropyl amino) propyl. In particular embodiments of the invention, X 2 is dimethyl amine, azetidino or aziridino, and R is 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3 (neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3 (isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2 (hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N morpholino) propyl, or 3-(hydroxyethyl, isopropyl amino) propyl. Specific examples of compounds in accordance with this embodiment 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 -CH 2 - or -S-;

X

4 is hydrogen or halogen; and

X

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

X

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

WO 2011/044394 PCT/US2010/051872 25 In some embodiments, R is suitably an optionally substituted primary alkyl-amino, an optionally substituted secondary or tertiary alkyl-amino-alkyl, alkyl-aryl, or an alkyl nonaromatic heterocycle, with the proviso that R is not a piperidino moiety. In sodie embodiments, the heteroatom is nitrogen. In some of these embodiments, R is a primary, secondary or tertiary alkyl-amino-alkyl, alkyl-aryl, or an alkyl-nonaromatic heterocycle, with the proviso that R does not include a piperidino moiety. Specific R groups include without limitation 2 -(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2 (hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3 (hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2-(cyclopropylmethyl amino) ethyl, 2 (methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl, and 3-(lH-imidazoyl) propyl. In embodiments of the invention within this group, R has the formula site of 9N-attachment H H0

X-(CH

2 )mN-(CH 2 )n-N--NH 2 *0 0 11

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 0 X-(CH Xyn-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 1E-4, 1E-6, 1E-18, IE-21, 1E-23 to 1E-26, 1E 35, 1E-38, 1E-39, lE-42 to IE-48, IE-68 to IE-76). As shown, inpreferred embodiments of formula (2), X 4 is H, chlorine or fluorine. In a particular preferred embodiment of formula (2), Y is S, X 4 is H, X 2 is I. In a particular preferred embodiment of formula (2), Y is CH 2 , X 4 is Cl, X 2 is I. In a particular preferred embodiment of formula (2), Y is CH 2 , X 4 is F, X 2 is I. In a particular preferred embodiment of formula (2), Y is S, X 4 is F, X 2 is I. Table 2E shows measured values for EC 5 0 in JNPL3 brain and SKBr3 cell lysates for compounds IE-2, IE21 and 1E-23 in accordance with this embodiment of the invention which incorporates a hydrogen as X 4 and in which Y is S. Desirably low values of EC5o were observed. C-II. In some embodiments of the invention, X 2 is an aryl group. In these embodiments, R may be any of the groups disclosed as a substituent at the 9-position nitrogen in this application, or in the various patents and patent applications cited herein. 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, cyclopropyhnethyl 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-(1H-imidazoyl) propyl. In embodiments of formula (2) within this group, R has the formula: site of 9N-attachrent X N, N,,, R1 R, where Ri is selected from COH, COMe, COEt, COnPr, COiNr, SO 2 Me, CH20X where X can be H or oxygen, nitrogen, sulphur or halogen containing alkyl of linear, branched or cyclic nature. In embodiments of the invention within this group, R has the formula site of 9N-attachment H H X-(CH2),-N-(CH2)n-N-S-NH 2 0 0 X-(CH2)n-O-S-NH 2 0 where m= 2-3 and n= 1-6. In embodiments within this group, R has the formula site of 9N-attachnent H0 X-(CHy-N-(CH2)nHNO HNt-OH where m= 2-3 and n= 1-6. In specific embodiments, X 2 is an aromatic heterocycle. In specific embodiments, X 2 is a furan, thiophene, pyrazole, imidazole, pyrrole, oxazole and thiazole. In specific embodiments of the X2 is a furan, thiophene, pyrazole, oxazole and thiazole or imidazole.

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

WO 2011/044394 PCT/US2010/051872 29 In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X 2 is 2-thiazolyl, 5 methyl-2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is CH 2 , X 4 is F, X 2 is 2-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 iE (Compounds 1E-5, 1E-7, IE-1I to 1E-13, IE-15 to IE-17, 1E-27, iE 29 to 1E-33, 1E-36, 1E-37, 1E-41, 1E-59 to 1E-76, 1E-84 and 1E-85). As shown, in preferred embodiments of formula (2) in which X 2 is an aryl group, X 4 is H, chlorine or fluorine. C-II. 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, X 2 is acetylene. In particular embodiments of formula (2), Y is S, X 4 is H, X 2 is acetylene. In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X 2 is acetylene. In particular embodiments of formula (2), Y is CH 2 , X 4 is F, X 2 is acetylene. In particular embodiments of formula (2), Y is S, X 4 is F, X 2 is acetylene. In these particular embodiments, R may be any one of the types of groups described above. Specific examples of compounds in accordance with this embodiment of the invention are listed in Tables 1E (Compounds 1E-8, 1E-14, 1E-19. 1E-20, 1E-22, 1E-40, IE-49 to 1E 58 and 1E-77 to 1E-82). As shown, in preferred embodiments of formula (2) in which X 2 is an alkynyl group, X 4 is H, chlorine-or fluorine. Table 2F shows a measured value for EC5o 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 EC50 was observed.

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

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

CH

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

NH

2 NSN X K YXa ~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-, 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 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 L4 bound to a nitrogen in the heterocyclic group. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3 (ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3 (allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2-(cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, and 3-(1H-imidazoyl) propyl. In some embodiments of the invention, X 2 is an aryl group. In particular embodiments, X 2 is aryl and R is 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-firan 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 L4 propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl or 3-(hydroxyethyl, isopropyl amino) propyl. In particular embodiments, X 2 is 2- or 3-thiophene and R is 2-(methyl, t-butyl amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl or 3-(hydroxyethyl, isopropyl amino) propyl. In particular embodiments, X 2 is 3-pyrazolyl and R is 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl, or 3-(hydroxyethyl, isopropyl amino) propyl. In some embodiments of the invention, X 2 is an alkynyl group. In some embodiments of the invention, X 2 is an alkynyl group, and R is 2-(methyl, t butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2 (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(N-morpholino) propyl or 3-(hydroxyethyl, isopropyl amino) propyl.

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

NH

2 N NrY \ 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 -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), 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 xN ,R1 , where R 1 is selected from COH, COMe, COEt, COnPr, COiPr, SO 2 Me, CH20X where X can be H or oxygen, nitrogen, sulphur or halogen containing alkyl of linear, branched or cyclic nature. In embodiments of the invention within this group, R has the formula site of 9N-attachment H H 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-attachnrnt H 0 X-(CH2 -- (CH2)4 HN-OH where m= 2-3 and n= 1-6.

X

2 may be any substituent shown to be attached at the same position in any of the compounds disclosed in the various patents and patent applications cited above, or as described above in Section B. In particular embodiments of the invention, X 2 is halogen, and R is suitably a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(1H-imidazoyl) propyl. In some embodiments of the invention, X 2 is an aryl group. In particular embodiments, X 2 is aryl and R is suitably a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino)-propyl, 3 (cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2- WO 2011/044394 PCT/US2010/051872 38 (methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(IH-imidazoyl) propyl. In some embodiments of the invention, X 2 is a heteroaryl group. In some embodiments, X 2 is a heteroaryl group and R is suitably a primary amino alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle 7 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, X 2 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, 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.

WO 2011/044394 PCT/US2010/051872 39 In particular embodiments, X 2 is 2- or 3-thiophene and R is suitably a primary amino alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle alkyl. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2 (methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2 (ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2 (isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino) propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(1 H-imidazoyl) propyl. In particular embodiments, X 2 is 3-pyrazolyl and R is suitably a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino)-propyl, 3 (cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2 (methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylnethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(1 H-imidazoyl) propyl. In some embodiments of the invention, X2 is an alkynyl group. In some embodiments of the invention, X 2 is an alkynyl group, and R is suitably a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2- WO 2011/044394 PCT/US2010/051872 40 (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, and 3-(1 H-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-(1H-imidazoyl) propyl. In some embodiments of the invention, X 2 is CN. In particular embodiments of the invention, X 2 is CN, and R is suitably 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-(1IH-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-(l H-imidazoyl) propyl. In particular embodiments of the invention, X 2 is dimethyl amine or aziridino, and R is suitably a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2 (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2- WO 2011/044394 PCT/US2010/051872 42 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, and 3-(1H-imidazoyl) propyl. Specific examples of compounds in accordance with this embodiment of the invention are listed in Tables IH 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 IA, with Xa, Xc, Xb and the bonds between them selected from a combination in the following table: Xa Bond Xc bond Xb C double C single 0 C double C single N C double C single S o single C double C N single C double C S single C double C N double C single 0 N double C single S N single C double N o single C double N S single C double N N double N single 0 WO 2011/044394 PCT/US2010/051872 43 4 N double N single S N double N single C 0 single N double N N single N double N S single N double N rC single N double N Y is -CH 2 - or -S-,

X

4 is hydrogen or halogen; and

X

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

X

2 may be any group shown to be attached at the same position in any of the compounds disclosed in the various patents and patent applications cited above, or as described above in B. In particular embodiments of the invention, X 2 is halogen, and R is an aminoalkyl (alkylamino) alkyl or (dialkylamino) alkyl. In particular embodiments, X 2 is halogen and R is suitably a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl, . Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylanino)-propyl, 3 (cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2- 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 (cyclopropylnethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(IH-imidazoyl) propyl. In some embodiments of the invention, X 2 is an aryl group. In particular embodiments, X 2 is aryl and R is suitably an amino alkyl, a secondary or tertiary alkyl-amino-alkyl, a 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-(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 trialkylanmonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3 (hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2-(cyclopropylmethyl amino) ethyl, 2 (methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(1H-imidazoyl) propyl. In particular embodiments, 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, X 2 is an alkynyl group, and R is suitably an amino alkyl, a secondary or tertiary alkyl-amino-alkyl, a trialkylammonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation WO 2011/044394 PCT/US2010/051872 46 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3 (ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3 (allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2-(cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino)propyl and 3-(lH-imidazoyl)propyl. In particular embodiments of the invention, X 2 is acetylene, and R is suitably an amino alkyl, a secondary or tertiary alkyl-amino-alkyl, atrialkylammonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3 (ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3 (allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2-(cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(1H-imidazoyl) propyl. In some embodiments of the invention, X 2 is CN. In particular embodiments of the invention, X 2 is CN, and R is suitably an amino alkyl, a secondary or tertiary alkyl-amino-alkyl, a trialkylammonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2 (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3- WO 2011/044394 PCT/US2010/051872 47 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(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-(1IH-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 trialkylammonialkyl 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 N .N \/ Xa X4' NN - Xb R (2) wherein: in which Xa and Xb are 0, Y is -CH 2 - or -S-,

X

4 is hydrogen or halogen; and

X

2 and R are in combinations as discussed below. G-I. In some embodiments of the invention, X 2 is an aryl group. In these embodiments, R may be any of the groups disclosed as a substituent at the. 9-position nitrogen in this application, or in the various patents and patent applications cited herein. See Table 8. In some embodiments within this group, R includes a heteroatom, such as nitrogen, oxygen or sulfur. In some embodiments, the heteroatom is nitrogen. In some of these embodiments, R is suitably a primary amino-alkyl, a secondary or tertiary alkyl-amino-alkyl, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t- WO 2011/044394 PCT/US2010/051872 49 butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2 (isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3 (cyclopentylamino)-propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3 (ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl, and 3-(IH-imidazoyl) propyl. In embodiments of formula (2) within this group, R has the formula: site of 9N-attachment xNR 1 N,R 1 where RI is selected from COH, COMe, COEt, COnPr, COiPr, SO 2 Me, CH 2 OX where X can be H or oxygen, nitrogen, sulphur or halogen containing alkyl of linear, branched or cyclic nature. In embodiments of the invention within this group, R has the formula site of 9N-attachment H H 0

X-(CH

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

-HN-OH

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

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 CH 2 , X 4 is Cl, X 2 is optionally substituted phenyl. In particular embodiments of formula (2), Y is CH 2 , X4 is F, X 2 is optionally substituted phenyl. In particular embodiments of formula (2), Y is S, X4 is F, X2 is optionally substituted phenyl. In particular embodiments of formula (2), Y is S, X 4 is H, X 2 is optionally substituted pyridine. In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X 2 is optionally substituted pyridine. In particular embodiments of formula (2), Y is CH 2 , X 4 is F, X 2 is optionally substituted pyridine. In particular embodiments of formula (2), Y is S, X 4 is F, X 2 is optionally substituted pyridine, In particular embodiments of formula (2), Y is S, X 4 is H, X 2 is optionally substituted isooxazole. In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X 2 is optionally substituted isooxazole. In particular embodiments of formula (2), Y is CH 2 , X 4 is F, X 2 is optionally substituted isooxazole. In particular embodiments of formula (2), Y is S, X 4 is F, X 2 is optionally substituted isooxazole. In particular embodiments of formula (2), Y is S, X 4 is H, X 2 is optionally substituted imidazole. In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X 2 is optionally substituted imidazole. In particular embodiments of formula (2), Y is CH 2 , X4 is F, X 2 is optionally substituted imidazole.

WO 2011/044394 PCT/US2010/051872 52 In particular embodiments of formula (2), Y is S, X 4 is F, X 2 is optionally substituted imidazole. In these particular embodiments, R may be any one of the types of groups described above. Specific examples of compounds in accordance with this embodiment of the invention are listed in Tables 4A, 4C, 4D, 4F, 4G and 4H. As shown, in preferred embodiments of formula (2) in which X2 is an aryl group, X 4 is H, chlorine or fluorine. Table 2G shows measured values for EC50 in JNPL3 brain cell lysates and in SKBr3 cell lysate for compounds 4A-1 to 4A-8, 4C1 to 4C-1 1, 4C14, 4C-16, 4C-38 to 4C-41, 4D-1 to 4D-3, 4D-16, 4D-17, 4F-1, 4G-I to 4G-7, 4G-9, 4H-1 to 41-7 in accordance with this embodiment of the invention which incorporates a hydrogen as X 4 and in which Y is S or a fluorine as X 4 and in which Y is -CH 2 -. Desirably low values of EC 50 were observed for several examples. G-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, cyclopropylnethyl 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-(IH-imidazoyl) propyl. In embodiments of formula (2) when X 2 is alkynyl, R has the formula: site of 9N-attachmnnt FR1 where R 1 is selected from COH, COMe, COEt, COnPr, COiPr, SO 2 Me, CH2OX where X can be H or oxygen, nitrogen, sulphur or halogen containing alkyl of linear, branched or cyclic nature. In embodiments of the invention when X 2 is alkynyl, R has the formula site of 9N-attachment H H 0 X-(CH2)m6-N-(CH2)n-N-S-NH2 0 0

X-(CH

2

),-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-attachnent H 0 X-(C nN-(CH-2)n HN-OH where m- 2-3 and n= 1-6. In specific embodiments, X 2 is acetylene. In particular embodiments of formula (2), Y is S, X 4 is H, X 2 is acetylene. In particular embodiments of formula (2), Y is CH 2 , X4 is Cl, X 2 is acetylene. In particular embodiments of formula (2), Y is CH2, 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 EC 50 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 X 4 and in which Y is -CH 2 -. Desirably low values of EC 5 o were observed. G-HL1. 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 trialkylamnonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino) propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3 (hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2-(cyclopropylmethyl amino) ethyl, 2 (methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(1H-imidazoyl) propyl. In a particular preferred embodiment of formula (2), Y is S, X 4 is H, X 2 is CN. In a particular preferred embodiment of formula (2), Y is CH 2 , X4 is Cl, X 2 is CN. In a particular preferred embodiment of formula (2), Y is CH 2 , X4 is F, X 2 is CN. In a particular preferred embodiment of formula (2), Y is S, X 4 is F, X 2 is CN.

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

X-(CH

2 )-N-(CH)n-NS-NH 2 11 0 0 X-(CH2)n-O-S-NH 2 11 0 where m= 2-3 and n= 1-6, or site of 9N-attachnent H 0 x-(CH29-rN-(CH2)n HN-OH where m= 2-3 and n= 1-6. A specific example of a compound in accordance with this embodiment of the invention is listed in Table 4E. Table 21 shows measured values for EC 50 in JNPL3 brain cell lysates and in SKBr3 cell lysate for compounds (4E-1 to 4E-4) in accordance with this embodiment of the invention which incorporates a hydrogen as X 4 and in which Y is S or a fluorine as X 4 and in which Y is -CH 2 -. Desirably low values of EC 50 were observed for several examples. G-IV. In some embodiments of the invention, X 2 is a cycloalkyl (saturated carbocyclic) or cycloalkenyl. In these embodiments, R maybe any of the groups disclosed as a substituent at the 9-position nitrogen in this application, or in the various patents and patent applications cited herein. (See Table 8) In some embodiments within this group, R includes a nitrogen heteroatom. In a further embodiment within this group, R is suitably an amino alkyl, a secondary or tertiary alkyl-amino-alkyl, a trialkylammonicalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl. Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2-(methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2-(ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2-(isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3- 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.-(1 H-imidazoyl) propyl. In embodiments of formula (2) within this group, R has the formula: sie of 9N-attachment NR1 where R, is selected from COH, COMe, COEt, COnPr, COiPr, SO 2 Me, CH 2 OX where X can be H or oxygen, nitrogen, sulphur or halogen containing alkyl of linear, branched or cyclic nature. In embodiments of the invention within this group, R has the formula site of 9N-attachment H H0

X-(CH

2

-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 when X 2 is aryl, R has the formula site of 9N-attachment H 0 X-(CH n-7N-(CH2)n HN-OH where m= 2-3 and n= 1-6. In specific embodiments, X 2 is a cycloalkyl with one ring.

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

X

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

X

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

X

2 is an aryl group containing a sulfur atom in the aryl ring are shown in Table 4D. Table 2G shows results for ECso for Hsp90 binding in SKBr3 breast cancer cells and JNPL3 brain cell lystates for some of the compounds shown in Table 4D. All of the compounds show good activity in both experimental systems. In Table 4D, compounds 4D-16 and 4D-17 have X2= 2-thiazolyl, including both a nitrogen and an oxygen. Examples of compounds within this seventh embodiment of the invention, in which

X

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

EC

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

X

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

EC

5 o for Hsp90 binding in SKBr3 breast cancer cells and JNPL3 brain cell lysates were determined for some of the compounds listed in Table 4G. The results are summarized in Table 2K. Particularly good results were observed for compounds 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. EC5 0 for Hsp90 binding in SKBr3 breast cancer cells and JNPL3 brain cell lysates were determined for some of the compounds listed in Table 4H. The results are summarized in Table 2L. H. Structures of formula 1B in which Xa and Xb are 0 In accordance with an eighth embodiment of the invention, the compounds have general formula IB, in which both Xa and Xb are 0, and Xc and Xd are CH2. Thus, compounds of this embodiment are represented by the formula: 0 0

NH

2 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-L In some embodiments of compounds in accordance with formula (3), X 2 is halogen. In these embodiments, R is suitably an amino-alkyl, a secondary or tertiary alkyl anino-alkyl, a trialkylammonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl, with the proviso that R does not include a piperidino moiety.

WO 2011/044394 PCT/US2010/051872 60 Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2 (methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2 (ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2 (isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino) propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2 -(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(1H-imidazoyl) propyl. In specific embodiments of the invention, X2 is . In particular embodiments of the invention X 2 is I, Y is S and X 4 is H. Specific examples of compounds within this group are shown in Table 5A. Examples of compounds within this group, in which X 2 is a halogen, are shown in Table 5A (5A-1 to 5A-19). Table 2M shows EC 50 values for binding of Hsp90 in JNPL3 brain cells for some of the compounds of Table 5A. All show values of less than 100 nM. H-I. In some embodiments of compounds in accordance with formula (3), X 2 is aryl. In these embodiments, R 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 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-(1H-imidazoyl)propyl. In embodiments of formula (2) when X 2 is aryl, R has the formula: site of 9N-attachNnt X" N, R1 where R 1 is selected from COH, COMe, COEt, COnPr, COiPr, SO 2 Me, CH2OX where X can be H or oxygen, nitrogen, sulphur or halogen containing alkyl of linear, branched or cyclic nature. In embodiments of the invention when X 2 is aryl, R has the formula site of 9N-attachment H H 0

X-(CH

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

X-(CH

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

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, X 4 is H, X 2 is 2-, 3-furn or 5 methyl-2-fiuranyl. In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X 2 is 2-, 3- furan or 5 methyl-2-furanyl. In particular embodiments of formula (2), Y is CH 2 , X 4 is F, X 2 is 2-, 3-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 , X4 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 , X4 is Cl, X 2 is 2- or 3- pyrazole. In particular embodiments of formula (2), Y is CH 2 , X4 is F, X 2 is 2- or 3-pyrazole. In particular embodiments of formula (2), Y is S, X 4 is F, X 2 is 2- or 3-pyrazole. In particular embodiments of formula (2), Y is S, X4 is H, X 2 is 2-thiazolyl, 5-methyl 2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is CH 2 , 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-tbiazolyl, 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.

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, X4 is F, X 2 is 2-thiazolyl, 5-methyl 2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In these particular embodiments, R may be any one of the types of groups described above. Examples of compounds in which X 2 is an aryl group containing an oxygen atom in the aryl ring, are shown in Table 5B. Table 2N shows measured values for ECs 0 in JNPL3 brain cell lysates for compounds 5B-1, 5B-7, 5B-33 and 5B-34 in accordance with this embodiment of the invention which incorporates a fluorine as X4 and in which Y is -CH 2 - or a hydrogen as X4 and in which Y is S. Desirably low values of EC5 0 were observed. Examples of compounds in which X 2 is an aryl group containing a sulfur atom in the aryl ring are shown in Table 5C. Examples of compounds in which X 2 is a 5-membered aryl rings containing 2 nitrogens in the ring are shown in Table SD. Table 20 shows measured values for EC 50 in JNPL3 brain cell lysates for compounds 5D-2 and 5D-4 in accordance with this embodiment of the invention which incorporates a fluorine as X4 and in which Y is -CH 2 - or a hydrogen as X4 and in which Y is S. Desirably low values of ECso were observed. An embodiment of the invention has the structure shown in formula (3), in which Y is

-CH

2 -or S, X4 is hydrogen of fluorine, X 2 is X 2 is a pyrazolyl, particularly a 3-pyrazolyl, or an imidazolyl. Preferred R groups of this type are as listed above. H-H. In some embodiments of the invention, X 2 is an alkynyl group. In these embodiments, R may be as described above in Section H-Il. In specific embodiments, X 2 is acetylene. In particular embodiments of formula (2), Y is S, X4 is H, X 2 is acetylene. In particular embodiments of formula (2), Y is CH 2 , X4 is Cl, X 2 is acetylene. In particular embodiments of formula (2), Y is CH 2 , X 4 is F, X 2 is acetylene. In particular embodiments of formula (2), Y is S, X4 is F, X 2 is acetylene.

WO 2011/044394 PCT/US2010/051872 64 In these particular embodiments, R may be any one of the types of groups described above. Specific examples of compounds in accordance with this embodiment of the invention are listed in Tables 5E. As shown, in preferred embodiments of formula (2) in which X 2 is an alkynyl group, X 4 is H, chlorine or fluorine. H-IV. In some embodiments of the invention, X 2 is a cyano group. In these embodiments, R is suitably an amino alkyl, a secondary or tertiary alkyl-amino-alkyl, a trialkylammonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl, with the proviso that R does not 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-(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 , X4 is Cl, X 2 is CN. In a particular preferred embodiment of formula (2), Y is CH 2 , X 4 is F, X 2 is CN. In a particular preferred embodiment of formula (2), Y is S, X4 is F, X 2 is CN. In other embodiments in which X 2 is cyano or cyanoalkyl group, R is site of 9N-attachment H H 0

X-(CH

2 )m-N-(CH 2 )n-N--NH 2 I I 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-attachment H X-(CH2)mN-(CH 2 )n HN-OH where m= 2-3 and n= 1-6. Specific examples of compounds in accordance with this embodiment of the invention are listed in Table 5F. H-V. In some embodiments of the invention, X 2 is an amino group. In these particular embodiments, R may be any of the R groups described in Section H-II. In a particular preferred embodiment of formula (2), Y is S, X 4 is H, X 2 is azetidino. In a particular preferred embodiment of formula (2), Y is CH 2 , X 4 is Cl, X 2 is azetidino In a particular preferred embodiment of formula (2), Y is CH 2 , X 4 is F, X 2 is azetidino In a particular preferred embodiments of formula (2), Y is S, X 4 is F, X 2 is azetidino. A specific examples of a compounds in accordance with this embodiment of the invention is listed in Table 5G H-VL. In some embodiments of the invention, X 2 is a cycloalkyl or cycloalkenyl. In these particular embodiments, R may be any of the R groups described in Section H-II. In specific embodiments, X 2 is a cycloalkyl with one ring. In specific embodiments, X 2 is a cyclopropane, cyclobutane or cyclopentane. In particular embodiments of formula (2), Y is S, X 4 is H, X 2 is cyclopentyl. In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X 2 is cyclopentyl. In particular embodiments of formula (2), Y is CH 2 , X 4 is F, X 2 is cyclopentyl. In particular embodiments of formula (2), Y is S, X 4 is F, X 2 is cyclopentyl. A specific examples of a compounds in accordance with this embodiment of the invention is listed in Table 5H WO 2011/044394 PCT/US2010/051872 66 I. Structures of formula 1B in which Xa and/or Xb is a heteroatom, but not both 0 In accordance with a ninth embodiment of the invention, the compounds have general formula 1B, in which one or both of Xa or Xb is a heteroatom such as 0, N or S, with the proviso that both of Xa and Xb are not 0 (see Section H). Specific examples of compounds within this group are shown in Table 6A. I-I. In some embodiments of compounds in accordance with formula (3), X 2 is halogen. In these embodiments, R is suitably an amino-alkyl, a secondary or tertiary alkyl amino-alkyl, a trialkylammonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl, with the proviso that R is not a piperidino moiety. . Specific R groups include without limitation 2-(methyl, t-butyl- amino) ethyl, 2 (methyl, isopropyl amino) ethyl, 3-(neopentyl amino) propyl, 2-(isobutyl-amino) ethyl, 2 (ethyl, isopropyl amino) ethyl, 3-(isopropyl amino) propyl, 3-(t-butyl- amino) propyl, 2 (isopropyl amino) ethyl, 2-(hydroxyethyl, isopropyl amino) ethyl, 3-(cyclopentylamino) propyl, 3-(cyclopentyl, methyl amino) propyl, 3-(ethylamino) propyl, 3-(ethyl, methyl amino) propyl, 2-(neopentyl amino) ethyl, 3-(methyl, isopropyl amino) propyl, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2-(methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylnethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(IH-imidazoyl) propyl. In specific embodiments of the invention, X 2 is I. In particular embodiments of the invention X 2 is I, Y is S and X4 is H. I-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-(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) propel, 3-(ethyl, isopropyl amino) propyl, 3-(hydroxyethyl, isopropyl amino) propyl, 3-(methyl, propargyl amine) propyl, 2 (methyl, propargyl amine) ethyl, 3-(allyl, methyl amino) propyl, 3-(propyl, cyclopropylmethyl amino) propane, 3-(hydroxyethyl, cyclohexyl amino) propyl, 2 (cyclopropylmethyl amino) ethyl, 2-(methyl, isobutyl amino) ethyl, 3-(N-morpholino) propyl and 3-(IH-imidazoyl) propyl. In embodiments of formula (2) when X 2 is aryl, R has the formula: site of 9N-aftachnent xN R 1 xN R 1 where R, is selected from COH, COMe, COEt, COnPr, COiPr, SO 2 Me, CH 2 OX where X can be H or oxygen, nitrogen, sulphur or halogen containing alkyl of linear, branched or cyclic nature. In embodiments of the invention when X2 is aryl, R has the formula site of 9N-attachment 0 H Hii

X-(CH

2 -N-(CH2)n-N-SNH 2 0

X-(CH

2 )n-O--NH 2 0 where m= 2-3 andn= 1-6. In embodiments when X 2 is aryl, R has the formula WO 2011/044394 PCT/US2010/051872 68 site of 9N-attachment H 0 X-(CH2Xyg-N--(CH2)4 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 fin, 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, X2 is 2-, 3-furan or 5 methyl-2-furanyl. In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X 2 is 2-, 3- furan or 5 methyl-2-furanyl. In particular embodiments of formula (2), Y is CH 2 , 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, X4 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 CH2, 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, 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, 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, X 2 is 2-thiazolyl, 5-methyl 2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is CH 2 , X4 is Cl, X 2 is 2-thiazolyl, 5 methyl-2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl.

WO 2011/044394 PCT/US2010/051872 69 In particular embodiments of formula (2), Y is CH2, X 4 is F, X 2 is 2-thiazolyl, 5 methyl-2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is S, X 4 is F, X 2 is 2-thiazolyl, 5-methyl 2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is S, X 4 is H, X2 is 2-thiazolyl, 5-methyl 2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X2 is 2-thiazolyl, 5 methyl-2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is CH2, X 4 is F, X 2 is 2-thiazolyl, 5 methyl-2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In particular embodiments of formula (2), Y is S, X 4 is F, X 2 is 2-thiazolyl, 5-methyl 2-thiazolyl, 2-oxazolyl or 5-methyl-2-oxazolyl. In these particular embodiments, R may be any one of the types of groups described above. I-II. In some embodiments of the invention, X 2 is an alkynyl group. In these embodiments, R may be as described above in Section I-IL. In specific embodiments, X 2 is acetylene. In particular embodiments of formula (2), Y is S, X4 is H, X 2 is acetylene. In particular embodiments of formula (2), Y is CH 2 , X 4 is Cl, X 2 is acetylene. In particular embodiments of formula (2), Y is CH 2 , X 4 is F, X 2 is acetylene. In particular embodiments of formula (2), Y is S, X 4 is F, X 2 is acetylene. In these particular embodiments, R may be any one of the types of groups described above. I-IV. In some embodiments of the invention, X 2 is a cyano group. In these embodiments, R is suitably an amino alkyl, a secondary or tertiary alkyl-amino-alkyl, a trialkylaimonioalkyl 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-(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 CH 2 , X 4 is F, X 2 is CN. In a particular preferred embodiment of formula (2), Y is S, X 4 is F, X 2 is CN. In other embodiments in which X 2 is cyano or cyanoalkyl group, R is site of 9N-attaclhent H H0? X-(CH2),-N-(CH2)n-N-S-NH2 0 0

X-(CH

2 )n-O-S-NH 2 0 where m= 2-3 and n= 1-6, or site of 9N-attach nent H X-(CH2)m-N-(CH2)n HNOH where m= 2-3 and n= 1-6. I-V. In some embodiments of the invention, X 2 is an amino group. In these particular embodiments, R may be any of the R groups described in Section I-II. In a particular preferred embodiment of formula (2), Y is S, 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 WO 2011/044394 PCT/US2010/051872 71 In a particular preferred embodiment of formula (2), Y is CH 2 , X 4 is F, X 2 is aziridino. In a particular preferred embodiment of formula (2), Y is S, X 4 is F, X 2 is aziridino. J. Structures of formula 1B in which Xa. Xc. Xd and Xb are all carbon In accordance with a tenth embodiment of the invention, the compounds have general formula I B, in which Xa, Xc, Xd and Xb are all carbon connected by single or double bonds. In these embodiments, R may be any of the groups disclosed as a substituent at the 9-position nitrogen herein or in the various patents and applications cited above. (See Table 8) In some embodiments, when X 2 is aryl, R includes a nitrogen heteroatom. In these embodiments, R is suitably an aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or trialkylanunonioalkyl 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-(lH-imidazoyl) propyl. In embodiments of formula (2) when X 2 is aryl, R has the formula: site of 9N-atachment X " 'N , R 1 N , R where R, is selected from COH, COMe, COEt, COnPr, COiPr, SO 2 Me, CH 2 OX where X can be H or oxygen, nitrogen, sulphur or halogen containing alkyl of linear, branched or cyclic nature.

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 H0 X-(CH2)m -N-(CH2)n-NS -NH2 00

X-(CH

2 )n-O-S-NH 2 0 where u-- 2-3 and n= 1-6. In embodiments when X 2 is aryl, R has the formula site of 9N-attachnrnt H 0 X-iCH rN-(H 2 )n' HWOH where m= 2-3 and n- 1-6. Specific examples of compounds within this embodiment of the invention are shown in Table 6B. Table 2P shows measured values for EC 50 in JNPL3 brain cell lysates for compounds 6B-25 in accordance with this embodiment of the invention which incorporates a hydrogen as X4 and in which Y is S. Desirably low values of ECs 0 were observed. K. Structures of formula 1C In some embodiments of the present invention having the general formula 1C, the compounds of the invention can be represented by the general formula: WO 2011/044394 PCT/US2010/051872 73

NH

2 N' N R OR 1 (4) in which RI is alkyl, for example methyl or ethyl, Y is S or CH 2 ,

X

4 is H or halogen,

X

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

X-(CH

2 )mN-(CH 2 )nS-N-NH 2 0 0 x-(CH2)n-O-S-NH2 0 where m= 2-3 and n= 1-6. In embodiments of formula (3) R has the formula site of 9N-attachmrnt H 0 X-(CHi2yn-N-(CH2)n HN-OH where m= 2-3 and n= 1-6. In some embodiments, X 2 is alkynyl, such as acetylene. Examples of such structures are shown in Table 7A In some embodiments, X 2 is cyano or cyanomethyl. Examples of such structures are shown in Table 7B. In some embodiments, X 2 is a heterocycle, including without limitation aziridine, azetidine, oxetane, thietane, tetrahydrofuran, tetrahydropyrrole, tetrahydrothiophane, imidazolidine, oxazolidine, thiazolidine, azirine, oxirine, pyrroline, pyrrole, dihydrofliran, firan, dihydrothiophene, thiophene, pyrazole, imidazole, 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 EC5o 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 X4 and in which Y is S. Desirably low values of EC5o were observed, although X 2 = -OCH 3 was observed to be less active than 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 24OnM) and 4G-9 vs 7E-6 (5.5nM vs 32nM). L. Structures in which X, is alkvnvl In accordance with a ffirther aspect of the present invention, compounds are provided in accordance with any of formulas (1A), (1B) or (iC) in which X 2 is alkynyl. In these compounds, Y is CH 2 , S, 0, C=O, C=S, N or any other linking group disclosed in a compound with the same scaffold structure herein or in the patents and patent applications cited above;

X

4 is H or halogen or any other group disclosed at this position in a compound with the same scaffold structure herein or in the patents and patent applications cited above; Xa, Xb, Xc and Xd are any group(s) disclosed at this position herein or in the patents and patent applications cited above; and R is any R group disclosed at this position of the same scaffold structure herein or in the patents and patent applications cited above. (See Table 8) In some embodiments, Zi, Z2, and Z3 are all nitrogen. In some embodiments, Zi and Z3 are nitrogen and Z2 is carbon. In some embodiments, Z3 is carbon. M. Structures in which X 2 is Furan, Thiophene. Pyrazole. Oxazole or Thiazole In accordance with a further aspect of the present invention, compounds are provided in accordance with any of formulas (lA), (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, Z1, Z2, and 73 are all nitrogen. In some embodiments, Z 1 and Z3 are nitrogen and Z2 is carbon. In some embodiments, Z3 is carbon. Synthetic Methods Compounds in accordance with formulas (IA) and (IB) can be made through the application of the following methodologies.

NH

2

NH

2 x ISH a,b NN NP N N' N N HN H 5 or 6 member ring

NH

2 X, NH 2 X2 C, d N N\ - N N\ N NN () n=1,2 (() n=1,2

NR

1

R

2

NR

1

R

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

CO

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

WO 2011/044394 PCT/US2010/051872 77

NH

2

NH

2 HOOC - N" NH 2 a, b N N + HN N NF N N 5 or 6 member ring

NH

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

NR

1

R

2

NR

1

R

2 (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 *C. Scheme 2. General Methods: 'H and "C NMR spectra were recorded on a Bruker 500 MHz instrument. Chemical shifts are reported in 8 values in ppm downfield from TMS as the internal standard. 'H data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q= quartet, br = broad, m = multiplet), coupling constant (Hz), integration. "C chemical shifts are reported in 3 values in ppm downfield from TMS as the internal standard. High resolution mass spectra were recorded on a Waters LCT Premier system. Low resolution mass spectra were obtained on a Waters Acquity Ultra Performance LC with electrospray ionization and SQ detector. High-performance liquid chromatography analyses were performed on a Waters Autopurification system with PDA, MicroMass ZQ, and ELSD detector, and a reversed phase column (Waters X-Bridge C18, 4.6 x 150 mm, 5 pm) using a gradient of; method A (a) H 2 0 + 0.1% TFA and (b) CH 3 CN + 0.1% TFA, 5 to 95% b over 10 minutes at 1.2 mL/min; method B (a) H20 + 0.1% TFA and (b) CH 3 CN + 0.1% TFA, 20 to 90% b over 16 minutes at 1.0 mL/min. Column chroniatography was performed using 230-400 mesh silica gel (EMD). Specific compounds were synthesized as follows; WO 2011/044394 PCT/US2010/051872 78

NH

2

NH

2 YS N, Ni -07 o N' N 0 a 0 NH NH PU-H71 Reagents and conditions: (a) RB(OH) 2 , PdCl 2 (PPh 3

)

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

)

2

C

2 (4 mg, 0.00584 nmol) 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), 10:1) to give 19.8 mg (73%) of DZ2-388. 'H NMR (500 MHz, MeOH-d 4 ) 8 8.14 (s, 1H), 7.28-7.34 (m, 3H), 7.17-7.21 (m, 2H), 7.12 (s, 1H), 6.90 (s, IH), 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) 8 156.0, 153.4, 152.1, 151.1, 150.3, 149.4, 142.3, 141.8, 130.4, 129.1, 128.7,120.3, 119.8, 115.7, 112.2, 103.8, 52.2, 43.2, 41.1, 27.6, 19.3; HRMS (ESI) m/z [M+H]* calcd. for C 24

H

27

N

6 0 2 S, 463.1916; found 463.1905; HPL: method A R, = 6.50, method B R, = 7.40. 8-(6-(4-tert-butylphenyl)benzo[d] [1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H purin-6-amine [DZ2-3901. 4-tert-Butylphenylboronic acid (15.6 mg, 0.0876 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (0.5 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This WO 2011/044394 PCT/US2010/051872 79 was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2

C

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

CI

2 :EtOAc:MeOH-NH 3 (7N), 4:5:2:1) to give 25.0 mg (83%) of DZ2-390. 'H NMR (500 MHz, MeOH-d) 8 8.11 (s, 1H), 7.27 (d, J = 8.4 Hz, 2H), 7.14 (s, IH), 7.12 (d, J 8.4 Hz, 2H), 6.86 (s, IH), 6.06 (s, 2H), 3.93 (t, J= 6.9 Hz, 2H), 2.92 (septet, J= 6.5 Hz, 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); "C NMR (125 MHz, MeOH-d) 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

3 5

NA

2 S, 519.2542; found 519.2545; HPLC: method A RI = 7.43, method B Rt = 9.45. 8-(6-(3,5-bis(tdfluoromethyl)phenyl)benzo[d] [1,3Jdioxol-5-ylthio)-9-(3 (isopropylamino)propyl)-9H-purin-6-amine [DZ2-3911. 3,5 Bis(trifluoromethyl)phenylboronic acid (22.6 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (0.5 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H 2 0 (0.1 mL) and Pd(PPh 3

)

2

C

2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 3 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2 Cl 2 :EtOAc:MeOH-NH 3 (7N), 4:5:2:1) to give 24.4 mg (70%) of DZ2-391. 'H NMR (500 MHz, CDC 3 ) 8 8.22 (s, I H), 7.79 (s, 3H), 7.12 (s, IH), 6.86 (s, 1H), 6.09 (s, 2H), 5.71 (br s, 2H), 4.07 (t, J= 6.6 Hz, 2H), 2.82 (septet, J= 6.2 Hz, 1H), 2.49 (t, J= 6.5 Hz, 2H), 1.95 (m, 2H), 1.12 (d, J= 6.3 Hz, 6H); 13 C NMR (125 MHz, CDC 3 ) 8 154.1, 152.3, 151.5, 149.6, 148.6, 147.5, 142.1, 137.2, 131.2 (q, J = 33 Hz), 129.6, 123.1 (q, J= 270 Hz), 121.3, 119.6, 119.4,114.9, 110.8, 102.4, 49.5, 42.8, 40.6, 28.8, 21.7; HRMS (ESI) mn/z [M+H]* calcd. for C 26

H

2 5

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] [1,3Jdioxol-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 H 2 0 (0.1 mL) and Pd(PPh 3

)

2

C

2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 3 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2 Cl 2 :EtOAc:MeOH-NH 3 (7N), 4:5:2:1) to give 25.3 mg (85%) of DZ2-392. 'H NMR (500 MHz, CDC1 3 ) S 8.24 (s, IH), 7.13 (d, J= 8.7 Hz, 2H), 6.93 (s, IH), 6.83 (s, 1H), 6.67 (d, J= 8.7 Hz, 2H), 6.01 (br s, 2H), 5.98 (s, 2H), 4.02 (t, J= 6.7 Hz, 2H), 2.97 (s, 6H), 2.78 (septet, J= 6.3 Hz, IH), 2.44 (t, J= 6.7 Hz, 2H), 1.87 (m, 2H), 1.10 (d, J= 6.3 Hz, 6H); "C NMR (125 MHz, CDCl 3 ) 6 154.4, 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 C2 6

H

32

N

7 0 2 S, 506.2338; found 506.2330; HPLC: method A Rt = 5.72, method B R = 5.12. 9-(3-(isopropylamino)propyl)-8-(6-(thiophen-2-yl)benzo[d] [1,3Jdioxol-5-ylthio)-9H purin-6-amine [DZ2-3951. 2-Thienylboronic acid (11.2 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2 C1 2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 5 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2 Cl 2 :MeOH-NH3 (7N), 12.5:1) to give 12.4 mg (45%) of DZ2-395. 'H NMR (500 MHz, CDC1 3 /MeOH-d 4 ) S 8.17 (s, iH), 7.33 (dd, J= 1.4, 4.9 Hz, iH), 7.07 (s, iH), 7.04 (s, 1), 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, iH), 2.62 (t, J= 6.8 Hz, 2H), 2.00 (m, 2H), 1.19 (d, J= 6.6 Hz, 6H); 13 C NMR (125 MHz, CDC13/MeOH-d 4 ) S 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) mn/z [M+H]* called. for CnH25N 6 02S 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-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6 amine [DZ3-4]. 2-Furanylboronic acid (9.8 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2 Cl 2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90*C for 3.5 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2 Cl2:MeOH-NH 3 (7N), 12.5:1) to give 19.1 mg (72%) of DZ3-4. 'H NMR (500 MHz, CDCl3/MeOH-d 4 ) 8 8.18 (s, IH), 7.49 (d, J= 1.8 Hz, 1H), 7.25 (s, 1H), 6.96 (s, IH), 6.71 (d, J= 3.3 Hz, IH), 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, I H), 2.61 (t, J= 6.9 Hz, 2H), 2.00 (m, 2H), 1.14 (d, J= 6.3 Hz, 6H); "C NMR (125 MHz, CDCl 3 /MeOH-d4) 8 154.3, 152.2, 151.2, 150.9, 149.5, 148.14, 148.08, 142.4, 129.0, 119.2, 117.5, 114.5, 111.5, 110.0, 109.0, 102.3, 42.8, 41.0, 28.5, 21.2; HRMS (ESI) m/z [M+H] called. for C 22 H2N 6 0 3 S, 453.1709; found 453.1705; HPLC: method A R, = 6.23, method B Rt = 6.82. 9-(3-(isopropylamino)propyl)-8-(6-(4-methoxyphenyl)benzo[d [,3jdioxol-5-ylthio)-9H purin-6-amine [DZ3-3]. 4-Methoxyphenylboronic acid (13.3 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 nimol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H 2 0 (0.1 mL) and Pd(PPh 3

)

2 C1 2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90*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), 12.5:1) to give 20.5 mg (71%) of DZ3-3. 'H NMR (500 MHz, CDCl 3 ) 8 8.25 (s, 1H), 7.19 (d, J= 8.7 Hz, 2H), 6.95 (s, IH), 6.86 (d, J= 8.7 Hz, 2H), 6.82 (s, 1H), 6.00 (s, 2H), 5.92 (br s, 2H), 4.01 (t, J= 6.7 Hz, 2H), 3.82 (s, 3H), 2.75 (septet, J= 6.3 Hz, 1H), 2.43 (t, J = 6.7 Hz, 2H), 1.85 (in, 2H), 1.07 (d, J= 6.3 Hz, 6H); 13 C NMR (125 MHz, CDC 3 ) 8 159.2, 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]* calcd. for

C

25

H

2 9

N

6

O

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

)

2

C

2 (4 mg, 0.00584 amol) were added and the reaction mixture was heated under nitrogen at 90*C for 3.5 It Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2

CI

2 :MeOH-NH 3 (7N), 12.5:1) to give 14.8 mg (55%) of DZ3-5. 'H NMR (500 MHz, CDC1 3 /MeOH-d 4 ) 8 8.53 (dd, J= 1.6, 4.8 Hz, 2H), 8.19 (s, 1H), 7.25 (dd, J= 1.6, 4.5 Hz, 2H), 7.11 (s, 11H), 6.89 (s, 1H), 6.11 (s, 2H), 4.07 (t, J= 6.8 Hz, 2H), 2.82 (m, 1H), 2.51 (t, J= 6.8 Hz, 2H), 1.91 (in, 2H), 1.13 (d, J= 6.3 Hz, 6H); "C NMR (125 MHz, CDCI 3 /MeOH-d) 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/z [M+H]* called. for C23H 26

N

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

)

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

CI

2 :EtOAc:MeOH-NH3 (7N), 4:5:2:1) to give 13.9 mg (44%) of DZ3-6. H NMR (500 MHz, CDCI 3 ) 5 8.23 (s, IH), 7.44 (d, J= 8.2 Hz, 2H), 7.13 (d, J= 8.2 Hz, 2H), 7.01 (s, 1H), 6.81 (s, 1H), 6.05 (s, 2H), 5.69 (br s, 2H), 4.08 (t, J= 6.0 Hz, 2H), 2.91 (in, 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, 6H); "C NMR (125 MHz, CDCl3/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) n/z [M+H]* called. for C 24

H

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

)

2 Cl 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, CDC 3 /MeOH-d 4 ) 8 8.17 (s, 1H), 7.51 (s, 1 H), 7.44 (s, IH), 7.07 (s, IH), 6.97 (s, 1H), 6.49 (s, 1H), 6,08 (s, 2H), 4,17 (t, J= 6.9 Hz, 2H), 2.93 (septet, J= 6.4 Hz, iH), 2.64 (t, J= 7.1 Hz, 2H), 2.02 (in, 2H), 1.17 (d, J= 6.4 Hz, 6H); 13 C NMR (125 MHz, CDCI 3 /MeOH-d 4 ) 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) m/z [M+H] 4 caled. for C 2 2

H

2 5

N

6 0 3 S, 453.1709; found 453.1711; HPLC: method A R, = 6.18, method B R, = 6.67. 5-(6-(6-amino-9-(3-(isopropylamino)propyl)-9H-purin-8-ylthio)benzo[d] [1,3]dioxol-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 H 2 0 (0.1 mL) and Pd(PPh 3

)

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

CI

2 :EtOAc:MeOH-NH 3 (7N), 2:2:1:0.5) to give 9.5 mg (34%) of DZ3-33. 'H WO 2011/044394 PCT/US2010/051872 84 NMR (500 MHz, CDC1 3 /MeOH-d4) 5 9.57 (s, 1), 8.18 (s, 1H), 7.36 (d, J= 3.8 Hz, 1H), 7.32 (s, IH), 7.07 (s, 1H), 6.98 (d, J= 3.8 Hz, IH), 6.12 (s, 2H), 4.32 (t, J= 6.7 Hz, 2H), 3.31 (septet, J= 6.6 Hz, 1H), 2.93 (t, J= 6.8 Hz, 2), 2.30 (m, 2H), 1.42 (d, J= 6.6 Hz, 6H); 1 3 C NMR (125 MHz, CDCl 3 /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, 192; HRMS (ESI) m/z [M+H]* called. for C23H 2

N

6

O

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

)

2 Cl 2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 4 h. DMF was removed under reduced pressure and to the resulting residue was added CH 2 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. 'H NMR (500 MHz, CDCl 3 /MeOH-d4) 8 8.17 (s, 1), 7.04 (s, IH), 7.01 (s, 1H), 6.88 (m, 1H), 6.27 (m, 1N), 6.21 (m, 1H), 6.03 (s, 2H), 4.17 (t, J= 6.8 Hz, 2H), 3.29 (septet, J= 6.6 Hz, 1 H), 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 22

H

26

N

7 0 2 S, 452.1869; found 452.1872; IPLC: method A Rt = 6.13, method B R, = 6.43. 8-(6-(1H-pyrazol-4-yl)benzo[dJ [1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H purin-6-amine [DZ3-301. 1-Boc-pyrazole-4-boronic acid pinacol ester (25.8 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmnol) and NaHCO 3 (14.7 mg, 0.1755 mmnol). 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 WO 2011/044394 PCT/US2010/051872 85 removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2 Cl2:EtOAc:MeOH-NH 3 (7N), 2:2:1:0.5) to give 13.7 mg (53%) of DZ3-30. 'H NMR (500 MHz, CDCl3/MeOH-d4) 8 8.17 (s, 1H), 7.58 (s, 2H), 7.10 (s, 1H), 6.95 (s, 1H), 6.06 (s, 2H), 4.08 (t, J= 6.9 Hz, 2H), 2.89 (septet, J=6.4 Hz, IH), 2.57 (t, J= 7.2 Hz, 2H), 1.91 (m, 2H), 1.14 (d, J= 6.4 Hz, 6H); ' 3 C NMR (125 MHz, CDC13/MeOH-ds) 8 154.0, 152.1, 151.2, 149.7, 148.9,147.5,133.6, 132.0, 119.8, 119.1, 117.9, 115.3, 110.9, 102.1, 49.2, 42.9, 40.8, 28.3, 21.3; HRMS (ESI) m/z [M+H]* called. for C 2 1

H

25

N

8 0 2 S, 453.1821; found 453.1819; HPLC: method A R, = 5.60, method B R, = 4.87. 9-(3-(isopropylamino)propyl)-8-(6-(5-methylfuran-2-yl)benzo[d] [1,3]dioxol-5-ylthio) 9H-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 H 2 0 (0.1 mL) and Pd(PPh 3

)

2 Cl2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 90*C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2

CI

2 :EtOAc:MeOH-NH 3 (7N), 4:9:2:1) to give 11.5 mg (42%) of DZ3-35. 'H NMR (500 MHz, CDC13) 8 8.25 (s, IH), 7.19 (s, 1H), 6.84 (s, IH), 6.63 (d, J= 3.1 Hz, IH), 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* calcd. for C 23

H

2 7

N

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

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) 8 8.17 (s, 1H), 7.14 (s, IH), 7.12 (s, IH), 6.10 (s, 2H), 4.35 (t, J= 6.9 Hz, 2H), 3.99 (s, 2H), 3.08 (septet, J= 6.5 Hz, 1H), 2.82 (t, J= 7.0 Hz, 2H), 2.25 (m, 2H), 1.27 (d, J= 6.5 Hz, 6H); "C NMR (125 MHz, CDCl 3 /MeOH-d4) 5 154.2, 152.1, 152.0, 151.5, 150.8, 148.6, 147.7, 129.5, 119.2, 117.6, 116.2, 110.3, 102.7,49.8,42.5, 40.7, 27.7, 22.9, 20.4; HRMS (ESI) m/z [M+H]> called. for C 20

H

24

N

7 0 2 S, 426.1712; found 426.1712; HPLC: method A R, = 5.69, method B R, = 4.57. 8-(6-(1H-pyrrol-3-yI)benzo[d] [1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H purin-6-amine [DZ3-411. 1-Boc-pyrrole-3-boronic acid pinacol ester (30.9 mg, 0.1053 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 C1 2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 90*C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2 Cl 2 :EtOAc:MeOH-NH3 (7N), 2:2:1:0.5) to give 7.9 mg (30%) of DZ3-41. 'H NMR (500 MHz, CDCl 3 /MeOH-d4) 8 8.16 (s, 1H), 7.02 (s, IH), 6.99 (s, IH), 6.86 (m, iH), 6.76 (m, IH), 6.21 (m, 1H), 6.02 (s, 2H), 4.07 (t, J= 6.9 Hz, 2H), 2.95 (septet, J= 6.4 Hz, 1H), 2.59 (t, J= 7.1 Hz, 2H), 1.96 (m, 2H), 1.19 (d, J= 6.4 Hz, 6H); "C NMR (125 MHz, CDCl3/MeOH-d) 5 154.4, 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) m/z [M+H]* calcd. for C2H 2 6

N

7 0 2 S, 452.1869; found 452.1862; HPLC: method A Rt = 6.02, method B Rt = 6.27. 9-(3-(isopropylanino)propyl)-8-(6-(1-methyl-1H-pyrazol-5-y)benzo[d] [1,3]dioxol-5 ylthio)-9H-purin-6-amine [DZ3-441. 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 900C 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), 2:2:1:0.5) to give 20.1 mg (74%) of DZ3-44. 'H NMR (500 MHz, CDCI 3 ) 8 8.25 (s, 1H), 7.40 (d, J= 1.8 Hz, 1H), 7.05 (s, 1 H), 6.80 (s, IH), 6.08 (s, 2H), 6.06 (d, J= 1.8 Hz, 1H), 5.91 (br s, 2H), 4.10 (t, J= 6.7 Hz, 2H), 3.67 (s, 3H), 2.85 (septet, J= 6.3 Hz, 1H), 2.53 (t, J= 6.7 Hz, 2H), 1.97 (in, 2H), 1.13 (d, J= 6.3 Hz, 6H);

'

3 C NMR (125 MHz, CDCI 3 ) 6 154.4,152.7,151.7, 149.3, 149.0, 147.0, 140.6, 138.5, 127.7, 123.3, 120.0, 113.8, 111.7,107.4,102.5,49.6,43.2, 41.1, 37.1, 29.1, 22.0; HRMS (ESI) tn/z [M+H]* calcd. for C22H27NsO 2 S, 467.1978; found 467.1985; HPLC: method A R = 5.74, method B R = 5.20. 8-(6-(1H-pyrazol-3-yl)benzo[dJ [1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H purin-6-amine [DZ3-46]. 1H-pyrazole-3-boronic acid (33 mg, 0.293 mmol) was added to PU-H71 (50 mg, 0.0975 mmol) and NaHCO 3 (24.6 mg, 0.293 mmol). DMF (2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H 2 0 (0.2 mL) and Pd(PPh 3

)

2

C

2 (7 mg, 0.0098 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2

CI

2 :EtOAc:MeOH-NH 3 (7N), 2:2:1:0.5) to give 3.7 mg (8%) of DZ3-46. 1H NMR (500 MHz, CDCl 3 /MeOH-d4) 8 8.17 (s, 1H), 7.59 (d, J= 2.0 Hz, iH), 7.10 (s, iH), 7.07 (s, 1H), 6.38 (d, J= 2.0 Hz, IH), 6.08 (s, 2H), 4.19 (t, J= 6.8 Hz, 2H), 3.31 (septet, J= 6.6 Hz, 1H), 2.89 (t, J= 7.2 Hz, 2H), 2.10 (in, 2H), 1.39 (d, J= 6.6 Hz, 6H); 13 C NMR (125 MHz, CDCl 3 /MeOH-d4) 8 154.5, 152.2, 152.1, 150.7, 149.5, 148.5, 148.3, 119.3, 119.1, 114.6,114.5,111.0, 110.9, 106.1, 102.3, 51.1, 41.7,40.3,26.0, 18.7; HRMS (ESI) n/z [M+H]* calcd. for C 21

H

25

N

8 0 2 S, 453.1821; found 453.1826; HPLC: method A R = 5.65, method B R, = 4.83. 9-(3-(isopropylamino)propyl)-8-(6-(isoxazol-4-yl)benzo[d] [1,3]dioxol-5-ylthio)-9H purin-6-amine [DZ3-49]. 4-Isoxazoleboronic acid pinacol ester (20.5 mg, 0.1053 mmol) was WO 2011/044394 PCT/US2010/051872 88 added to PU-H71 (30 mg, 0.0585 mmol) and NaHC0 3 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H 2 0 (0.1 mL) and Pd(PPh 3

)

2

C

2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 60 0 C for 4 h. Solvent was removed under reduced pressure and the resulting residue was attempted to be purified by preparatory TLC (hexane:CH 2 Cl 2 :EtOAc:MeOH-NH 3 (7N), 4:7:2:1) to give 7.4 mg (28%) of an inseparable mixture of DZ3-49 and DZ3-39 in a ratio of approximately 71:29, respectively, as determined by HPLC. 'H NMR (500 MHz, CDC3/MeOH-d) 8 8.66 (s, IH), 8.45 (s, I H), 8.17 (s, I H), 7.18 (s, IH), 7.01 (s, IH), 6.13 (s, 2H), 4.37 (t, J= 7.0 Hz, 2H), 3.27 (septet, J= 7.1 Hz, IH), 2.89 (t, J= 7.1 Hz, 2H), 2.22 (in, 2H), 1.38 (d, J= 6.5 Hz, 6H); MS (ESI) m/z [M+H]* 454.1; HPLC: method AR, = 5.67 (DZ3-39, 29%) and 5.87 (DZ3-49, 7 1%); method B R, = 4.58 (DZ3-39, 34%) and 5.57 (DZ3-49, 66%). 4-(6-(6-amino-9-(3-(isopropylamino)propyl)-9H-purin-8-ylthio)benzo[d] [1,3]dioxol-5 yl)benzaldehyde [DZ3-50]. 4-Formylphenylboronic acid (13 mg, 0,0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then 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 C12:EtOAc:MeOH-NH (7N), 2:2:1:0.5) to give 18.8 mg (66%) of DZ3-50. 'H NMR (500 MHz, MeOH-d4) 5 10.01 (s, IH), 8,15 (s, IH), 7.85 (d, J= 8.1 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.14 (s, IH), 6.93 (s, I H), 6.13 (s, 2H), 4.05 (t, J= 6.8 Hz, 2H), 2.99 (septet, J = 6.4 Hz, 1H), 2.62 (t, J= 6.9 Hz, 2H), 1.99 (m, 2H), 1.24 (d, J= 6.4 Hz, 6H); "C NMR (125 MHz, MeOH-d 4 ) 8 192.3, 154.1, 151.9, 151.0, 149.8, 148.8, 148.5, 146.4, 139.5, 135.3, 130.0, 129.4, 119.0,117.7,115.0,110.8, 102.4, 49.9, 42.2, 40.3, 27.4, 20.2; HRMS (ESI) Dm/z [M+H]* called. for C 25 H27N 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-aniino-8-(6-(3,5-bis(trifluoromethyl)phenyl)benzo[d][1,3]dioxol-5 ylthio)-9H-purin-9-yl)propylamino)hexylcarbamate [TT-V-43A]. Bis(trifluoromethyl)phenylboronic acid (22.7 mg, 0.0878 mmol) was added to PU-H7 I -C6 linker (39.2 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (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 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2

CI

2 :MeOH

NH

3 (7N), 10:1) to give 27.7 mg (63%) of TT-V-43A. 'H NMR (500 MHz, CDCI 3 ) 5 8.17 (s, 1H), 7.78 (s, 3H), 7.14 (s, IH), 6.89 (s, 1H), 6.12 (s, 2H), 5.80 (br s, 2H), 4.68 (br s, IH), 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 H4j 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-anino-8-(6-(3,5-bis(trifluoromethyl)phenyl)benzo[dj [1,3]dioxol-5-ylthio)-9H1 purin-9-yl)propyl)hexane-1,6-diamine [TT-V-47B]. TT-V-43A (26 mg, 0.0344 mmol) was dissolved in CH 2

CI

2 (1.2 mL) and TFA (0.3 mL) was added and stirred at it for 45 min. Then solvent was removed under reduced pressure and residue dried under high vacuum for 2 h to give TT-V-47B. Purified by preparatory TLC (hexane:CH 2 C1 2 :MeOH-NH 3 (7N), 7:1) to give mg (%) of TT-V-47B. 'H NMR (500 MHz, CDC1 3 /MeOH-d4) 5 8.04 (s, IH), 7.67 (s, IH), 7.64 (s, 2H), 7.12 (s, 1H), 6.84 (s, 1H), 6.04 (s, 2H), 3.97 (t, J= 6.7 Hz, 2H), 2.85 (t, J= 7.0 Hz, 21), 2.84 (t, J= 6.9 Hz, 2H), 2.77 (t, J= 7.0 Hz, 2H), 2.06 (m, 2H), 1.71 (m, 2H), 1.63 (m, 2H), 1.28 (m, 4H); HRMS (ESI) m/z [M+H]* called. for C 2

,H

32

F

6

N

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

WO 2011/044394 PCT/US2010/051872 90 00

NH

2

NH

2 N I N t NXN2 F FI HN HN PU-DZ13 Reagents and conditions: (a) RB(OH) 2 , PdCl 2 (PPh 3

)

2 , NaHCO 3 , H20, DMF, 90*C. Scheme 4. Suzuki coupling of PU-DZ13. 2-fluoro-8-((6-(furan-2-yl)benzo[d][1,3]dioxol-5-yl)methyl)-9-(2-(isobutylamino)ethyl) 9H-purin-6-amine [DZ3-25]. 2-Furanylboronic acid (9.8 mg, 0.0877 mmol) was added to PU-DZ13 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H 2 0 (0.1 mL) and Pd(PPh 3

)

2

C

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

CI

2 :MeOH-NH3 (7N), 20:1) to give 19.1 mg (72%) of DZ3-25. 'H NMR (500 MHz, CDC13/MeOH-d4) 8 7.46 (d, J= 1.4 Hz, 1H), 7.08 (s, IH), 6.64 (s, iH), 6.46 (dd, J = 1.4, 3.2 Hz, iH), 6.34 (d, J= 3.2 Hz, 1H), 6.00 (s, 2H), 4.34 (s, 2H), 4.08 (t, J= 6.3 Hz, 2H), 2.85 (t, J= 6.3 Hz, 2H), 2.38 (d, J= 6.8 Hz, 2H), 1.70 (m, 1H), 0.88 (d, J= 6.7 Hz, 6H); 13 C NMR (125 MHz, CDC]s/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) n/z [M+H]* caled. for C 23

H

26

FN

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

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

)

2

C

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

C

2 :MeOH-NH 3 (7N), 20:1) to give 23.4 mg (88%) of DZ3-26. 'H NMR (500 MHz, CDC 3 ) 8 7.49 (in, 1 H), 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, 211), 1.70 (m, IH), 0.83 (d, J= 6.7 Hz, 6H); ' 3 C NMR (125 MHz, CDCl 3 ) 5 158.9 (d, J= 208.5 Hz), 156.2 (d, J = 20.3 Hz), 152.7 (d, J= 18.2 Hz), 152.2, 147.5, 146.9, 143.1, 140.1, 127.0,125.7,124.7, 116.6, 111.8, 110.2, 109.4, 101.4, 57.5,48.5, 43.0, 31.9,28.1, 20.4; HRMS (ESI) m/z [M+H]* called. for C 23

H

26

FN

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

)

2

C

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

CI

2 (1.5 mL) and TFA (0.3 mL). The mixture was stirred for 5 h at rt, then solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2

CI

2 :EtOAc:MeOH-NH 3 (7N), 4:15:2:1) to give 5.2 mg (20%) of DZ3-31. 'H NMR (500 MHz, CDCI 3 /MeOH-d4) 8 6.91 (s, 1H), 6.84 (dd, J= 1.4,2.5 Hz, 1 H), 6.65 (s, 1H), 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, 211), 2.55 (d, J= 7.0 Hz, 2H), 1.88 (m, 1H), 0.96 (d, J= 6.7 Hz, WO 2011/044394 PCT/US2010/051872 92 611); 1 3 C NMR (125 MHz, CDC13/MeOH-d 4 ) 8 158.8 (d, J= 208.1 Hz), 156.4 (d, J= 20.0 Hz), 152.9, 152.3 (d, J= 21.2 Hz), 147.4, 129.8, 127.9, 126.7, 118.5, 110.5,109.3,108.7, 108.6, 101.5, 56.6, 47.4,41.1, 31.6,27.1, 20.2; HRMS (ESI) m/z [M+H] calcd. for

C

23 H27FN 7 0 2 , 452.2210; found 452.2212; HPLC: method A R = 7.02, method B Rt= 8.30. 5-(6-((6-amino-2-fluoro-9-(2-(isobutylanino)ethyl)-9H-purin-8 yl)methyl)benzo[d][1,3]dioxol-5-yl)furan-2-carbaldehyde 1DZ3-341. 2-Formyl-5 furanylboronic acid (12.3 mg, 0,0877 mmol) was added to PU-DZ13 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2 Cl 2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2 Cl 2 :EtOAc:MeOH-NH 3 (7N), 2:2:1:0.5) to give 2.0 mg (7%) of DZ3-34. 'H NMR (500 MHz, CDC1 3 /MeOH-d 4 ) 8 9.47 (s, 1H), 7.27 (d, J= 3.7 Hz, 111), 7.20 (s, 1), 6.77 (s, 1), 6.63 (d, J= 3.7 Hz, 111), 6.06 (s, 211), 4.45 (s, 211), 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

26

FN

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

)

2

C

2 (4 mg, 0.00584 nnol) 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:CH 2

CI

2 :EtOAc:MeOH-NH 3 (7N), 2:2:1:0.5) to give 10.6 mg (40%) of DZ3-32. 'H NMR (500 MHz, CDCl3/MeOH-d 4 ) 8 7.50 (s, 2N), 6.83 (s, IH), 6.69 (s, 1H), 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); "C NMR (125 MHz, CDC1 3 /MeOH-d4) S 158.6 (d, J= 208.3 Hz), 156.3 (d, J= 19.6 Hz), 152.3, 152.1 (d, J= 21.2 Hz), 147.3, 147.1, 126.4, 126.2, 120.1, 115.8, 110.7, 109.9, 101.4,56.3,47.3,40.8,31.9, 27.0,20.0; HRMS (ESI) m/z [M+H]* calcd. for C 2 2

H

26

FN

8 0 2 , 453.2163; found 453.2162; HPLC: method A Rt = 6.23, method B Rt = 6.55. 2-fluoro-9-(2-(isobutylaino)ethyl)-8-((6-(5-methylfuran-2-yl)benzo[d][1,3]dioxol-5 yI)methyl)-9H-purin-6-amine [DZ3-361. 4,4,5,5-Tetramethyl-2-(5-methy-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 0 C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2 C12;EtOAc:MeOH-NH 3 (7N), 4:15:2:1) to give 15.6 mg (57%) of DZ3-36. 'H NMR (500 MHz, CDC1 3 ) 8 7.04 (s, 1H), 6.53 (s, 1H), 6.26 (d, J= 3.1 Hz, 1H), 6.21 (br s, 2H), 6.05 (d, J= 3.1 Hz, 1H), 5.94 (s, 2H), 4.37 (s, 2H), 3.98 (t, J= 6.3 Hz, 2H), 2.80 (t, J= 6.2 Hz, 2H), 2.34 (s, 3H), 2.31 (d, J= 6.8 Hz, 2H), 1.64 (m, 1H), 0.83 (d, J= 6.7 Hz, 6H); HRMS (ESI) m/z [M+H]* calcd. for C 24

H

28

FN

6 0 3 , 467.2207; found 467.2200; HPLC: method A Rt = 7.29, method B Rt = 9.13. 8-((6-(IH-pyrrol-3-yl)benzo[d [1,3]dioxol-5-yl)methyl)-2-fluoro-9-(2 (isobutylamino)ethyl)-9H-purin-6-aine [DZ3-38]. 1-Boc-pyrrole-3-boronic acid pinacol ester (30.9 mg, 0.1053 mmol) was added to PU-DZ13 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (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 0 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, CDCI 3 ) 8 8.72 (hr s, 1H), 6.85 (s, 1 H), 6.83 (in, IH), 6.76 (in, IH), 6.62 (s, IH), 6.34 (hr s, 2H), 6.23 (in, IH), 5.91 (s, 2H), 4.29 (s, 2H), 3.84 (t, J= 6.3 Hz, 2H), 2.67 (t, J= 6.3 Hz, 2H), 2.28 (d, J= 6.8 Hz, 2H), 1.60 (in, IH), 0.82 (d, J= 6.6 Hz, 6H); ' 3 C NMR (125 MHz, CDCI 3 ) 8 158.8 (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 3H27FN 7 0 2 , 452.2210; found 452.2204; HPLC: method A Rt = 6.77, method B R, = 7.93. 2-(6-((6-amino-2-fluoro-9-(2-(isobutylamino)ethyl)-9H-purin-8 yl)methyl)benzo[d][1,3]dioxol-5-yl)acetonitrile [DZ3-40]. 4-Isoxazoleboronic acid pinacol ester (20.5 ing, 0.1053 mmol) was added to PU-DZ13 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

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

CI

2 :EtOAc:MeOH-NH3 (7N), 4:7:2:1) to give 8.3 mg (%) of DZ3-40. 'H NMR (500 MHz, CDC13/MeOH-d 4 ) 8 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, CDC1 3 / MeOH-d) S 158.7 (d, J= 210.4 Hz), 156.6 (d, J= 20.1 Hz), 152.1 (d, J= 18.2 Hz), 150.5, 148.1, 147.7, 126.7, 122.4, 117.9, 116.1,110.6,109.9, 101.8,56.5, 47.4, 41.2,31.3,27.1, 21.5, 20.0; HRMS (ESI) mnz [M+H]* calcd. for C 2 tH 25

FN

7 0 2 , 426.2054; found 426.2048; HPLC: method A Rt = 6.48, method B R, = 7.10. 8-((6-(1H-pyrazol-3-yl)benzo[d] [1,3]dioxol-5-yl)methyl)-2-fluoro-9-(2 (isobutylamino)ethyl)-9H-purin-6-amine [DZ3-43]. IH-pyrazole-3-boronic acid (11.8 mg, 0.1053 mmol) was added to PU-DZ13 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction WO 2011/044394 PCT/US2010/051872 95 mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2 Cl 2 (8 mg, 0.0117 nmmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 4.5 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2 C1 2 :EtOAc:MeOH-NH 3 (7N), 2:2:1:0.5) to give 3.5 mg (13%) of DZ3-43. 'H NMR (500 MHz, CDCl 3 /MeOH-d 4 ) $ 7.63 (d, J= 2.15 Hz, 1H), 6.95 (s, 1H), 6.82 (s, 1H), 6.34 (d, J= 2.15 Hz, 1H), 6.01 (s, 2H), 4.35 (t, J= 6.8 Hz, 2H), 4.29 (s, 2H), 2.98 (t, J= 6.9 Hz, 2H), 2.64 (d, J= 7.0 Hz, 2H), 1.96 (m, 1H), 0.99 (d, J= 6.7 Hz, 6H); ' 3 C NMR (125 MHz, CDC 3 / MeOH-d 4 ) S 158.8 (d, J= 208.7 Hz), 156.6 (d, J= 19.3 Hz), 152.4, 152.2 (d, J = 18.7 Hz), 148.3, 147.3, 127.1, 115.94, 115.93, 110.3, 110.1, 105.6, 101.8, 56.3, 47.4,40.5, 31.5, 27.0, 20.2; HRMS (ESI) m/z [M+H]* called. for C22H 2 6

FN

8

O

2 , 453.2163; found 453.2149; HPLC: method A R, = 6.37, method B R, = 6.93. 2-fluoro-9-(2-(isobutylamino)ethyl)-8-((6-(1-methyl-1H-pyrazol-5 yl)benzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-6-amine [DZ3-451. 1-Methyl-I-H-pyrazole 5-boronic acid pinacol ester (18.2 mg, 0.0877 mmol) was added to PU-DZ13 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then 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 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, IH), 6.76 (s, IH), 6.74 (s, IH), 6.28 (br s, 2H), 6.17 (d, J= 1.5 Hz, IH), 6.01 (s, 2H), 3.99 (s, 2H), 3.90 (t, J= 6.3 Hz, 2H), 3.66 (s, 3H), 2.76 (t, J= 6.3 Hz, 2H), 2.31 (d, J= 6.8 Hz, 2H), 1.72 (m, 1H), 0.84 (d, J= 6.7 Hz, 6H); 1 3 C NMR (125 MHz, CDCl 3 ) 8 159.0 (d, J= 208.7 Hz), 156.4 (d, J= 20.0 Hz), 152.8 (d, J= 18.5 Hz), 151.5, 149.0, 147.1, 141.3, 138.8, 129.4, 123.4, 116.6,110.7,109.9, 106.9, 101.9, 57.8, 48.7, 43.1, 36.9, 31.8, 28.3, 20.6; HRMS (ESI) m/z [M+Hjcalcd. for C2 3

H

2 8FNO2, 467.2319; found 467.2323; HPLC: methodA Re=6.37, method B Re = 6.90.

WO 2011/044394 PCT/US2010/051872 96 2-fluoro-9-(2-(isobutylamino)ethyl)-8-((6-(thiophen-2-yl)benzo[d] [1,3]dioxol-5 yl)methyl)-9H-purin-6-amine [DZ3-48]. 2-Thienylboronic acid (11.2 mg, 0.0877 mmol) was added to PU-DZ13 (30 mg, 0.0585 mmol) and NaHCO 3 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H 2 0 (0.1 mL) and Pd(PPh) 2 Cl 2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 2 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2

CI

2 :EtOAc:MeOH-NH3 (7N), 2:2:1:0.5) to give 18.3 mg (67%) of DZ3-48. 'H NMR (500 MHz, CDC1 3 /MeOH-d4) 5 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, 111), 6.74 (s, 111), 6.01 (s, 2H), 4.19 (s, 211), 3.99 (t, J= 6.5 Hz, 2H), 2.78 (t, J= 6.5 Hz, 2H), 2.37 (d, J= 6.9 Hz, 2H), 1.70 (m, IH), 0.88 (d, J= 6.7 Hz, 6H); "C NMR (125 MHz, CDCI3/MeOH-d 4 ) 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]* called. for C23H26FNO 2 S, 469,1822; found 469.1830; HPLC: method A Rt = 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 H 2 0 (0.1 mL) and Pd(PPh 3

)

2 Cl 2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 60 0 C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH2Cl 2 :EtOAc:MeOH-NH3 (7N), 2:2:1:0.5) to give 7.8 mg (29%) of an inseparable mixture of DZ3-51 and DZ3-40 in a ratio of approximately 44:56, respectively, as determined by HPLC. MS (ESI) m/z [M+H]* 454.4; HPLC: method A Rt = 6.46 (DZ3-40, 56%) and 6.65 (DZ3-51, 44%); method B R, = 7.08 (DZ3-40, 65%) and 7.52 (DZ3-51, 35%).

WO 2011/044394 PCT/US2010/051872 97

NH

2 NH 2 NNN N a N N aN~ '>_s R S N N HN HN PU-HZ151 Reagents and conditions: (a) RB(OH) 2 , PdC2(PPh 3

)

2 , NaHCO 3 , H20, DMF, 90*C. Scheme 5. Suzuki coupling of PU-HZ151. 8-(6-(furan-2-yl)benzo[d][1,3]dioxol-5-ylthio)-9-(2-(neopentylamino)ethyl)-9H-purin-6 amine [TT5-53A]. 2-Furanylboronic acid (42.4 mg, 0.379 mmol) was added to PU-HZ151 (66.4 mg, 0.126 nmol) and NaHC0 3 (63.6 mg, 0.756 mmol). DMF (2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.4 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 ) 6 8.30 (s, 1 H), 7.49 (d, J= 1.3 Hz, 1 H), 7.17 (s, 1H), 6.84 (s, IH), 6.75 (d, J= 3.3 Hz, iH), 6.48 (dd, J= 1.8, 3.3 Hz, IH), 5.97 (s, 2H), 5.89 (br s, 2H), 4.18 (t, J= 6.5 Hz, 2H), 2.86 (t, J= 6.5 Hz, 2H), 2.25 (s, 2H), 0.83 (s, 9H); 13 C NMR (125 MHz, CDC3) 5 154.6, 153.0, 151.7, 151.1, 148.4, 147.9, 146.8, 142.2, 127.2, 120.8, 120.0,112.8,111.5, 110.0, 108.7, 101.9,61.9,49.6,43.9,31.5,27.6; HRMS (ESI) m/z [M+H] t called. for C23H27NO3S, 467.1865; found 467.1870; HPLC: method AR, = 6.78, method B R, = 7.83.

WO 2011/044394 PCT/US2010/051872 98 8-(6-(5-methylfuran-2-yl)benzo[d] [1,3]dioxol-5-ylthio)-9-(2-(neopentylamino)ethyl)-9H purin-6-amine [DZ3-56]. 4,4,5,5-Tetramethyl-2-(5-methyl-furan-2-yl)-(1,3,2)dioxaborolane (17.7 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 H 2 0 (0.1 mL) and Pd(PPh 3

)

2 C1 2 (8 mg, 0.0113 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 4.5 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2 C12:MeOH-NH 3 (7N), 15:1) to give 9.3 mg (34%) of DZ3-56. 'H NMR (500 MHz,

CDCI

3 /MeOH-di) 6 8.19 (s, 1H), 7.24 (s, 1H), 6.89 (s, IH), 6.62 (d, J= 3.2 Hz, 111), 6.05 (d, J= 3.2 Hz, 1H), 6.03 (s, 2H), 4.36 (t, J= 6.0 Hz, 2H), 3.04 (t, J= 6.0 Hz, 2H), 2.47 (s, 2H), 2.33 (s, 3H), 0.95 (s, 9H); "C NMR (125 MHz, CDCI 3 /MeOH-d) 8 154.5, 152.4, 152.3, 151.2, 149.4, 149.2, 148.5, 147.7, 129.1, 119.4, 117.4, 114.3, 111.2, 108.6, 107.8, 102.2, 61.4, 49.3, 43.2, 31.4, 27.7, 13.7; HRMS (ESI) m/z [M+H]* calcd. for C2 4

H

29

N

6 0 3 S, 481.2022; found 481.2002; HPLC: method A R, = 6.89, method B R, = 7.58. 9-(2-(neopentylamino)ethyl)-8-(6-(thiophen-2-yl)benzo[d] [1,3]dioxol-5-ylthio)-9H-purin 6-amine [DZ3-58]. 2-Thiopheneboronic acid (10.9 mg, 0.0853 mmol) was added to PU HZ151 (30 mg, 0.0569 nmol) 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, CDCl1/MeOH-d 4 ) & 8.18 (s, 1H), 7.32 (dd, J= 1.6,4.7 Hz, 1H), 6.98-7.03 (m, 411), 6.07 (s, 211), 4.29 (t, J= 5.4 Hz, 2H), 3.03 (t, J= 5.4 Hz, 211), 2.48 (s, 211), 0.97 (s, 911); 1 3 C NMR (125 MHz, CDCI 3 /MeOH d 4 ) 6 154.3, 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) m/z [M+H]* called. for

C

23

H

2 7

N

6 0 2

S

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

WO 2011/044394 PCT/US2010/051872 99 8-(6-(1H-pyrrol-3-yI)benzo[d] [1,3]dioxol-5-ylthio)-9-(2-(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 NaHC0 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 nmol) were added and the reaction mixture was heated under nitrogen at 900C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2

C

2 :MeOH

NH

3 (7N), 20:1) to give 10.1 mg (38%) of DZ3-59. 'H NMR (500 MHz, CDC 3 /MeOH-ds) S 8.15 (s, 1H), 7.03 (s, 1H), 6.95 (s, iH), 6.85 (in, 1H), 6.76 (in, IH), 6.20 (dd, J- 1.7, 2.4 Hz, 1H), 6.01 (s, 2H), 4.24 (t, J= 5.7 Hz, 2H), 2.98 (t, J= 5.7 Hz, 2H), 2.50 (s, 2H), 0.98 (s, 9H); "C NMR (125 MHz, CDCl 3 /MeOH-d4) 8 154.3, 152.1, 149.6, 149.3, 146.8, 135.7, 122.3, 119.3, 118.6, 117.9, 117.4, 114.5, 111.1, 109.4, 101.9,61.0,49.3,42.7,31.2,27.7; HRMS (ESI) m/z [M+H]* called. for C23H 2 sN 7

O

2 S, 466.2025; found 466.2016; HPLC: method A Rt = 6.86, method B Rt = 7.20. 8-(6-(furan-3-yl)benzo[dJ [1,3]dioxol-5-ylthio)-9-(2-(neopentylamino)ethyl)-9H-purin-6 amine [DZ3-60]. 3-Furanylboronic acid (9.5 mg, 0.0853 mmol) was added to PU-HZ151 (30 mg, 0.0569 mmol) and NaHCO 3 (14.3 mg, 0.1707 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H 2 0 (0.1 mL) and Pd(PPh 3

)

2

C

2 (8 mg, 0.0113 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2 Cl2:MeOH-NH 3 (7N), 20:1) to give 13.8 mg (52%) of DZ3-60. 1 H NMR (500 MHz, CDCl3/MeOH-d4) 5 8.17 (s, 1H), 7:50 (s, 1H), 7.43 (d, J= 1.5 Hz, 1H), 7.02 (s, 1H), 6.94 (s, 1H), 6.49 (d, J= 1.5 Hz, iH), 6.06 (s, 2H), 4.29 (t, J = 5.9 Hz, 2H), 3.02 (t, J= 5.8 Hz, 2I), 2.46 (s, 2H), 0.94 (s, 9H); ' 3 C NMR (125 MHz, CDC1/MeOH-d,) 5 154.3, 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) m/z

[M+H]

t called. for C23H27N6O3S, 467.1865; found 467.1845; HPLC: method A Re = 6.65, method B R= 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]. 1H-Pyrazole-3-boronic acid (19 mg, 0.1707 mmol) was added to PU-HZ151 (30 mg, 0.0569 mmol) and NaHC0 3 (14.3 mg, 0.1707 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

2

C

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

C

2 :MeOH-NH 3 (7N), 15:1) to give 6.5 mg (25%) of DZ3-61. 'H NMR (500 MHz, CDC3/MeOH-d) 5 8.18 (s, 1H), 7.58 (d, J= 2.0 Hz, 1H), 7.05 (s, 2H), 6.40 (d, J= 2.0 Hz, 1H), 6.06 (s, 2H), 4.36 (t, J = 6.0 Hz, 2H), 3.01 (t, J= 6.0 Hz, 2H), 2.51 (s, 2H), 0.97 (s, 9H); "C NMR (125 MHz,

CDCI

3 /MeOH-d4) 5 154.6, 152.3, 150.8, 149.4, 148.6, 148.5, 120.1, 119.2, 114.5, 110.9, 106.0, 102.3, 61.2, 49.1, 42.5, 31.1, 27.5; HRMS (ESI) m/z [M+Hf caled. for C22H27NO 2 S, 467.1978; found 467.1972; HPLC: method A R, = 6.50, method B Rt = 6.61.

WO 2011/044394 PCT/US2010/051872 101

NH

2 a b N N, H 2 N I N N H 0 s6-1 S6-2 S6-3

NH

2 | NS N NN I H 0 N 1 N 0 H -6-4 S6-5 d, e d, e

NH

2 N N. NNH 2 NNN N n=, 0 N RHN RH n= 1, 2 RHN S64 PU-WS4 n= 2, R= isopropyl PU-WS9 n= 1, R= isobutyl PU-WS21 n= 1, R= neopentyl Reagents and conditions: (a) NaNO 2 , KI, AcOH/TFA, 0*C; (b) 8-mercaptoadenine, Cs 2 C0 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 0 C. Scheme 6. Synthesis of PU-WS4, PU-WS9 and PU-WS21. 6-iodo-2,3-dihydrobenzofuran (S6-2). A solution of 2,3-dihydrobenzofuran-6-amine (S6-1; 0.74 g, 5.5 mmol) in acetic acid (25 mL) and TFA (2 mL) was cooled in an ice bath for 5 minutes. NaNO 2 (0.454g, 6.6 mmol) was added in 3 portions followed by KI (2.73 g, 16.4 mmol). The resulting mixture was stirred at 0*C for 15 minutes and quenched with 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 ) S 7.14 (d, J= 7.6 Hz, 1H), 7.11 (s, IH), 6.89 (d, J= 7.6 Hz, 1H), 4.54 (t, J= 8.7 Hz, 2H), 3.14 (t, J= 8.7 Hz, 2H); "C NMR (125 MHz, CDC1 3 ) 8 161.1, 129.4, 127.1, 126.4, 118.7, 91.7, 71.6, 29.4. 8-(2,3-dihydrobenzofuran-6-ylthio)-9H-purin-6-amine (S6-3). To a solution of S6-2 (50 mg, 0.2 mmol) in DMF (2 mL) was added 8-mercaptoadenine (34 mg, 0.2 mmol), Cs 2

CO

3 (99.4 mg, 0.3 mmol) and 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) S 8.14 (s, 1H), 7.24 (d, J= 7.6 Hz, IH), 7.07 (d, J=7.3 Hz, 1H), 6.97 (s, IH), 4.62 (t, J= 8.7 Hz, 2H), 3.25 (t, J= 8.7 Hz, 2H); MS (ESI) m/z 285.8 [M+H]*; HRMS (ESI) m/z [M+H] calcd. for C 1 3 H1 2

N

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

(CH

2 C1 2 :MeOH, 100:0 to 90:10) to afford S6-4 (48 mg, 53%) as a yellow gum. 'H NMR (500 MHz, CDC1 3 ) 8 8.26 (s, 1H), 7.79 (s, 1H), 7.12 (s, iH), 4.65 (t, J= 8.8 Hz, 2H), 3.28 (t, J= 8.7 Hz, 2H); MS (ESI) m/z 412.0 (M+H)*. 8-(5-iodo-2,3-dihydro-benzofuran-6-ylsulfanyl)-9-(3-isopropylamino-propyl)-9H-purin 6-ylamine (PU-WS4). A mixture of S6-4 (54 mg, 0.13 mmol), Cs 2

CO

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

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

/CD

3 0D) 8 8.26 (s, 1H), 7.77 (s, 1H), 7.07 (s, 1H), 4.65 (t, J= 8.7 Hz, 2H), 4.47 (t, J= 6.9 Hz, 2H), 3.20-3.33 (m, 3H), 3.01 (t, J= 7.5 Hz, 2H), 2.33 (m, 2H), 1.34 (d, J= 6.5 Hz, 6H); MS (ESI) m/z 511.2 [M+H]*; HRMS (ESD m/z [M+H]* called. for C 1 9

H

2 4INOS, 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 CO3 (71 mg, 0.22 mmol) and 1,2-dibromoethane (69 mg, 0.365 mmol) in anhydrous DMF (1 mL) was stirred at rt for 2 h. Solvent was removed under reduced pressure and the residue purified by chromatography

(CH

2 Cl 2 :MeOH:AcOH). The resulting solid was dissolved in DMF (2 mL) and isobutylamine (0.241 g, 0.33 mL, 3.3 mmol) was added and the solution stirred overnight at rt. The reaction afforded PU-WS9 (15 mg, 40%; over two-steps) as a pale yellow solid. 'H NMR (500 MHz, CDCl 3 ) & 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]* called. for C19H2 4

IN

6 OS, 511.0777; found 511.0790. 8-((5-iodo-2,3-dihydrobenzofuran-6-yl)thio)-9-(2-(neopentylamino)ethyl)-9H-purin-6 amine (PU-WS21). Following the procedure to make PU-WS9, compound PU-WS21 was obtained as a white solid. 'HNMR (500 MHz, CDC 3 , S): 7.56 (s, 1H), 6.60 (s, 1H), 4.47 (t, J = 8.7 Hz, 2H), 4.37 (m, 2H), 3.06-3.11 (in, 4H), 2.45 (s, 2H), 0.83 (s, 9H); HRMS (m/z): [M+H]* called for C 2 0H26IN 6 0S 525.0933; found 525.0927.

WO 2011/044394 PCT/US2010/051872 104

NH

2

H

2 N >~~~\ b NN N -N HNN N S64 $7-1 S7-2

NH

2

NH

2

NH

2 N ,N, - e NN 0, N" N NN' N N HN S7-3 Br HN 87-4 PU-WS10 Reagents and conditions: (a) NIS, CH 3 CN, 0*C, 20 min.; (b) 8-mercaptoadenine, neocuproine, CuI, NaOt-Bu, DMF, 1 10*C; (c) NaNO 2 , KI, AcOH/TFA, 0*C; (d) 1,3-dibromopropane, Cs 2

CO

3 , DMF, rt; (e) isopropylamine, DMF, rt. Scheme 7. Synthesis of PU-WS1O. 5-iodo-2,3-dibydrobenzofuran-6-amine (S7-1). To a solution of 2,3-dihydrobenzofuran-6 amine (S6-1; 95 mg, 0.7 mmol) in acetonitrile (3 mL) cooled in an ice-bath was added NIS (158 mg, 0.7 mmol). After stirring at 0 *C for 20 min, the mixture was condensed and purified by flash chromatography (hexane:EtOAc, 90:10 to 20:80) to yield S7-1 (180 mg, 98%) as a yellow solid. 'H NMR (500 MHz, CDC1 3 ) 8 7.38 (s, 1H), 6.26 (s, 1H), 4.53 (t, J= 8.5 Hz, 2H), 3.09 (t, J= 8.4 Hz, 2H); MS (ESI) m/z 261.9 [M+H]*. 8-(6-amino-2,3-dihydrobenzofuran-5-ylthio)-9H-purin-6-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), Cu (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, 1H), 6.35 (s, IH), 4.57 (t, J= 8.5 Hz, 2H), 3.14 (t, J= 8.4 Hz, 2H); MS (ESI) m/z 301.0 [M+H]*. 8-(6-iodo-2,3-dihydrobenzofuran-5-ylthio)-9H-purin-6-amine (S7-3). To a solution of S7-2 (25 mg, 0.08 mmol) in acetic acid/TFA (5 mL/I mL) cooled in ice-bath was added NaNO 2 (7 mg, 0.1mmol) and KI (27 mg, 0.16 mmol). The mixture was stirred at 0*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. 'H NMR (500 MHz, CD 3 0D) 8 8.13 (s, iH), 7.57 (s, iH), 7.44 (s, IH), 4.66 (t, J= 8.5 Hz, 2H), 3.22 (t, J= 8.6 Hz, 2H); MS (ESI) n/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 tL, 0.16 mmol) and Cs 2

CO

3 (20 mg, 0.06 mmol) and the resulting mixture was stirred at rt for 40 minutes. The mixture was condensed under reduced pressure and the residue was purified by flash chromatography to yield S7-4 (6.2 mg, 34%). 'H NMR (500 MHz, CDC 3 ) a 8.31 (s, lH), 7.37 (s, 2H), 6.00 (br s, 2H), 4.62 (t, J= 8.7 Hz, 2H), 4.36 (t, J= 6.7 Hz, 2H), 3.42 (t, J= 6.2 Hz, 2H), 3.18 (t, J= 8.9 Hz, 2H), 2.39 (m, 2H); MS (ESI) m/z 531.9/533.9 [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 mL) was stirred for 12 h. Solvent was removed under reduced pressure and the residue purified by preparative thin layer chromatography (CHC1 3 :MeOH-NH 3 (7N), 20:1) to afford PU-WS1O (4.0 mg, 60%) as a pale yellow solid. 'H NMR (400 MHz, CDC 3 ) 8 8.27 (s, lH), 7.69 (s, 1H), 7.27 (s, 1H), 5.93 (br s, 2H), 4.66 (t, J= 8.8 Hz, 2H), 4.29 (t, J= 7 Hz, 2H), 3.33 (t, J= 8.7 Hz, 2H), 2.74 (septet, J= 6.2 Hz, 1H), 2.58 (t, J= 6.8 Hz, 2H), 1.98 (in, 2H), 1.05 (d, J= 6.5 Hz, 6H); "C NMR (100 MHz, CDC1 3 ) 8 162.0,154.4, 152.7, 151.9, 147.8, 141.7, 130.2, 128.6, 121.1, 120.0, 74.1, 71.7, 48.9, 44.0, 41.6, 30.9, 30.2; MS (ESI) m/z 511.1 [M+H]*.

WO 2011/044394 PCT/US2010/051872 106

NH

2 NH2 N a,b,c N NN X N or a, d,c XN or a, d, e, c RHN RHN PU-DZ8 X 1

=CH

2 , X 2 =F, n= 2, R= isopropyl PU-WS3 X,=CH 2 , X 2 =F, X,=CN, n=2, R= isopropyl PU-H71 X 1 =S, X 2 =H, n 2, R= isopropyl PU-WSS X 1 =S, X 2 =H, X 3 =CN, n= 2, R= isopropyl PU-HZI0 X 1 =S, X 2 =H, n= 1, R= isobutyl PU-WS6 X1=S, X 2 =H, X9=CCt-Bu, n= 2, R= isopropyl PU-HZISI X 1 =S, X2=H, n= 1, R= neopentyl PU-WS7 X 1 =S, X 2 =H, Xa=CCPh, n= 2 R= isopropyl PU-DZ13 X1=CH2 PU-WS8 X 1 =S, X2=H, X 3 =CCH, n= 2, R= isopropyl

X

1 C X 2 =F, n= 1, R= soutyl PU-WSI X 1 =S, X2=H, X=CCH, n= 1, R= isobutyl PU-WS19 X 1 =S, X 2 =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) Boc2O, Et 3 N, THF, rt, 12h; (b) PdCl2(dppf), Zn(CN) 2 , Zn, DMF, 130*C; (c) 10% TFA-CH 2

CI

2 , it, 2-5h; (d) CuI, PdC 2 (PPh 3

)

2 , t-butylacetylene or phenylacetylene or trimethylsilanylacetylene, Et 3 N, DMF, 90*C, 24h; (e) KOH, MeOH, it, 2h. Scheme 8. Synthesis of PU-WS3, PU-WS5, PU-WS6, PU-WS7 and PU-WS8, PU-WS16, PU-WS19 and PU-WS20. 6-[6-anino-2-fluoro-9-(3-isopropylanino-propyl)-9H-purin-8-ylmethyl] benzo[1,3]dixole-5-carbonitrile (PU-WS3). A solution of PU-DZ8 (118 mg, 0.231 mmol), (Boc) 2 0 (55 mg, 0.254 rmol) and triethylamine (16 mg, 0.231 nimol) 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-DZS (120 mg, 85%; MS (ESI) m/z 613.05 [M+H]'). To a solution of Boc protected PU-DZS (26 mg, 0.04 nimol) in DMF (3 mL) was added PdCl 2 (dppf) (17 mg, 0.02 mmol), Zn(CN) 2 (10 mg, 0.08 mmol) and Zn (3 mg, 0.04 mL) and the resulting mixture was stirred at 130'C overnight. The reaction mixture was condensed under reduced pressure and the residue was purified by flash chromatography (CHCI 3 :MeOH-NH 3 (7N), 20:1) to yield Boc-protected PU-WS3 as a white solid. To a solution of this in 2 mL of CH 2 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

(CHCI

3 :MeOH-NH 3 (7N), 20:1) to yield PU-WS3 as a white solid in quantitative yield (12 mg, 59% for three steps). 'H NMR (500 MHz, CD 3 0D) 6 7.13 (s, IH), 6.96 (s, IH), 6.03 (s, 2H), 4.31 (s, 2H), 4.25 (t, J= 7 Hz, 211), 3.26 (m, 1H), 3.01 (t, J= 7.5 Hz, 2H), 2.14 (m, 2H), 1.23 (d, J =6.5 Hz, 6H); 3 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-ylsulfanyl]benzo [1,3]dixole-5 carbonitrile (PU-WS5). The procedure for the preparation of PU-WS3 was followed starting from PU-H71. The reaction afforded PU-WS5 (6.5 mg, 32% for three steps) as a white solid. 'H NMR (500 MHz, CDC1 3

/CD

3 0D) $ 8.21 (s, 1H), 7.22 (s, 1H), 7.19 (s, I), 6.19 (s, 2H), 4.40 (t, J= 7 Hz, 211), 3.09 (septet, J= 6.5 Hz, 111), 2.83 (t, J= 7.5 Hz, 2H), 2.26 (m, 2H), 1.25 (d, J= 6.5 Hz, 6H); MS (ESI) m/z 412.2 [M+H]*; HRMS (ESI) m/z [M+H]* calcd. for Cj 9 H22N 7 0 2 S, 412.1556; found 412.1560. 8-[6-(3,3-dimethyl-but-1-ynyl)-benzo[1,3]dioxol-5-ylsulfanyl]9-(3-isopropylamino propyl)-9H-purin-6-ylamine (PU-WS6). A solution of PU-H71 (70 mg, 0.137 mmol), (Boc) 2 0 (35 mg, 0.161 mmol) and triethylamine (13 mg, 0.137 nmol) 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 CuI (4 mg, 0.1 mmol), PdC1 2 (PPh 3

)

2 (14 mg, 0.02 mmol), t-butylacetylene (72 pL, 0.59 mmol) and triethylamine (137 iL) 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

C

2 was added TFA (1.5 mL) and stirred at RT for 2 Irs. The mixture was condensed and purified by flash chromatography to afford PU-WS6 (97 mg, 52 % for three steps) as a white solid. 'H NMR (500 MHz, CDC1 3

/CD

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

/CD

3 OD)8 50.5, 41.3, 40.2, 30.3, 27.8, 25.9, 18.5; MS (ESI) m/z 467.3 [M+H]*; HRMS (ESI) m/z [M+H]* calcd. for C 2 4H31N 6 0 2 S, 467.2229; found 467.2233. 9-(3-isopropylamino-propyl)-8-(6-phenylethynyl-benzo [1,3]dixool-5-ylsulfanyl)-9H purin-6-ylandne (PU-WS7). The procedure for the preparation of PU-WS6 was followed with phenylacetylene (65 IL, 0.59 mmol) to afford PU-WS7 (46 mg, 34% in three steps) as a white solid. 'H NMR (500 MHz, CDC 3

/CD

3 0D) S 8.2 (s, 1H), 7.30-7.40 (m, 5H), 7.08 (s, 1H), 6.96 (s, IH), 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); ' 3 C NMR (125 MHz, CDCI 3

/CD

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

C

26 H27N 6 0 2 S, 487.1903; found 487.1913. 8-(6-ethynyl-benzo[1,3]dioxol-5-ylsulfanyl)-9-(3-isopropylanino-propyl)-9H-purin-6 ylamine (PU-WSS). 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 C1 2 and was stirred at rt for 2 hrs. The mixture was concentrated under reduced pressure and the residue chromatographed to afford PU-WS8 (5.2 mg, 26% for four steps) as a pale yellow solid. 'H NMR (500 MHz, CDC 3 ) 8 8.32 (s, 1H), 6.99 (s, IH), 6.84 (s, IH), 6.00 (s, 2H), 5.61 (br s, 2H), 4.31 (t, J= 7 Hz, 2H), 3.31 (s, IH), 2.71 (m, 1H), 2.56 (t, J = 7 Hz, 2H), 1.97 (m, 2H), 1.02 (d, J = 6.5 Hz, 6H); MS (ESI) m/z 411.2 [M+H]*; HRMS (ESI) m/z [M+H]* calcd. for

C

20 H23N 6 0 2 S, 411.1603; found 411.1605. 8- ((6-ethynylbenzo[d][1,3]dioxol-5-yl)thio)-9-(2-(isobutylamino)ethyl)-9H-purin-6 amine (PU-WS16). Following the procedure to make PU-WS8, PU-WS16 was obtained as a white solid. 'H NMR (500 MHz, CDC 3 ) 5 8.24 (s, IH), 6.91 (s, 1H), 6.77 (s, 1H), 6.01 (s, 2H), 5.78 (br s, 2H), 4.33 (t,J= 6.1 Hz, 2H), 3.24 (s, 1H), 2.92 (t, J= 6.1 Hz, 2H), 2.38 (d, J WO 2011/044394 PCT/US2010/051872 109 = 6.8 Hz, 2H), 1.63 (m, IH), 0.77 (d, J= 6.6 Hz, 6H); "C NMR (125 lHz, CDC1 3 ) 8155.1, 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 (ES) m/z [M+H]* calcd. for C 20 H22N 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. 'H NMR (500 MHz, CDC1 3 ) 8 8.32 (s, 1H), 6.97 (s, 1H), 6.83 (s, 1H), 5.98 (s, 2H), 5.76 (br s, 2H), 4.35 (m, 2H), 3.06 (s, 1H), 2.97 (m, 2H), 2.33 (s, 2H), 0.82 (s, 9H); 1 3 C NMR (125 MHz, CDC1 3 ) 8 154.5, 152.9, 151.5, 149.1, 147.9, 146.5, 120.1, 117.7, 112.9, 111.9, 102.2, 82.3, 81.0, 61.9, 49.8, 43.9, 31.5, 27.7; HRMS (ESI) m/z [M+H] t called. for C21H 2 5

N

6 0 2 S, 425.1760; found 425.1753. 8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9-(2-(isobutylamino)ethyl)-9H purin-6-amine (PU-WS20). Following the procedure to make PU-WS8, PU-WS20 was obtained from PU-DZ13 as a white solid. 1 H NMR (MeOH-d 4 , 500 MHz) S: 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); 1 3 C NMR (MeOH d4, 125 MHz) 8: 159.8, 158.1, 152.6, 151.4, 149.8, 147.2, 134.3, 116.2, 114.2, 112.5, 109.8, 102.3, 80.9, 57.5, 43.0, 32.6, 29.8, 28.2, 20.5.

WO 2011/044394 PCT/US2010/051872 110

NH

2 ac N ' N. H b,c S d

H

2 NaO It N HN-s 00 59-1 59-2 S9-3 0j

NH

2

NH

2 N'-N N\ N\ W- >-S e N N O O X ~0 Br 0 NHR 0 PU-HT165 X=CH 2 , R= isobutyl S9-4 X=CH 2 PU-HT175 X=CH 2 , R= neopentyl S9-5 X=CH 2

CH

2 PU-RK11 X=CH 2

CH

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

CH

2 , R= 1-imidazoyl Reagents and conditions: (a) NaNO 2 , 10% HC1, 0*C; KI, 0*C to rt; (b) 8-mercaptoadenine, neocuproine, Cul, NaOt-Bu, DMF, 110*C, 24 h; (c) NIS, TFA, CH 3 CN, rt; (d) 1,2-dibromoethane or 1,3-dibromopropane, Cs 2

CO

3 , DMF, rt; (e) isobutylarnine or neopentylamine or isopropylamine or imidazole, DMF, rt. Scheme 9. Synthesis of PU-HT165, PU-HT175, PU-RKI 1, PU-RK12. 6-Iodo-2,3-dihydrobenzo[b][1,4]dioxine (S9-2). 2,3-dihydrobenzo[b][1,4]dioxin-6-amine (S9-1; 5 g, 33 mmol) was dissolved in 10% HC1 solution and cooled to 0*C. Then, 30 mL of a cold aqueous solution of NaNO2 (4.6 g, 66 mmol) was added over a period of 15 min and the reaction mixture was stirred at 0*C for an additional 10 mn, followed by the addition of urea (1.6 g, 27 mmol). After 15 min, 40 mL of a suspension of KI (16.5 g, 100 mmol) in water/CH 2 CI2 (1:1) was added. The reaction mixture was stirred overnight at room temperature then extracted with CH2C1 2 , dried over MgSO 4 . And condensed under reduced pressure and the residue was purified by flash chromatography (hexane:EtOAc, 100:0 to 90:10) to afford S9-2 (7.4 g, 86%) as a colorless oil. 1H NMR (500 MHz, CDC 3 ) 8 7.28 5 (s, IH), 7.13 (d, J= 8.5 Hz, 1H), 6.63 (d, J= 8.5 Hz, 1 H), 4.27-4.24 (i, 4H).

WO 2011/044394 PCT/US2010/051872 111 8-(7-Iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-9H-purin-6-amine (S9-3). To a solution of S9-2 (1.26 g, 4.8 mmol) in DMF (15 mL) was added 8-mercaptoadenine (0.400 g, 2.4 mmol), neocuproine (0.056 g, 0.24 mmol), CuI (0.044 g, 0.24 mmol) and NatOBu (0.460 g, 4.8 mmol). The reaction mixture was stirred at 110 *C for 24h. Solids were filtered and the filtrate was condensed under reduced pressure. The residue was flash chromatographed (CHC1 3 :MeOH:AcOH, 60:0.5:0.5 to 30:0.5:0.5) to yield 0.578 g (80%) of intermediate coupling product (MS (ESI) m/z 301.9 [M+H]). To 0.400 g (1.4 mmol) of this and NIS (0.945 g, 4.2 mmol) in acetonitrile (15 mL) was added TFA (540 pL, 0.800 g, 7 mmol) and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (CHCl 3 :MeOH:AcOH, 60:0.5:0.5 to 30:0.5:0.5) to give S9-3 (0.436 g, 73%). 'H NMR (DMSO-d 6 , 500 MHz) 8 8.37 (s, 1H), 8.03 (br s, 2H), 7.47 (s, 1H), 7.10 (s, 1), 4.25-4.27 (in, 4H); MS (ESI) mz 427.9 [M+H]*. 9-(2-Bromoethyl)-8-(7-iodo-2,3-dihydrobenzo[b] [1,4]dioxin-6-ylthio)-9H-purin-6-amine (S9-4). A mixture of S9-3 (0.213 g, 0.5 mmol), 1,2-dibromoethane (0.500 g, 2.5 mmol) and Cs 2

CO

3 (0.184 g, 0.75 mmol) in anhydrous DMF (6 mL) was stirred at room temperature for 3h. Solids were filtered and the filtrate was condensed under reduced pressure to give a residue that was purified by preparative thin layer chromatography (CHCl 3 :MeOH-NH 3 (7N), 20:1) to give S9-4 (0.107 g, 40%). 'H NMR (CDC 3 , 500 MHz) 8 8.29 (s, 1H), 7.36 (s, 1H), 7.00 (s, 1H), 6.23 (br s, 2H), 4.62 (t, J= 7.0 Hz, 2H), 4.16-4.24 (in, 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 S9-3 (0.213 g, 0.5 mrmol), 1,3-dibromopropane (0.512 g, 2.5 mmol) and Cs 2

CO

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

(CHC

3 :MeOH-NH3 (7N), 20:1) to give S9-5 (0.104 g, 38 %). 'H NMR (CDC 3 , 500 MHz) 8 8.26 (s, IH), 7.32 (s, IH), 6.94 (s, 1 H), 5.6 (br s, 2H), 4.27 (t, J= 7.0 Hz, 2H), 4.10-4.17 (in, 4H), 3.32 (t, J= 7.0 Hz, 2H), 2.26 (in, 2H); MS (ESI) m/z 547.9/549.8 [M+H]*.

WO 2011/044394 PCT/US2010/051872 112 3-(7-lodo-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 CI2:MeOH) to give 0.040 g, 78%) of PU-HT165 as a yellow solid. 'H NMR (500 MHz, CDC1 3 ) 6 8.24 (s, iH), 7.37 (s, 1H), 6.94 (s, iH), 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 (m, 1H), 0.92 (d, J= 6.0 Hz, 6H); "C NMR (125 MHz, CDCl 3 ) 6 155.4, 152.8, 151.4, 147.7, 145.5, 145.2, 128.9, 127.5, 122.0, 120.5, 91,6, 64.9, 64.7, 57.3,49.0,43.9,28.0,21.0; MS (ESI) m/z 527.1 [M+H]*. 8-(7-Iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-9-(2-(neopentylanmino)ethyl)-5,9 dihydro-4H-purin-6-amine (PU-HT175). S9-4 (0.052, 0.097 mmol) and neopentylamine (0.426 g, 4.9 mmol) in DMF (1 mL) was stirred overnight at rt. Solvent was removed under reduced pressure and the resulting residue was purified by chromatography (CH2CI 2 :MeOH) to give 0.038 g (73%) of PU-HT175 as a yellow solid. 'H NMR (500 MHz, CDC1 3 ) 6 8.31 (s, 1H), 7.37 (s, 1H), 6.94 (s, 1H), 5.79 (br s, 2H), 4.33 (t, J= 6.5 Hz, 2H), 4.20-4.24 (m, 4H), 2.99 (t, J= 6.5 Hz, 2H), 2.34 (s, 2H), 0.84 (s, 9H); 13 C NMR (125 MHz, CDC 3 ) 6 154.5, 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-(isopropylanino)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, CDC 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, iH), 2.61 (t, J= 6.7 Hz, 2H), 2.07 (m, 2H), 1.11 (d, J= 6.7 Hz, 6H); "C NMR (125 MHz,

CDC

3 ) 6 154.4, 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-(1H-imidazol-1-yl)propyl)-8-(7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-9H purin-6-amine (PU-RK12). S9-5 (0.045 g, 0.082 mmol) and imidazole (0.056 g, 0.82 mmol) in DMF (1 mL) was stirred overnight at rt. Solvent was removed under reduced pressure and the resulting residue was purified by chromatography (CH2C12:MeOH) to give 0.029 g (67%) of PU-RK12. 'H NMR (500 MHz, CDC1 3 ) 8 8.34 (s, 1H), 7.62 (s, 1H), 7.39 (s, 1H), 7.09 (s, 1H), 6.98 (s, 1H), 6.94 (s, 1H), 5.70 (br s, 2H), 4.19-4.28 (in, 6H), 4.00 (t, J= 7.5 Hz, 2H), 2.25 (in, 2H); 1 3 C NMR (125 MHz, CDC] 3 ) 8 154.5, 153.2, 151.8, 146.3, 145.0, 144.7,137.1, 129.6, 128.3, 126.9, 121.3, 120.1, 118.7, 90.9, 64.3, 64.2,44.3,41.0, 31.8; MS (ESI) m/z 536.1 [M+H] . 0 0 0 0\0 0-a C NI- 2 /\ d NH 2 (ODIC -0) N N 0I N 3 H H 2 N NN F N SIO-1 30-10H3 SIM- 310-4 0 0 0 0 0 0 NH 2

NH

2

/\NH

2 N N> N- N N .±. F-"N N F N N NH S10-5 Br R s10-6 D 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-tetraaminopyrimidine, tiphenyl phosphite, pyridine, microwave irradiation at 220*C, 75 min.; (d) HF/pyridine, NaNO 2 , 0 *C to rt, 1 h; (e) NIS, TFA, CH 3 CN, rt 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[b][1,4]dioxin-6-yl)acetic acid (S1O-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 0 C for 14 h. After cooling to rt, WO 2011/044394 PCT/US2010/051872 114 the reaction mixture was diluted with 150 mL of CH 2

CI

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

CH

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

SO

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

SO

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

(CHZCI

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, CDCI 3 /MeOH-d4) 8 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-9H-purin-6-amine (S1O-4). To a solution of S10-3 (1.00 g, 3.35 mmol) in HF/pyridine (2A mL) at 0 *C, NaNO 2 (0.3 g, 4.36 mmol) was slowly added. The reaction was brought to room temperature and further stirred for 1 h. Following dilution with CH 2 Cl 2 (20 mL), the excess HF was quenched by stirring for I h with CaCO3 (1.19 g). The mixture was dried under reduced pressure and subsequently purified by chromatography (CH 2

CI

2 :MeOH:AcOH, 90:1:0.5) to give 1.15 g (96%) of S10-4. H NMR (500 MHz, CDCl 3 /MeOH-d4) 8 6.75-6.84 (in, 3H), 4.24 (s, 4H), 4.04 (s, 2H); MS (ESI) m/z 302.3 [M+H]*.

WO 2011/044394 PCT/US2010/051872 115 2-fluoro-8-((7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-9H-purin-6-amine (S1O-5). S10.4 (0.310 g, 1.03 mmol), NIS (0.301 g, 1.34 mmol), CH 3 CN (20 mL), TFA (2.34 g, 1.56 mL, 20.5 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]) along with diiodinated compound (m/z 554.1 [M+H]). LC-MS shows ratio of S10-5 to diiodinated compound to be 83:17. This mixture was not separated but used further in the following step. 'H NMR (500 MHz, CDCI 3 /MeOH-d4) 6 7.37 (s, iH), 6.82 (s, 1H), 4.25 (s, 4H), 4.18 (s, 2H); MS (ESI) m/z 428.2 [M+H]. 9-(2-bromoethyl)-2-fluoro-8-((7-iodo-2,3-dibydrobenzo[b][1,4]dioxin-6-yl)methyl)-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 Cl 2 :MeOH:AcOH, 200:1:0.5 to 120:1:0.5) to give 0.360 g (85%) of a mixture of S1O-6 (m/z 534.0/536.2 [M+H]) along with diiodinated compound (m/z 659.5/661.9 [M+H]). LC MS shows ratio of titled compound to diiodinated compound to be 80:20. This mixture was not separated but used further in the following step. 2-fluoro-8-((7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-9-(2 (isobutylamino)ethyl)-9H-purin-6-amine [DZ3-731. S10-6 (0.360 g, 0.674 numol) 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

CI

2 :MeOH:MeOH-NH3 (7N), 120:0.5:0.5 to 60:0.5:0.5) to give 0.220 g of a mixture of DZ3-73 along with the diiodinated compound. This mixture was separated by reverse phase HPLC ((a) H20 + 0.1% TFA and (b) CH 3 CN + 0.1% TFA, 10 to 75% b over 22 minutes at 16 mL/min) to give 0.196 g (58%) of DZ3-73. 'H NMR (500 MHz, CDC 3 ) 6 7.35 (s, 1H), 6.57 (s, 1H), 6.37 (br s, 2H), 4.24 (s, 2H), 4.20 (s, 4H), 4.08 (t, J= 6.4 Hz, 2H), 2.91 (t, J= 6.4 Hz, 2H), 2.37 (d, J= 6.3 Hz, 2H), 1.64 (m, 1H), 0.85 (d, J= 6.2 Hz, 6H); 13 C NMR (125 MHz,

CDCI

3 ) 6 158.8 (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) t/z [M+H]* called. for C 20

H

25

F]N

6 0 2 , 527.1068; found 527.1066; HPLC: method A R, = 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 yl)methyl)-9H-purin-6-amine [DZ4-841. S1O-6 (8 mg, 0.0149 mmol) and tert-butylamine (109 mg, 157 1d) in DMF (0.5 mL) was stirred overnight at rt. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2

CI

2 :EtOAc:MeOH-NH 3 (7N), 7:2:1:0.5) to give 6 mg (77%) of DZ4-84. 'H NMR (500 MHz, CDC 3 ) 5 7.36 (s, 1H), 6.55 (s, IH), 5.86 (br s, 2H), 4.29 (s, 2H), 4.17-4.23 (m, 4H), 4.04 (t, J= 6.4 Hz, 2H), 2.85 (t, J= 6.4 Hz, 2H), 0.99 (s, 9H); MS (ESI) m/z 527.1 [M+H] N a b B OH 0Br 0 S11-1 S11-2 S11-3 Si1-4 I NH2 H 2 N 02N N O2N N H2 S11-5 S11-6 S11-7 311-8

NH

2 NH2 N2 N N- N N NI- j - -)\/ N N N 0 N N SN N 0 H 311-9 Br NHR S11-10 S11-11 Reagents and conditions: (a) NaBH 4 , AcOH, THF, rt; (b) dibromoethane, acetone, H 2 0, K 2 C0 3 , reflux; (c) NBS, DMF, 80*C; (d) KNO 3 , H 2 S0 4 ; (e) Nal, Cut N,N'-dimethylethylenediamine, dioxane, I 104C; (f) Fe, NH 4 CI, isopropanol, reflux; (g) 8-mercaptoadenine, neocuproine, CuI, NaOtBu, DMF, 115*C; (h) NaNO 2 , KI, AcOH, 0*C; (i) Cs 2

CO

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

WO 2011/044394 PCT/US2010/051872 117 Scheme 11. Synthesis of Morpholine-type compounds S11-11. ON NH2 a 0 2 N N b O2N N HN N CrOH O O0 S12-1 S12-2 S12-3 S12-4 d NH 2

NH

2 S S e_ NN -N. dIN ~ ~ ~ ~ N N N ~-.N N H N-N S12-5 $12-6 N 12-7 NH

NH

2

N

2 N N N NNt _ S \S> N, N N N /N n=1,2 /N (0 n=1,2 / Br NHR S12-8 S12-9 Reagents and conditions: (a) 1,2-dibromoethane, K 2 C0 3 , DMIF, 125 0 C; (b) Mel, DMF, 0*C then rt; (c) Pd/C, H2, MeOll, rt; (d) NaNO 2 , AcOH, KI, 0*C; (e) 8-mercaptoadenine, neocuproine, CuL, NaOtBu, DMF, I15 0 C; (f) NIS, CH 3 CN, rt; (g) Cs 2

CO

3 , 1,3 dibromopropane or 1,2-dibromoethane, DMF, rt; (h) NIH 2 R, DMF, rt. Scheme 12. Synthesis of Morpholine-type compounds S 12-9. 6-Nitro-3,4-dihydro-2H-benzo[b] [1,4]oxazine [S12-2]. To a solution of 2-amino-4 nitrophenol (S12-1; 1.5 g, 9.7 mmol) in 50 mL of DMF was added K 2 C0 3 (4.04 g, 29.2 mmol) and 1,2-dibromoethane (1 mL, 11.7 mmol). The resulting mixture was stirred at 125 *C under argon overnight. The resulting mixture was concentrated under vacuum and purified by flash chromatography to give S12-2 (1.2 g, 68%) as a yellow solid. 'H NMR (CDCl3, 500 MHz) 8 7.55-7.58 (dd, J= 2.7, 8.9 Hz, 1H), 7.48 (d, J= 2.6 Hz, 1H), 6.81 (d, J= 8.9 Hz, WO 2011/044394 PCT/US2010/051872 118 1H), 4.34 (m, 2H), 4.12 (br s, IH), 3.47 (m, 2h); "C NMR (CDC 3 , 125 MHz) 5 149.4, 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 mmol) in 30 mL of DMF was added NaH (106 mg, 4.4 mmol) and stirred at 0 "C for 30 min. To the resulting mixture was added Mel (229 pL, 3.7 mmol) and kept stirring at rt for 2 h. The reaction mixture was concentrated in vacuum and purified by flash chromatography to give compound S12-3 (564 mg, 79%) as yellow solid. 'H NMR (CDCl 3 , 500 MHz) S 7.56 (d, J= 8.8 Hz, IH), 7.45 (s, IH), 6.76 (d, J= 8.8 Hz, IH), 4.36 (m, 2H), 3.32 (m, 2H), 2.95 (s, 3H); "C NMR (CDC 3 , 125 MHz) 8: 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-anine [S12-4]. To a solution of S12-3 (560 mg, 2.9 mmol) in 20 mL of methanol was added Pd/C powder (10%, 96 mg). The resulting suspension was stirred at rt under hydrogen overnight. The reaction mixture was filtered, concentrated in vacuum and purified by flash chromatography to give S12-4 (420 mg, 89%) as a yellow solid. 'H NMR (CDC1 3 , 500 MHz) 8 6.56 (d, J= 8.3 Hz, 1 H), 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); "C NMR (CDCI 3 , 125 MHz) S 140.8, 137.4, 137.0, 116.2, 104.8, 100.4, 64.6, 49.5, 38.7. 6-Iodo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine IS12-51. 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 0 3 , washed with brine, dried over MgSO 4 and purified by flash chromatography to give S12-5 (1.86 g, 53%) as a yellow solid. 'H NMR (CDCI 3 , 500 MHz) 8 6.64 (d, J= 8.3 Hz, iH), 6.56 (s, 1H), 6.48 (d, J= 8.4 Hz, 1H), 4.25 (m, 2H), 3.24 (m, 2H), 2.85 (s, 3H); "C NMR (CDC 3 , 125 MHz) S 138.1, 126.6, 120.5, 117.6, 111.9, 83.7, 64.8, 48.7, 36.5.

WO 2011/044394 PCT/US2010/051872 119 ab, c d M COOH NHBoc bNH 2 S13-1 S13-2 S13-3

NH

2

H

2 N

NH

2 S13-4 S13-5

NH

2

NH

2 1- e g N~ N. NS 9 H N HN S13-6 DZ4-52-NS Reagents or conditions: (a) (C 6

H

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

CH

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

CI

2 , rt; (d) 8-mercaptoadenine, neocuproine, CuT, NaOtBu, DMF, I115*C; (e) K1, NaNO 2 , HCI, H120, < 5*C; (f) 1,3-dibromopropane, Cs 2

CO

3 , DMF, rt; (g) isopropylamine, DMF,. rt. Scheme 13. Synthesis of DZ4-52-N9. tert-Butyl naphthalen-2-ylcarbamate (S13-2). 2-Naphthoicacid (S13-1; 2.5 g, 14.3 mimol) in tert-BuOH (85 mL) and toluene (85 mL) was treated with Et 3 N (2.3 mL, 16.4 mmol), 3 A molecular sieves (16.7 g) and diphenyl phosphorylazide (3.5 mL, 16.4 mmol). The reaction mixture was refluxed for 24 h. After cooling to rt, solid was filtered off through Celite and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (75 mL) and washed with IN aqueous HCl (2 x 50 mL), saturated aqueous NaHCO 3 (2 x 50 mL), dried over sodium sulfate and concentrated under reduced pressure. Chromatography (10% EtOAc in hexanes) afforded 2.5 g (71%) of S13-2. 'H NMR (500 MHz, CDCI 3 ) 6 7.99 (s, WO 2011/044394 PCT/US2010/051872 120 1H), 7.72-7.78 (m,3H), 7.44 (t,J= 7.8 Hz, lH), 7.31-7.38 (m, 2H), 6.61 (brs, 1H), 1.55 (s, 9H); MS (ESI) n/z 244.02 [M+H]*, 2-Amino-3-iodonaphthalene (S13-3). To a solution of S13-2 (1.0 g, 4.11 mmol) in 20 mL dry THIF under argon at -20 0 C was added tert-butyl lithium (1.5 M solution in pentane, 6.9 mL, 10.27 mmol) dropwise and was stirred for 2 h at -20 *C. After cooling to -78 0 C, a solution of diiodoethane (2.9 g, 10.27 mmol) in 10 mL dry THIF was added dropwise and then allowed to warm to rt for 3 h. A saturated aqueous NH 4 Cl solution was added, and the solution was extracted with diethyl ether. The organic layer was washed with 10% sodium thiosulfate solution and dried over MgSO 4 . The solvents were evaporated under reduced pressure and the residue was purified by chromatography (3% EtOAc in hexanes) to afford 1.1 g of a 79/21 mixture (NMR) of regioisomeric 3-iodo and 1-iodo Boc-protected 2 aminonaphthalene, respectively. This mixture (1.1 g) was dissolved in dichloromethane (12.5 mL), and trifluoroacetic acid (12.5 mL) was added dropwise at rt. After stirring for 1 h at rt, the solution was neutralized with a concentrated NaOH solution. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over MgSO 4 , concentrated under reduced pressure and the resulting residue was purified by chromatography (0.5% EtOAc in hexanes) to afford 0.50 g (45%) of S13-3. 'H NMR (500 MHz, CDCl 3 ) S 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); "C NMR (125 MHz, CDC 3 ) S 144.3, 139.5, 135.3, 129.9, 127.5, 127.2, 126.3, 123.7, 109.0, 88.7; MS (ESI) m/z 269.96. 8-(3-aminonaphthalen-2-ylthio)-9H-purin-6-amine (S13-4). A mixture of 8 mercaptoadenine (20.7 mg, 0.124 mmol), neocuproine hydrate (3.9 mg, 0.0 185 mmol), CuI (3.5 mg, 0.0185 mmol), sodium tert-butoxide (23.7 mg, 0.24 mmol), S13-3 (100 mg, 0.37 mmol) and DMF (2 mL) were heated at 115'C for 20 h. The solvent was removed under reduced pressure and the residue was purified by preparatory TLC (CH 2 Cl 2 :MeOH-NH3 (7N), 10:1) to give 14 mg (37%) of S13-4 as a solid. 'H NMR (500 MHz, CDCl3/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, 1H), 7.24-7.30 (m, 1H), 7.20 (s, 1H); MS (ESI) m/z 308.95 [M+H]t.

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

(CH

2

CI

2 :MeOH-NH 3 (7N), 8:1) to give 8 mg (42%) of S13-5 as a solid. 'H NMR (500 MHz, CDCl3/MeOH-d 4 ) 5 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 (S13-6). S13-5 (8 mg, 0.019 mmol), Cs 2

CO

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

CO

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

CI

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

WO 2011/044394 PCT/US2010/051872 122 H

O

2 N 2N H2NjNH2 H2N NH S14-1 S14-2 14-3 NH 2 H .N NH2 I N 11- N -f N 11 N g S h)- S/ N N N H N H -t S14-4 S14-5 S14-4

NH

2 INH, N N h N N,, N - b N N t r=1,2 () n=l2 Br RHN S14-7 S14-8 Reagents and conditions: (a)Ac 2 0, dioxane, 0*C to rt; (b) KNO 3 , H 2 S0 4 , 0"C to rt; (c) NaNO 2 , KI, AcOH, 0*C to rt; (d) Fe, NH 4 CI, isopropanol, reflux; (e) 8-mercaptoadenine, CuI, nBu 4 NBr, NaOt Bu, mv; (f) NaNO 2 , KI, AcOH, 0*C; (g) 1,3-dibromopropane or 1,2-dibromoethane, Cs 2

CO

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

WO 2011/044394 PCT/US2010/051872 123 ab 0 2 N)l, 0 2 N

H

2 N S15-1 S15-2 S15-3

NH

2

H

2 N NH 2 H2 Y t.e N N, N _S N~- N, -6 K)>N. N N N HH 815-4 S15-- S15-6

NH

2 I NH 2 NH2 N N -NN - NN N -- _N g S h SN'N N N N N n=-1,2 RH n= 1, 2 HN Sr RHN S15-7A n= 1 PU-WS25 n= 1, R= neopentyl 815-7B n=2 PU-WS26 n= 1, R= isobutyl PU-WS29 n= 2, R= isopropyl PU-WS27 Reagents and conditions: (a)Ac20, dioxane, 0*C to rt; (b) KN03, H 2 SO4, 0*C to rt; (c) NaNO 2 , KI, AcOH, 0*C to rt; (d) Fe, NH 4 Cl, isopropanol, reflux; (e) 8-mercaptoadenine, CuI, nBu 4 NBr, NaOt Bu, my; (f) NaNO 2 , KI, AcOH, 0*C; (g) 1,3-dibronopropane or 1,2-dibromoethane, Cs 2

CO

3 , DMF, rt; (h) isopropylamine or isobutylamrine or neopentylamine, DMF, rt; (i) Cul, PdCI 2 (PPh 3

)

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

SO

4 , cooled in ice bath.

KNO

3 in 15 mL of concentrated H 2 SO4 was added dropwise. The resulting solution was stirred at 0 *C for 2 h and then at rt for 2 h. The reaction mixture was poured into 150 g of ice and the resulting yellow precipitate was filtered and washed with cold water to give S15-2 (7.1 g, 43%). 'H NMR (500 MfAHz, CDCI 3 ) 8 7.94 (s, IH), 6.65 (s, 1H), 6.02 (br, 2H), 2.83 (m, 4H), 2.06 (m, 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. 'HNNMR (500 MHz, CDCI 3 ) S 7.83 (s, IH), 7.71 (s, IH), 2.95 (in, 41), 2.11 (in, 2H). 5-amino-6-iodo-indane (S15-4). To a solution of S15-3 (1.65 g, 5.7 mmol) in isopropanol (100 mL) and saturated aqueous NH 4 CI solution (20 mL) was added 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 ) 6 7.44 (s, 1H), 6.59 (s, IH), 3.88 (s, 21), 2.74 (m, 4H), 1.98 (in, 2H); 13 CNMR (125 MHz, CDCl 3 ) S 146.2, 144.9, 136.5,134.1,111.0, 32.8, 31.8, 26.1; MS (ESI): m/z 259.99 [M+H]t. 8-((6-amino-2,3-dihydro-1H-inden-5-yl)thio)-9-H-purin-6-amine (S15-5). The mixture of 8-mercaptoadenine (64 mg, 0.38 nmol), S15-4 (100 mg, 0.38 mmol), CuI (14.7 mg, 0.07 mmol), sodium t-butoxide (111 mg, 1.15 mmol) and tetrabutylammonium bromide (24.9 mg, 0.07 mmol) in anhydrous DMF (4 mL) was vortexed and heated at 190 *C under microwave for 1h. The resulting mixture was condensed and purified by flash chromatography (methylene chloride/methanol, gradient 0 to 10%) to give S15-5 (54 mg, 47%) as a while solid. 'HNMR (500 MHz, MeOH-d4/CDCI 3 ) 8 8.11 (s, 111), 7.36 (s, 111), 6.81 (s, 1H), 2.85 (m, 4H), 2.06 (in, 2H); MS (ESI): m/z 299.02 [M+H]*. 8-((6-iodo-2,3-dihydro-1H-inden-5-yl)thio)-9-H-purin-6-anine (S15-6). To a solution of S15-5 (54 mg, 0.18 mmol) in acetic acid (5 mL) cooled in ice bath was added NaNO 2 (15 mg, 0.22 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 ) 5 8.12 (s, iH), 7.84 (s, 1N), 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, CDC1 3 ) 5 8.36 (s, 1H), 7.75 (s, 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); 1 CNMR (125 MHz, CDC1 3 , 5): 155.9, 153.9, 152.4, 149.8, 148.9, 148.1, 137.6, 132.8, 131.1, 101.7, 46.3, 33.9, 29.7, 26.8; MS (ESI): m/z 516.15, 518.16 [M, M+2]. 8-((6-iodo-2,3-dihydro-1H-inden-5-yl)thio)-9-(2-(neopentylamino)ethyl)-9H-purin-6 amine (PU-WS25). To a solution of S15-7A (31 mg, 0.06 mmol) in DMF (1.5 mL) was added neopentylamine (250 uL). The reaction mixture was stirred at rt overnight and condensed under vacuum. PU-WS25 (28 mg, 89%) was obtained following preparatory TLC (methylene chloride/methanol, 10/1) as a white solid. 'H NMR (500 MHz, CDClj) 5 8.32 (s, IH), 7.73 (s, IH), 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 2 tH 28

IN

6 S, 523.1141; found 523.1140. 8-((6-iodo-2,3-dihydro-1H-inden-5-yl)thio)-9-(2-(isobutylanino)ethyl)-9H-purin-6 amine (PU-WS26). To a solution of S15-7A (6 mg, 0.01 mmol) in DMF (1 mL) was added isobutylamine (150 uL). The reaction mixture was stirred at rt overnight and condensed under vacuum. PU-WS26 (5.9 mg, 99%) was obtained following preparatory TLC (methylene chloride/methanol, 10/1) as a white solid. 'HNMR (500 MHz, CDCI 3 ) 5 8.31 (s, 1H), 7.74 (s, WO 2011/044394 PCT/US2010/051872 126 1H), 7.11 (s, 1H), 5.73 (br, 2H), 4.43 (in, 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 (in, 2H), 1.81 (m, 1H), 0.92 (m, 6H); HRMS (m/z): [M+H]* calcd for C 20

H

26 1N 6 S 509.0984; found 509.0990. 9-(3-bromopropyl)-8-((6-iodo-2,3-dihydro-1H-inden-5-yl)thio)-9H-purin-6-amine (S15 7B). To a solution of S15-6 (30 mg, 0.07 mmrol) in DMF (3 mL) was added 1,3 dibromopropane (37 gL, 0.86 mmol) and Cs 2

CO

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

H

2 6 1N 6 S 509.0984; found 509.1003. 8-((6-ethynyl-2,3-dihydro-1H-inden-5-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. 1H NMR (CDC1 3 , 500 MHz) 6 8.32 (s, I H), 7.41 (s, I H), 7.13 (s, IH), 5.67 (br s, 2H), 4.42 (m, 2H), 3.48 (s, 1H), 3.02 (m, 2H), 2.77-2.91 (in, 4H), 2.39 (s, 2H), 2.06 (in, 2H), 0.89 (s, 9H); HRMS (ESI) m/z [M+H]* calcd. for C2H 2 gN 6 S, 421.2174; found421.2164.

WO 2011/044394 PCT/US2010/051872 127 COOEt OH HO COOEt O ~EtOOC N0 HOOC COOEt COOFt S13-4 S13-1 S13-2 S13-3 - KNH2 HOOC N HONC H S S166-6 S16-7

NH

2

NH

2 NN N N - h_ F N N F F H F N N S16-8 S16-9

NH

2 NH 2 I - N - _ F NF Br RHN S16-10A n=2 PU-WS18 n= 2, R= isopropyl S16-10B n=1 PU-WS17 n= 1, R= isobutyl PU-WS22 n= 1, R= neopentyl - Reagents and conditions: (a)EtOH, H 2

SO

4 , reflux; (b) 2-bromomethylmalonate, Nai, DME, 11 0*C; (c) PPA, toluene, reflux; (d) NaOH, MeOH, rt, then HCI; (e) Pd/C, H 2 (2 atm.), MeOH; (f) 2,4,5,6-tetraaminopyrimidine, triphenyl phosphite, pyridine, microwave, 21 0*C; (g) HF/pyridine, NaNO 2 , 0*C to rt; (h) NIS, TFA, ACN; (i) 1,3-dibromopropane or 1,2 dibromoethane, Cs 2

CO

3 , DN, rt; (h) isopropylamine or isobutylamine or neopentylamine, DMF, rt. Scheme 16. Synthesis of PU-WS 17, PU-WS 18, 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 (in, 1H), 6.69-6.78 (in, 31H), 4.12 (in, 2H), 3.53 (s, 2H), 1.21 (in, 3H). Diethyl 2-((3-ethoxy-2-oxoethyl)phenox)methyl)malonate (S16-3). To a solution of S16-2 (11.8 g, 65.5 nunol) 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 bromomethylmalonate (11.8 mL, 78 mmol) dropwise. The reaction mixture was stired 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 ) 8 7.19 (t, 1H), 6.80-6.86 (in, 3H), 4.81 (in, 1H), 4.12 (in, 2H), 3.97 (in, 2H), 3.74 (in, 211), 3.63 (in, 211), 3.55 (s, 21H), 1.19 (in, 91); 1 3 C NMR (125 MHz, CDC 3 ) 8 171.3, 158.8, 135.6, 129.5, 121.8, 115.6, 113.3, 100.5,68.5, 62.5,60.7,41.3,15.4,14.1. Ethyl 2-(benzofuran-6-yI) acetate (S16-4). To a solution of S16-3 (6 g, 17 nunol) in 100 mL of toluene was added 3 g of polyphosphoric acid. The resulting mixture was refluxed overnight, condensed and purified by flash chromatography to give S16-4 (1.42 g, 41%) as colorless oil. 'H NMR (500 MHz, CDC 3 ) 6 7.31-7.42 (in, 3H), 6.95 (in, 1H), 6.51 (s, 1 H), 3.94 (in, 2H), 3.51 (s, 21), 1.02 (in, 31); "C NMR (125 MHz, CDC1 3 ) 6 171.6, 155.2, 145.1, 130.6, 126.4, 124.3, 121.1, 112.2, 106.4, 60.9, 41.5,14.2. 2-(benzofuran-6-yI) acetic acid (S13-5). To a solution of S16-4 (3 g, 14.7 nmol) 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 HCl, and adjusted pH to 2. The reaction mixture was condensed, purified by flash chromatography to yield S16-5 as a white solid in quantitative yield. 'H NMR (500 MHz, MeOH-d 4 ) 6 7.73 (s, 11), 7.53 (d, J=7.9 Hz, 1H), 7.43 (s, 1H), 7.15 (d, J= 8.0 Hz, 1H), 6.79 (s, 1H), 3.70 (s, 2H); 1 3 C NMR (125 MHz, MeOH-d 4 ) 6 175.7, 156.6, 146.6, 132.5, 127.7, 125.4, 121.9, 113.0, 107.4, 41.9. 2-(2,3-dihydrobenzofuran-6-yl)acetic acid (S16-6). To a solution of S16-5 (1.8 g, 10 mmol) in 20 mL of methanol was added Pd/C (10%, 120 mg) and stirred at rt under H 2 (2 atm) WO 2011/044394 PCT/US2010/051872 129 overnight. The reaction mixture was filtered, washed with cold methanol, evaporated to dryness and purified by flash chromatography to give S16-6 (1.6 g, 88%) as a white solid. 'H NMR (500 MHz, MeOH-d 4 ) 6 7.12 (d, J= 7.6 Hz, 1H), 6.73 (d, J= 7.9 Hz, 1H), 6.71 (s, 1H), 4.55 (m, 2H), 3.56 (s, 2H), 3.16 (m, 2H); "C NMR (125 MHz, MeOH-d 4 ) 6 177.9, 160.4, 133.3, 126.2, 124.8, 121.5, 110.5, 71.5, 41.1,29.4. 8-((2,3-dihydrobenzofuran-6-y)methyl)-9H-purine-2,6-diamine (S16-7). The mixture of 2,4,5,6-tetraaminopyrimidine (200 mg, 1.4 mmol), S16-6 (254 mg, 1.4 mmol) and triphenyl phosphite (451 piL, 1.7 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-dj) 6 7.16 (in, IH), 6.79 (in, 1H), 6.73 (s, 1H), 4.57 (in, 2H), 4.12 (s, 211), 3.18 (in, 2H); MS: m/z 283.2 (M+H). 8-((2,3-dihydrobenzofuran-6-yl)methyl)-2-fluoro-9H-purin-6-amine (S16-8). A plastic tube charged with S16-7 (0.72 g, 2.5 mmol) was cooled in ice bath, added HF/pyridine (73%, 1.76 mL) and stirred to dissolve. To the resulting mixture was added NaNO 2 (0.23 g, 3.3 mmol) in portions and kept stirring for 5 min. The reaction mixture was allowed to warm up to rt and stirred for 3 h. CaCO 3 (0.68 g) was added to quench excess HF. The resulting suspension was stirred for I h, filtered, concentrated in vacuo and purified by flash chromatography to give S16-8 (0.45 g, 62%) as a yellow solid. 'H NMR (500 MHz, MeOH d 4 ) 5: 7.16 (in, 1H), 6.77 (in, 1H), 6.71 (s, 1H), 4.57 (in, 2H), 4.12 (s, 2H), 3.19 (in, 2H); MS: m/z 286.0 (M+H)*. 2- fluoro-8-((5-iodo-2,3-dihydrobenzofuran-6-yl)methyl)-9H-purin-6-amine (S16-9). To a suspension of S16-8 (0.45 g, 1.6 mmol) in 50 mL acetonitrile was added 1 mL of TFA. To the resulting solution was added NIS (1.06 g, 4.7 mmol) and the reaction mixture was stirred at A for 3 h. It was then evaporated to dryness and purified by flash chromatography to give S16-9 (0.408 g, 63%) as a yellow solid. 'H NMR (500 MHz, MeOH-di) 8 7.67 (s, 1H), 6.76 (s, 1Hl), 4.59 (in, 2H), 4.28 (s, 2H), 3.21 (in, 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 DMF was added 1,3-dibromopropane (150 pL) and Cs 2

CO

3 (80 mg, 0.24 mmol). The resulting mixture was stirred at rt for 2 h, evaporated to dryness and purified by preparatory TLC to give S16-1OA (23 mg, 36%) as a white solid. H NMR (500 MHz, MeOH-d) 6 7.48 (s, IH), 6.31 (s, 1H), 4.35 (m, 2H), 4.12 (s, 2H), 3.92 (m, 2h), 3.14 (m, 2H), 3.01 (m, 2H), 2.03 (m, 2H); MS: rn/z 530, 532 (M, M+2)-. 2-fluoro-8-((5-iodo-2,3-dihydrobenzofuran-6-yl)methyl)-9-(3-(isopropylamino)propyl) 9H-purin-6-amine (PU-WS1S). To a solution of S16-1OA (15 mg, 0.03 mmol) in 1 mL of DMF was added isopropylamine (0.5 mL), stirred at rt overnight, evaporated to dryness and purified by flash chromatography to give PU-WS18 (13 mg, 90%) as a white solid. 'H NMR (500 MHz, MeOH-ds) S 7.67 (s, 1H), 6.72 (s, 1H), 4.63 (m, 2H), 4.26 (m, 4H), 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]* calcd. for C 2 0

H

25

N

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

CO

3 (110 mg, 0.34 mmol). The resulting mixture was stirred at t for 2 h, evaporated to dryness and purified by preparatory TLC to give bromide intermediate S16-10B. To a solution of S16-1OB (10 mg, 0.19 mmol) in I mL of DMF was added isobutylamine (100 uL), stirred at rt overnight, evaporated to dryness and purified by flash chromatography to give PU-WS17 as a white solid. 'H NMR (MeOH d4/CDC 3 , 500 MHz) 6: 7.67 (s, 1H), 6.62 (s, IH), 4.59 (t, J = 8.7 Hz, 2H), 4.29 (s, 2H), 4.15 (t, J = 6.5 Hz, 2H), 3.22 (t, J = 8.7 Hz, 2H), 2.93 (t, J = 6.5 Hz, 2H), 2.45 (d, J = 6.9 Hz, 2H), 1.69 (m, 1H), 0.88 (d, J = 6.8 Hz, 6H); HRMS (ESI) m/z [M+H] t caled. for C 2 0

H

25

FIN

6 0, 511.1119; found 511.1113. 2-fluoro-8-((5-iodo-2,3-dihydrobenzofuran-6-yl)methyl)-9-(2-(neopentylamino)ethyl) 9H-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 pL) and Cs 2

CO

3 (110 mg, 0.34 mmol). The resulting WO 2011/044394 PCT/US2010/051872 131 mixture was stirred at rt for 2 h, evaporated to dryness and purified by preparatory TLC to give bromide intermediate S16-10B. To a solution of S16-1OB (65 mg, 0.13 mmol) in I mL of DMF was added neopentylamine (50 pL), stirred at rt overnight, evaporated to dryness and purified by flash chromatography to give compound PU-WS22 as a white solid. 'H NMR

(CDC

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, 2H), 2.34(s, 2H), 0.91 (s, 9H); HRMS (ESI) m/z [M+H]* called. for C 2 tH 2 7 F1N 6 0, 525.1275; found 525.1249. B0b 0 2 N( c H d Br )t Br'~'> S17-1 S17-2 817-3 S17-4

NI-

2 HN 0 e NH 2 N N N N0 H H N '- N\ v IL - rs -J:Nx N N n=12 ( )n=1,2 NHR Br S17-7 17 Reagents and conditions: (a) HNO 3 , H 2

SO

4 ; (b) NaI, CuI, N,N'-dimethyiethylenediamine, dioxane, 11 04C; (C) Fe, H~C1; (d) 8-mercaptoadenine, neocuproine, CuI, NaOtBu, DMF, 115 0 C; (e) KI, NaNO 2 , HCI, < 54C ;(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 ACHN>AcHr S18-1 S8-2 S18-3 8184 o O NH 2

H

2 N I-', AcHN H2N S18-5 S18-6 S18-7 0 NH2 NH2 I S- 'S Act- N 2 N N N N-I N N __ ANN N -- N N O n=1,2 0 n=1,2 Br Br 81848 S18-9 S18-10 Reagents and conditions: (a) Ac 2 O, CH 2

C

2 , rt; (b) Br 2 , AcOH, 10*C; (c) Cr0 3 , AcOH/H 2 0, 50-55*C; (d) Nal, Cul, N,N'-dimethylethylenediamine, dioxane, 110 0 C; (e) 6M HCI (aq.), reflux; (f) 8 mercaptoadenine, neocuproine, Cuf, NaOtBu, DMF, 115*C; (g) KI, NaNO 2 , HC, <5 0 C ; (h) Cs 2

CO

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

NH

2 p NH2 X _Z a or b ' NZ_ ) ( )n 1,2 ( )n 1,2 NHR NHR PU-HJP18 X= H, Z= S, n= 2, R= isopropyl, X= 2-furanyl PU..RK1I X= H, Z= S, n 2, R= isopropyl PU-HJP19 X= H, Z= S, n= 2, R= isopropyl, X= 3-pyrazolyl PU-HTI5 X= H. Z= S, n= 1, R= isobutyl PU-HJP23 X= H, Z= S, n= 1, R= isobutyl, X= 2-furanyl DZ3-73 X= F, Z= CH2, n= 1, R= isobutyl TT-VI-53A X= F, Z= CH2, n= 1, R= isobutyl, X= 2-furanyl Tr-VI-64A X= F, Z= CH 2 , n= 1, R= isobutyl, X= 3-pyrazolyl PU-HJP20 X= H, Z= S, n= 2, R= isopropyl, X= 2-oxazolyl Reagents or conditions: (a) boronic acid, PdCI 2 (PPh 3 )2, NaHCO3, H20, DMF; (b) XSn(Bu) 3 , LiCl, Pd(PPh 3

)

4 , DM, 90*C WO 2011/044394 PCT/US2010/051872 133 Scheme 19. Cross-coupling reactions of PU-RKI 1, PU-HT165 and DZ3-73. 8-((7-(furan-2-yl)-2,3-dihydrobenzo[b [1,4jdioxin-6-yI)thio)-9-(3 (isopropylamino)propyl)-9H-purin-6-amine [HJP18]. 2-Furanylboronic acid (8 mg, 0.0712 mmol) was added to PU-RK11 (25 mg, 0.0475 mnol) and NaHCO 3 (12 mg, 0.1425 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H20 (0.1 mL) and Pd(PPh 3

)

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

(CH

2

CI

2 :MeOH-NH3 (7N), 20:1) to give 10.2 mg (45%) of HJP18. 'H NMR (500 MHz,

CDCI

3 /MeOH-d 4 ) 8 8.29 (s,1H), 7.47 (s, IH), 7.26 (d, J= 3.8 Hz, IH), 6.89 (s, iH), 6.73 (d, J= 3.9 Hz, IH), 6.46 (in, IH), 4.25 (in, 4H), 4.16 (t, J= 6.2 Hz, 2H), 2.67 (in, 1H), 2.47 (t, J = 7.1 Hz, 2H), 1.86 (in, 2H), 1.01 (d, J= 6.2 Hz, 6H); 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/z 467.14 [M+H]*. 8-((7-(1H-pyrazol-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thio)-9-(3 (isopropylamino)propyl)-9H-purin-6-amine [HJP19]. IH-Pyrazole-3-boronic acid (6.4 mg, 0.057 mmol) was added to PU-RK11 (20 mg, 0.038 mmol) 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 mL) and Pd(PPh 3

)

2

C

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

(CH

2 CI2:MeOH-NH 3 (7N), 15:1) to give 7.6 mg (43%) of HJP19. Additionally, 15.9 mg of unreacted PU-RK1 1 was recovered for an actual yield of 86%. 'H NMR (500 MHz, CDCl3/MeOH-d 4 ) 8 8.18 (s, 1H), 7.53 (d, J= 2.4 Hz, 1H), 7.15 (s, 1H), 7.14 (s, 1H), 6.36 (d, J= 2.4 Hz, 1N), 4.29 (in, 4H), 4.19 (t, J= 6.6 Hz, 2H), 2.75 (septet, J= 6.1 Hz, 1N), 2.52 (t, J= 6.6 Hz, 2H), 1.93 (in, 2H), 1.06 (d, J= 6.1 Hz, 6H); MS (ESI) m/z 468.0 [M+H]*.

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

)

2 C1 2 (2.4 mg, 0.0034 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 12 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2 Cl 2 :MeOH-NH 3 (7N), 20:1) to give 1.8 mg (23%) of HJP23. 'H NMR (500 MHz, CDCl 3 ) 5 8.29 (s, 1H), 7.48 (d, J= 1.8 Hz, 1H), 7.26 (s, 1H), 6. 90 (s, IH), 6.74 (d, J= 3.2 Hz, IH), 6.47 (in, 1H), 5.63 (br s, 2H), 4.20-4.30 (in, 6H), 2.90 (t, J= 6.0 Hz, 2H), 2.38 (d, J= 6.8 Hz, 2H), 1.65 (in, IH), 0.85 (d, J= 6.9 Hz, 6H); HRMS (ESI) m/z [M+H]* calcd. for C23H 2 7N 6

O

3 S, 467.1865; found 467.1884. 2-fluoro-8-((7-(furan-2-yl)-2,3-dihydrobenzo[b] [1,4]dioxin-6-yl)methyl)-9-(2 (isobutylamino)ethyl)-9H-purin-6-aniine [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 0 C for 12 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC

(CH

2 C1 2 :MeOH-NH 3 (7N), 20:1) to give 20.9 mg (94%) of TT-VI-53A. 'H NMR (500 MHz, CDCl/MeOH-d4) 5 7.45 (d, J= 1.8 Hz, 1H), 7.13 (s, 1H), 6.60 (s, 1H), 6.44 (dd, J= 1.8, 3.3 Hz, IH), 6.35 (d, J= 3.3 Hz, 1H), 4.34 (s, 2H), 4.26 (s, 4H), 4.05 (t, J= 6.4 Hz, 2H), 2.85 (t, J= 6.4 Hz, 2H), 2.35 (d, J= 6.9 Hz, 2H), 1.67 (in, 1H), 0.85 (d, J= 6.7 Hz, 6H); "C NMR (125 MHz, CDC13/MeOH-d4) 6 158.8 (d, J= 209.1 Hz), 156.3 (d, J= 19.5 Hz), 152.8, 152.2, 143.9, 142.9, 142.2, 126.0, 124.1, 118.7, 117.7, 117.6, 116.3, 111.6, 108.2, 64.6, 57.5, 48.6, 43.1, 31.8, 28.2, 20.6; HRMS (ESI) m/z [M+I]* calcd. for C2H28FN 6 0 3 , 467.2207; found 467.2203; HPLC: method A Rt = 7.05, method B Rt = 8.74.

WO 2011/044394 PCT/US2010/051872 135 8-((7-(1H-pyrazol-3-yl)-2,3-dibydrobenzo[b][1,4]dioxin-6-yl)methyl)-2-fluoro-9-(2 (isobutylamino)ethyl)-9H-purin-6-anine [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 H20 (0.2 mL) and Pd(PPh 3

)

2 C1 2 (8 mg, 0.0114 mnol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 12 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC

(CH

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

H

28

FN

8

O

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

)

4 (6.7 mg, 0.0095 mmol) was added and the reaction mixture was heated under nitrogen at 90"C for 12 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2

CI

2 :MeOH-NH 3 (7N), 20:1) to give 4.7 mg (27%) of HJP20. Additionally, 7 ing of unreacted PU-RK1 1 was recovered for an actual yield of 45%. 'H NMR (500 MHz, CDC1 3 ) 8 8.32 (s, 1H), 7.70 (s, 1H), 7.54 (s, 1H), 7.26 (s, IH), 6.59 (s, 1H), 5.79 (br s, 2H), 4.20-4.34 (in, 6H), 2.67 (in, J= 6.1 Hz, 1H), 2.50 (t, J= WO 2011/044394 PCT/US2010/051872 136 6.8 Hz, 2H), 1.93 (in, J= 7.1 Hz, 2H), 0.99 (d, J= 6.4 Hz, 6H); MS (ESI) m/z 468.15 [M+H]*.

NH

2

NH

2 R S~ aorb

OCH

3 OCH3 HN HN EC102 Reagents or conditions: (a) RB(OH) 2 , PdCI 2 (PPh 3

)

2 , NaHCO 3 , H 2 0, DMF; (b) CuI, PdCl 2 (PPh 3

)

2 , trimethylsilanylacetylene, Et 3 N, DMF, 90*C. Scheme 20. Cross-coupling reactions of EC102. 8-(2-(furan-2-yl)-5-methoxyphenylthio)-9-(2-(neopentylamino)ethyl)-9H-purin-6-anine [TT-V-138]. 2-Furanylboronic acid (8.2 mg, 0.0732 mmol) was added to EC102 (25 mg, 0.0488 mmol) and NaHCO 3 (12.3 mg, 0.1464 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then 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 0 C for 5 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2 Cl 2 :MeOH-NH 3 (7N), 20:1) to give 20.7 mg (94%) of TT-V-138. 'H NMR (500 MHz, CDCl 3 ) 8 8.31 (s, 1H), 7.62 (d, J= 8.7 Hz, IH), 7.50 (d, J= 1.8 Hz, 1IH), 6.86 (dd, J= 2.6, 8.7 Hz, IH), 6.70-6.73 (m, 2H), 6.49 (dd, J= 1.8, 3.3 Hz, 1H1), 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); 3 C NMR (125 MHz, CDCl 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]* called. for C23H 29

N

6

O

2 S, 453.2073; found 453.2071; HPLC: method A R, = 6.76, method B R, = 7.29. 8-(5-methoxy-2-(thiophen-2-yl)phenylthio)-9-(2-(neopentylaniino)ethyl)-9H-purin-6 amine [TT-V-139}. 2-Thiopheneboronic acid (18.8 mg, 0.147 mmol) was added to EC102 (25 mg, 0.0488 mmol) and NaHCO 3 (24.6 mg, 0.293 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 (0.25 mL) and Pd(PPh 3 )2Cl 2 (10.4 mg, 0.0148 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for 5 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH2C12:MeOH-NH 3 (7N), 20:1) to give 16.2 mg (71%) of TT-V-139. 'H NMR (500 MHz, CDCI 3 /MeOH-d) 8 8.19 (s, 1H), 7.45 (d, J= 8.5 Hz, IH), 7.30-7.33 (in, IH), 6.99-7.04 (in, 3H), 6.97 (dd, J= 2.6, 8.5 Hz, IH), 4.24 (t, J= 6.1 Hz, 2H), 3.82 (s, 3H), 2.97 (t, J= 6.1 Hz, 2H), 2.41 (s, 2H), 0.91 (s, 9H); 13 C NMR (125 MHz, CDCl3/MeOH-d4) 8 159.9, 154.6, 152.4, 150.9, 147.6, 140.4,133.2, 130.8, 129.3, 127.6, 127.1, 126.2, 119,5,118.9,114.6, 61.4,55.6,49.3,43.3, 31,3, 27.6; HRMS (ESI) m/z [M+H]* caled. for C2 3 H2 9

N

6

OS

2 , 469.1844; found 469.1830; HPLC: method A Rt = 6.84, method B R = 7.48. 8-(5-methoxy-2-(1H-pyrazol-3-yl)phenylthio)-9-(2-(neopentylamino)ethyl)-9H-purin-6 amine [TT-V-140]. IH-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 H 2 0 (0.2 mL) and Pd(PPh 3

)

2 Cl 2 (8.2 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 90*C for 7 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH2Cl 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%. 'H NMR (500 MHz, CDC13/MeOH-d) 8 8.19 (s, 1H), 7.58 (d, J= 2.1 Hz, IH), 7.50 (d, J= 8.5 Hz, IH), 7.03 (d, J= 2.4 Hz, 1H), 6.99 (dd, J= 2.6, 8.6 Hz, 1H), 6.40 (d, J= 2.1 Hz, IH), 4.42 (t, J= 6.1 Hz, 2H), 3.81 (s, 3H), 3.02 (t, J= 6.1 Hz, 2H), 2.52 (s, 2H), WO 2011/044394 PCT/US2010/051872 138 0.98 (s, 9H); "C NMR (125 MHz, CDC1 3 /MeOH-d 4 ) 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) m/z [M+H]* calcd. for C22H 2 9 NgOS, 453.2185; found 453.2186; HPLC: method A Rt = 6.61, method B R, = 6.82. 8- ((2-ethynyl-5-methoxyphenyl)thio)-9-(2-(ieopentylandno)ethyl)-9H-purin-6-ainne (PU-WS31). Following the procedure to make PU-WS8, PU-WS31 was obtained from EC1O2 as a white solid. 'H NMR (CDC1 3 , 500 MHz) 5: 8.35 (s, IH), 7.46 (d, J= 8.4 Hz, 1H), 6.75 (m, 2H), 5.65 (br, 2H), 4.35 (t, J = 6.3 Hz, 2H), 3.72 (s, 3H), 3.30 (s, 1H), 2.97 (t, J = 6.3 Hz, 2H), 2.31 (s, 2H), 0.87 (s, 9H); MS (ESI) m/z 411.3 (M+H)*.

NH

2 I

NH

2 R 0 0 NH NH PU-H471 ZNN N N N H 2 NNN F N FN N IN N HNM HN PU-DZ13 Reagents and conditions: (a) RSn(Bu) 3 , LiCl, Pd(PPh 3

)

4 , DMF, 90 0

C.

WO 2011/044394 PCT/US2010/051872 139 Scheme 21. Stille coupling of PU-171 and PU-DZ13. 9-(3-(isopropylamino)propyl)-8-(6-(oxazol-2-yl)benzo[d [1,3jdioxol-5-ylthio)-9H-purin 6-amine [DZ4-20]. A mixture of PU-H71 (30 mg, 0.0585 mmol), 2-(tri-n butylstannyl)oxazole (83.8 mg, 49 l, 0.234 mmol), LiC1 (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

CI

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

H

24

N

7 0 3 S, 454.1661; found 454.1650; HPLC: method A 1, = 5.77, method B Rt = 5.28. 9-(3-(isopropylamino)propyl)-8-(6-(thiazol-2-yl)benzo[d] [1,3jdioxol-5-ylthio)-9H-purin 6-amine [DZ4-21]. A mixture of PU-H71 (30 mg, 0.0585 mmol), 2-(tri-n butylstannyl)thiazole (87.6 mg, 72.4 l, 0.234 mmol), LiC1 (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 0 C for 18 h. Then additional 2-(tri-n-butylstannyl)thiazole (21.9 mg, 18 1i, 0.0585 mmol) was added and the reaction mixture was heated under nitrogen at 90*C for an additional 18 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH 2 Cl 2 :EtOAC:MeOH-NH3 (7N), 2:2:1:0.5) to give 17.6 mg (64%) of DZ4-21. 'H NMR (500 MHz, CDCl3/MeOH-d 4 ) & 8.20 (s, IH), 7.87 (d, J= 3.3 Hz, IH), 7.45 (s, I), 7.44 (d, J= 3.3 Hz, 1 H), 6.98 (s, 1H), 6.11 (s, 2H), 4.21 (t, J= 6.9 Hz, 2H), 2.78 (septet, J= 6.3 Hz, 1H), 2.55 (t, J= 6.9 Hz, 2H), 1.98 (in, 2H), 1.09 (d, J= 6.3 Hz, 6H); HRMS (ESI) m/z [M+H]+ called. for C 2 IH24N702S2, 470.1433; found 470.1438; HPLC: method A Rt = 5.86, method B 1& = 5.66.

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

)

4 (4.5 mg, 0.0039 mmol) were added and the reaction mixture was heated under nitrogen at 90 0 C for an additional 18 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC two times (hexane:CH 2 Cl 2 :EtOAC:MeOH-NH 3 (7N), 2:2:1:0.5 then CH 2

C

2 :MeOH-NH 3 (7N), 20:1) to give 5.5 mg (31%) of DZ4-23. 'H NMR (500 MHz,

CDCI

3 /MeOH-d4) 8 7.68 (s, IH), 7.53 (s, 1H), 7.12 (s, iH), 6.84 (s, 1H), 6.07 (s, 2H), 4.74 (s, 2H), 4.41 (t, J= 6.4 Hz, 2H), 3.15 (t, J= 6.4 Hz, 2H), 2.59 (d, J= 6.9 Hz, 2H), 1.88 (m, 1H), 0.96 (d, J= 6.8 Hz, 6H); HRMS (ESI) m/z [M+H] calcd. for C22H 2 5

FN

7 0 3 , 454.2003; found 454.1995; HPLC: method A Rt = 6.61, method B Rt = 7.58. 2-fluoro-9-(2-(isobutylamino)ethyl)-8-((6-(thiazol-2-yl)benzo[d][1,3]dioxol-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 pI, 0.156 mmol), LiC1 (3.3 mg, 0.078 mmol) and Pd(PPh 3

)

4 (9 mg, 0.0078 mmol) in DMF (1 mL) was evacuated and back filled with nitrogen. This was repeated four times then the reaction mixture was heated under nitrogen at 90 0 C for 18 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC two times (hexane:CH 2 C1 2 :EtOAC:MeOH-NH3 (7N), 2:2:1:0.5 and

CH

2

C

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

CDCI

3 /MeOH-d 4 ) 5 7.77 (d, J= 3.3 Hz, IH), 7.36 (d, J= 3.3 Hz, 1H), 7.17 (s, 1H), 6.80 (s, 1H), 6.05 (s, 2H), 4.58 (s, 21H), 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) nz [M+H]* caled. for

C

22

H

25

FN

7 0 2 S, 470.1774; found 470.1770; HPLC: method A Rt = 6.68, method B Rt = 7.79.

WO 2011/044394 PCT/US2010/051872 141

NH

2 NH 2 R N NH NH PU-H71 Reagents and conditions: (a) alkene (R), Pd(PPh3) 4 , i-Pr 2 NEt, NMP, 55-100 0 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 mol) in NMP (1 mL) was evacuated and back filled with nitrogen. This was repeated four times, then DIEA (15.1 mg, 21 gL, 0.117 mmol), cyclopentene (80 mg, 103 gL, 1.171 mmol) and Pd(PPh) 4 (6.8 mg, 0.00586 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 CI2:MeOH, 7:3) to give 9.2 mg (35%) of TT-VI-1 16. 'H NMR (500 MHz, CDCI 3 /MeOH-d4) & 8.16 (s, 1fH), 6.99 (s, 1H), 6.82 (s, 1H), 6.01 (s, 2H), 5.98 (m, 1H), 5.63 (m, IH), 4.41 (t, J= 6.4 Hz, 2H), 3.39 (m, 1H), 3.34 (septet, J= 6.6 Hz, 1 H), 2.95 (t, J= 6.4 Hz, 2H), 2.22-2.52 (m, 5H), 1.50-1.59 (m, 1H), 1.44 (d, J= 6.6 Hz, 6H); HRMS (ESI) m/z [M+H]* called. for C23H 2 9N 6

O

2 S, 453.2073; found 453.2064; HPLC: method A Rt = 6.51, method B Rt = 7.79. 8-(6-(2,5-dihydro-1H-pyrrol-2-yl)benzo[d] [1,3]dioxol-5-ylthio)-9-(3 (isopropylamino)propyl)-9H-purin-6-anine [DZ3-141]. A solution of PU-H71 (30 mg, 0.0585 mmol) and N-Boc-2,3-dihydro- 1 H-pyrrole (19.8 mg, 20.2 pL, 0.117 mmol) in NMP (1.5 mL) was evacuated and back filled with nitrogen. This was repeated four times, then DIEA (15.1 mg, 21 sL, 0.117 mmol) and Pd(PPh 3

)

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

(CH

2 C1 2 :MeOH-NH 3 (7N), 15:1) and the resulting residue was dissolved into 2 mL of

CH

2 Cl 2 :TFA (4:1) and stirred for 1 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH 2 Cl 2 :MeOH-NH 3 (7N), 10:1) to give 6.0 mg (23%) of DZ3-141. 'H NMR (500 MHz, CDC 3 /MeOH-d4) S 8.19 (s, 1H), 6.98 (s, 2H), 6.04 (in, 1H), 6.01 (s, 2H), 5.74 (in, 1H), 5.62 (d, J= 2.0 Hz, IH), 4.31 (t, J= 6.9 Hz, 2H), 3.81-3.88 (in, 1H), 3.89-3.95 (in, 1H), 2.87 (septet, J= 6.3 Hz, 1H), 2.68 (t, J= 6.7 Hz, 2H), 2.14 (in, 21H), 1.15 (d, J= 6.3 Hz, 6H); HRMS (ESI) m/z [M+H]* caled. for C22H28N702S, 454.2025; found 454.2046; HPLC: method A R = 5.27, method B Rt = 2.72. 8-(6-(2,3-dihydrofuran-2-yl)benzo[dj [1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl) 9H-purin-6-amine [DZ3-142]. A solution of PU-H71 (30 mg, 0.0585 mmol) in NMP (1.5 mL) was evacuated and back filled with nitrogen. This was repeated four times, then DIEA (15.1 mg, 21 L, 0.117 mmol), 2,3-dihydrofuran (82 mg, 88 pL, 1.17 mmol) and Pd(PPh 3

)

4 (13.5 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 55*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

C

2 :MeOH-NH 3 (7N), 2:1:2:0.5, then CH 2

CI

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

CDC

3 ) 8 8.23 (s, 1 H), 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, iH), 5.72 (br s, 2H), 4.93 (in, iH), 4.35 (t, J= 6.8 Hz, 2H), 2.95-3.55 (in, 21H), 2.70 (t, J= 6.5 Hz, 2H), 2.39-2.47 (m, 1H), 2.22 (in, 2H), 1.25 (d, J= 6.2 Hz, 6H); HRMS (ESI) m/z [M+H] t called. for C22H27NO 3 S, 455.1865; found 455.1865; HPLC: method A Re = 6.07, method B Rt = 6.49. 8-(6-(2,3-dihydrofuran-3-yl)benzo[d] 11,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl) 9H-purin-6-amine [DZ3-143]. A solution of PU-H71 (30 mg, 0.0585 mmol) in NMP (1.5 mL) was evacuated and back filled with nitrogen. This was repeated four times, then DIEA (15.1 mg, 21 pL, 0.117 monl), 2,5-dihydrofuran (82 mg, 88 gL, 1.17 mmol) and Pd(PPh 3

)

4 (13.5 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 55 0 C for 20 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC two times (CH 2 Cl 2 :MeOH-NH 3 (7N), 10:1, then WO 2011/044394 PCT/US2010/051872 143 hexane:EtOAc:CH 2 Cl 2 :MeOH-NH 3 (7N), 2:1:2:0.5) to give 5.0 mg (19%) of DZ3-143. 'H NMR (500 MHz, CDCl3/MeOH-d4) 8 8.18 (s, 1H), 7.02 (s, 1H), 7.00 (s, 1H), 6.55 (m, iH), 6.04 (s, 2H), 4.99 (m, IH), 4.64-4.69 (m, iH), 4.45 (m, iH), 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 C22H27N 6 0 3 S, 455.1865; found 455.1862; HPLC: method A R, = 6.04, method B Rt = 6.32.

NH

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

)

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

)

2 , trimethylsilanylacetylene, Et 3 N, DMF, 90*C; (c) KOH, MeOH, rt. Scheme 23. Cross coupling reactions of PU-WS21. 8-(5-(furan-2-yl)-2,3-dihydrobenzofuran-6-ylthio)-9-(2-(neopentylamino)ethyl)-9H purin-6-amine [PU-WS23]. Following the procedure to make PU-DZ3-4, compound PU WS23 was obtained as a white solid. 'HNMR (500 MHz, CDC1 3 ) 8 8.31 (s, IH), 7.49 (s, 2H), 6.68 (d, J= 3.4 Hz, IH), 6.58 (s, 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 C 24

H

29

N

6 0 2 465.2073; found 465.2077.

WO 2011/044394 PCT/US2010/051872 144 9-(2-(neopentylamino)ethyl)-8-(5-(thiophen-2-yl)-2,3-dihydrobenzofuran-6-ylthio)-9H purin-6-amine [PU-WS241. Following the procedure to make PU-DZ2-395, compound PU WS24 was obtained as a white solid. 'HNMR (500 MHz, CDC 3 ) 8 8.31 (s, 1 H), 7.32 (m, 1H), 7.27 (s, iH), 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 C 2 4H 29

N

6 0 2 481.1844; found 481.1825. 8-(5-ethynyl-2,3-dihydrobenzofuran-6-ylthio)-9-(2-(neopentylamino)ethyl)-9H-purin-6 amine [PU-WS28]. Following the procedure to make PU-WS8, compound PU-WS28 was obtained as a white solid. 'HNMR (500 MHz, CDC 3 , 5): 8.33 (s, 1H), 7.36 (s, 1H), 6.59 (s, 1 H), 5.70 (br, 2H), 4.58 (t, J= 8.7 Hz, 2H), 4.41 (m, 2H), 3.33 (t, J= 8.7 Hz, 2H), 3.49 (m, 2H), 3.02 (s, 2H), 2.44 (s, 2H), 0.91 (s, 9H); HRMS (m/z): [M+H]* calcd for C 22

H

27

N

6 0S 423.1967; found 423.1968. H2N 0 AcHN-b AcHN H2N S2-1 S24-2 S24-3 S24-4 NH

NH

2 -N

NH

2 -N ~N o~NN 2 N NN Ny C 5 _ e N N N NO H 1,n=2 ~, 2 S24-5 S24-6 Brn1 RHN S24-7 S24-8 Reagents and conditions: (a) Ac2O, AcOH rt; (b) ICI, CH 2

C

2 , AcOH, rt; (c) NaOH, EtOH, H 2 0, reflux; (d) parafornaldehyde, NaBH 3 CN, MeOH, 50*C; (e) 8-mercaptoadenine, neocuproine, Cul, NaOtBu, DMF, 115*C; (f) Cs 2

CO

3 , 1,3-dibromopropane or 1,2-dibromoethane, DM1F, rt; (g) amine, DMF, rt. Scheme 24. Similarly, WO 2011/044394 PCT/US2010/051872 145 H2N H2N H, l 0 H2 I z NH 2 - N d 0 iJ:N N_ Th/ N" N H2N HR 1,2 e r 6-nebered ring RHN corresponding to appropriate 2-jodoamine HN H2N l N Scheme 25. Synthesis of various bromides required for alkylation of the purine skeleton.

NH

2 X

NH

2 X2 Cs2R-BrM NF XHN Cs 2 C0 3 , DIMF X 4 N N % R 5 or 6- 5or6 membered ring membered ring WO 2011/044394 PCT/US2OIO/051872 146 HC(OEt) 3 H Br Sr OH CHCC 111Br n=1,2 Ph 3 P, 08r 4 TWACH0IN NBOC NH

CH

3 S0 2 Cl p,f Br OH 2 o=1g2 )n=1,20 - Br _~1,2 N Bx0 r-,-Br -S NH-' Ito n=r1,2 WO 2011/044394 PCT/US2010/051872 147 0 0+Bu TIPS H H TlPS t-butylpero eN n-U 4 NF N %dC N LiAH4 Pd(OAo) 2 / COOn-Bu COOn-Bu COOn-Bu Bc BOH H, O N N N AcBOC20 05r 4 TA HO HoI BF Sr '1. CSONCO 2.TA HC(O Et / AcC ~ CH30 2 C H 2 0

N-

2 N N N Br Br Br Br r OH 0 Br SN 1)TsCI N NH 6NK 2) LiBr HO Br-NH 2 NHH Br NH2 o O Br , OH Br,, ... SCl o 0 0 MeNH 2 Br..... -NH-~ 0 PPh 3 - -. rHCHAS2C H, CBr 4 : Br-SOCI HO -- S0, WO 2011/044394 PCT/US2OIO/051872 148 Table IA No. Name tA-i PU-WS1O 8-((6-iodo-2,3-dilaydrobenzofuran-5-yl)thio)-9-(3 (isopropylamino)propyl)-9H-purin-6-amine tA-2 8-((6-iodo-2,3-dihydrobenzofhran-5-yl)thio)-9-(2-(isobutylamino)ethyl) 9H-purin-6-amine tA-3 1 -(6-amnino-8-(6-iodo-2,3-dihydrobenofiuan-5-ylthio)-9H-purm-9-yl)-3 (tert-butylamino)propan-2-ol tA-4 2-fluoro-8-((6-iodo-2,3-dihydrobenofuran-5-yl)methyl)-9-(2 (isobutylamino)ediyl)-9H-purin-6-amine lA-5 2-chloro-8-((6-(fuira-2-yl)-2,3-dihydrobenofuran-5-yl)methyl)-9-(3 (isopropylaxnino)propyl)-9H-puiin-6-amine tA-6 2-fluoro-8-((6-iodo-2,3-dihydrobenofura-5-yl)methyl)-9-(3 (isopropylarnino)propyl)-9H-purin-6-amine 1A-7 8-((6-(furan-2-yl)-2,3-dihydrobenofiimn-5-yl)thio)-9-(3 - ~(isopropylamino)propyl)-9H-purin-6-anmine 1A-8 8-((6-ethynyl-2,3-dihydrobenzofhran-5-yl)thio)-9-(3 - ~(isopropylamino)propyl)-9H-purin-6-anmine, 1A-9 5-((6-aniino-9-(3-(isopropylamino)propyl)-9H-purin-8-yl)thio)-2,3 dihydrobenzoffira-6-carbonitrile IA-10 8-((6-(azixidin-1I-yl)-2,3-dibydrobenzofura-5-yl)methyl)-2-fluoro-9-(2 _________(neopentylanmino)ethyl)-9H-purin-6-anmine IA-l1 8-((6-iodo-2,3-dihydrobenofiua-5-yl)thio)-9-(2-(isobutylamino)ethyl) _________9H-purin-6-amine IA-12 3-(2-(6-amino-8-(6-(5-methylfuan-2-yl)-2,3-dihydrobenzofiran-5 ylthio)-9H-purin-9-yl)ethyl)piperidine-1-sulfonanide IA-13 1 -(3-(2-(8-(6-(1 H-pyrazol-3-yl)-2,3-dihydrobenzofrra-5-ylthio)-6 amino-9H-purin-9-ylethy1)piperidin-1I -yl)ethanone IA-14 4-(3-(6-amino-8-(6-ethynyl-2,3-dihydrobenzfixra-5-ylthio)-9H-putin-9 yl)propyl)piperidine-1I -carbaldehyde lA-i5 1-(3-(2-(6-amino-2-fluoro-8-((6-(fuira-2-yl)-2,3-dihydrobenoftra-5 yl)methyl)-9H-purin-9-yl)ehiyl)piperidin-1I -yl)ethanone lA-16 N-(2-((2-(6-amino-8-((6-(fiuan-2-yl)-2,3-dihydrobenofuira-5-yl)hio) 9H-purin-9-yl)ethyl)amino)ethyl sulfamide lA-17 3-((2-(6-amino-8-((6-(fuiran-2-yl)-2,3-diaydrobenzofura-5-yl)tio)-9H - purin-9-ylI)ethyt)amio)-N-hydroxypropanmide lA-18 2-fluoro-8-((6-iodo-2,3-diaydrobenzofiran-5-yl)laio)-9-(3 (isopropytammio)propyl)-9H-purin-6-amine WO 2011/044394 PCT/US2OIO/051872 149 -4 tA-19 2-chloro-8-((6-iodo-2,3-dihydrobenofura-5-yl)methyl)-9-(2 (isobutylamino)ethyl)-9H-purin-6-amine IA-20 9-(2-aminoethyl)-2-fluoro-8-((6-iodo-2,3-dihydrobenzofuran-5 yl)methyl)-9H-purin-6-amme IA-21 9-(3-aminopropyl)-8-((6-iodo-2,3-dihydrobenzofiiran-5-yl)thio)-9H - purfi-6-amine IA-22 9-(2-aininoethyl)-8-((6-iodo-2,3-dihydrobenzofLiran-5-yl)thio)-9H-purin _________6-amine IA-23 9-(3-(tert-butylamino)propyl)-8-((6-iodo-2,3-dihydrobenzofiirn-5 _________yl)thio)-9H-purin-6-amine IA-24 i-(6-amino-8-((6-iodo-2,3-dihydrobenzofhm-5-yl)thio)-9H-purin-9-yl) _________3-(isopropylamnino)propan-2-ol 1A-25 1-(3-(6-anmino-2-fluoro-8-((6-iodo-2,3-dihydrobenzof~ran-5-yl)methyl) __________9H-purin-9-yl)propyl)pyrrolidin-3-one IA-26 I -(3-(6-amino-8-(6-iodo-2,3-dihydrobenzofuran-5-ylthiio)-9H-purin-9 _________yl)propyl)pyrrlidin-3-one IA-27 5-(6-amino-8-(6-iodo-2,3-dihydrobenzoftiran-5-ylthio)-9H-puiin-9 ylpentane- I -sulfonamide IA-28 I -(6-amiino-2-fluoro-8-((6-iodo-2,3-dihydrobenzoftwan-5-yl)methyl)-9H _________purin-9-yl)-3-(isopropylamino)propan-2-ol 1A-29 8-((6-ethynyl-2,3-dihydrobenofhra-5-yl)methyl)-2-fluoro-9-(5 - (methylsulfonyl)pentyl)-9H-purin-6-amine IA-30 2-fluoro-8-((6-iodo-2,3-dihydrobenzofuran-5-yl)methyl)-9-(2-(1 (methylsulfonyl)pyrrolidin-3-yl)ethyl)-9H-pu-in-6-amine IA-31 N-(4-(6-amino-2-fluoro-8-((6-iodo-2,3-dihydrobenzofhran-5-yl)nethyl) 9H-purin-9-yl)butyl)methaesulfonamide 1A-32 1-(6-amino-8-((6-ethynyl-2,3-dihydrobenzofuran-5-yl)methyl)-2-fluoro 9H-purin-9-yl)-3-(isopropylaniino)propan-2-ol 1A-33 6-(6-amino-8-((6-ethynyl-2,3-dihydrobenofhran-5-yl)methyl)-2-fluoro _________9H-purin-9-yl)hexanamide 1A-34 I -(4-(2-(6-amino-8-((6-ethynyl-2,3-dihydrobenzofuran-5-yI)methyl)-2 fluoro-9H-purin-9-yl)ethyl)piperidin-I -yl)ethaone IA-35 8-((6-ethynyl-2,3-dihydrobenzofuran-5-yl)methyl) 2-fluoro-9-(2-(I -(metliylsulfonyl)piperidin-3 _________yl)ethyl)-9H-purin-6-amine 9-(3-(isopropylamino)propyl)-8-((6-(5 methylfura-2-yl)-2,3-dihydrobenzofuir-5 yl)thio)-9H-punin-6-amine 9-(3-(tert-butylamino)propyl)-8-((6-(5-methylftiran 2-yl)-2,3-dihydrobenzofLiran-5-yl)thio)-9H-purin-6 amine __________9-(3-(tert-butylamino)propyl)-8-((6- WO 2011/044394 PCT/US2OIO/051872 150 -4 (diinethylamino)-2,3-dihydrobenzofiara-5-yl)thio) 9H-purin-6-aniine WO 2011/044394 PCT/US2OIO/051872 151 1 -(4-(2-(6-amino-8-((6-(dimethylamino)-2,3 dihydrobenzofuran-5-yl)thio)-9H-purin-9 yl)eflhyl)piperidin-1-yl)efhanone IA-40 8-((6-(dimethylamino)-2,3-dihydrobenzofuran-5-y)thio)-9-(2-(1 __________(methylsulfonyl)piperidin-3-yl)ethyl)-9H-purin-6-amine 1A41l 4-(3-(6-amino-8-(6-(aziridin-1-yl)-2,3-dihydrobenzofliran-5-ylthio)-9H _________purin-9-yl)propyl)piperidine-1I -carbaldehyde 1A-42 8-((6-(furan-2-yl)-2,3-dihydrobenzofura-5-yl)thio)-9-(2-(1 (methylsulfonyl)piperidin-3-yl)ethyl)-9H-purin-6-ainine IA-43 8-((6-(dimethylaino)-2,3-dihydrobenzofin-an-5-yI)methyl)-2-fluoro-9-(2 (isobuty1amino)ethy1)-9H-purin-6-arnine 1A-44 8-((6-(dimnethylamino)-2,3-dihydrobenzofiaa-5-yl)thio)-9-(2 ___________(nec'pentylanaino)ethyl)-9H-purin-6-amine IA-45 9-(3-(tert-butylamino)propyl)-8-((6-(oxazol-2-yl)-2,3-dihydrobenzofuran-5 ___________yl)thio)-9H-purin-6-aniine IA-46 1-(3-(2-(6-arnino-8-(6-(oxao1-2-yl)-2,3-dihydrobenzofiia-5-ylthio)-9H-purin __________9-yl)ethyl)piperidin-1 -yl)ethanone IA-47 4-(3-(6-amino-8-(6-(oxazol-2-yl)-2,3-dihydrobenzofur-5-ylthio)-9H-purin-9 yl)propyl)piperidine- 1-carbaldehyde 1A-48 9-(2-(1-(methylsulfonyl)piperidin-3-yl)ethyl)-8-((6-(oxazol-2-yl)-2,3 dihydrobenzofiira-5-yI)thio)-9H-purin-6-amine lA-49 1-(2-(3-6-anino-8-(6-iodo-2,3-dihydrobenzofura-5-ylthio)-9H-purin-9 __________ l)propyl)pyrrolidin-t-y)ethanone IA-50 9-(3-(tert-butylamino)propyl)-8-(f6-(5-methyloxazol-2-yl)-2,3 dihydrobenzofiiran-5-yl)thio)-9H-purin-6-amine 1A-51 9-(3-(tert-butylamino)propyl)48-((6-(thiazo-2-yl)-2,3-dihydrobenzofwan-5 - ~yl)thio)-9H-purin-6-ammne IA-52 9-(3-(tert-butylamino)propyl)-8-((6-(5-methylthiazo-2-yl)-2,3 - dihydrobenofiuran-5-yl)thio)-9H-purin-6-atine Table 1B No. Name lB-1 PU-WS9 8-((5-iodo-2,3-dihydrobenzofurn-6-yl)thio)-9-(2-(isobutylamino)ethyl)-9H-purin 6-amine 1-2 PIJ-WS4 8-((5-iodo-2,3-dihydrobenzofurn-6-yl)thio)-9-(3-(isopropylamino)propyl)-9H _________punin-6-amine WO 2011/044394 PCT/US2OIO/051872 152 -41B-3 PU-WS17 2-fluoro-S-((5-iodo-2,3-dihydrobenzfurn-6-yl)methyl)-9-(2 (isobutylamino)ethyl)-9H-purin-6-amine IB-4 PU-WS18 2-fluoro-S-((5-iodo-2,3-dihydrobenzfura-6-yl)methyl)-9-(3 NlB-5 8-ff5--(-pyaol-3y-2,3-dhydrobenofiar-6-yl)ethio)-9-(2 (isobutylamino)thyl)-9H-puin-6-amine 1-6 8-((5-cyclopntyl)-2,3-dihydrobenzofuran-6-yl)thio)-9-(3-(isopropylamino)propyl) 9H-purin-6-aniine lB-7B 8-((5-(iethylano-2,3-dihydrobera-6-yl)methyl)-2-o-9-(2 (isobutylamino)ethyl)-9H-purin-6-mine lB-l8 6-((6-atin-2-urao--l(3-ioproylmfno- yl)9Hi-unn--lmty)2 dihyobemnoiran--pbourile-nin lB-9l 2-oh loptl3dhdoro-9-(3-(isoio)9-(4ipropylamino)propyl)-8-(-5mtyfun2y) dhdoezfun--lmty)9H-purin-6-aniine lB-19 4-2(-n--((5 hny-,-chynyl-2,-dihrobnoia-6-yl) thi2-lo-9-purn ylsoetyapieineh- -earbaldehyd e I-11 1 6-(-(6-mino-2-fuoro-4(5-(fplinn2-y1 )--hdrobpian-yI)methy1) 19dh-prob9-ethipe5 rbiil-ethnn 1B-12 N2hl--(-mopylino pryl-8-((5-(fizranfur-2-y)-2,3-diyrbnoirn6y~ho-Hprn 9-yrethyfaninoeyl)ufme)9- 6ain 1B-13 3-((2-(6-anino-8-((5-thynyl-2,3-dihydrobenzofuiran-6-yI)thio)-9H-purin-9 yI)ethyl)amprin--ydrxdyprpde 1B-14 9-(-(2-(obtylainoetyl)-8-((5-(thiph-2-yI)-2,3-dihydrobenofuan-6-y)thio) ______9H-purin-9-anleypiedi-ylthne 1B-15 3-(3--(6-ain-8-(5-o 2yl-2,3-d ihydrobea -6-y~hio)-9H-puin-oy)2 oxointhylaoliinoe1-eslarbmdhde lB-19 32-lor ~o-8-((5-ethynyl-2,3-dihydrobefran--yI6etyl)tb-9- n isb9 lmn-eh1 9-urin-6-amine lB-18 6-(3(6-amino--hloo--(3-ioproylmiofpropylti)-9H-purin--yle opyl-2 ___________ irdaezoidin--carbonitrile lB-19 2-chloro-8-((5-(dethylax-2,3-dihydrob cnzofra-6-yl)methyl)-9-(2 (neopetylaniino)ethyl)-91-prin-6-mine IB-22 8-((5-cyclopentyI-2,3-dihydrobezofian-6-yI)thio)-2-fluoro-9-(3 (isopropylamino)propyl)-9H-purin-6-amine 1B-23 1-(3-(6-amaino-8-(5-iodo-2,3-dihydrobenzfur-6-ylthio)-9H-purin-9 yI)propylprrlidin-3 -one IB-24 PU-WSZL 8-((5-iodo-2,3-dihydrobenzofhr-6-yI)thio)-9-(2-(neopentylanmino)ethyl)-9H ________ I purin-6-am~ne I-25 PU-WS22 2-fluoro-8-((5-iodo-2,3-dihydrobenofurn-6-yI)methyl)-9-(2 _________(neoentylanmino)ethyl)-9H-purin-6-anmine WO 2011/044394 PCT/US2OIO/051872 153 L4 IB-26 PU-WS23 8-((5-(fira-2-yl)-2,3-dihydrobezofira-6-yl)thio)-9-(2-(neopentylamino)ethyl) _________9H-purin-6-amine IB-27 PU-WS24 9-(2-(neopentylaniino)ethyl)-8-((5-(thiophen-2-yl)-2,3-dihydrobenzokran-6 _________yl)thio)-911-purin-6-amine N IB-28 PU-WS28 8-((5-ethyny1-2,3-dihydrobet~ofuran-6-y1)thio)-9-(2-(neopentylamino)ethy1)-9H purin-6-amine IB-29 9-(3-amiinopropyl)-8-((5-iodo-2,3-dihydrobenzfiia-6-yl)thio)-9H-purin-6-armine lB-S0 9-(2-aniinoethyl)-2-fluoro-8-((5-iodo-2,3-dihydrobenzofiirn-6-yl)methyl)-9H __________purin-6-ainine lB-3l 9-(2-ammnoethyl)-8-((5-iodo-2,3-dihydrobenzoffia-6-yflthio)-9H-purin-6-anune IB-32 9-(3-(tert-butylamino)propyl)-8-((5-iodo-2,3-dihydrobenzofiaa-6-yl)tbio)-9H _________purin-6-aniine IB-33 2-fluoro-8-((5-(5-methylkran-2-yl)-2,3-dihydrobezofuran-6-yl)methyl)-9-(2-( __________(mthylsulfonyl)piperidin-3-yl)ethyl)-9H-purin-6-amine IB-34 1-(3-(6-amino-8-(5-iodo-2,3-dihydrobenzofuran-6-ylthio)-9H-purin-9-yl)propyl)-4 _________hydroxypyrrolidin-2-one IB-S5 N-(3-(6-amino-8-((5-iodo-2,3-dihydobenzofiaa-6-yl)thio)-9H-purin-9 ________I yl)propyl)methanesulfonaniide IB-36 1-(3-(6-amino-8-(5-ethynyl-2,3-dihydrobt~ofiarn-6-ylthio)-9H-purin-9 __________yI)propyl)pymrlidin-3-one IB-37 8-(5-iodo-2,3-dihydrobenzofira-6-ylthio)-9-(2-(l -(methylsulfonyl)pyrrolidin-3 yI)ethyl)-9H-purin-6-amine LB-S8 N-(3-(6-ainino-8-((5-ethynyl-2,3-dihydrobenzofuira-6-yI)thio)-9H-purin-9 yl)propyl)methmresulfonamide IB-39 I -(4.{2-(6-amino-8-((5-ethynyl-2,3-dihydrober~ofhran-6-yl)thio)-9H-purin-9 __________yl)ethyl)piperidin-I -yl)ethanone WO 2011/044394 PCT/US2OIO/051872 154 -4 IB40l 8-((5-thynyl-2,3-dihydrobenofuran-6-yl)thio)-9-(2-( I -(methylsulfonyl)piperidin 3-yl)ethyl)-9H-purin-6-amine IB-41 5-(6-amino-8-(5-ethynyl-2,3-dihydrobenoffira-6-ylthio)-9H-purin-9-yl)pnte 1-sulfonamide IB-42 I -(4-(2-(6-amino-8-((5-(fura-2-yl)-2,3-dihydrobenzfurn-6-yl)thio)-9H-purin-9 yl)ethyl)piperidin- 1-yl)ethanone IB43 8-(5-(5-methylfiuran-2-yl)-2,3-dihydrobenzofiian-6-ylthio)-9-(2-(1 __________(methylsulfonyl)piperidin-3-yl)ethyl)-9H-purin-6-amine IB-44 2-(3-(6-anaino-8-(5-(5-methylfuran-2-yl)-2,3-dihydrobenzfura-6-ylthio)-9H purin-9-yl)propyl)pyrrolidine-lI -earbaldehyde 1B-45 N-(2-(6-anuino-S-((5-ethynyl-2,3-dihydrobenzofura-6-yI)thio)-9H-pmin-9 yl)ethyl) N'-methyl-sulfiric diamide IB-46 9-(3-(tert-butylanino)propyl)-8-((5-(oxazl-2-yl)-2,3-dihydobenzofiman-& yl)thio)-9H-purin-6-amine 1B-47 9-(3-(tert-buty1anino)propy1)-8-((5ethynyI-2,3-dihydrobnzfiman-6-y1)thio)-9H __________purin-6-amine IB-48 9-(3-(tert-bfitylanilno)propyl)-8-((5-(dimethylamino)-2,3-dihydrobnzfian-6 ______ yl)thio)-9H-purin-6-antine IB-49 1-(6-mino-8-((5-iodo-2,3-dihydrobenzot'un-6-yI)thio)-9H-purin-9-yl)-3 ________I (isopropylaniino)propan-2-ol IB-50 1-(4-(2-(6-amno-8-((5-(oxazol-2-yI)-2,3-dihydrobenzffira-6-yl)thio)-9H-purin __________9-yI~ethylbpiperidin- 1 -yI)ethanone LB-51 9-(2-(1-(methylsulfonyl)piperidin-3-yl)ethyl)-8-((5-(oxazol-2-yI)-2,3 _________dihydrobenzofiara-6-yl)thio)-9H-purin-6-anuine IB-52 3-(3-(6-amiino-8-(5-iodo-2,3-dihydrobenofurn-&ylthio)-9H-pmin-9 __________yI)propyl)pyrrolidine- 1 -sulfonamide IB-53 9-(3-(tert-butylamiino)propyl)-8-((5-(5-methyloxazol-2-yl)-2,3-dihydrobenzofura ______ 6-yi)thio)-9H--purin-6-anuine IB-54 9-(3-(tert-butylaniino)propyl)-8-((5-(thiazol-2-yl)-2,3-dihydrobezoflsr-6 ________I yl)thio)-9H-purin-6-amine IB-55 9-(3-(tert-butylamino)propyl)-8-((5-(5-methylthiazol-2-yl)-2,3-dihydrobenzfiin __________6-yl)thio)-9H-purin-6-amine 1B-56 6-(6-amiino-8-(5-iodo-2,3-dihydrobenofija-6-ylthio)-9H-purin-9-yl)hexanamide 1B-57 5-(6-anino-8-(5-iodo-2,3-dihydrobenofisa-6-ylhio)-9H-purin-9-yl)pentne-1 ________sulfonamde IB-58 3-(6-amiino-8-(5-ethynyl-2,3-dihydrobenofura-6-ylthio)-9H-purin-9-yl)propyl __________sulfamte Table IC No. Name IC-i 8-((6-iodo-2,3-dihydrobenzorblthiophen-5-yl)thio)-9-(3 _____________(isopropylaniino)propyl)-9H-uin--amine IC-2 8-((6-iodo-2,3-dihydrobenzo[blthiophen-5-yl)thio)-9-(2-(isobutylamino)ethyl) 9H-puri-6-amine 1C-3 8-((6-iodo-2,3-dihydrobeno[b]thiophen-5-yl)thio)-9-(3 _____________(isopropylamno)propyl)-9H-purin-6-arnine 1C-4 2-fluoro-8-((6-iod,-diyrbuobtipen5yehl--2 WO 2011/044394 PCT/US2OIO/051872 155 -4 (isobutylamino)ethyl)-9H-purin-6-anline iC-S 2-chloro-S-((6-(fura-2-yl)-2,3-dihydrobenz[b]thiophen-5-yl)methyl)-9-(3 (isopropylanino)propyl)-9H--purin-6-amine 1C-6 8-((6-(IH-iniidazol-4-yl)-2,3-dihydrobenzo[blthiophen-5-y)methyl)-2-fluoro-9 ____________(3-(isopropylamino)propypl)-9H-purin-6-amine 1C-7 8-((6-(fura-2-yl)-2,3-dihydrobenzo[b]thiophen-5-yl)thio)-9-(3 (isopropylarmino)propyfl-9H-pui-6-anaine ic-s 8-((6-ethynyl-2,3-dihydrobenzo[blthiophen-5-yl)thio)-9-(3 (isoprpylamno)propyl)-9H--puxn-6amne 1C-9 5-((6-amino-9-(3-(isopropylanmino)propyl)-9H-purin-8-yl)thio)-2,3 dihydrobenzo[b]thiophene-6-carbonitrile IC-10 8-((6-(aziridin-1 -yI)-2,3-dihydrobenzo]thiophn-5-y)methy)-2-fluoro-9-(2 neo enIlaniino ethyI -9-purin-6-amine ic-ti 8-((6-iodo-2,3-dihydrobenzo[blthiophen-5-yl)thio)-9-(2-(isobutylaimino)ethyl) 9H-purin-6-amine IC-12 1 -(4-(2-(6-amino-S-((6-(fuiran-2-yI)-2,3-dihydrobenzob]thiophen-5-yl)thio)-9H purin-9-yI)ethyl)piperidin-1-yI)ethanone. tC-13 4-(2-(8-((6-(1H-pyrazol-3-yI)-2,3-dihydzobeno[blthiophen-5-y)thio)-6-amino 9H-purin-9-yI)ethyl)piperidine-l1 cabaldehyde tC-14 4-(2-(6-amino-8-((6-ethyny-2,3-dihydrobno[bthiophen-5-y)thio)-9H--purin-9 yl)ethyl) pip eridine-l1 cabaldehyde IC-i5 1-(4-(2-(6-amnino-2-fiuoro-8-((6-(fwzan-2-yI)-2,3-dihydrobenzo[bjthiophen-5 yI)methyl)-9H--purin-9-yl)ethyl)piperidin-1-yl)ethanone 1C-16 N-(2-((2-(6-amino-8-((6-(fura-2-yl)-2,3-dihydrobenzofblthiophen-5-yI)thio) 9H-purin-9-yI)ethyl)amino)ethyl)sulfarmide iC-17 3-((2-(6-amino-8-4(6-(fiiran-2-yl)-2,3-dihydrobez[bthiophn-5-y)thio)-9- Ipurin-9-yl)ethyl)a-ino)-N-hydroxypropanamide iC-i8 9-(3-nminopropyl)-8-((6-iodo-2,3-dihydrobeno[bjthiophen-5-yl)thio)-9H-purin 6-amine tC-t9 9-(2-arniinoethyl)-2-fluoro-8-((6-iodo-2,3-dihydrobenzo[blthiophen-5-yI)metliyl) ___________9H1-purin-6-aniine IC-20 9-(2-anminoethyl)-8-((6-iodo-2,3-dihydrobenzo[blthiophen-5-yl)thio)-9H-purin-6 amine iC-21 9-(3-(tert-butylamino)propyl)-8-((6-iodo-2,3-dihydrobenzo[blthiophen-5-yl)thio) ___________9H1-purin-6-amine Table iD NO. Name 1D-i 8-((5-iodo-2,3-dihydrobenzo[blthiophen-6-yl)thio)-9-(2-(isobutylainino)ethyl) _____________9H-purin-6-amme iD-2 8-((5-iodo-2,3-dihydroberio[b]thiophen-6-yl)thio)-9-(3 ______________(isopropylaraino)propyl)-9H-purin-6-amine iD-3 2-fluoro-8-((5-iodo-2,3-dihydrobenzo[b]thiophen-6-yl)mthyl)-9-(2 (isobutylaniino)ethyl)-9H-purin-6-amine 1D-4 2-fluoro-8-((5-iodo-2,3-dihydrobenzo[bjthiophen-6-yI)methyl)-9-(3 (isapropylamino)propyl)-9H-purin-6-aniine iD-S 8-((5-iodo-2,3-dhydrobenzo[bjthiophen-6-yl)thio)-9-(2-(isobutylamino)ethyl) 9H1-puri-6-aine LD-6 8-((5-(furan-2-yl)-2,3-dihydrobenz[blthiaphen-6-yl)thio)-9-(3- WO 2011/044394 PCT/US2OIO/051872 156 -4 (isopropylamino)propyl)-9H-puin-6-amine 1D-7 8-((5-(dimethylanmino)-2,3-dihydrobenz[b]thiophen-6-yI)methyl)-2-fluoro-9 (2-(neopentylanaino)ethyl)-9H-purin-6-anminc 1D-8 8-((5-(IH-pyrazo1-3-y1)-2,3-dihydrobeo[b]thiophen-6-y1)thio)-9-(2 (isbutylamino)ethyl)-9H-purin-6-amine 1D-9 S-((5-cyclopenty1-2,3-dihydrobenzo[b~thiophen-6-y1)thio)-9-(3 (isoprpylantino)propyl)-9H-purin-6-anmine 1D-10 8-((5-ethyny1-2,3-dihydrobenz[b]hiophx-6-y1)methy1)-2-fluoro-9-(2 (isobutylamino)ethyl)-9H-purin-6-aniine 1D-11 6-((6-antino-2-fluoro-9-(3-(isopropylanmino)propyl)-9H-purin-8-yl)methyl)-2,3 dihydrobenzolblthiophene-5-cabonitrile 1D-12 2-chloro-8-((5-(fura-2-yl)-2,3-dihydrobenz[b]thiophcn-6-yl)methyl)-9-(3 (isopropylamino)propyl)-9H-purin-6-antine ID-13 4-(2-(6-anmino-8-((5-ethynyl-2,3-dihydrobenzo[b]thiophen-6-yl)thio)-9H-pirin 9-yl)ethiyl)piperdine- 1-cabaldehyde 1D-14 1-(4-(2-(6-amino-2-fluoro-8-((5-(fur-2-yl)-2,3-dihydrobenzo[b]hiophen-6 yl)methyl)-9H-purin-9-yl)ethyl)piperidin-1 -ylethmnone 1D-15 N-(2-((2-(6-amino-8-((5-(furan-2-yl)-2,3-dihydrobenzo[b]thiophen-6-yI)thio) ____________ I 91-puin-9-yI)ethyl)amino)ethyl)sulfamide 1D-16 3-((2-(6-amino-8-((5-ethynyl-2,3-dihydrobenzo[b]thiophen-6-yl)thio)-9H ______________purin-9-yI)ethyl)anmino)-N-hydroxypropanide WO 2011/044394 PCT/US2OIO/051872 157 -4 1D-17 2-chloro-8-((5-iodo-2,3-dihydrobenzo[b]thiophen-6-yl)methyl)-9-(3 ______________(isopropylamino)propyl)-9H-purin-6-amine 1D-18 9-(3-amfiopropyl)-S-((5-iodo-2,3-dihydlrobeno[b]thiophen-6-yl)thio)-9H _____________pmrn-6-axnine 1D-19 9-(2-aninoethyl)-2-fluoro-8-((5-iodo-2,3-dihydrobenzo~bliophen-6 yI)methyl)-9H-purin-6-armne 1D-20 9-(2-amiinoethyl)-S-((5-iodo-2,3-dihydrobenz[blthiophen-6-yl)thio)-9H-purin 6-amine ID-21 9-(3-(tert-butylamino)propyl)-8-((5-iodo-2,3-dihydrobenzo[b]thiophen-6 Iyl)thio)-9H-purin-6-amine Table 1E No. Name 1E-1 1-(6-anmino-8-(6-iodo-2,3-dihydro-IH-inden-5-ylthi6)-9H-purin-9-yl)-3-(tert butylaniino)propan-2-ol 1E-2 PU-WS26 8-((6-iodo-2,3-dihydro-IH-inden-5-yl)thio)-9-(2-(isobutylamino)ethyl)-9H-punn-6 amine 1E-3 1-(3-(6-aniino-S-(6-iodo-2,3-dihydro1H-inden-5-ylthio)-9H-purin-9 yl)propyl)pynfolidin-3 -one 1E-4 2-fluoro-8-((6-iodo-2,3-dihydro-1H-inden-5-yl)methyl)-9-(2-(isobutylamiino)ethyl)-9H pur-6-ame iE-5 2-chloro-S-((6-(furn-2-y)-2,3-dihydro-lH-inden-5-y)niethy1)-9-(3 (isopropylamino)propyl)-9H-puria-6-amine iE-6 2-fluoro-8-((6-iodo.2,3-dihydo-1H-inden-5-y)methy)-9-(3-(isopropylamino)propy) ________9H-purin-6-aznine 1E-7 S-((6-(finn-2-yl)-2,3-dihydro-1H-inden-5-yl)thio)-9(3-(isopopylamino)popyl)-9H purin-6-ammne IF-S 8-((6-ethynyl-2,3-dihydro-1H-inden-5-yl)thio)-9-(3-(isopropylamino)propyl)-9H-purin 6-amine 1E-9 6-((6-arino-9(3isopropylanino)propyl)-9H-purin-8-yl)thio)-2,3-dihydo1H-indene ________5-carbonitrile I-10 S-(6-(azetidin-1 -yI)-2,3-dihydro-H-inder-5-yI)methyl)-2-fluoro9-(2 ______I (neopentylamino)ethyl)-9H-purin-6-anmine iF-li 9-(3-(isopropylanmino)propyl)-8-((6-(oxaol-2-yl)-2,3-dihydro-1H-inden-5-yl)thio)-9H purin-6-axnine 1E-12 1-(3-(2-(6-amino-S (-((oxaol-2-yl)-2,3-dihydro-IH-inden-5-ylthio)-9H-purin-9 ________yl)ethyl)piperidin-lI-yl)ethanone WO 2011/044394 PCT/US2OIO/051872 158 1E-13 3-(2-(8-(6-(1H-pyrazol-3-yl)-2,3-dihydro-1H-inden-5-ylthio)-6-aino-9H-purin-9 _______yl)ethyl)piperidine-1-carbaldehyde 1E-14 1-(3-(2-(6-anaino-8-(6-ethynyl-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9 - yI)ethyl)pipefidin- 1 -yl)ethanone IE-15 2-fluoro-9-(3.-(1-(methylsulfonyl)pyrrolidin-3-yI)propyl)-8-((6-(oxazol-2-yl)-2,3 - dihydro-IH-inden-5-yl)methyl)-9H-purin-6-amine N IE-16 N-(2-((2-(6-aniino-8-((6-(oxazol-2-y)-2,3-dihydro-1H-indn-5-y)thio)-9H-puin-9 ________yl)ethyl)amino)ethyl)sulfanaide 1E-17 3-(2-(6-amino-8-(6-(oxazol-2-yl)-2,3-dihydro-1H-inden-5-ylthio)-9H-puin-9 _______yl)ethylamino)-N-hydroxypropananide jr-is 1-(3-(3-(6-amnino-8-(6-iodo-2,3-dihydro-1H-indn-5-ylthio)-9--purin-9 _______yI)propyl)pyxrolidin- 1-yI)ethanone 1E-19 1-(3-(3-(6-amino-8-(6-ethynyl-2,3-dihydro-IH-inden-5-ylthio)-9H-purin-9 _______ l)propyl)pyrrolidin-l-yI)ethanone 1E-20 2-chloro-8-((6-ethynyl-2,3-dihydro-1H-inden-5-yl)methyl)-9-(3 _______(isopropylamio)propyl)-9H-puri-6-amine 1E-21 PU-WS25 8-((6-iodo-2,3-dihydro-1H-indei-5-yI)thio)-9-(2-(neopentylamino)ethyl)-9H-prin-6 amne 1E-22 PUJ-WS27 8-((6-ethynyl-2,3-dihydro-IH-inden-5-yI)thio)-9-(2-(neopentylaniino)ethyl)-9H-puin 6-amine IE-23 PU-WS29 8-((6-iodo-2,3-dihydro-1H-inden-5-yI)thio)-9-(3-(isopropylamino)propyl)-9H-purm-6 amne 1E-24 9-(3-aminopropyl)-8-ff6-iodo-L3dihydro-H-indn-5-y)tio)-9H-puin-6-amine IE-25 9-(2-aminoethyl)-8-((6-iodo-2,3-dihydro-1H-inden-5-yl)thio)-9H-purin-6-amine 1E-26 9-(3-(tert-butylatnino)propy1)-8-((6-iodo-2,3-dihydro-1H-inden-5-yl)thio)-9H-puuin-6 I ne 1E-27 9-(3-(isopropylanino)propyl)-8-((6-(5-methyloxaol-2-yI)-2,3-dihydro-IH-inden-5 _______yl)thio)-9H-purin-6-aniine IE-28 1-(4-(3-(6-amino-8-(6-(dimethylamino)-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9 yl)propyl)piperidin- 1 -yI)ethanone 1E-29 1-(3-(2-(6-amino-2-fluoro-8-((6-(4-methylthiazol-2-yI)-2,3-dihydw-1H-inden-5 _____ yl)methyl)-9H-purin-9-yl)ethyl)piperidin-i -yl)ethanone IE-30 8#(6-(5-methyloxaoi-2-yI)-2,3-dihydro- 1H-inden-5 -y)thio)-9-(2-(1 (methylsulfonyl)piperidin-3-yl)ethyl)-9H-purin-6-aniine 1E-31 9-(3-aminopropyl)-8-(6-(5-methyloxazol-2-yl)-2,3-dihydro-1H-inden-5-yl)thio)-9H Ipurin-6-amine IE-32 9-(3-(tet-butylanino)propyl)-2-luoro-8-(f6-(4-methylthizol-2-y)-2,3dihydro-1H inden-5-yl)methyl)-9H-purin-6-amine iF,33 8-((6-(1H-pyrazoi-3-yl)-2,3-dihydro-1H-inden-5-yl)niethyl)-9-(3-(tert butylamino)propyl)-2-fluoro-9H-purin-6-amine IE434 8-(6-(aziridin-1-yI)-2,3-dihydro-1H-inden-5-ylthio)-9-(3-(1-(methylsulfonyl)pyrrolidin - 3-yl)propyl)-9H-purin-6-amie IE-35 1-(3-(6-amino-2-fluoro-8-((6-iodo-2,3-dihydro-1H-inden-5-y)methyl)-9H-purin-9 yl)propyl)pyrrolidin-3-one 1E-36 8-((6-(5-niethyloxazoI-2-y1)-2,3-dihydro-1I--inden-5-y1)thio)-9-(2 (neopentylamino)ethyl)-9H-purin-6-amine IE-37 1-(6-amiino-S-((64-5-methylokazo-2-yl)-2,3-dihydro-1H-inde--yl)thio)-9H-purin-9- WO 2011/044394 PCT/US2OIO/051872 159 _______yl)-3-(isopropylamino)propan-2-ol 1E-38 5-(6-aniino-8-(6-iodo-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9-yl)-N-methylpentane 1-sulfonamide IE-39 5 -(6-amino-8-(6-iodo-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9-yl)pentne-I _______sulfonamide 11E40 5-(6-antno-8-(6-ethynyl-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9-yl)pentanesulfonamnide IE-41 1-(2-(4-(6-amnino-S-(6-(5-methylfiuran-2-yI)-2,3-dihydro-1H-inden-5-ylthio)-9H-purin _______9-yl)butvl)pyrolidin-1-yl)ethanone IE-42 I -(3-(6-amino-8-(6-iodo-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9 _______yI)propyl)pymrlidin-3-ol IE-43 6-(6-amiino-S-(6-iodo-2,3-dihydro-IH-inden-5-ylthio)-9H-purin-9-yl)hexanmide 1E-44 1-(3-(3-(6-arnino-2-fluoro-8-((6-iodo-2,3-dihydro-1H-inden-5-yl)methyl)-9H-purin-9 yl)propyl)pyrrolidin- 1-yl)ethanone 1IE-45 5-(6-anmino-2-fluoro-S-((6-iodo-2,3-dihydro-1H-inden-5-yl)methyl)-9H-purin-9-yl)-N niethylpentane- 1 -sulfonamide IE-46 5-(6-amino-2-fluoro-8-((6-iodo-2,3-dihydro-IH-inden-5-yl)methyl)-9H-puin-9 Iyl)pentane-1-sulfonamide 1E-47 9-(3-(tert-butylamino)propyl)-2-tluoro-8-((6-iodo-2,3-dihydro-1H-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-(neopentylammno)ethyl) 9H-pmrn-6-amine IE-49 I -(4-(3-(6-amino-8-(6-thynyl-2,3-dihydro-IH-inden-5-ylthio)-9H-purin-9 yl)propyl)piperidin- 1-yl)ethanone 1E-50 1-(3-(2-(6-amino-S-((6-ethynyl-2,3-dihydro-1H-inden-5-yI)methyl)-2-luoro-9H-purin 9-yI)ethylpprdin-i -yl)ethanone 1E-51 9-(3-(tert-butylanmino)propyl)-S-(6-effiyxy-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-6 amine IE-52 9-(3-(tert-butylamnino)propyl)-8-((6-ethynyl-2,3-dihydro-1H-inden-5-yl)methyl)-2 Ifluoro-9H-purin-6-aniine IE-53 6-(6-amino-8-((6-ethynyl-2,3-dihydro-IH-rnden-5-yl)methyl)-2-fluoro-9H-punin-9 yl)hexanamide 1E-54 1-(3-(6-amino-8-((6-ethyxny-2,3-dihydro-1H-inden-5-yl)methyl)-2-fluoro9H-purin-9 yl)propyl)pyrrolidin-3-one 1E-55 4-(6-amino-8-((6-ethynyl-2,3-dihydro-1H-inden-5-yl)methyl)-2-tluoro-9H-purin-9 ylhbutane- 1-sulfonamde 1E-56 8-((6-ethynyl-2,3-dihydro-1H-inden-5-yl)methyl)-2-fluoro-9-(3 (isopropylanmino)propyl)-9H-purin-6-amine IE-57 8-((6-ethynyl-2,3-dihydro-1H-inden-5-yl)methyl)-2-fluoro-9-(2 (neopentylamino)ethyl)-9H-purin-6-nine IE-58 I-acetyl-3-(3-(6-amino-8-(6-ethynyI-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9 yl)propyl)imidazlidin-2-one IE-59 9-(3-(tert-butylamnino)propyl)-8-(6-(oxaol-2-yl)-2,3-dihydro-1H-inden-5-ylthio)-9H p rn--mn IE-60 9-(3-(tert-butylamino)propyl)-8-(6-(5-methyloxaol-2-yl)-2,3-dihydro-IH-inden-5 Sylthio)-9H-pRin-6-anaine IE-61 8-(6-(1H-pyraol-3-yI)-2,3-dihydro1H-inden-5-ylthio)-9-(3-(tert-butylamino)propyl) 9H-purin-6-amine IE-62 1-(3-(2-(6-anmino-8-(6-(5-methyloxaol-2-yI)-2,3-dihydro-1H-inden-5-ylthio)-9H-purin _______9-yI)ethyl)piperidin-1-yl)ethanone WO 2011/044394 PCT/US2OIO/051872 160 IE-63 6-(6-aniino-8-(6-(oxazo-2-y)-2,3-dihydro-1 H-inden-5-ylthio)-9H-purin-9 yl)hexanmde 1E64 1-(3-(6-amino-8-(6-(4-methyloxazo-2-yl)-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9 yl)propyl)pyrrolidin-3-one IE-65 6-(6-amino-2-fluoro-8-((6-(oxazol-2-yl)-2,3-dihydxo-1H--inden-5-yl)methyl)-9H-purin 9-yl)hexanamide 1E-66 1-(3-(6-amino-2-fluoro-8-((6-(oxao1-2-yI)-2,3-dihydro-1H-inden-5-y)methy)-9H purin-9-yl)propyl)pyrrolidin-3-one 1E-67 5-(6-amino-2-fluoro-8-((6-(oxazol-2-yI)-2,3-dihydxo1H-inden-5-yI)methyl)-9H-purin 9-yI)pentane-1-sulfonaniide 1E-68 8-((6-iodo-2,3-dihydro-IH-inden-5-yI)thio)-9-(2-(1-methylpiperidin-2-yl)ethyl)-9H ________purin-6-amine IE-69 8-((6-iodo-2,3-dihydxo-1H-inden-5-yl)thio)-9-(2-(1 -naethylpiperidin-3-yI)ethyl)-9H _______purin-6-amine IE-70 8-((6-iodo-2,3-dihydxo-1H-inden-5-yl)thio)-9-(2-(1 -(naethylsulfonyl)piperidin-3 ________y1~thy1)-9H-purin-6-amine 1E-71 3-(2-(6-amino-8-((6-iodo-2,3-dihydro-IH-inden-5-yl)thio)-9--purin-9 _______I yl)ethyl)piperidine-lI-sulfonamide IE-72 2-fluoro-8-((6-iodo-2,3-dihydro-1H-inden-5-y)methyl)-9-(2( I-methylpipenidin-2 _______ l)ethyl)-9H--purin-6-amine 1E-73 2-fluoro-8-((6-iodo-2,3-dihydro-1H-inden-5-y)methyl)-9-(2( I-methylpiperidin-3 ________yl)ethyl)-9H-purin-6-amine IE-74 2-fluoro-8-((6-iodo-2,3-dihydro-1H--inden-5-yl)naethyl)-9-(2-(1 _____ (methylsulfonyl)piperidin-3-yI)ethyl)-9H--purin-6-amine IE-75 3-(2-(6-amino-2-fluoro-8-((6-iodo-2,3-dihydxo-1H-inden-5-yl)methyl)-9H-purin-9 yI)ethyl)piperidine-l -sulfonamide IE-76 9-(3-tert-butylamino)propyl)-2-fluoro-8-((6-iodo-2,3-dihydo-IH-inden-5-yI)aethyl) 9H-purin-6-armine 1E-77 8-((6-ethynyl-2,3-dihydro-IH-inden-5-yI)thio)-9-(2-( I-methylpiperidin-2-yl)ethyl)-9 _____ pui-6 -amine IE-78 8-((6-ethynyl-2,3-dihydro-IH-inden-5-yI)thio)-9-(2-(I -methylpiperidin-3-yl)ethyl)-9- ________puin-6-anaine IE-79 3-(2-(6-amino-8-((6-ethynyl-2,3-dihydro-H-inden-5-yl)methyl)-2-fluoro-9H-pudin-9 Iyl)ethyl)piperidinc-1-sulfonamide 1-8O 8-((6-ethynyl-2,3-dihydro-IH-inden-5-yI)thio)-9-(2-(l -(naethylsulfonyl)piperidin-3 ________ y)ethyl)-9-purin-6-amine IE-81 8-((6-ethynyl-2,3-dihydro- IH-inden-5-yI)methyl)-2-fluoro9-(2-(l -methylpiperidin-2 ________yI)ethyl)-9H-purin-6-amine IE-82 8-((6-ethynyl-2,3-dihydro-1H-inden-5-y)naethyl)-2-fluoro-9-(2-(1-methylpiperidin-3 - yl)ethyl)-9H-purin-6-aniine 1E-83 9-(3-(tert-butylamino)Propyl)-8-(6-(4-methylthiazol-2-yl)-2,3-dihydro-1H-inden-5 ylthio)-9H-purin-6-amine 1E-84 2-fluoro-9-(2-(1 -nethylpiperidin-2-yI)ethyl)-8-((6-(oxaol-2-yl)-2,3-dihydro-IH-inden ________5-yI)niethyl)-9H-purin-6-amine IEf85 2-fluoro-9-(2-(1 -methylpiperidin-3-yl)ethyl)-8-((6-(oxazol-2-yl)-2,3-dihydro-1H-inden ________5-flmethyl)-9H-purin-6-anmine Table IF INo. Name WO 2011/044394 PCT/US2OIO/051872 161 -4IF-i 8-(f6-iodoindolin-5-yl)thio)-9-(2-(isobutylamino)ethyl)-9H-purin-6-amine iF-2 2-fluoro-S-q(6-iodoindolin-5-yl)methyl)-9-(2-(isobutylamino)ethyl)-9H-purin-6-aniine 1F-3 8-((6-(YH-pymzol-3-yl)indolin-5-yflthio)-9-(2-(isobutylamino)ethyl)-9H-purin-6-mine 1F-4 8- (6-thynlindolin-5-yI thio)-9- 2-(isobutylamino ethyI -9H-purin-6-amine IF-5 8-((6-(1H-pyrrol-3-yl)indolin-5-yl)methyl)-2-fluoro-9-(2-(isobutylamiino)ethyl)-9H _______purin-6-aniine N1F-6 5-((6-amino-9-(3-(isopropylaminb)propyl)-9H-purin-8-yl)thio)indoline-6-carbonitrile WO 2011/044394 PCT/US2OIO/051872 162 117J-7 8-((6-(furan-2-yl)-1I -methylindolin-5-yl)thio)-9-(3-(isopropylamino)propyl)-9H-purin ______6-amine IF-8 S-((6-cyclobutyl-1 -methylindolin-5-yl)methyl)-2-fluoro-9 -(2-(isobutylamino)ethyl) _______9H-purin-6-anine IF-9 I -(5-((6-amino-2-fluoro-9-<2-(neopentylamino)ethyl)-9H-purin-8-yl)methyl)-6 ____ (aziridin-1-yl)indolin-1 -yl)ethanone N IF-10 I-(4-(2-(6-aniino-8 -((6-(fiuran-2-yl)indolin-5-yl)thio)-9H-prin-9-yl)ethyl)piperidin-1I _______yl)ethanone 11F-11 4-(2-(S-((6-(1H-pyraol-3-yI)indolin-5-yI)thio)-6-arniino9H-purin-9 ____ yI)ethyl)piperidine- 1 -carbaldehyde IF-12 4-(2-(6-amino-S-((6-ethynyl-1-methylindolin-5-yl)thio)-9H-purin-9 - yI thyI pipridine-1 -carbaldehyde iF-13 I -(4-(2-(6-amino-2-fluoro-8-((6-(fuiran-2-yl)indohin-5-yl)methyl)-9H-purmn-9 ylbethyl~piperidin- 1 -yl)ethanone IF-14 N-(2-((2-(6-amnino-8-((6-(furan-2-yl)indolin-5-yl)thio)-9H-purin-9 ____yl)ethyl)anmino)ethyl)sulfanaide IF-15 3-((2-(6-amino-8-((6-(fura-2-y1)indolin-5-yl)thio)-9H-purin-9-yl)ethyl)amino)-N - hydroxyropanamide IF-16 2-chloro-8-((6-iodoindolin-5-yl)methyl)-9-(2-(isobutylamino)ethyl)-9H-purin-6-amine iF-i7 9-(3-aminopropyl)-8-((6-iodoindolin-5-yl)thio)-9H-purin-6-anine iF7-18 9-(2-aminoethy1)-8-((6-iodoindolin-5-yflthio)-9H-purin-6-amrine IF-i9 9-(3-(tert-butylanuino)propyl)-8-((6-iodoindolin-5-yl)thio)-9H-purin-6-amine IIF-20 8-((6-iodoindolin-5-yl)thio)-9-(3-(isopropylamino)propyl)-9H-purin-6-amine Table 1G No. Name 10-1 1-(6-(6-amino-9-(3-(isopropylarnino)propyl)-9H-purin-8-ylthio)-5-iodoindolin- _______yl)ethanone 1G-2 2-fluoro-8-((5-iodoindolin-6-yl)methyl)-9-(2-isobutylamino)ethyfl-9H-purin-6-anmine 1G-3 8-((5-(1H-pyrazol-3-yl)indolin-6-yl)thio)-9-(2-(isobutylanino)ethyl)-9H-purin-6-anmine 10-4 8-((5ethynylinolin-6-yl)thio)-9-(24isobutYlaino)ethyl)-9H-purin-6-anine 10-5 8-((5-(1H-pyrrol-3-yl)indolin-6-yl)methyl)-2-fluoro-9-(2-(isobutylaino)ethyl)-9- _______purin-6-armine WO 2011/044394 PCT/US2OIO/051872 163 -4 16-6 6-((6-arnino-94-(-sopropylamino)propyl)-9H-purin-8-yl)thio)indoline-5-carbonitrile 16-1 8-((5-(fura-2-yl)-1 -methylindolin-6-yl)thio)-9-(3-(isopropylamino)propyi)-9H-punin 6-amine 1G-8 8-((5-cyclobutyl-1-niethylindolin-6-yl)methyl)-2-tluoro-9-(2-(isobutylamino)ethyl) ______9H-puri-6-amine 1G-9 1 -(6-((6-amino-2-fluoro-9-(2-(neopxtylamino)ethy1)-9H-punin-8-y)methy)-5 _____ (aziridin-l1-yI)indolhn-1I-yl)ethanone 1G-10 1-(4-(2-(6-amiino-8-((5-(fizra-2-yI)indolin-6-yl)thio)-9H-piirin-9-yl)ethyl)piperidin-1 ________yl)ethanone 1G-11 8-(5-(iH-pyraol-3-yl)indolin-6-ylthio)-9-(2-(1-(methylsulfonyl)piperidin-3-y)ethyl) ________9H-purin-6-aniine 1G-12 3-(2-(6-amino-8-(1 -thyl-5-ethynylindolin-6-ylthio)-9H-purin-9-yl)ethyl)piperidine-I ________carbaldehyde 16-13 1-(3-(2-(6-amino-2-fluoro-8-((1 -nethyl-5-(5-methylfuran-2-yl)indolin-6-yl)niethyl) ________9H-purin-9-yI)ethyl)piperidin-1 -yletbanone IG-14 N-(2-((2-(6-amino-8-((5-(furan-2-yl)indolin-6-yl)thio)-9H-purin-9 _________yl)ethyl)amino)ethyl)sulfaniide IG-15 3-(2-(6-amrino-8-(5-(5-niethylfiira-2-yl)indolin-6-ylthio)-9H-purin-9-yI)ethylanvno) N-hydroxypropanantde IG-16 1-(3-(4-(6-amino-8-(5-iodo-1 -methylindolin-6-ylthio)-9H-purin-9-y)butyl)pyrolidin 1 -yl)ethanone 1G-1'7 9-(3-aniinopropyl)-8-((5-iodoindolin-6-yl)thio)-9H-purin-6-amrne IG-18 9-(2-amninoethyl)-8-((5-iodoindolin-6-yl)thio)-9H-purin-6-ammne 6 19 2-(3-tert-butylaminolpropyl-S-( 1-thyl-5-iodoindolin-6-ylthio)-9H-purin-6-amine 162 -(-oo- mthlnoln6ylo -9-3-isopropylamino)propyl)-9H-purin-6-amine 16-21 I1-(3-(6-amino-8-(5-iodo-1-methylindolin-6-ylthio)-9H-purin-9-yl)propyl)pyaolidin-3 one Table 1H No. Name 1H-1 6-((6-amino-9-(2-(isobutylamino)ethyl)-9H-purin-8-yl)thio)-5-iodo-2,3-dihydro-1H indmx-1-one IH-2 6-((6-amiino-9-(3-(isopropylamino)propyl)-9H-purin-8-yl)thio)-5-iodo-2,3-dihydro IH-inden-1 -ne 1H-3 6-((6-amino-2-tluoro-9-{2-(iobutylanv~no)ethyl)-9H-punin-8-yl)methyl)-5-iodo-2,3 _______dihydro- IH-inden- I-ne 1H-4 6-((6-amiino-2-fluoro-9-(3-(isopropylami~no)propyl)-9H-purin-8-yl)methyl)-5-iodo ____ 2,3-dihydro-1H-indmx-1-one 1H-5 6-(6-amino-9-(2-hydroxy-3-(isopropylamino)propyl)-9H-pmin-8-ylthio)-5-iodo-2,3 1____ dihydro-1H-indmx-l-one 1H-6 6-((6-amino-9-(3-(isopropylamino)propyl)-9H-purin-8-yl)thio)-5-(furan-2-yl)-2,3 dihydro-1H-mnden-1-one 111-7 6-((6-amino-2-fiuoro-9--(2-(neopentylamino)ethyl)-9H-purin-8-yI)methyl)-5 _______(dimethylamino)-2,3-dihydro-IH-inden-1-one 1ff-S 6-((6-amino-9-(2-(isobutylamino)ethyl)-9H-purin-8-yI)thio)-5-(1H-pyaol-3-y) _______2,3-dihydro-I -inden-I -ne IH-9 6-ff6-amnino-9-(3-(isopropylamino)propyl)-9H-purin-8-yl)thio)-5-cycloproy-2,3- WO 2011/044394 PCT/US2OIO/051872 164 _______dihydro-1H-inden-lI-one IH-10 6-((6-amino-2-fluoro-9-(2-(isobutylamnino)ethyl)-9H-purin-8-yI)methyl)-5-ethynyl _______2,3-dihydro-1H-inden-1I -one IH-II 6-((6-amino-2-fluoro-9-(3-(isopropylamino)propyl)-9H-purin-8-yl)methyl)-I -oxo _______2,3-dihydro-1 H-indene-5-carbontrile 1IH-12 6-((6-ami~no-2-chloro-9-(3-(isopropylamino)propyl)-9H-purm-8-yl)methyl)-5 _____ (fiirn-2-yl)-2,3-dihydro-1IH-inden-1 -one 1H-13 4-(2-(6-amino-8-((6-ethynyl-3-oxo-2,3-dihydro-IH-inden-5-yl)thio)-9H-purin-9 _______ l)ethyl)piperidine-l1-carbaldehyde 1H.14 6-((9-(2-(l -acetylpiperidin-3-yI)ethyi)-6-amiino-2-fluoro-9H-purin-S-yl)methyl)-5 _______(5-methylfuira-2-yl)-2,3-dihydro-IH-inden-1-one IH-15 N-(2-((2-(6-antno-8-((6-(fin-2-y)-3oxo-2,3-dihydro-1H-iden-5-y)thio)-9H _____ purim-9 -yl) ethyl) aio)ethyl) sub'amde IH-16 3-((2-(6-anino-8-((6-ethynyl-3-oxo-2,3-dihydro-IH-inden-5-yl)thio)-9H-purin-9 yl)ethyl)amio)-N-hydroxypropananmide 1H-17 6-((6-amino-9-(2-(isobutylanaino)ethyl)-9H-purin-8-yl)thio)-5-iodo-2,3-dihydro-IH indene-1 -thic'ne IH-18 6-((6-amiino-2-fluoro-9-(3-(isopropylamrino)propyl)-9H-punin-8-yI)methyl)-5-iodo I2,3-dihydro- 1H-indene-1I-thione IH-19 6-((6-amiino-9-(3-aminopropyl)-9H-purin-8-yI)thio)-5-iodo-2,3-dihydro-1H-inden 1-one IH-20 6-((6-anaino-9-(2-amiinoethyl)-2-fluoro-9H-purin-8-yI)methyl)-5-iodo-2,3-dihydro I H-inden- 1 -ne IH-21 6-((6-amino-9-(2-aminoethyl)-9H-purin-8-yl)thio)-5-ido-2,3 -dihydro- H-inden-1 one IH-22 6-((6-antino-9-(3-(tert-butylamino)propyl)-9H-purin-8-y)thio)-5-iodo-2,3-dihydo 1 H-inden-1-one 1H-23 3-(2-(6-amino-8-(6-iodo-3-oxo2,3-dihydro-IH-inden-5-ylthio)-9H-purin-9-. yI)ethyl)pyn-lidine-lI-carbaldehyde 1H-24 6-(6-amiino-9-(2-(l -(methylsulfonyl)pyrrolidin-3-yl)ethyl)-9H-purin-8-ylthio)-5 iodo-2,3-dihydro-1H-inden-1-one IH-25 N-(3-(6-am~ino-2-fluoro-8-((6-iodo-3-oxo-2,3-dihydro-IH-inden-5-yl)methyl)-9H purin-9-yI)propyl)methanesulfonanmide IH-26 6-((6-anaino-9-(2-(I -(methylsulfonyl)piperidin-3 -yl)ethyl)-9H-purin-8-yl)thio)-5 (lH-pyrazoI-3-yI)-2,3-dihydo-lH-indx-l-one IH-27 6-((6-amino-9-(3-(tert-butylamino)propyl)-9H-purin-8-yl)thio)-5-(5-methylfuran-2 yl)-2,3 -dihydo- I H-inden-1 -one IH-28 6-((6-amino-9-(3-(tert-butylamino)propyl)-9H-purin-8-yI)thio)-5-(5-methylthiazol I___ 2-yI)-2,3-dihydro-IH-inden-1 -one IH1-29 6-((6-amino-9-(3-(tert-butylamino)propyl)-9H-purin-8-yl)thio)-5-(thiophen-2-yI) 2,3-dihydro- 1H-inden- I -one IH-3O 2-(3-(6-amino-8-(6-iodo-3-oxo-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9 Syl)propyl)azetidine-lI cabaldehyde 111-31 6-((6-amnino-9-(3-(tert-butylamino)propyl)-2-fluoro-9H-purin-8-yl)methyl)-5 ethyny1-2,3-dihydro-1H-inden-1-one IH1-32 6-((6-amino-9-(2-(1 -(methylsulfonyl)piperidin-3-yI)ethyl)-9H-purin-8-yl)thio)-5 (dimethylamino)-2,3-dihydro-1 H-inden-I -one IH-33 6-((6-amiino-9-(3-(tert-butylami~no)propyl)-2-fluoro-9H-purin-8-yl)methyl)-5-(5 1methyloxazo-2-yl)-2,3-dihydro-l H-inden-lI -one IH-34 6-((9-(2-(l -acetylpiperidin-4-yl)ethyl)-6-amino-2-fluoro-9H-purin-8-yI)methyl)-5- WO 2011/044394 PCT/US2OIO/051872 165 -4 (5-niethylthiazol-2-yI)-2,3-dihydro-1H-inden-1 -ne 111-35 N-(3-(6-amino-2-fluoro-S-((6-(5-methyloxaol-2-yl)-3-oxo-2,3-dihydro-IH-inden 5-yl)methyl)-9H-purin-9-yI)propyl)methanesulfonamide 1I1-36 1-(3-(6-amnino-8-(6-iodo-3-oxo-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9 yl)propyl)pyrrolidin-3-one IH11-37 1 -(3-(6-amino-8-(6-iodo-3-oxo-2,3-dihydro-1H-inden-5-ylthio)-9H-purin-9 _______yl)propyl)pyrrolidin-2-ne WO 2011/044394 PCT/US2010/051872 166 Table 2A Compound # Name EC 5 0 ; binding to EC 5 o; binding JNPL3 brain to SKBr3 cell Hsp9O(nM) Hsp9O(nM) 1B-1| PU-WS9 5.5 ND 1B-2 PU-WS4 8.0-14 ND 1A-1 PU-WS10 132.9-346 ND Table 2B Compound # Name EC 50 ; binding to EC 5 0 ; binding JNPL3 brain to SKBr3 cell Hsp9O(nM) Hsp9O (nM) IB-3 PU-WS17 17.3 ND IB-4 PU-WS18 33.3 ND IB-24 PU-WS21 10.8 ND IB-25 PU-WS22 8.0 ND Table 2C Compound # Name EC 50 ; binding to EC 5 0 ; binding JNPL3 brain to SKBr3 cell Hsp9O(nM) Hsp9O(nM) 1B-26 PU-WS23 12.2 ND IB-27 PU-WS24 25.4 ND Table 2D Compound # Name ECso; binding to EC 5 0 ; binding JNPL3 brain to SKBr3 cell E Hsp9O (nM) Hsp9O (nM) 1B-28 PU-WS28 | 8.1 ND Table 2E Compound # Name ECso; binding to EC 5 0 ; binding JNPL3 brain to SKBr3 cell Hsp9O (nM) Hsp9O (nM) IE-2 PU-WS26 3.6 ND IE-21 PU-WS25 7.2 ND IE-23 PU-WS29 4.5 ND Table 2F Compound # Name ECo; binding to EC 5 0 ; binding JNPL3 brain to SKBr3 cell Hsp90 (nM) Hsp9O (nM) 1E-22 | PU-WS27 t_15 ND WO 2011/044394 PCT/US2010/051872 167 Table 2G Compound # Name ECso; binding to ECso; binding JNPL3 brain to SKBr3 cell Hsp9O(nM) Hsp9O(nM) 4A-1 DZ2-388 270 645 4A-2 DZ2-390 2,666 6,240 4A-3 DZ2-391 >100,000 >100,000 4A-4 TT-V-47B 8,287 15,010 4A-5 DZ2-392 1,388 2,520 4A-6 DZ3-3 438 1,030 4A-7 DZ3-6 732 1,385 4A-8 DZ3-50 2,333 >3000 4C-1 DZ3-4 11 22 4C-2 DZ3-27 48 86 4C-3 DZ3-25 3.9 5.2 4C-4 DZ3-26 14 26 4C-5 TTS-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 4B-4 PU-WS16 13.7 ND 4B-13 PU-WS19 8.6 ND 4B-14 PU-WS20 <200 ND Table 21 Compound # Name EC 5 o; binding to ECso; binding JNPL3 brain to SKBr3 cell Hsp90 (nM) Hsp9O (nM) 4E-1| PU-WS3 218.8 ND 4E-2 PU-WS5 285 ND 4E-3 DZ3-39 542 1126 4E-4 DZ3-40 46 93 Table 2J Compound # Name EC5o; binding to EC 50 ; binding JNPL3 brain to SKBr3 cell Hsp9O (nM) Hsp90 (nM) 41-12 | TT-VI-11 ND 394 WO 2011/044394 PCT/US2010/051872 169 Table 2K Compound # Name ECso; binding to EC 5 D; binding JNPL3 brain to SKBr3 cell Hsp9O(nM) Hsp90(nM) 4G-1 DZ3-30 374 1024 4G-2 DZ3-32 107 128 4G-3 DZ3-43 2.6 7.2 4G-4 DZ3-44 >300 >300 4G-5 DZ3-45 >300 >300 4G-6 DZ3-46 4.0 5.5 4G-9 | DZ3-61 ND 5.5 Table 2L Compound # Name ECSD; binding to EC5o; binding JNPL3 brain to SKBr3 cell Hsp9O(nM) Hsp9O (nM) 4H-1 DZ3-29 309 740 4H-2 DZ3-31 89 121 411-3 DZ3-41 57 161 4H-4| DZ3-59 ND 24.6 4H-6| DZ3-38 23 47 411-7 DZ3-141 ND 26,653 Table 2M Compound # Name EC5o; binding to ECso; binding JNPL3 brain to SKBr3 cell Hsp90 (nM) Hsp90 (nM) 5A-1 PU-RK11 ND 34.5 5A-2 PU-HT165 ND 34.6 5A-3 PU-HT175 ND 34.8 5A-4 PU-RK12 ND 62.8 5A-5 DZ3-73 ND 9.4 5A-6 DZ4-84 45.1 ND WO 2011/044394 PCT/US2010/051872 170 Table 2N Compound # Name EC 5 o; binding to EC 50 ; binding JNPL3 brain to SKBr3 cell Hsp9O (nM) Hsp9O (nM) SB-1 HJP18 ND 6.9 SB-7 TT-VI-53A ND 5.3 5B-33 HJP23 46.3 ND 5B-34 HJP20 ND 3.5 Table 20 Compound # Name EC 5 o; binding to EC 5 o; binding JNPL3 brain to SKBr3 cell Hsp9O (nM) Hsp9O (nM) 5D-2 HJP19 ND 11.2 5D-4 TT-VI-54A ND 7.7 Table 2P Compound # Name EC 5 o; binding to ECso; binding JNPL3 brain to SKBr3 cell F Hsp9O (nM) Hsp9O (nM) 6B-25 DZ4-52-N9 ND 97.0 Table 20 Compound # Name ECso; binding to EC 5 o; binding JNPL3 brain to SKBr3 cell Hsp9O (nM) Hsp9O (nM) 7A-20 PU-WS31 <200 ND 7C-13 TT-V-138 ND 84 7D-3 TT-V-1 39 ND 240 7E-6 TT-V-140 ND 32 WO 2011/044394 PCT/US2OIO/051872 171 Table 3A No. Name 3A-1 2-fluoro-8-((5-(furan-2-yI)benzofura-6-yl)methyl)-9-(2 ______________(neopentylamino)ethyl)-9H-purin-6-amine 3A-2 2-fluoro-8-((5-iodo-iH-indol-6-yl)methyl)-9-(2-(neopentylamino)ethyl) ______________9H-purin-6-aniine 3A-3 N-(2-((2-(6-anmino-8-((5-(furan-2-yI)benzo[b]thiophen-6-yl)thio)-9H ______________purin-9 -yE) ethyl) amino et hyI)sul fami de 3A-4 3-((2-(8-((1-acetyl-5-(fiiran-2-yl)-IH-indol-6-yl)thio)-6-ariino-9H ______________purin-9-yl)ethyl)amino)-N-hydroxypropanaide 3A-5 8-((5-(azetidin-1 -yl)benzfiirn-6-yl)thio)-9-(2-(isobutylamino)ethyl) 9H-purin-6-aniine 3A-6 8-((5-iodobenz[b]thiophen-6&yI)thio)-9-(2-(isobutylanmino)ethyl)-9H Ipm . n-6-anie 3A-7 8-((5-( IH-pyrazo-3-yl)-IH-indol-6-yl)thfio)-9-(3 (isopropylamnino)propyl)-9H-purin-6-aniine 3A-8 8-((5-ethynyl-IH-indol-6-yl)thio)-9-(2-isobutylaniino)ethyl)-9H-purin 6-amine 3A-9 6-((6-aniino-9-(2-(isobutylamino)ethyl)-9H-purin-8-yl)thio)- -methyl IH-indole-5-carbonitrile 3A-10 9-(3-anminopropyl)-8-(fS-iodobenzofura-6-yl)thio)-9H-purin-6-anmine 3A-11 9-(2-aminoethyl)-8-((5-iodobenzfamn-6-yl)thio)-9H-purin-6-aniine 3A-12 9-(3-(tert-butylarino)propyl)-8-((5-iodobenzofiiran-6-yl)thio)-9H-purin 6-amine 3A-13 2-fluoro-8-((5-iodobenofuran-6-yl)methyl)-9(2 (neopentylanmino)ethyl)-9H-purin-6-anmine 3A-14 1 -(4-(2-(6-anmino-2-fluoro-8-((5-(5-methylfuran-2-yl)benofuran-6 ______________yl)methyl)-9H-purin-9-yl)ethyl)piperidin-1-yI)ethanone 3A-15 9-(3-(tert-butylamino)propyl)-8-((5-ethynylbenzofuran-6-yl)thio)-9H ______________purin-6 -amine 3A-16 2-fluoro-8-((5-(5-niethyloxazol-2-yl)benzoffiarn-6-yl)methyl)-9(2 (neopentylanvino)ethyl)-9H-purrn-6-aniine 3A-17 9-(3-(tert-butylamino)propyl)-8-((5-(dimethylamino)benzofra yl)thio)-9H-purin-6-amie 3A-18 8-((5-iodobenzofi a-6-y1)thio)-9-(2-(1 -(methylsulfonyl)piperidin-3 Iyl)ethyl)-9H-purin-6-amine 3A-19 8-((5-(1H-pyrazo-3-yl)benzofiiran-6-yl)thio)-9-(2 (neopentylaniino)ethyt)-9H-purin-6-anmine 3A-20 N-(3-(6-amino-8-((5-(aziridin-t-yl)benzofura-6-yl)thio)-9H-purin-9 _____________yl)propyl)methanesulfonamde 3A-21 3-(6-atmino-8-((5-iodobenzfurn-6-yl)thio)-9H-purin-9-yl)propyl sulfamte 3A-22 9-(3-(tert-butylanaino)propyl)-8-((5-(oxaol-2-yl)benzofura-6-yl)thio) 9H-puri-6-amine 3A-23 8-((5-ethynylbenzofiira-6-yl)thio)-9-(2-(neopentylatnino)ethyl)-9H ______________ purn-6-amine 3A-24 I -(6-amino-8-((5-iodobenzofuran-6-y)thio)-9Hpria9-y)-3-tet WO 2011/044394 PCT/US2OIO/051872 172 butylamo)propan-2-ol 3A-25 8-((5-iodobenzofiua-6-yl)thio)-9-(3-(isopropylanmino)propyl)-9H ______________purin-6-a mine 3A-26 9-(3-(tert-butylamino)propyl)-8-((5-(5-methylthiazo-2-yl)benzofuiran-6 yl)thio)-9H-purin-6-amine Table 3B No. Name 3B-1 5-((6-amino-9-(2-(isobutylamiin)ethyl)-9H-purin-8-yl)thio)benofirn 6-carbonitrile 3B-2 S-((6-iodobenzfuran-5-yl)thio)-9-(2-(isobutylamino)ethyl)-9H-purin-6 amie 3B-3 8-((6-(firan-2-yl)benzofiua-5-yl)thio)-9-(2-(isobutylamino)ehyl)-9H purin-6-amine 3B-4 N-(2-((2-(6-anmino-8-((6-(fian-2-y)benofi~an-5-yl)thio)-9H--puri-9 yl)ethyl)ainiino)teeth)sulfamide 3B-5 3-((2-(6-amino-S-((6-(fiirn-2-yl)benzfura-5-yl)thio)-9H-puin-9 yl)ethyl)amino)-N-hydroxypropanaimide 3B-6 2-fluoro-S-((6-(fura-2-yl)-IH-idol-5-yl)methyl)-9-(2 (neopentylanmino)ethyl)-9H-purin-6-anine 3B-7 8-((6-(aztidin-1 -yl)-1H-indol-5-yl)thio)-9-(2-(isobutylamino)ehyl)-9purin-6-aniine 3B-8 9-(2-(isobutylamino)ethyl)-8-((6-(pyrrolidin-1 -yl)-IH-indol-5-yl)thio 911-purin-6-ainine - (isopropylamino)propyl)-9H-purin-6-amine 3B-10 2-fluoro-8-((6-iodo-1-isopropyl-IH-indol-5-yl)methyl)-9-(2 (isobutylaniino)ethyl)-9H-purn-6-amne 3B-11 2-fluoro-8-((6-(ffiirn-2-yl)benzo[b]thiophen-5-yl)methyl)-9-(3 __________I (isopropylamino)propyl)-9H-purin-6-axnine 3B-12 2-fluoro-S-((6-iodobenzo[blthiophen-5-yl)methyl)-9-(2 ____________(neopentylamino)edhyl)-9H-purin-6-amiie 3B-13 S-((6-(IH--pyrrol-3-yl)benzo[b]thiophen-5-yl)methyl)-2-fluoro-9-(2 ____________(isobutylamnino)ethyl)-9H-purin-6-amine 3B-14 8-((6-cthynylbenzo~b]thiophen-5-yl)methyl)-2-fluoro-9-(2 - (isobutylamino)ethyl)-9H-purin-6-anaine 3B-15 2-chloro-8-((6-ethynylbeno[b]thiophen-5-yl)methyl)-9-(2 ____________(isobutylanaino)ethyl)-9H-purin-6-anmine 3B-16 S-((6-(azetidin-1-yl)-1H-indol-5-yl)thio)-9-(2-(isobutylamino)ethyl)-9H ___________purin-6-amine 3B-17 8-((6-(aziridin-1-yl)-1 H--indol-5-yl)thio)-9-(2-(isobutylamino)ethyl)-9H __________1 punn-6-ame 3B-18 9-(3-aminopropyl)-8-((6-iodobenzofira-5-yl)thio)-9H-puin-6-nane 3B-19 9-(2-anainoethyl)-8-((6-iodobenofiimn-5-yl)thio)-9H-purin-6-amine 3B-20 9-(3-(tert-butylamlirn)propyl)-8-((6-iodobenzofiirn-5-yl)thio)-91 purin-6-amine 3B-21 1-(4-(2-(6-amino-2-fluoro-S-((6-(5-methylfira-2-yl)benzofura-5 - yl)methyl)-9H-purin-9-yl)ethyl)piperidin-1 -yflethanone 3B-22 9-(34tert-butylamino)propy)-8-(f6ethnylbenzofi r-5-yl)thio-911- WO 2011/044394 PCT/US2OIO/051872 173 L4 puxn-6-amine 3B-23 2-fluoro-8-((6-(5-methyloxazol-2-y)benzofizra-5-yl)methyl)-9-(2 ____________(neopent-ylatmino)ethyl)-9H-purin-6-anine 3B-24 9-(3-(tert-butylamino)propyl)-8-((6-(dimethylamino)bezoffia-5 ____________yl)thio)-9H-purin-6-aine 3B-25 8-((6-iodobenzofuran-5-yl)thio)-9-(2 -(I -(methylsulfonyl)piperidin-3 ________ yl)ethyfl-9H-purin-6-amine 3B-26 8-((6-(IH-pyrazol-3-yl)benofura-5-yl)thio)-9-(2 ____________(neopentylamino)ethyl)-9H-purin-6-amine 3B-27 N-(3-(6-amino-8-((6-(azridin-1 -yl)benzofi a-5-yI)thio)-9H-purin-9 ____________ l)propyl)niethanesulfonamide 3B-28 3-(6-amino-8-((6-iodobenzfura-5-yl)thio)-9H-punin-9-yI)propyl ____________sulfamte 3B-29 9-(3-(tert-butylamino)propy)-8-((6-(oxz1-2-y)be,~ofiirn-5-y1)thio) _________9H-purin-6-amine 3B-30 8-((6-ethynylbezofira-5-y)thio)-9-(2-(neopentylamino)ehyl)-9H _______ purin-6-amine 3B-31 I -(6-anino-8-((6-iodobenzofi a-5-y1)thio)-9H-purin-9-y1)-3-(tert butylaniino)propan-2-oI 3B-32 8-((6-iodobeiaoffira-5-yI)thio)-9-(3-(isopropylaxino)propyl)-9H ___________ pui-6-anaine 3B-33 9-(3-(tert-butylanaino)propyl)-8-((6-(5-rnethylthiazol-2-yl)benzofuran-5 - yI)thio)-9H-purin-6-amine 3B-34 I -(3-(6-amaino-8-(6-iodobenzfizran-5-ylthio)-9H-purin-9 ____________yl)propyl)pyrrolidin-3-ol 3B-35 1-(3-(6-amiino-8-(6-iodobenzofuran-5-ylthio)-9H-purin-9 ___________yl)propyl)pyrolidin-3 Table 3C No. Name 3C-1 6-((6-arnino-9-(2-(isobutylami~no)ethyl)-9H-purin-8-yl)thio)berio[dJoxaole-5 carbonitie 3C-2 8-((5-(fulra-2-yl)benzo[dltbiazo-6-yl)thio)-9-(2-(neopentylamino)ethyl)-9H purin-6-anaine 3C-3 2-fluoro-8-((5-(fura-2-yl)benzodloxazol-6-yl)methyl)-9-(2 (neopentylamino)ethyl)-9H-purin-6-armine 3C-4 8-((5-(azetidin-1 -yl)benzo[d~oxazol-6-yl)thio)-9-(2-(isobutylanaino)ethyl)-9H purin-6-ame 3C-5 9-(2-(isobutylanino)ethyl)-8-((5-(pyrrolidin-1 -yI)benzo[dlthiazol-6-yl)thio)-9H purin-6-amine 3C-6 8-((5-ethynylbenz[dlthiazol-6-yI)methyl)-2-fluoro-9-(2-(isobutylamino)ethyl) __________9H-purin-6-amnne 3C-7 N-(2-((2-(6-anino-8-((5-iodobt~o[dloxao1-6-yI)thio)-9H-purin-9 ________I ylethyl)amino)ethyl) sulfamide 3C-8 3-((2-(6-anin-8-((5-(fiira-2-yl)benz[d]oxaol-6-yl)thio)9H-purin-9 __________yl)ethyl)amino)-N-hydroxypropananilde WO 2011/044394 PCT/US2OIO/051872 174 Table 3D No. Name 3D-I 5-((6-amino-9-(2-(isobutylanino)ethyl)-9H-puin-8-y)thio)- I H ... ______ benzo[dlimidaz.ole-6-carbonitrile 3D-2 8-((6-(furan-2-yl)-1H-betro[d]imidazol-5-yl)thio)-9-(2 (neopentylamino)ethyl)-9H-purin-6-armine -d 3D-S 2-fluoro-8-((6-(furan-2-yl)-1H-benzold]irnidazol-5-yl)methyl)-9-(2 ____________(neopentylarnino)ethyl)-9H-purin-6-aniine 30-4 8-((6-(azetidin-1 -yl)-IH-benzo[dliniidazol-5-yl)thio)-9-(2 ____________ isobutylamino)ethyfl-9H-purin-6-aamine 3D-5 9-(2-(isobutylazniino)ethyl)-8-((6-(pyrroldin-1-yl)- H-benzo[d]imidaz.oi-5 ____________yl)thio)-9H-purin-6-amrne c ___________________ 3D-6 j8-((6-ethynriyl-1 -methy1-iH-benzo[d]imidazo-5-yl)mety)-2-1Iimro-9-(2 ____________(isobuty ,ailino)-thy1)-9H-purin-6-amne ___________ 9H-pmrn-9-vl)ethy)ami~rn)ethyl)methanesiiiforanide 3D-9 I 5-((6-amino-9-(2-(isobuylamino)ethy)-9H-purini ___________ yl)thio)benzo Ed] oxaole-6-carbonitrile 3D-10 8-((6-iodobenzo[d]oxazol-5-yI)thiio)-9-(2-(n.eopentylamino)ethy)-9H *purin-6-almtile 3D-1I 5-((6.-amino-9(2<isobutylamino)etbyl)-9H-piwn8 yflthio~benzo[d]thiazole-6-carbonitrile 3D-1 2 8-((6-(furan-2-yl)benzo[djthiazol-5-yI)thio)-9-(2-(neopentylamino)ethyl) 911-purin-6-amine 3D-13 2-tluoro-8-((6-(furan-2-yl)beno[d~oxazol-5-yl)methyl)-9-(2 (neopentylamnino)ethyfl-9H-purin-6-atnine 3D14 8-((6-(azetidin-1 -yl)benzo~d]oxazol-5-yl)thio)-9-(2-(isobutylamino)ethyl) ____________9fl-purin-6-aniine 3D-15 9-(2-(isobutylarntno)ethyl>)8-((6-(pyrolidin-1 -yl)beno[d]thiazol-5 ____________yI)thio)-9H-purin-6-annine 3D-16 8-((6-ethynylbenoldjthinocl-5-yl)methyl)-2-fluoro-9-(2 ___________(isobutylaniino)ethyl)-9H-purin-6-anmine Table 3E No, Name 3E-1 6-((6-amino-9-(2l-(isobutylarnitio)eth. yl)-9H-purin-8-yl)thio)benzo[d][ I ,2,3]oxadiazk->' carbonitill e 3E-2 I 9,((5-(ran-2-yl)benzo[d][1 .2,3]thiadiazol-6-y-i)thio)-9-(2-(neopcntviarnino)ezhyl)-9H-purin 6amine 3E-3 2- %oro-84((5-f~ran-2-vi)bcnzoidIl[ I ,2,3]oixadiazol-6&yI)rnethvl)-9-(2 ___________(neopentylamino)ethyl)-9H-parin-6-amine 3E-4 -(-(zti-I-yl)benzo~d] [I ,2,3]oxadiazol-6-yl)thio)-9-(2-(isobutylamino)ethyl)-91 __________ jpuin-6-aniine 3E-5 2 9-2(sbtlmoehl-8-((5-(pymrlidin-1 -y)benod[ ,2,3]thiadiazol-6-yI)thio -91{- WO 2011/044394 PCT/US2OIO/051872 175 __________ purin-6-amne SE-6 S-((5-effynylbenzo[d][ I,2,3]thiadiazob6-vl)rnethyfl-2-fluoro -9-(2-(isobuiylaino)ethyl)-9H _________ jpmn-6-amine 3E-7 N-(2-((2-(6-amino-8-<(5-iodobenzo[d] [1 ,2,3joxadiarol-6-yl)thio)-9H--purin-9 ___________yflethyl)amino)ethyl)suffairide 3E-8 3-((2-(6-amino-8-((5-(fiian-2-yl)bnzo~d]1 ,2,3]oxadiazol-6-yI)tliio)-9H-purin-9 _________ yi)ethyl)amino)-N-hydroxyrpropanarnjde 3F-9 15-((6-anmino-9-(2-(isobutylamnino)ethyI)-9H-purin-8-y1)thio)-3H-indazole-6-carbontrile 3E-10 8-((6-(furan-2-yl)-311-indazol-5-yl)thio)-9-(2-(neopentylanino)ethyl)-9H-purin-6-anine 3E-11 2-fluoro-8-((6-(firn-2-y)-3H-indazol-5-yI)meihyl)-9-(2-(neopentylamino)ethyl)-9H-ptuin ___________6-amnine 3E-12 j8-(6-(azetidin-1 -y)-31--indaol-5-ythio)-42isobutyamino)ethyl)9H-purin-6-amine Table 3F1 No. Name 3F-I 5-((6-"rn.no-9-(2-(isobutylamno)ethyl )-9H-purin-S ______________ yl)tlio~berzofd](i ,2,3]oxadiazole-6-carbcnitrik. MF-2 8-((6 (IH-pyazol-3-yl)berzo[4][1 .2,3]oxadiazol-5-yl)thie)-9-(' ______________ eopenvLamino)etbyi)-9H-prin-6-a.niine z-loo8F((uan2y)IH3nod F I,2,3ltriazoi-5-yl)rnethyl)-9-(2 _____________(neopentylanino)ethyl)-9H-purn-6-amine 3F-4 S-((6-(azetidin-1 -yI)benzo[d] F I,21,3]Ihiadiazc'-5-yI)thio)-9-(2 I(isobutyianiino)ethyl)-911-puin-6-amine 3F-5 9(%-(isobutylanrino)ethyl)-S-((5-(pynolidin-1 -yl)-3H-indazol-6-yl)thio)-9H purin-6-amnine 3F-6 8-((6-ethynyl- I-metlhyl-IH-benzo(d][ 1,2,3] triazol-5-yI)methyl)-2-fluoro-9 .12j sbutgV~iano)cthyO)-9H-purin-6-ainine H3-7 N-(2-((2-(6-aniino-84((6-iodobenzo[d] [1 ,2,3]oxadiazol-5-yl)thio)-9H-purin ______________9-yl)ethyl)anuino)ethyI)sulfarnide 3F-8 3-((2-(6-amino-8-((5-(ffiran-2-yl)-3H-indazol-6-yflthio)-9H-purin-9 ______________yI)cthyl)amino)-N-hydroxypropn -ide 3F-9 6-((6-amino-9-(2-(isobutylamino)ethyl)-911-prin-8-y)thio)-3H-ndzoe-5 ______________ arbonitrile 3F-10 8-((6-iodobenzo[d][I ,2,3loxadiazol-5-ylflhio)-9-(2-(neopenty lamino)ethyl) ___________ j9H-punn6-awme ______________________ 3F-11 5-((6-arniino-9-(2-(isobutlIaniino)eth yl)-9H-purin-8 ________________ylirhio)benzo[d][ I ,2,3]thiadiazole-6-carbonitrile 3F-13 2-: ~ oS-((6-(fran-2-yl)bedd1 ,3thiadiaox--y)iao-5y)ev)-9-(2 _____________ ( eopentvlamino)ehy)-911-purin-6-amiv.e 3F414 S ((6-(aetidin-1-yl)benzo[d]' 1 ,2,3]oxadiazob-5-vi)thio)-9-(2 ________________(tsoburylanino)ethyl)-911-purh,-6- A*Ine 3F-15 9-(2-(isobiiiylainino)ethyl)-8--ff64pyrrciidinl -yl)benzo[dj [ i,2,3]thiadiazol ______________5 yl )thio)-9H-punin-6-arnjne 3F416 S ((5-ethyrtyi-3Hi-indaz.oI-6-yl)merhyl)-2-flnoro-9-(2-(isobutylainino)ethyl) 9-punin-6-ain WO 2011/044394 PCT/US2010/051872 176 Table 4A No. Name 4A-1 DZ2-388 9-(3-(isopropylanino)propyl)-8-(6-pheny1benzo[d][ 1,3]dioxol-5-ylthio) 9H-purin-6-amine 4A-2 DZ2-390 8-(6-(4-tert-butylphenyl)benzo[d][1,3]dioxol-5-ylthio)-9-(3 -_(isopropylamino)propyl)-9H-purin-6-amine 4A-3 DZ2-391 8-(6-(3,5-bis(trifluoromethyl)phenyl)benzo[d][1,3]dioxol-5-ylthio)-9-(3 (isopropylamino)propyl)-9H-purin-6-amine 4A-4 TT-V-47B NI-(3-(6-amino-8-(6-(3,5-bis(trifluoromethyl)phenyl)benzo[d][1.3]dioxol ______________5-ylthio)-9H-purin-9-yl)propyi)hexane-1,.6-diamrine 4A-5 DZ2-392 8-(6-(4-(dimethylamino)phenyl)benzo[d][1,3]dioxol-5-ylthio)-9-(3 (isopropylamino)propyl)-9H-purin-6-amine 4A-6 DZ3-3 9-(3-(isopropylanino)propyl)-8-(6-(4-methoxypheny1)benzo[d][1,3]dioxoI 5-yithio)-9H-purin-6-aminc 4A-7 DZ3-6 8-(6-(4-bromophenyl)benzo[d][1,3]dioxol-5-ylthio)-9-(3 (isopropyIanino)propyl)-9H-purin-6-*arnine 4A-8 DZ3-50 4-(6-(6-amino-9-(3-(isopropylamino)propyl)-9H-purin-8 ylthio)benzo[dl ,3ldioxol-5-y1)benzaldehyde 4A-9 4-(2-(6-amino-8-(6-phenylbenzo[d][1,3]dioxol-5-ylthio)-9H-parin-9 y)ethy)piperidine-1-carbaldehyde__ 4A-10 1-(4-(2-(6-amino-2-fluoro-8-((6-phenylbenzo[d[1,3]dioxol-5-yl)methyl) 9H-purin-9-yl)ethyl)piperidin-1-yl)ethanone 4A-11 N-(2-((2-(6-anino-8-((6-phenylbenzotd][1,3]dioxol-5-yl)thio)-91H-purin-9 _ L)ethyl)amino)ethyl)sulfamide 4A-12 3-(2-(6-amino-S-(6-phenvlbenzo[d][1,3]dioxol-5-ylthio)H-purin-9 y3lethylamino)-N-hydroxypananide 4A-13 9-(3-aminopropyl)-8-(6-phenylbenzo[d][1,3]dioxol-5-ylthio)-9H-purin-6 amine Table 4B No. Name 41 PU-WS8 8-(6-ethynylbenzo[d][ ,3]dioxo1-5-yihio)-9-(3-(isopropylamino)propy) 9H-purin-6-amine 4B-2 PJ-WS6 8-(6-(3,3-dimethylbut-1-yny1)benzo[d]1,3]dioxol-5-ylthio)-9-(3 4B-3 PU-WS7 9-(3-(isopropylarmino)propyl)-8-(6-(phenylethynyl)benzo[d][1,3]dioxol-5 ylthio)-9H-purin-6-amine WO 2011/044394 PCT/US2OIO/051872 177 4B1-4 PU-WS16 purin-6-=rine 4B-5 1-(3-(2-(6-amino-S-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9l-puin-9 yl)ethyl)pipedidin- 1 -yl)ethanone __________ 4B-6 84(6-ethynylbenzo[dj [l ,3ldioxol-5-ylthio)-9-(2 -( I N________ (me thylsulfonyl)piperidin-3-yl)ethyl)-9H-puin-6-amine 6B1-7 1 -(3-(4-(6-aniino-8-((6-ethynylbenzo[d][I,3]dioxol-5-yl)methyl)-2-fluoro 4B-8 5-(6-anmino-8-((6-ethynylbenzo[d][1I,3]dioxol-5-yI)methyl)-2-fiuoro-9H ______________purn 9-yI)pentane-1 -sulfonamide 4B1-9 3-(2-(6-amino-2-chloro-8-((6-ethynylbenzo~d)[1I,3)dioxol-5-yl)methy1) ______________911 purin-9-yl)ethyl)pipcridine-1 -cabaldehyde 4B1-10 I3-(2-(6-arnino-8-((6-ezhynylbenzo[d] (1,3Jdoxol-5-yI)rnethyl)-2-fluoro ___________9H-purin-9-vfleihyl)piperdine-i -sulf onaide 41 I N-(2-((2-(6-arnino-8-((6etnmybezo~d[1 ,3)dioxol-5-ylthio)-9Hf-pmin 411-12 ' (2-(6-aino-8-(6-eihynylbenzo[d][ 1,3]dioxol-5-ylthio)-91{-purin-9 yI)ethylarnino)-.NIyoxrparid 4B1-13 PIJ-WS19 8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9-(2}--neopen-yliinio)eth yl) ______________9H-jpnrin-6-anine 4B1-14 PU-WS20 8-((6-ethynylbeno~d][ I ,3]dioxol-5-yI)methyl)-2-fluoro-9-(2 _______________(isobuitylamino)ethyl)-911-prin-6-amine 4B1-15 9-(3-aminopropyl)-8-(6-ethynylbenzo[d[ I ,3]dioxol-5-ylthio)-9H-pmin-6 amine 4B1-16 9-(2-aminoetbyl)-8-(6-ethynylbenzo[d][1 ,3]dioxol-5-ykthio)-9H-purin-6 amine 4B1-17 9-(3-(tedt-butylamino)propvl)-S-(6-ethmyylbenzo[dJ[ 1 ,3Jdioxol-5-ylthio) _______________9H-purin-6-amine 4B-18 1-(3-(6-amino-8-(6-ethynylbeno[d][ 1 ,3]dioxol-5-y4thio)-9H-purin-9 yl)propyl)pyrrolidin-3 -one 4B1-19 3-(2-(6-aniino1-8-((6-ethynylbewzo[d][ 1 ,3ldioxol-5-yl)thio)-911-purin-9 ______________vl)ethyl)niperidine-1 -sulfonaide 4B1-20 64 6-arnino-8-(6-cthvnylbenz o[d][1 ,3]di.oxolI-5-vlthio)-9H-purin-9 _________________yI)hiexananmide 4B1-21 1-ain--6ehnbezd]I.3]dioixol-5-vlthio)-9H-purin-9-yl)-3 _________________(tetbtvlami)propax-2-ol 4B1-22 6-(6-amino-8-((6-elhynylben~o[d][ I ,3]dioxol-5-yI)methyl)-2-luoro-9H _______________pumi-9-yI)hexanmide 4B1-23 1 -(2-((2-(6-amnino-S-(6-ethxnylbenzo[dlr I ,3]dioxol-5-ylthio)-9-I-puin-9 _______________ viehylamaino~rnethvl)pyrrolidin-i vl)et.hanone 4B1-24 5-(6-amino-8-(6-ethiynylbnzo[di[1 ,3]dioxol-5-ylthioc)-9H-purin-9 _______________yI)pentane-1 -sulfonamide 4B-25 I-(3-(2-(6-amino-8-((6-ethynylbenzo[d)[ 1,3]dioxol-5-yl)metliyl)r2-fluoro _______________9H-purin-9-yl)ethyl)piperidin-1-yl ethanone 4B-26 8-((6-etbynylbe,,oi[f .3dioxol y~ehl-2tur--2 WO 2011/044394 PCT/US2OIO/051872 178 (neopentylamno)etliyI)-9H-purin-6-amrne 4B-27 8-((6-etinyibeizo[d ][1 .3]oxol-5-vI)methyl)-2-fluoro-9-(3 ______________(isopropylariilno)propyi)-9Hi-purini-6-amne 4B1-28 9-(3-(tert-butylamino)propyfl-8-(6ethynylbenzo[4J[1I,3)dioxol-5 vI)methyl)-2-fluoro-9H-pmrin-6-amine 4B8-29 84(6-ethynylbero~dI1[1 ,3]dioxol-5-yI)nmethyl)-2-fluoro-9-(2-( 1 (methylsulfonyi Itedin-3-yl)ethyb-9H-purin-6-amne 4B-30 I -(3-(6-amino-S-((6-ethynylbezordi1[1 ,3]dioxol-5-yl)methyl)-2-fluoro _______________9H-purin-9-yl)propyl)pyrrolidin-3-one 4B8-31 8-((6-ethynylbenzo[d][1 ,3]dioxol-5-yI)mcthyl)-2-fluoro-9-(2-(1 .................... ethylpiperidin-3-yI)ethyl)-9H-purin-6-amine 4R1-32 8-(6-ethynylbeozo[di[I ,3i dioxol-5-ylthio)-9-(2-( 1-methyipiperidin-2 yl)ethyl)9fl-puri ____________________ 4B-33 1 -(2-((2-(6-amino-8-((6-ethynylbenzo[d][1 ,3]dioxol-5-yI)methyl)-2 ______________ flnoro-9H-puin-9-yi)ethviamino)methvflnynolidi- -fdhnn 4B8-34 8-(6-ethyriylbcnzo[d][ 1,3]dioxoi-5-ylthio)-9-( -tn-ethylpiperidin-3 ____________ --- --- y I)ethvl'i-9H-purin-6-arnane 4B-35 j 8-((&-ethynvylbenzo'd] [1,3]dioxol-5-yI)m.ethyl)-2-fiu oro-9-(2-(I _______________ ethylpir.c-'din-2-yl)ethyl)-9Wipurin- -amin Table 4C No. Name 4C-1 DZS-4 8-((6-(Thran-2-yl)beno[d][ I ,3]dioxol-5-yl)thio)-9-(3-(isopropylamino)propyl)-9H ___________p~rin-6-aminc 4C-2 DZS-27 S-((6-(fiira-3-yl)benzo[d][1 ,3]dioxol-5-yI)thio)-9-(3-(isopropylanino)propyl)-9H _________ purin-6-amiiie 4C-3 D73-25 2-flnoro-8-((6-(furan-2-yl)benzo(d][i ,3]dioxol-5-yI)methiyl)-9-(2-(isobutylamino)ethyl) _________ 911-purin-6-amnine 4C-4 DZ3-26 2-fluoro-8-((6-(furan-3-yl)benzo[d][1 ,3]dioxol-5-yI)nmethyl)-9-(2-(isobutylamino)ethyl) _________ I9H-purin-6-arnine 4C-5 TT5-53A 8-((6-(faran-2-yI)benzo[d][1,3]dioxoI-5-yI)thio)-9-(2-(neopcntylamino)et: w1)-9H-puhin __________6-amine 4C-6 DZS-33 5-(6-((6-aminco-9-(S-(isopropyiarnino)propyl)-9H-purin-8-yI)thioybenzo[d,]3dioxo-5 __________ -yl)furan-2-carbaldehye 4C-7 D23-34 5-(6-((6-amino,-2-fluoro-9-(2-(isobuty lamino)cthyl)-9H-purin-8 I ___________yl~mezhyflbenzofdj[ ,3]dioxol-5-yI)filran-2-catbafltchyde ______ 4C-8 DZ3-35 9-(3-(isopropylamino)propyl)-8-((6-(5-methylfuran-2-y)benzo[d[1 ,31dioxo1l-5-y1)thio) 4C-9 DZ3-36-mn 4C.____ Hpri--mn _________ 2fluro9-(-(sohtylmio~ehyl-8((6(5tnehvlhrn-2yl~eno~drl,3]dioxol-5- WO 2011/044394 PCT/US2OIO/051872 179 _________ Jyl)mcthyl)-9H-purin-6-arnine 4C-10 DZ-49 I9-(3-(isopropylarno)propyi)-8-((6-(isoxazolA-yl)benzo[d][1 ,3]dioxob-5-yI)thio,,)-9H 4C-11 DZ3-51 2-fluoro-9-(2-(isobutylaniJno)ethyI)-8-((6-(isoxazo1-4-yl)benzo[d][1 ,3)dioxol-5 40-12 ylhnethyfl-9H-purin-6-anaine 4C-128-((6-(5-(aminomethyl)fuan-2-yl)benzo[d][ 1,3]doxol-5-yl)thio)-9-(3 _________ -(isopropyl~mino)propyl)-9H- 6-an~Thfl 4C-13 8-((6-(5-(ami~nomethyl)fnran-2-yl)benzo[d][ 1,3ldioxoI-5-yI)methyl)-2-fluoro-9-(2 4C-14 DZ3-60 S-((6-(fhra-3-yl)benzord]I1 ,3]dioxol-5-yi)thio)-9-(2-(neopentyaiino)ethyl)-9H-pnrin 6-amine 4C-15 S-6-(5-rnethyloxa.zo}-2-yl)benzo[d][1 ,3]di oxol-5-vlthio)-9-(2-(nieopentvlamino)ethyl) _________ 9H-prin-&arnine 4C-16i DZ-3-56 8-((6-(5-methylfiraw21-y1)benzo[d][ 1,3]dioxol-5-yI)thio4-9-(2-(neopentylani)ethyl) ___________ 911pta-9-v~pro1.o~y~idin-3-one __________________ 4C-18 8-((6-(5-(aniinon eti vl)furan-2-y1)benzo(d]r1,3]dioxol-5-Y1)thio)-9-(2 _____________(neopentylammro~cthy)-9H-Eurin-6-amne 4C-19 I (3-(-6a no8(-5mt. li a2-ibn d[1 ,3]diox~oi-5-yithic)-9H-purin-9 ____________yi)ethy1}rpiperidin-1-yflethanonie 4C-20 8-(6-(5-methylfiiran-2-yl)benzo[d) 1 ,3]dioxol-5-yltbio)-9-(2-( 1 ___________(methy lsulfonyI)pipeidin-3-yl)ethyl)-9H-purin-6-amiine 4C-21 1-(3-(2-(6-anmino-2-fluoro-8-((6-(5-methylfuran-2-yl)benzo(d][1 ,3]dioxol-5-yl)methyl) 4C-22 4-(2-(6-amino-2-fluoro-8-((6-(f'uan-2 yl)benzo[dJ[I ,3)dioxol-5-yi)rnethyl)-9H.-puin-9 ______________ yI)ethyl)pipenidane--carbaldchyde __________ 4C-23 I -(3-(6-aniino-8-(6-(oxazol-2-yl)benzo[d][1,3]dioxol-5-ylthio)-9H-purirn9 ____________ ~ ~ ~ yl~ ___________ y opytipyrrolidin-3-onc 4C-24 6-(6-amino-8-(6-(5-methyloxazol-2-y)beizo[d][1,3)dioxol-5-ylthio)-9H-purin-9 40-25yI)hexanamide 4C-25 6(6-amiino-2-fluoro-8-<(6-(5-rnethvioxazol-2-yI)benzo[d)[ I,3)dioxol-5-yl)methyl)-9H ____________purin-9-y~lhexanamide F 4C-27 (-(6(,amino-2-floro-8-((6-(5-rnethynfran-2-yI)benzo[d][i,3)dioxo1-5-yI)tnthylI _________91H-purin-9-yi)ethyl)piperidin-t-y)eth nne 4C-28 14(3-(2-(6-am ino- S-(6-(5-rnethvloxazol-2-yI)benzo[di[1 ,3]dioxol-5-ylthio)-9H-purini-9 - yl)ethyl)pipRindin-1-yI)ethanone 4C-29 1(3-(2-(6-amino-21-fluoro4S((6-(-nehyoxzcl-2-yl)beno[d[1,S]dioxol-5 4C-36 3-(2-(6-anwlno-2-chkr-(6-(5-mehyoxso-2-yl)benzo[d] [I,3]dioxoI-5-yi!rnethtyl) -(4-(-(6-mino8-((6(5-(mi1oethyl~pfurne--lnzo d e ]ixl5y~ho-1 4C-31 T 9I26-r~n -84(-puratin9y1ethyl)pipriin--ulfonaide 3] ioxl ________-9H _________ _____- - purin-9-yI)ethyl)piperidin-1-yl)ethanone 4C-32 ...... -'3- 2- -aio8(65-aiothlozo2yfeo(d( 1,3]dioxol-5-yl)methyl)- WO 2011/044394 PCT/US2OIO/051872 180 -4 2-fluoro-911-rurin-9-yIehVI piperidin-1 -fehan.... 2 -fluoro-9-(3-(isopropylamiino)propyl)-8-((6-(5-metiyloxazo 2-yl)benzo[d][1 ,3]dioxol-5-ylftnethyl)-9H-puzin-6-amine 9-(3-(tert-butylanmino)propy}-2-flnoro8-(6(5-nethyloxazol2 yl)benofd3[ I 3]dioxol-5-yl)methyl)-9H-purin-6-amine yl 2ro[d][1 ,3]dioxo1-5-yl)thio)-9H-piuini-9 I yl)ethyl)amino)etbl) suifami&e 3-(2-(&-amino-S-(&6(5-miethylforn-2-y1)benzo[dir I ,3]dioxol-5 DZA-20 9-(3-(isopropylamino)propyl)-3-((6-(oxazol-2 yI)benzo[d3[ I,3]dioxol-5-yl)thio)-911-purin-6-arnine DZ4-23 2-fluoro-9-(2-(isobuwylanino)ethyI)-8-((6-(oxazol-2 yl)benzo[d][1I,3]dioxol-5-yl)methyl)-9H-purin-6-aniine _______ _____ ____-~DZ3-142 8-((6-(2,3-dihydrofuran-2-yl)beno[d][I ,3]dioxoi-5-yl)thio)-9 (3-(isopropylarmino)propyl)-9H-purin-6-anine DZ34143 S-((6-(Z-,3-dihydrofurani-y1l)benzo[dJ[1 ,3Aoxol-S-vl)thio)-9 (3-(isopropyiamino)propyl)>9H-purin-6-amme yl)tenzo[d][1I,3]dioxol-5-ylthio)-9H-puriu-6,-amine 9-(2-amirnoethyl)-2-fluoro-8-((6-(5-nethylfian-2 _______~Yflbeno d I3JgjpoI- 1mt )-9H-purin-6-amine WO 2011/044394 PCT/US2OIO/051872 -4 9-(3-(tert-butylamnino)propyl)-8-(6-(5-nethyfran-2 yt)benzord][1 ,3]dioxol-5-ylthio)-9H-purin-6-amine 9-(3-(tert-butylamaino)propyl)-8-((6-(oxazot-2 yI)bce ord]r I,3]dioxo1-5-y1)dbio)-9H-purin-6-amnine 1-44-(2}6-amiino-8-((6-(oxzo-2-yI)benzo~d] [ ,3]dioxol-5 y1)thio)-9H-purin-9-y1)ethyi)pip-ridix-I-yI)ethanone 8-((6-(5-rniethyloxazol-2-yl)benzo'd] [1 ,3]dioxol-5-yiA)thAk+)9-(21 (I -(rnTysulfonyl)piperidin-3-y1)ethyl)-9I-I-purin-6-aminie 9-(3-(tet-bntvlamino)propyl)-84(6-(5-mnethvloxazoi-2 yl)benz~'41 ,3jdioxol-5-yl)tio)-9H-purin-6-aniine I -(6-amino-8-(6-(5-znethylfra-2-y)benzo[dj1 ,3]dioxol-5 ylthio)-9H-purin-9-y)-3-(teit-buylaniino)propan-2-o1 I -(6-amino-8-((6-(5-metliyloxazo-2-y)benz~d 1(1 ,3]dioxoI-5 yl)thio)-9H-purin-9-yl)-3-(isopropylami no)propan-2-o 2-(3-(6-amino-8-(6-(5-mebyiftiran-2-y)benzc~d]' LI,3]dioxoI-5 ylthio)-9H-purin-9-yl)propvib iridine-1-catbaldehyde 5-(6-amino-8-(6-(5-methyloxazol-2-y)benzo[d][ 1,3]dioxol-5 __________ylthio)-9H-puirin-9-yI)pentane-1-sulfonamide WO 2011/044394 PCT/US2OIO/051872 -4 84(6-(5-methyloxazol-2-yl)benzord)[ I,3]dioxol-5-ylthio)-9-}3 (I -(meihyisulfonyl)py,-olidin-3-yl)propyl)-9B-purin-6-amine I -(3-(6-aniino-8-(6-(5-mcthyloxazol-2-yl)benzo[d][1I,3jdioxol 5-ylthio)-9H-purin-9-yl)propyl)pyrrolidin-3-one 9-(3-(tert-butylamino)propyl)-2-fluoro-8-((6-(oxazol-2 yl)benzo[d][ 1, 3]dioxol-5-v1)rnethvl)-9tbpurin-6-arnine 5-(6-amino-fluoro-8-((6&(5-mehylffiran-2 yl)benzo[dl 1 ,3jdioxol-5-yl)rnethiyl)-93-purin-9-yI)pernane-1 sififonarnide vIlbenzoAd)[i,3]d',xo1-5-vlI)methyI)-9H-puin-9-yl)hexanamide 2-fluoro-9-(3-(isopropylaniio)propyl)-8-f6-(5-methylfran2 yl)benzo[d]L I,3)dioxoI-5-y1)metbyl)-9H-p~irin-6-arnine 9-(3-(tert-butylarnino)propyl)-2-fluoro-8-((6-(5-methylfuran-2 yI)benzo[d][1I,3]dioxol-5-yl)methyl)-9H-purin-6-amine *9-3-aminoropyl)-2-fluoro-8-((6-(5-methyifuran-2 yI)benzo[d]1[1,3]dioxoI-5-yI)methyl)-9H-pinn-6-anine 9-(3-aminopropyi)-2-fluoro-8-((6-(5-mehyoxzo-2 ybbenzo[d][1 ,3]dioxol-5-y)vethy)-9H-puin-6-awine Table 4D WO 2011/044394 PCT/US2OIO/051872 183 NO. Name 4DA DZ2-395 9-(3-(isopropylamino)propyl)-8-((6-(thiophen-2-y)benzo[d[ 1,3]dioxo1-5-y1)thio)-9H 4D4~~ -irn6-amine 4D-2 0Z3-48 2 fhtioro-9-(2-(isobutylarnino)cthyl)-S-((6-(thiophen-2-yl)benzo[dl l,3)dioxol-5 4D-3 DZ3-58 9-(2-(neopen~yIamino)ethyl)-8-((6-(thiopen-2-y)benzo[d][1 ,3]dioxol-5-yI)thio)-9H ____________pun n-6-amin e 4D-4 9-(3-(isopropylamino)propyl)-8-((6-(thiophen-3-yl)benzo[d [1 ,3jdioxol-5-yl)thio)-9- ___________ptirin-6-a mine 4D-5 2-fluoro-9-(2-(isobutylanimino)ethyl)-8-((6-(thiopben-3-yl)benzo[d][1,3ldioxol-5 ___________yI)methvlj-9H-prin-6-atnhie 4D-6 9-("2-(neoveny'amino)ethyi)-8-((6-(thiophen-3-y')benzo[dJ[ 1 3]dioxo1-5-y1)zhiio)-9H * 4D-7 I }4-(2-(6-amino-S-((6-(thiophen-2 -yl)benzo[di[1I,3]dioxo1-5-yI)thio)-9{-painin-9 ____________ Iotl)piperidin-i -vi)effianone y1)ethy1 l~iperidine-1 -carbialdehydie 4D-9 1-(44(2-(&-ainino-2-flIuoro-8-((6-(thiophen-2-yl)berofdF 1 3]dioxol-5-yI)methyl)-9H ____ __purin-9-vl)ethyljpiperidin-i-yi)ethanone_ 4D-10 4-(2-(&6amino-2Afluoro-8-((6-(thiophen-2-yi)benzo[d][i ,3]dioxol-5-yI)methyl)-9H ___________purin-9-yl)ethyl)piperidine-1 -carbaidehv de 4D-11 4-(2-(6-amino-8-((6-(thiophien-3-yl)benzod)1[1,3)dioxol-5-yI)thio)-9H-purin-9 ___________yflethyl)piperidine-I -carbaldehlyde 4D-12 4-(2-(6-amino-2-lluoro-8-((6-<thiopheni-3-yl)benzo[d]t1 ,3)dioxol-5-yl)methyl)-9pin-9-yI)ethybpiperidine-1I -carbaldehyde 6D0-13 4-(2 -(6-amino-2-chloro-8-((6-(thiophen-3-yl)benzo[d1[ 1,3]dioxol-5 -y)methyl)-91I 4D-14 N -(2-((2-(65-amnino-8 -((6-4t1iophen-2-yI)bezo~d][ 1 ,3]dioxol-5 -yl)thio)-9--pnrin-9 yI)ethyl)amino)ethyl) sulfanmide 4D-15 3-((2-(6-amnino--((6-(thiophen-2-y)ben~o[d][1,3]dioxol-5-yl)thio)-91-puin-9 __________yl)ethyl)amino)--:yxpran id 4D-16 0Z4-21 9-(3 -(isopr-pyiam~ino)propyl)-8-((6-(thizol-2-y)benzo[d[ 1,3]dioxol-5-yl)Ehio)-9H ___________purin-6-armne 4D-17 1174-24 2.luoro-9-(2-(isobntyiarnrno)ethyl)-8-((6-(thiiazol-2-y)benzo[d[ i,3]iooi 4D-18 9-(3-amiinonropyI) S ((6-(thiophen.-2-yi ybemzo'd][i ,3]dioxoi-5-yl)thio)-9H-nrnin-6 aimno 4D-19 9-(3-(tert-buwitlamino)propyl)-S-((6-(h.ophen-2-yl )benzord]( I,3]d ioxo-5-yI)thi)-9 __________purin-6-amine * 4D-20 9-(3-(tert-tutyirni)propyl)-8-((6-(thiazob-2-y)ber.zo[d][1 ,3]dioxol-5-y)thio)-91 __________ purin-&-amine ___________________ 4D-21 9-(3-(tert-buiylaininio)propyl)-S-((6-(5-meliylthiophn-2-y)bno~d [1 ,3]dioxoI- 5 __________y1)thio)-9H-Durin-6-amine 4D-22 9-(3-(tefl-bntylamino)propy)-8-(6-(5-methylthiazo1-2-y1)benzo[d][1I,3]dioxol-5- WO 2011/044394 PCT/US2010/051872 184 . yl)thio)-9H-purnn-6-amine 4D-23 1-( 3

-(

2 -(6-amino-8-(6-(5-methylthiazol-.yl)benzo[d] [1,3]dioxol-5ylthio)-9H1-purin-9 yl)ethyi)piperidin-l-yl)ethanone 4D-.24 1-(6-amino-8-((6-(5-methylthiophen-2-y1)beno[d][1,3]dioxol-5-yl)thio)-9H-purin-9 yl)- 3 -(isopropylamino)propan-2-o 4D-25 1-( 6 -amino-8-((6-(5-methylthizo1-2-yl)beno[d[1,3jdioxol-5-y)thio)-9H-purin-9-y1) _________ 3-(iVsopropylamino)propan-2-ol ________________________ 4D-26 6 -(6-amino-8-(6-(5-methylthiophen-2-yl)benzo[dr[1,3]dioxol-5-ylthio)-9H-purin-9 yl)hexanamide 4D-27 5-(6-amino-8-(6-(5-methylthiazol-2-yl)benzo[d][1,3]dioxol-5-ylthio)-9H1-purin-9 yl)pentane-1-sulfonamide 4D-28 9-(3-(1-(methylsulfony)pyrrolidin-3-yl)propyl)-8-(6-(5-methylthiopheu-2 yl)benzod][1,3ldioxol-5-ylthio)-..9H-purin-6-amine 4D-29 2-( 2 -(6-amino-8-(6-(5-methylthiazol2-yl)benzo[d][1.3]dioxol-5-vIthio)-9H-purin-9 y1)rbethy)pyn-oidine-1-carbaldehyde D-3 2fluoro92-(isobutylanino)ethyl)-8-((6-(5-methylthiophen-2-yl)benzo[d][1,3]dioxo! - ~~5-vI)mnethvi-9H-prin-6-amine _____________ 4D-31 8-((6-(5-methylthiophen-2-y)benzojd[ i,3]dioxol-5-yl)tIio)-9-(2 _______ (neopentylamino)ezhyl)-9H-purin-6-amne 4D-32 2-fluoro-9-(2-(isobutylamino)ethyl)-8-((6-(5-methylthiazol-2-yl)bnzo[d)[1,31dioxo1-5 y1)methy)-2H-purin-6-am ine 4D-33 8-((6-(5-methylthiazol-2-yl~benzo[d][1,3]dioxo1-5-yl)thio)9-(2-(neopentylamino)ethy) _________9H- purin-6-ammne Table 4E No.F Name 4E-1 PU-WS3 6-((6-amino-2-fluoro-9-(3-(isopropylamaino)propyl)-9H-purin-8 1 y1)methy)benzo[d][1,3]dioxole-5-carbonitrile 4E-2 PU-WS5 6-((6-amino-9-(3-(isopropylamino)propyl)-9H-purin-8-yl)thio)benzo(d][1,3]dioxole-5 carbonitrile 4E-3 DZ3-39 i 2-(6-((6-anino~9-(3-(isopropylamino)propyl)-9H-purin-8-yl)thio)benzo[d][I,3]dioxol-5 yl)acetonitrile 4E-4 DZ3-40 2-(6-((6-amino-2-fluoro-9-(2-(isobuitylamino)ethyt)-9H-puin-8 y1)_mhybenzod[1.3Idioxol-5-yl~acetonitrile 6E-5 rN-(2-((2-(6-amnino-8-((6-(canomnehyl)benzo[d)[ i,3]dioxol-5-yI)thio)-9H-purin-9 yl)ethyflamino)ethyl)sufamide 4E~6 3~((2-(6-amino-8-((6-cyanobenzo[d][1,3]dioxol-5-y1)thio)-9H-purin-9-yl)ethy1)amino)-N hydo-xvpropanamjde - - - - - 4E-7 6-((6-amino-2--chloro-9-(3 -(isopropylamiino)propy1.)-9H-puirin-8 -lxnmethybenzod][1,3]dioxole-5-carbonitrile Table 4F No. Name .4-1 IDZ3-5 WO 2011/044394 PCT/US2OIO/051872 185 9(3}isopropylamino)propyU)-8-(6-{pyridin-yI)benzo[d][ I,3]dioxol-5 , thicX.9H-purin-6rnne Table 5A No. Name 5A-1 PU-RK11 S-((7-iodo-2.3-dihvdrobenzo[b][1,4]dioxin-6-yI)thio)-9-(3 . .. ._____ ..... sorplaioprpl-H-purn-6aminc~ty)9-ui--mn SA-2 PhJ-HT165 8-((7-iodo-2,3-dihydrobenzo[b][ 1 ,4ldioxin-6-yl)thio)-9 (2-(neopenyamino)ethyl)-9TI-PtIrin-6-amine PU-RK12 dihydrobenzo[b][1,4]diOxin-t5-yl)thio)-9H-puirin-6-amine PU-0Z3-73 2-flnoro-8-((7.--iodo-2 ,3-dihiydrobenzo[b](1 ,4]dio xin-6 yI)methyi)-9-(2-(isobutylarniino)ehyi.)-9H-purin-6-a.mine PU-DZ4-84 9-(2-(tert-buylarmino)etlhy1)-2-fluoro-8-((7-iodo-2,3 dihiydrobenzcb][ ,4]Jdioxin-6-yl)methyl)-9H-purin-6 amnine 9-(3-aminopropyl)-8-((7-iodo-2,3 dihydrobcnzo~bi[ I,4]dioxin-6-yl)thio)-9H-punin-6-aniine 9-(2-aiminoethyl)-8-((7-iodo-2,3 dihydroberio[b][1 .4]dioxirn-6yl)tliio)-9H-purin-6-anmine 9-(3-(tet-buyarrino)propy1)-8-((7-iodo-2,3 dihydrobeno[bJ[ I ,4]doxin-6-yl)thio)-9H-pnrin-6-ainie I -(6-aminio-a-(C7-iodo-21,3-dihyrobenol b)I ,4]dioxin 6-vL)thio' )-9H-puirin-9-yI)-3-i(isopropylarmino)propan-2-1l 5-(6-amiino-a-(7-iodo-2,3-dihydrobenz ofb)[i,4ldiioxin-& ylthio)-91--purin-9-yl)nentan-! -sulfonaide WO 2011/044394 PCT/US2OIO/051872 186 1-(3-(6-amino-8-(7-iodo-2,3 dihydrobewo[tJ[1 ,4)dioxin-6-ylthio)-9ll-puht-9 yl)propyl)pyrrolidin-3 one 6-(6-arnino-8-(7-iodo-2,3-dihydroben zo[b]f I,4]dioxin-6 ylthio)-91{-purin-9-y1)bexaaide 9-(3-(tert-butylanmno)propyi)-2-fluioro-S-((7-iodo-2,% dihydrohbenzo~b][1,4]dioxin-6-yl)methyl)-9H-prnin-6 alne dihydrobcnzo[b][ l,4]dioxiiv6-ylthio)-91-pnLrin-9 yl)hutyl)pyfrolidin-b-vl ethanom 2-fluoro-8-((7,-iodo-2,3-dihydrobenzo[b]j I,4]dioxin-6 yI)methiyl)-9-(3-(isopropylainino)propyl)-9H-purin-6 dihydrobenzo[b][1.,4]dioxin-6-yl)methyl)-9H-purin-9 yl)propyl)pyrrolidin-3-one I dihydrobenzo[bJ(1,4]dioxin-6-yI)methyl)-9H-puin-9 vfhe-xananide 5-(6-amino-i2-fluorw8g-((7-iodo-2,3 yl~penta-I-sulfonarmde ____________- ______________ _________ __________j Table 5B No. Name 5B-1 SI S-((7-(finan-2-yl)-2,3-dih.ydrobenzo[b[. 4]clioxin-6-yI)thio)-9-(3-(isopropylanino)prpyi)-911 nuhin-6-arnine 5B-2 1i-(3-(6-arnino-4(t(oxzol-2-yl)-,3-, hydroenzo[b[ t,4jdioxin-6-ylthio)-91-urn9 _1 j ro~pvl~ m idim,3 -onec SB_____ 2:38-( L -t;l!a-2YL-3- 2beR~ WO 2011/044394 PCT/US2OIO/051872 187 ___________ l)thio)-9H-purn-6-arnine 5B-4 6-(6-amino-2-fluoro-8+{7-(5-methyloxazol-2-yI)-2,3-dihydrotenzo[h] [1.4]dioxin-6-yl)motlbyI) ___________9H-pudin-9-ylffhexanaride 5B-5 6-(&5arninoQ-8-(--(5-rnethyloxazo1-2-yI)-2,3-diliydrobenzo[b][1,4]dioxin-6-ykthio)-91I-purin-9 ___________yl hexananide 5B-6 2-fhioro-8-((7-(5-methylfuran-2-yl)-2,3-dihydrobeno[b][ 1,4]dioxin-6-ylftnethyl)-9-(2-(b (.methysuftiry)piperidin-3-yl)cthy)911-puirin-6-a-mine 5B-7 jTT--SS-5A 12-flnioro-8-((7-(faan-2-yI)-2,3-dihydrobenzo[bfll ,4]dioxin-6-yi)rnethyl)-9-(2 SB-8 j I -(3-(2-(6-arnino-2-fluoro-8-((7-(5-nethyLfiira-2-yI)-2.3-dihydrobezo~b[1,4]dioxin-6 Iyl)mcthyl)-9H-prin-9-yl)ethyl)piperidin-1-vI)ethanone 5B-9 18-(7-(5-niethylfrran--2-yl.)-2,3-dihydroheuzob[1,4]dioxin-6-ylthio)-9-Q-(1 1(methylsulfory1)piperiin-3-yI)etliyl)-9H-,rnn-6-amne 511 10 h2-fluoro-9-(2-(isotutylamnino)ethyl>8-((7-(5-nethylfiyair2-y)-2,3 ____ ______dihvdrobenzo~bll,4]dioxini-6-yl)methyi)-9H-pmii-6aine 5fl ~ h-(3-(6-an~ino-2-fluoro-S-Qj7-(5-methyloxazob-2-yl)-2,3-d iydrobenzof[bj ,4jdioxin-6 I -_______ ljetyl):9H-purin9-yIlrpy yn~d n-3 e 5B-12 h 8-((7-(5-(aminomethyl)furan-2-yl)-2,3-dihydrobenzo[b][1,4)dioxin-6-yl)methyl)-2-fluoro-9-Q2 511-13 18-(7-(5-methyloxzoi-2-yl)-2,3-dih-ydr-obeno[b][1,4]dioxin-6-ythio )-9-(2 __________ (eoenrla~iio~ffyl-9H-purin-6-amine 5B-14 t-(3-(2-(6-arnino8-(7-(5-rnethylfwan-2-yl)-2,3-dihydrobenzofb][ I,4]dioxin-6-ylthio)-9H ______ Turi~nn-9-1ehIpprdn-1 -yl)ethanone ______ _____________ 58-15 &-((7-(5-methyifixan-2-yl)-2,3-dihydrobenzo[b][I ,4]d.ioxim6-yl)thio)-9-(2 __________ *(neopentylamyinojethyl)-9H-puirin-6-aininie 5B-16 8-((7-(isoxazo-y1)-2 3-dihvdrobeno[b][ 1,4]dioxin-6-yI)thie)-9-(2-(ncopentylamino)ethy) __________9B-purin-6-an~ne 5B-17 I -(3-(2-(6-amaino-8-(7-(5-rnethyloxazol-2-yI)-2,3-diihydrobenzo[b [ I 4]dioxin-6-ykchio)-9Hf ___________ urin-9-yl)ethyl piporiin- -vl)ethano,,e 5B-18 8-(7-.-(5-(ar~iomethyl)furan-2-y)-2,3-diiydrobezo[]F I,4]dioxin-6-yl)thio)-9-(2 5B-9 I5-(6-ant-.o-8-(7-(5-rnethylft'ran-2-y1)-2,3-dihydrohenzo~b][ t,4]dioxin-6-ylthio)-9--purin-9 ____________yl)pentatne-I-sulfonamide 5B1-20 5-(6-amino-S-(7-(5-nmethvloxazol-2-yI)-2,3-dihydroberzo[b]1,4]doxin-6-ylhio)-91-purin-9 ___________yl)pcntanel -silfonanmide SB 21 I-(4(246amino2-choro--((7-(fura-2-yl)-23-dihydrobezob][1 ,4]dioxin-6-yl)methvl)-9H I __________ [purn-9yI~thi~pperdin-1yl)ethanonc 5B-22 I-(4-(246-arinjo-8-((7-(5-metlylkran-2-y)-2,3-dilhydrobenzo[b][i,4]dioxin-6-v)thio)-9H ____________purin-9-yl)ethvl)pioeridin-1-yl)etbanone 511-23 1 6an o2-loog(7(5-tyfun2-l-,- ~ ydoez~]14]dioxin-6 ______________I 1eh)-9H-purin-9-yI)ethy)~iperidini-1-yI)ethanone 5B-24 1J-(3 -(6-amriro-8 47-(5 -metliylfhran-2 -yi)-2,3-dihydrobenzo[b][II ,Aidioxin-6-ylthio)-9H-purin-9 ___________ y)propy)pyrrplidin-3-one 5B-25 9-(3-(tert-hutylamino)nropyl)-8-(7-(5-rnetbylfrnan-2-y)-2.3-dihydrobenzob] [ 1,4]dioxin-6 I __________ ylthioYl-H-unirn-anmne ___________ 5B-26 2-chloro-S-((7-(5-nrthvlfurn-2-y)-2,3-dhydrobenzo[b][1,4]dioxin-6&y)nethyl)-9-(2-(1 ____________ retlivlsnlfon~yf2Lpyolidin-3-yl)ethyl)-911-purin-6-amine 58-271-(3-(2-(6-arin~o-8-(7-(5-(aniinomethyl)fiiran-2-yi)-2,3 -dihydrohenzob] [ I ,4]dioxin-6-yi thio) __________9H-purn-9-y)etl)piperdin-1I -yl)ethanone WO 2011/044394 PCT/US2OIO/051872 188 511-28 1 -(3-(24(6-amino-8-((7-(5-(aminometyl)flian-2-y)-2,3-dihydrobrxo[b][1 ,4]dioxin-6 ___________yImethy1])-2-4fluoro-9H-pntin-9-y)et gpprDi1-)ehne 511-29 5-(6-arnino-2-fluoro-8-((7-(5-methvftian-2-yl)-2,3-dihydrobezo~b][I,41dioxin-6-yi)nmethyl) __________9H-pumi-9-yI)Dentane-1 -slfonarnide SB-30 4-(2-(6-amirc-2-ehoro-8-((7-(soxazo-4-yl)-,3-dhydrobezofb[,4dioxcin.-yl)meihyl)-91 __________purin-9-yi~ethyllpiperidiine-ltcarbaldehvde 511-31 N-(24((2-(6-airino-8-((7-(furah-2-yl)-2,3-dihvdrobezo[b][1 ,4]dioxin-C&yi)thio)-9H-purin-9 __________ylhethyl)ammio)ethyl)sulfamide SB3-32 3-((2-(6-amino-S-((7 -(fuan-2-yl)-2,3-ilhydrobezortlE 1,4]dioxin-6-yl)thio)-9H-purin-9 ___________ ylehvl)armino)-N-hydroxypropanarnie ...... __________________ 5B-33 1HJP23 I8-((7-(ftiran-2-yl)-2,3-dihydrobezo~b][1 ,4]dioxin-6-yl)thio)-9-(2-(isobutylamino)eti)-9H 5B-34 HWP20 9-(3-(isopropylainino)propyl)-8-((7-(oxazol-2-yl)-,3-dihydrobenzo[b[ 1,4]doxin-6-yI)thio) 9H-puriki-6-ainine 5B1-35 I9{(3-aminopropyl)-2-fluoro-8-((7-(5-methylfuran-2-yi)-2,3-dihydrobenz[b][1 ,4]dioxin-6 _________I yl)methyl)-9H-puiin-6-anine 5B1-36 9(3-amiinopropyi)-8-(7-(5-methvlfura-2-yl)-2,3-dihydrobenzoFbl[1 ,4]dioxir-6-ylthio)-9P1 5B3-37 9-(3-Qten-butylaminro)propyI)-S-(7-(5-methiylftuxan-2-yl)-2,3-dihydrobenzo[hj[1I,4]di;oxin-6& ___________ylittio)-9H-pnrip-6-amine 5B3-38 i:9-(3-amiinoprop yl)-8-((7-(oxazol-2-yl)-2.3-dihvdwhbenzo[b][i ,4)daoxin-6-vl)thio)-9Hl-purn6 amine 5B1-39 9-(3(Len butylamino)propyl)-S-((7-(oxazol-2-yl)-2,3-dihydrcbenzo[b);[ I,4]dioxin-6-yl)thio) 5340 9-(3-(ted btl~~n~roy)8(7(-ehvoao--i-,3dhdoeo [,4)dioxin-6 SB-41 I-(4-(2-(6-marnno-8-((7-(5-,nethyloxazol-2-yl)-2,3-dihydrobenzo[b][ ,4jdioxin-6-yi)thio)-9H __________Durln-9-y)ethvl)plpericlin-1-yl~ethanone 51342 -((7-(5-niethyloxaz.ol-2-yl)-2,3-dihydroben zo[b1[ 1,4]dioxin-6-ylIhio)-9-(2-(i __________ methlsofony~pieddi-3-l~etwl)91I-puin-6-amine SB-43 1-(6-amiino-8-((7-(5-methylftran-2-yI}-2,3-dihydrobcnzojh][1,4jdioxin-6-yl)thio)-9H-purin-9 ___________y?)-3-isopropvliarino)propan-2-ol 51B44 7 1-(6-amino-8-((7-(5-niethyloxazo-2-yl)-2,3-diiyrobenzo[b][1 ,4]dlioxin-6-yi)thio)-9H-purin-9 ____________yI)-3-isopropylamino ~ropan-2-ol 5B1-45 6-(6-amino-2-fluoro-8-((7-(5-methylfurar-2-y)-2,3-dihydroezohJ[1,4]dioxin6-y)methy) _______________~~9-prin9-1) ___________________ul~y~yh>avade 5B3-46 N-(3-(6-ami~no-8-((7-(5-methyloxazol-2-yl)-2,3-dihydrobe,zo[b][1 ,4jdioxin-6-yl)thio)-9H purin-9-y1)propyl)methanesulfonarmide 511-41 i-(2-(4-(6-ainno-8-(7-(5-methyloxazol-2-yl)-2,3-dihydrobenzorb]ri,4)dioxin-6-yltbio)-9H ____________puin-9-yl~butyl)pyrrolidin-I -yl'jethanone 513-48 9-(3-aw-inopropvl)-2-fhiuoro-S-((7-(5-methyloxazol-2-vI)-2,3-dihydrobenzo[bJ[1dioxin-6 ____________ ~ ~ ~ Y y[methylj-9H-pRi~n-6-a~mme ___ ____ 51B-49 2-fluoro-9-(3-(isopropylamino)propyl)-8-((7-(oxzoi -- yl)-2,3-dihydrobrto[b1[1 ,4]dioxin-6 Y1)nm-ethv)-9H-pin-a'e SB-SO 2-fluoro-9-(3-(isopropylamino)propyi)-8-((7-(5-methyloxazol--yl)-' 3 ____________dihydrobenzorblrI,4]dioxin-6-yI)nietbyl)-9H-purin-6-arnin 5B-51 9-3(et-uya I .4]l)2iur-"7(xo-2y)23-iyrbmob l dioxin-6 __________ _______________ yI)nethvl)-9H-pudin-6-amine WO 2011/044394 PCT/US2OIO/051872 189 I 9-(S-(tert-butylarmino)propyl)-2-fluoro-S-((7-(5-nethykoxazo-2-y)-2,3 ______........ dihydrobenzojbJ(,ldo -6-yl)metliyl)-9H-pudn-6-amine 5B-53 6-(6-amino-2-flnoro-S-((7-(5--methyloxazol-S-yl)-2,3-dihydrobenzo[t][1 ,4]dioxin-6-yl)methyl) ___________911-punin-9-yI) hexanarnide 5B-54 5-(6-amrio-2-fiaoro-8-((7-(5-rnahyoxazol-2yl)-2,3-dihydrobezo(hJ L1,4ldioxin-6-yl)rnethyl) _______ 9H-purin-9-yI)pentne-1-sulfonamide 5B3-55 1 -(3- 6-amino-2-fluoro4S-((7-(5-methyloxazo-2-y)-2,3-dilhydrobenzo[b][ I 4]dioxin-& __________yl)mieihyl)-9H-purin-9-yi)propyl)pyrr.olidis-3-onc F "-3 1(3 -(6-amino-2-fluoro-8-((740oxa201-2-yl)-2,3-diiydrobenzohlL I,4]dioxiri-6-yI)nrthyl)-9H purin-9-yl)propyl)pyrolidin-3-one Table 5C No. Name 5C-i i 9-(3Aisopropvlarnino)propyi)-8-((7-(thiophqen-2-ylfr2,3-dihydroberaoh][ I ,4jdioxin-6 ___________ yl)ihio)-911-purin-6-arnine SC-2 2-fhioro-9-(2-(isotvtylamrino)ehbyl)-8-((7-(Qhiophien-2-yI)-2,3 ___ ___ ___ I d jd obe- o j b][ I,4ldio xin-5-yl)m ethyl)-9H -piur~h- &a maine 5C-3 9-2-(neopentylamino)ethyl)-8-((7-(thiophen-2-y)-2,3-dihydobcno[b][1,4idioxi-6 ___________ I)thio)-9H-purin-6-arnnne 5C-4 9-(3-(isopropylami~no)propyl)-8-((7-('thiophen-3-yl)-2,3-dlihvdrobcnzo[b[1,4dioxin-6 __________ ~1tn~o-91I-purin-6-artmne ___________________ SC-S 2-fhuor-o-9-(2-(isobntylamino)et.liyfl)--(7-(thioplien-3-yI)-2,3 __________dlhyd&obenzoybl1,4ldioxin-6-yflmethyI)-9H-puin-6-amine 5C-6 I -Q -(neopentylamino)ethyl)-8-((7-(thiophen-3-yl)-2,3-dhydrobenzofb][1,4dioxin-6 ___________yi)thio)-9H-purin-6-amine 5C7-7 1-(4-(2-(6-arnino-8-((Q-(thioplien-2-yl)-23-dih-ydrohenmo[b[1 ,4]dioxin-6-y)thio)-9 purin-9-yflethyl)pipcddGin-t -yl~etb.anone___________________ SC-8 4-(2-(6-amino-8-((7-(thiophen-2-yl}-2,3-dihydobenzofb]1 ,4]dioxin.-6-yl)thio )-9H prin-9-yI)ethyI)pipcridino- 1-carbaichyde i 5C7-9 1 -(4-({24&amino-2-fluoro-S-((7-(thiophen-2-yl)-2,3-dihydrobenzo(b][1I,4]dioxin-6 yI)nmethyl)-9H-purii-9-y)ethyl~ppeidin-1 -yI)ezhanone 5C-11I 4-(2-(6-amino-8-Q7-(thiophien-3-yl),-2,3-dihydrobenzo[]EI ,4]dioxin-6-yl)thic')-9H __________ urin-9-yl)ethyl)Dipedidine- 1-carbaiehyde 5C7-13 4-(2 -amino-2hloro-8-((7-(thiophen- -y)-2,3-dihyxohezobI 1 ,4jdioxin-6 __________ Iyi)n thyl)-9H-parin-9-yI)ethyl)pipedidine-1-earbaldehyde 5C-14 N-2((2-(6-amino-S-((7-(thiophen-2-yI)-2.3-diliydrobenzo[b][1 ,4]dioxin-y-i)thio)-9{ p2urmn-9-vI)ethiyl)anino)ethyl)su.famide SC-Is 3-((2-(6-arnino-8-((7-(tbiopien-2-yl)-2,3-dihydrobez [b][ I,4]dioxin-6-y)thio)-911 pmn-9-yI)ethvflatrino)-N-hydroxypropanamide 5C-I 6 9-(3-aninnpropyl)-8}((7-(thiophen-2-yl)-2,3-dihydrohenzob][ I,4]dioxin-6 yI)thio)-91-I-purin-6-amine 5C7-17 9-(3-(isorropylamino)propyl)-8-((7-(5-methylthiophen- -yl)-2,3 dihyd-otenzol][1,4]dioxir-6-y)thio)-9H-ourin-6-ami-e SC-is ]-(6-arino-8-((7-(5-rnethylthiophen-2-yi)-2,3-dihydrobenzo[ I,4]dioxin-6-yl)thio) ________ 9.H-pijrin-9-yI)-3-(isopropylatmino)propan-2-o 5C-I.9 1-(2-(3-(6-amino-8-(7-(5-methylthiazol-2-yl)-2,3-dihydrobezo[hlrl ,4]dioxin-6-ylthio> I 9fl-purin-9-yl)p opyl)pvrrolidin-. -yl)ethanone WO 2011/044394 PCT/US2OIO/051872 190 5C-20 19-(2-(1 -(methysuilfoyl)ppdi-3-y)ethy)((75inethvyljol-2y1>s23 sc-u 1 T-(6-a oM[,4]noxs(7(5 ityniazoy1D ,.iyobnob[ 4iixn6-y)hc. r -5C-22 9 -(3-(tert-bttylanino)propyI)-8-q(7-(thiazol-2-yI)2,3-shydoe&pc[ I ,4]dioxir,-6 yjtio)-9H-pain-6-amipe 50-23 9-3(tert-hutyla-no)propy)-8-((7(5niethiytiohen2yf-2.3 Table 5D No. 1Name SD-i 8 -((7-(!iN-pyrazo-4-yl)-2,3-dhydrobezo~b][l 4ldioxin-6-y1)thio-9-(3 -- (opo -Oa pylaun)pf-9H-purin-6-arme ________________ I8-(( 7 -(1fl--pyrazol-3-yl)-2.3-diliydrobenzo[b][ I,43dioxin-6--yI)thio)>9-(3 5D-3 S-(Q7-(1Hf--ypaol-4-yT)-2,3-dihydrobezoFbE I,43dioxin-6-yI~metiyl)-K2-fluoro-9-(2 ___________ isobiqlvamino)eth I-9H-pu rin-6-aniine 5D-4 TT-VTI-54A I -U(7-(1H-ryr o-3-yI)-2,3-dihydrobenzol [1,4]dioxin-6-yI)methyl)-S-fluoro-9-(2 (i.sobutv[amino)ethyfl-9H-purn-6-armine ________________ SD-5 I-(3-(X-(7-(1H-pyrazoI-3-yi)-2,3-dihydrobetzo~b]!i,4]dioxin,-6-yithio)-6-ahiino-9H I %utIfl 9-yj)propylpyrmidin-3 -one - -- I SD -6 18 ((7 (1H-pyrazcl1-3-yl)-2,3-dihydrobenzo7b][ I ,4]dioxin-6-yi)thio)-942 __________ (neopent1amino)eLiyl)-9H-purin-6-ane 5D7 1<4(2-(8-(Q7-(1H-py-aZoi-3-yl)-2,3-dihydroben~o[b][1 ,43dioxin-6-yl)thio)-6-antino-91 ___________ Ipurin9-yl)ethyI)jpidi--Iehnn 511-8 I ff(7 (1H1-pvrzol-3-y1)-2,3-dihydrobenmor[][4]dioxidn-6-yI)nethyl)-9-(2-ammnotiyl) 5D-9 'I(4(2-(-(7-( iB-pyrazol-3-yl)-2,3-dhydrobezo~b][1 ,4]dioxin-6-yi)methyl)-6-arnino I2-fhoro-9H-purin-9-yi)ethyl)piperidin-I -yl)ethanone 5fl-1O 1 1 (3-2(-(7( H-pyraol-3-yl)-2,3dhyrooob[I,4]dioxin-6-y)mLhyl)-6 -aro _______2-tluoro-9z-jrm9ychy pi LLnjy)mn 5D-11 8-((7-( IH-pyrazol-3-yl)-2,3-dihydrobenzo[b][ I,4]dioxin-6-yI)methyI)-2-~r-9(- -____ L(mLthylgW.fony1)p efddin-3-yjj)4h 1-H-p -6-anmine -9D-12 I-(3-(8-ff7-(IH-pvraol-3-yh-2,3-dihydroezo~b]il,4]dioxin-6yI)methyl)-6-anin-2- 1 ___________floro-9H-pmin-9-y)propyl)pvrrolidin-3-one SD-13 8-(7-(1IH-pyrazol-3-yl)r2,3-dihydrobenzob][1 4jdioxin-4-ylthio)-9-(2-(I li(rnet!,yl~nlfony1)iperdin-3-y)ehy1)-9U-p rdn-6-aminc 5D-14 N-q(2-((2-(S-((7 -(IH-pymzol-3-yI)-2,3-dihydrobenzo~b][1 ,4]dioxin-6-yI)thio)-6-amino SD-IS 3,-((2-(8-((7-(I-I-pyrazol-3-vI)-2,3Adihydrobenzo[b]I ,4]dioxma-6-yI)tliio)-6-aniino-9H Jp~j~9-eya~n n-N-hy rxypropaarde 5D1-16 8-((7-(IH-inmidazoi-4-yI)-2,3-dihydrobenzo[b][14doi--ytho--3 5D-17 8-((7-(]IH-pyrazcl-3-yi)-2,3-dihydrobenzo[bj[ I,4]dioxiiv6-yi)thio)9(-mnpoy __________9H-purin-&-annne SD-18 8-((7 (1 H-pyrazl-3-yQ)-2,3-dihydrobenzofbj[ I,4]dioxin-6-yl)tbio)-9-(3-(tert ibutylarnino~propyI)-9H-purin-6-armine WO 2011/044394 PCT/US2OIO/051872 SD-19 8-(-IH-pyrazo-3-yl)-2,3-dihydrobenzob][1 ,4]dioxin-6-yi)xrethvl)-9-(3-(tert bntylainino)propyl)-2-fluoo-9H-purin-6-amine ______________ 5D-20 9-(3-(isopropylaanino)propyI)-8-((7-methyl- 1H-pyrazol-3-yl>-2,3 dihydirotczorblfl 41dioxin,-6-y1)thio)-9iI-pttrin-6-arnine N ______ (neon~entylarmino)ethvl)-9H1-purin-6-amine 5L)42 9-(3-(tert-hutylamino)propyl)-2-fluoro-8-((7-(5-m ethyiH-pyrazol-3-yl)-2,3 dihydobcrizcb][ i,4ldioxin4--yl)methvl)-9H-puirin-&-amine 5D-23 I -(8-((7-(IH-pysrol-3-yl)-2,3-dihydrobenzorb [1 ,4]dioxin-6-yI)tho)-6-aiino-9 5D-24 l-(8-((7-(Ill-pyazo-3-yi)-2,3.dihyclobet~o[b][I ,4]dioxin-6-yi,)inethyl)-6-arin~io-2 ___________ fuoro-9H-Durin-9-yl)-3-4tet-rtylainino)propx-2-oI 5 8(7(HpyDo--l-3-iyrbno-]254doim6ymty)--rio-. __________tluor-M-purn--I)pentaiie-1.-sulfonarnide SD-26 6 (8 ((7}(IH-pyrazoi-3-yI)-2.3-dihydrobenze[1rl4]diexin-6-yI)merhyl)-6-anino-2 ___________fluoro-9H-purn-9-yl)hexanaide 5D-27 5 (8 (7-(1H-pyrazal-3-yI)-2,3-dihydrohenzo[b] [1 ,4]dioxin-6-ylthio)-6-anino-9H-purin ____________9-yl)pentane-1 -sulfonamide SD-28 6-(8-(7-(1H-pyrazol-3-yl)-2,3-dihydrohenzo[b] [1 ,4]dioxin-6-ylthio)-6-anmino-9H-purin ___________9-vl)hexanarnide Table 5E No.. Name SE-I S-q(7-ethyniyl-2,3-dihydrobenzo[bI[ 1,4]dioxin-6-yl)thio)-9-(3 (isopropvlantzino)propyl)-9H-purin-6-a wine 5E-2 3-(3-(6-amino-8{ 7-ethyyl-.3-dihydroben~o[][1,4]4ioxin-6-ylthio)-91 _________ urin-9-yl)prop yytolidipc-1-carbaldeih4e 5E-3 S-((7-ethynyl-2,3-dihydrobenzo[b)(1I,4]dioxin-6-yI~inethyl)-2-fluoro-9-(2 amine 5E-5 84((7-ethv~yI-2 ,3-dihydrobenzofb][1I,4]dioxia-6-yI)thioi-9-(2 (neopentylainino)ethyl)-9H-purin-6-arnine 5E-6 9-(2-atninoethyl)-8-((7-ethvnyi-2,3-dihydrobco ]Ijoi--iti)9-un 6-amine SE-;-7 1-(3-(2-(6-anilno-8-(7-elhynyl-2,3-dihydrobenzo[h][1 Aldioxin-6-ylitio)-9H-purin-9 __________yl)ethyl)piperidin-1-yl)cthianone SE8 8-(7-etiiyiwl-2,3-dihydrohenzo[b][1 ,4]dioxin-6-ylthio)-9-(2 -(i -- ~ (rnethylsulfoniyl)piperidin-3-yl)ethyfl)-9H-purin.-6-amine r E-9 S-((7-eihynyl-2,3-dihydrotenzo[b][I,]ixn6-Imty)2tloe9(-1 i(methyisulfony)pipedidir-3-ybethy)-9HN-puhnr-6-anine _________ 1 E-10 1-(3-(2-(6-arnino-S-((7-ethynvl-2,3-dihydrobenzo~bI[1,4]dioxin-6-yl)methyl)-2 1 E-11 3-(2-(6-amino-8-((7-etlynyl-2,3-dihydrobenzo[b][ I ,4]dioxin-6-yI)methyl)-2-fluoro 9H-viirin--9-yI)etbyl)yipe ie-1-carhaldehyde 5E-12 1-(3-(6-amirno-8-((7-ethynyl-2,3-4ibydxobepzo[bJ(I ,4]dioxin-6-ylI)methyl)-2-lhoro I ________9H-pniin-9-yI)propyl)pvrrolidin-3-une SE-iS 6-(6-amnino-8-((7-ethyyi-2,3 -d ihydrobenzob [ 1,4] dioxin-6-y)Mcthyl)-2-fl uoro-9 i_____ pluin-9-yl)hexananide WO 2011/044394 PCT/US2OIO/051872 192 _EHpurin-9-yflethyl)amino)etlwl)suifraindo SE-15 3-((2-(6-amino-S-((7-ethynyt-2,3-diliydrobenzo[b][ I.,4]dioxin-6-yl)thio)-9H-purin-9 SE-16 9-(3-aminopropyl)-8-((7-ethynyl-2,3-dihydrobcnzo[b][ I,4]dioxin-6-y)thio)-91 SF417 6-(6,-amino-8-(7-ethynyl-2,3-dihydrobenzo[b P ,4]dioxin-&-yltbio)-9H-purin-9 __________ylhexanamido e_________________ S E-18 5-(6-amino-S4(7-othynyl.-2,3-dihydiobetzo[b][ 1 4]dioxin-6-ylthio)-9H-purin-9 __________ yI)penum~e-l-sulfonamide 5E-1 9 !-(6-amino-8-((7-etvNmyi-2.3-dihydroten7.o[b][i,4]dioxin-6-yI tnethyl)-2-fluoro-9H __________ £L-9yl)-3(ter-btyiamino)propa-2-oI 5E-0 I1 (6-amino-8-((7-cthtyiyI-2,3-dihyd-obeiio[b][i ,4]dioxin-6-yi)tho)-9H-puirin-9-y) 13-4isopropylamino)propa-2-ol SE-21 54(6-amito-8-((7-cthy-2,3-dihydrobezo[b][1,4]dioxim6-yI)nothPy)-2-finoo-9H _________punin-9-vi)pentare-1-suifonarid(e 5E-22 84((7-ethynyl-2,V-ditydrobenzo(b][i A]dioxin-6&yl)mcthyl)-2-flhoro-9-43 __________(isoprnpylarnino)propyi)-9H-purin-6-amiae 5E-23 9-(3-(teit-butvlamino)propyl)-S-f(7-etbmnyl-2,3-dihydrobenzo[h][ 1,4]dioxin-6 Iyl)mothyl)-2-fluore-911purin-mine I SE-24 9-(3-aininopropyl) 8-((7-ethynl-2,3-dihydrobemobE1,4]dioxin-6-yl)netyl)-2 _ _ _ _ _ _ _ _ _ il o ro -9 1 1-p u fin -6 -a m in e 5E-25 94:3 (trtbutylamino)propyl)-8-(7-ethyyl-2,3-dih.ydrobenzo[b][1 ,4]dioxin-6-ylthio) _________9H-pmrn-6-amnine 5E.26 84"7-etliiyl-2,3-dihydrobenzo[b][1I,4]ldioxin-6-ylthio)-9-(2-(l -methylpiperidin-2 __________y Ihayl)-9H-purin-6-arnine 5E-27 8 (7-etliynyl-2,3-dihydrobenzo[b][1,4]dioxin-6-vlthio-9-(2-(1 -mothylpipedidin-3 __________yI'rthyl)-9H-purin-6-arnine 5E-28 S ((7-ethynyi-2,3-dihydroberzo[blr1,4]dioxin-6-yI)methy)-2-fluoro9-(2-(1 _________metbvlpipertdin-2-vl)ethyl)-9H-puin-6-armjne 5E-29 S ({7-ethyinyl-2,3-dihiydrobenzo[bi[i,4]dioxin-6-y)nehy)-2-flhoro-9-(2-(1 ________I methylpipcridin-3-ylI)ethyl)-9H-puhn-6-anmine Table SF No. Name SF-I. 7-((6-aitino-9-(3-(isopropylarnino)nropyl)-9H1-purin-8-yI)thio)-2,3 ________dihydroteuzo'bl( l,4]dioxine-6-carbonitdglc 5F-2 7-((6-amino-943-(isopropylamino)propyi)-9H-purin-8-yl)thio)-2,3 dihydrobenzofb][1I,4]dicndne-6-carbonitrile SF13 7-((6-arnino- -fkoro-9-(2-(isorylanwino)ethyl)-9H-purir-8-yl)nnihyl)-2,3 ________ diyrbnobJ[ 4]dioxine-6-carbonitile 5F-4 7(-ain-floro-9-(2-(isobutylarnino)etbyl)-9H-pun--y)methvI)-2,3 _________ dhydrobenzo[b][i ,4]dioxinc-6-carbonitrilc SF-5 7-(6-amino-9-(2-(,wopentylatnino)ethyi)-9H-purin-8-yi)thio)-2,3 ________ dihvdrobenzo[]i,4ldioxine-6-carbonit-ile 5F-6 hI(- o9(-tootl oety)9-ui--Iti>23 _________ y dhrobezbl I (,4ldioxine-6-carhoniftile 5F-7 I2-(7- ((6-anmino-2-fltioro-9-(2-(isobutylamino)ethyl)-9H-puiin-8-v)meliyl)-2,3 _______ Idihvdobenzo~bl[ I 4jdioxin-6-yllacetonitdle WO 2011/044394 PCT/US2OIO/051872 -4 193 S_____ 8 1 -pux(46in- -(-yletylanometyl)fmid-dihydrobenzo[b] [1 ,4]dicoxin-6-yl)thio) "I- N-2(-~iu r nin o-S- (7-(cya no et y I) -2,3id SF9 3-((2-(6-aniino-8-((7-(cyanomethyl)-2,3-dihydrobenzc[b[ I 4]dioxin-6-yI )thio)-9- 510 7-((6-anaino-2-chloro-9-(2-(isobutylarnino)ethyl)-9H-purn-8-yl)nethyl)-2,3 ________dihvdrobenzo~b][ I,4]dioxine-6-carbonitTile WO 2011/044394 PCT/US2OIO/051872 194 Table 5G No. Name 5G-1 S-((7-(azihidin- 1-yl)-2,3-dihydrobenszo[b][ I 4jdioxin-6-yl)thio)-9-(2 502 (neopentylarnino)ethyl)-91T-pnrin-6-amine 5G39-(2-(isobutylanrinc)ethyl)-S-((7-(pvrroiidin- i-yi)-2 ,3-dihydxobcnzo[b][ I,4]dioxin-6 _______ ylthi)-9-puin--amne ________ (neopentilarmino)eth)-9lPn6-mn 5G-5 18-((7-(azotidin-1-yI)-2,3Adilydrobenzo[b][1,4dioxiim-6-yl)mcthyl)-2-fluovo-9-(2 ____I_ (is'obutvlamino)eth yl)-91-I-puirin-6-amine r5G-6 L24bloro-9-(2-(isobutylan ino)ethyl)-8-((7-(pyrohidrn- l-yl)- 2

,

3 ________dih ydrobenzoiljj ,4jdioxin-6-yl)mehy1)-9H-ptufin-6-ar~ine 5Cr7 2-chloro-9-(2-(isobutylanmino)ethy1)-S-(('7-(pyrrolidin-1 -yl)- 2

.

3 _________[bj1, dixv6y~ely)-Hprn6amn I5S-8 1-(4-(2-(6-atnino-8-((Q-(asiridin-1-yl)-2,3-dhydrobeno'Lb]EI,4dioxin-6-y)hio)-9H _______ pnnin-9-vl)ethyl)piperidin-1 -yI)ethanone 5G-9 I (3 -(?A6-amino-8-(7-(azetidin-1 -yl)-2,3-dihydroh en~zo~b][1,4]dioxin-6-ylthio)-911 ________ pn-9 yl)ethyl)piperidin-I-yI)ethanione 5C-10 4-(2-(6-amino-2-chloro-S-((7-(pyrrlidin-1-yI)-2,3-dib'vdrotenwo~bjrl,4]dioxin-6 ________y1)irethyl)-9H-purin-9-yi)ethylpiperidine-1-cabaldehyde 5G-11 8-((7/-(dimethylarnino)-2,3-dihydrobenzo[b][ I,4]dioxin-6-yi)thio)-9-(2 ________isobu llarnio thy1 -91k purin-6-amine 5G-12 S-((7-(dirncthylamiino)-2,3-dih ydrobenzo[bjii 4jdioxin-6-yl)met'nyl)-2-fluoro-9-(2 _________ isobuwyla.nino)etbyl)-911-pumin-6-amine 5G-13 1-(3-(2-(6-aniino-8-(dimnethylan iro)-2,3-dihydrobrtsr[b]1,4]dioxin-6-ylthio)-9H _________purin-9-yl)ethiyl)piperidin-1-yl)ethanone 56-14 1-(3-(2-(6-amino4(7-(dimethyln,.iuo)-2,3-dihydrobenzo[bJ[ I,4]dioxin-6-yi)methyl) ________ -fluoro-91-purin-9-yI.)ethiy~pipridin1~lehn 50-15 -(7-(imcthylarnno)-2,3-dihydrobezorh] [1-4]dioxin-6-yltduio)-9-(24-(i _______(rethvlulfonvl)pi peidin-3-yI)ethyl)-9H-puin-6-a tie SG-16eff 8(7dimethylamino)-2.3-d;ihydrobenzob][1 ,4)dioxin-6-yi)rnethyI)-2-fluoro-9-(2-(1 (0-i-----lsnlfonyl )piperidin-3-yI)ethyl)-9H-purir-6-amine 5C1 S-((7-(ethvlanmino)-2,3-dihvdrobenzo[b)]r 1,4]dioxin-6-yI)thio)-9-(2 (isobutylanmino)ethyI)-9H-aifl6-amiflt 5G-18 1-(3-Q2-(6-ainio-8-(7-(ethylawnino> 23dihydrobenzo(b][1 ,4]dioxin-6-ylthio)-9H purin-9yl)ethyl)piperidin-1-yl)ethanone 5C,19 S-(7-(ethylarnino)-2,3-dihydrobenzob 1 ,4]dioxin-6&yrhio)-9-(2-(1 Syreth ;lsuilfonyl)pipeddn--y)etbyl)-9H.-purin-6-amine 5G-20 2-loc9(-iouyaioehl--(-ipoyain)23 _________dihydrobenzfbl[i,4ldioxin-6-y1)methyD)-9H-purin-6-amine 5G-21 8-(7-(isopropylatrino)-2,3-dihydrobenzo[b][1,4]dioxin-6-ylthio)-9-(2-(1 ________ (tnethiylsulfonyl)pipeddin-3-yl)ethyl)-9H-pxiin-6-anne 15G-22 I -(3-(2-(6-awino-2-flvoro-8-((7-(isopropylan'no)t23dihydrobezorb] 1,4]dioxin-6 I ______ lI)rnethyl)-9H-purin-9-yl)ethvl)piperidin-1-yI)ethaone 5G-23 i8-((l-(dimethylamino)-2,3-db.ydvobenzo[bi 1 ,4jdioxirr6-yl)thio)-9-(3 (isopropylamino)propylj-9H-Durin-6-amine. ._._._._._._._._.

WO 2011/044394 PCT/US2OIO/051872 195 SG-24 8-((7-(dimethyliarno)-2,3-dihydrobezo~b)[1 ,4]dioxin.-6-yl)thio)-9-(2-(1 ________(methMulfonyl)piperidin-3-yl)ethyl)-9H-punn-6-anine SG-25 5-(6-amino-8-(7-(dimethylamino)-2,3-dihydrobeno[h]:[i.4jdioxin-6-ylthio)-9H-purin-: -9:1I)pcAane-1-sulfonawride SG-26 6-(6-arnino-8-(7-(dirncthylamno)-2.3-dih.vdrobenzo[h ][i ,4jdioxin-6-ylthio)-911-purmn 9-yi)hexavrnide 943-27 9-(3-(tert-bntylamino)propyl)-8-((7-(dimnethylairino)-2,3-d.hydrobenzob][1I,4jdioxin-I 5G-28 !-(3-( 6-arnino-8 -{7-dimethylamino)-2,3Ailydrobenzo[bj I ,4]dioxin-6-ylthio)-9H __________pnrin-9-ytlpropyl)pyrrolidin-3-one Table 5H1 NO. Name 5ff-i 8-((7-cyclopropyl-2,3-dihydrobenzo[bI 1 ,4]dioxin-6-yl)thio)-9-(24(neopentlamino)ethyl) 9H-pmrn6-amlne 511-2 S-((7-eyclobutyl-2,3Adihydrobenzo[b] [ I ,4]dioxin-6-yl)thio)-9-(2-(i sobutylarinmo)cthy)-9H purin-6-amine 51H-3 8-((Q-eyelopentvl-2,3-dihydrobenzo~bJ[i ,4]diox~dn-6-yl)thio)-9-(2-(isobuzylarnino)ethyl)-911 ________ unn-6-amine 5H1-4 8-((7-eyelopropyi-2,3-dihydrobenzo(I1[i 1,4]dioxin-6-yl)merhyl)-2-fluoro-9-(2 515 8-((7 clobutyl-2,3-dihydrobenzo[h][ I ,4jdioxin-6-yl)methyl)-2-tluoro-9-(2 (isohuitylamibolethyl)-9H-ptrin-6-arine 511-6 S-((7-cyclopentyl-2,3-dihydrobenzo[b] 1 ,4]dioxin-6-yl)rnethvb-2-fluoro-9-(2 _______ isobuitylaniino)ethiyl)-9H-purin-6-arnine 5H-7 1 }4-(2K(6-amino-8-((7-eyclopropyl-2,3-di.hydroben2o~bI1[i,4]dioxin-6-yl)thio>-9H-purin-9 _______yI~ethyIlpiperidin-1 -vhetharorne 5-8 1 -(4-(2-(6-arnino-8-((7-cyelo~ropyl-2.3-dihvdrobenzo[b][1,4]dioxin-6-yl)netv.l)-2-fhaoro ________911piarin-9.ybethyl)p ipeidin.1 -yl)ethanone 511-9 1 -(4-(2-(6-airino-2-chloro-8-(U-cobutyl-2,3-dihydrobenzo[t][1 ,4]dioxin-6-yl)naethyi)-9H-I ________pujrn-9-yI)ethvl)piperidn-1I.-yl)ethanone 5H-10 4-(2-(6-arrino-8-((7-evciobtityl-2,3-dihydrobzo[b[ 1,4] dioxin-6-yI)thio)-9H-psin-9 yI~ethyf)Dipeddine-1I -carbaldehyde 5H11 4-(2 -(6-atvino-8-((7-cyclopentyl-2,3-dihydrobenzojh][1A4]dioxini-6-vl)methyl)-2-luoro-9H 51112 3-(6-amino-8-((7-cyclopropyl-2,3 -dihydrobeno(b 1[ 1 ,4]dioxin-6-yl)thio)-9H-purin-9 _______ lipropyl sulfamate SH-13 8-(Q7-cyclopropyl-2.3-dihydrobenzofh][i 4]dioxin-6-yl)thio)-9-(2-( 1 SH1-14 9-(3(ter-hutylaniino)propylj8-((-cyclopropyl-2,3-dihydrobenzo[b] [1 ,4]dioxin-6-yl)thio) ________91-purin-6-amine 5H-15 2-(3-(6-antino-8-(7-cyclobuyl-2,3-dihydobeizoqb][ I,4,]dioxin-6-ylthi o)-9H-purin-9 _______vflropyl)pyrroiidine-1-svlfonasnide 5H1-16 3-(S-(6-amino-8-(7-eyclopemnv-2,3-dihydroenzo [h][1,4]dioxin -6-vYthi)9-un _______ ylethyl pyrrolidinle-I -ulfon~mide 5H1-17 8-(7-cyclopentyl-2,3-dihydrobenzo[b][ I,4]dioxin-6-ylthio)-9-(2-(i -(n~ethylsu~ifoinyi)pipcridtn _______3-yl)ethyl)-9H-purin-6-arnine 5H1-18 ,9-(3-(tert-hutylarniino)propyl)-8-(7-cycloponty-2,3-dihydobenzo[b)I ,4]dioxin-6-ylthio)-9- WO 2011/044394 PCT/US2OIO/051872 -4 196 I SH-19 I -6aino,-8-(7-cyclopentyl-2,3-dihydrohenzo[t][1 ,4jdioxin-6--ylthio)-9H-purin-9-yfl-3 I ~(isopronylarmno)propan-2-ol _________________ Table 6A No. ]ame A4-1I 8-((7-iodo-2,3-dihydrobenzo[b]( I,4]oxoathiin-6-yl)thio)-9-(3-}isopropvlamino)propvl) I9-pu~rin-6-aine 6A-2 i -((7-(fua-2-yl)-2,3-dihiydrohenzo[b[1 ,4]oxathiin-6-yI)thio)-9-(3 _____ (isopropvlamino)propyl)-9H-prin-6-amine 6A-A 8-((-cthynyl-2,3-Uihydrobenzo[hJ[1 ,4]oxathiin-6-yI)thio)-9-(3 6,t4__ (iorpylarino)propyl)-9H-puin-6-anen 6A-4 4-(2(6-amino-8-((7-(firan--yl)-2,3-dihydrobenzo[b][1,4]oxathiin-6-yl)tbi)-91-purin 1____ 9-yi)cthyljpiperidine-1 -earhaiehyde 6A-5 I2-fluoro9-(2-(isobutylam.ino)ethy1>S, ((7-(pyrrdiiin- t-yl)-2.3 A dihydrobz~b[ ,ixthiin-6-yl)rnethyl)-9H-purin-6-amine 6A-6 (Q-(,p(aziridin-1-yl)-2,3dihydobezo[b[1 ,4joxathiin-6-vI)thio)-9-(2 F (neopntyamino)ehyl)-91--prin-6-amnne 6A-7 i.8-((6-(ftaran-2-yb)-2,3 -tihydrobenzoF[hJ I,4joxathiin-7-yljthio)-9-(3 ______ I(isopropylaino)proo yl)-9-prin6amne 6A-8 S -((6-.tliynyt1,3-diydrobenzo~b][ I ,]oxathiin-7-yl)thio)-9-(3 _____ (isoproplamino)propyl)-911-purin-6-anine 6A.9 i 4.(2-(6-amino-8-((6-(furan-9.yI)-2.dihydrobenzorblfl,4]oxathiin-7-y)thio)-9z-purin 6A0 9-Iehy ienidine- I -carbaldehvde 26A-or-9(-(ibuty lanmino)ethyl)-S-((6-(pynolidin- I -yl)-2,3 _______dihvdrobcnzo[b1 1,4]oxath iin-7-yl)methyl)-9H-purin-6-amine 6A-11I 8-((6-(aziridin-1I -yl)-2,3 -dihydrobenzolbj f 1,4]oxathiin-7,-yI)thio)-9-(2 _______(neopcntylamino)ethyI)-9-pudin-6-arnine 6A-1.2 S-((7-(finan.-2-ylO-4-rnethyl-34-Aihydro-2H-henzobE I,4]oxazin.-yi)thio)-9-(2 (neopenryian~ino)ethyl)- 1H-purin-6-arnine 6A-13 8-((4-metliyl-7-(1H-pyzazol-3-yl)-3,4-dihydro-2H-hcnzo[tJ[ 1,4]oxazin-6-yI)thio)-9-(2- 1____ (neopenrylanmino)ethy1)-9H-puri-6-ainine 6A-14 t 8((7- thynyl-4-methyl-3,4-dihydro-2H-bonzo[bl[ I Aloxazin-6-y)thio)-9-(2 6 15 (isobutylamino)ethyl)-9H1,pAi-&arniine 615I2 fluoro-8-{J7-(firan-2-yl)-rnethyh.34-dihydo-2-I-benzo[b][1.4]oxazin-6-yl)methyl) 19-(2-(neo]penrsrlatnino)ethiyl-9H-purdn-6-arnino 6A-16 :4-(z (6-aino-8-((7-(fiuran-2-yI)-4-methyi-3,4-dihydo-211-henzo[b] r 1,4]thiazin-6 _____ yl])thio)-9H-purin-9-yl)eth yl)pipeidine-1 -arbaldehyde _6A'-17 I ((6 a R n-2-yI)-4-methyl-3,4-dihydro-2H-benzo'b][1,4joxazin-i-yI)thio)-9-(3 A_ __ _ 18 so ropyam o)propyl)-9H-pufl1P6-amine A-1 94 (snoyarino)propyl)-8-((4-metllyI-6-{biophn-2-yl)-3,4-diiydro-2H _____ benzo[b][l1.4]oxazin-7-yl)thio)-9H-punin-6-amine 6A-19 4-(2-(6-amino-S-((6-(furan-2-yl)-4-meffiyi-3,4-dihydro-2H-benzo[b][ I,4]oxazin-7 ______ yi)thio)-911-purin-9-yl)ethyl)pipeaidine-1 -arbaldehyde i6A-20 i4-(2-(6-amino-8-((6-ethynyIA-methyl-3,4-dihydo-{-hen [b][1 ,4]oxazin-7-yI)thio) 6A 1 9H-purin-9-l ethylpprdn- eradhd A-1i8-((6-(azetidin-l -yl)-4-nietliyl-3,4-dihydro-QH-benzo[b]jl,4]oxazin-7-yl)tio)-9-(2 _____ I (isobiutylaitino)ethvl)-9H-purin-6-amine WO 2011/044394 PCT/US2OIO/051872 197 6A-22 I8-((6-(furan-2-yl)-4-methyl-3,4-dihydro-211-benzor'bi[ I,42thiazin-7-yi)thio)-9-(3 _______(isopropylamino)propyl)-9H-purin-6-amine 6A-23 18-((6-iodochrornn-7-y)thio)-9-(3-isopropyaino)royl-91-FTrn-5-aine 6A-24 8-((6-(ffran-2-yI)chroman7-yI)thio)-9-(3-(isopropylarmino)propyl)-9H-pui,,-6-anine 6A-25 184((6-tvlhohoa--Itho--3(opoyainprp)-Hpn6ame N 6-k-26 4-(2-(6-anino-8-((6-(Tan-2-vl)thiocbtonw7-yl)tio)-9Hpun- 9y~ethyl)pipend~ire ______1 -carbaldelbyd 6A-27 i -fluoro-9-(2-(isobnitylarnino)cthiyl)-8-((1 -methyl-6-(pynolidin-1 -yI)- 1.2,3,4 _______tctrAbvdrogqainolin-7-yl)methyfl-9H-purin-6-amine 6A-28 4-(6-amino-S-((6-(Th,-rnC-y1)-i ,2,3.,4-tetrahydroquinoin-7-vi)thio-9H-pu'n-9 ________yIlethvflpiperdn- cradhd 6A-29 8-((7-iodochroman-6&yI)thio)-9-(3-(isooropylamino)propyfl-9H-pumin-6anine 6A-30 8-((7-(ffuran-2-y)ehroman-6-yi)rhio)-9-(3-(isopropyiamino)propy1)-9H-pnrin-6-amine 6A-32 4-(2-(6-armno-S-((7-(fixrai-2-y)thiochroman-6-yl)thio)-9H-purin-9-y1)ethyI)pipedidine I -earbaldehyde 6A-33 2-fluoro-9-(2-(isobutylarffino)ethyl)-8-((7-(pynolid.in.-i-y1)-I .2,3,4-tetrahydroquinolin-6 ________y])retIhyl)-9H--punn-6--axine 6A-34 4-(2-(6-amirno-8-((7-(Thran-2-yI)- 1 -rnethyl-1,2,3.4-tetrahydroquinolin-6-v)tio)-QH purin-9-yl)ethyl)pipcriditc-I-carbaidohyde 6Ai3 2-ehloro-S-((7-iodo-2,3-ihydroben~o[h(1 ,4]oxathiin-6-yi )rnethyI)-9-(2 ________(isobutylamno)ethvb)-911pudn-6-amne 5A-36 2-ehtoro-S-((6-iodo-2,3-diliydrobcnzo[b][,4]oxathiin-7-y)mehy1)-9-(2 I _______(iso'butylaininlo)ethl)f-9H-purin-6-ainine 6A-37 _2-chloro-8-((6-iodochroman-7-ybrehl-44sbuyaioehI9Tpr)6ann 16A-38 9-(3-tert-buylamrno)propy)-84(64oochromn-7-y)t io)Y9H-purin-6-ainin CA-39 N-(3-(6-ariino-8}(6 t iodochromn,-7-y)hio)-9H-purin-9-ylpopx'l)ethanesufona nide 6A-40 3-(6-aino-8-((6-iodochroman-7-y)thio)-911-pudin-9-vl)propyI solfamate 6A-41 I 46-arino-8-((6-iodochroman-7-yI)tliio)-9H-pnrin-9-yl)-3-(isopropylamino)propn-2 6A-42 9-(34tert-butylaimno~propy)-8-ff6-ethyi'yichroman-7yothi)-H-putin-6-anine 6A-43 N-(3-(6-anmno-8-ft6-ethvnylckronan-7-vI)thio)-9H-purin-9 ________ yl))propyflntaeufnmd 16A-44 3-(6-arnino-8-((6-(furan-2-yI)chroman-7-y1)thio)-9H-purin-9-flpropy sulfarnate 16A-45 I -(6anino-4(6-m~iethyloxazoI-2-yI)ehroman-7-yl)thio)-9H-pmin-9-yI)-3 _______(sopropylamo)propan-2oI 6A"6 9-(3-(tert-butylamiino)propylD-8-((6-iodo-4-methyl-3,4-dihydro-2H-benzo~b]P 1,4]oxazin I- -io9H-purin-6-amine 6A-47 N-(4 (6 ain ((-iodo-4-methvi-3,4-dihydro-2HT-benzo[h][1 .4]oxazin-7-yl)thio)-9H1 _______pur 9 flpopy)methanesulfonamde 6A-48 I3-(6-aniino-8-((6-iodoA4-mefflyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-y)thio)-9H 1 urm -9 yl)propyl sulfamate A-9 1-(6-= min--((6-iod o-4-rnelhyl-3,4-dihydro-2H-betzo~b][1 ,4]oxaznl-Itio-H _______ urin-9 yI)-3-(isopropyiarno)popar.-2-ol I 6A-50O: 9-(3-(e btlmn~rpl--(-ehnt4mty-,-iyr-H _______ be,o[b][ I.,4lcxazin-7-vl)thio)-9H-puxin-6-arnin 6A-51 N43(6-aminio-8-((6-ethynylA-methyl-3,4-diydro-2H-ezo~b]1 ,4]oxazin-7-yl)thio) 1 punn-9-yl)propy])methanesvlfoitnide 1 6A-52 13-(6-amino-8-((6-(fiira-2-y)-4-~ethv1-3,4-4ihydo-21-bercfblr I,4]xzn7ylho WO 2011/044394 PCT/US2OIO/051872 198 _____ 9H-pum-9-yI~propyl suifamate 6A-53 I -(6-amino-8-((4-methyl6-(5-melyloxzo-2-y)-3,4-ihydro-2H-bezo[bE 1 4]oxazin ________7-y1)thio)-9H-purin-9-yI -ioropylamino)propan-2-o 6A-54 19-(3-(tert-buylarano)propyl)-S-((4-~thyl-6-(5-tnethyoxzo-2-y)-3,4-1ihydro-21 _____I benzob][ I,4Joxazin-7-ylflhio)-9H-puin-6-armne Table 6B No Name 621 -((3-iodn-5,6,7,8-tetrahydronaphtlialen-2-y1)thio)-9-(3-(isopropyi amino)propyl)-9H purin-6-amnine 6B2 2 -((3-%&do-5,6 p ,8-tetraliydronaphzhalen-2-yl)tlhio)-9-Q-.(isobutylamino)ethyi )-9H1-purin amno 6B- 3 8-((3-iodo-5,6,7",S-etraiydronapliaiav-2-yl)thio)-9-(2-(neopentvamino)ethiyl)-9H-purin 6-amine 6B-4 2-flnoro-8-((3-iodo-5,6,7,8-terhydronaptbilen-21-yl)methvl)-9-(2-4isob~la.mino)ethy) ________91--puin-6-amine 6B-5 2-ch oro-8-((3 -(ffian-2-y1)-5,6,7.8-tetrahydronaplhthalen-2 -vl)metivl)-9-(3 _______(isonrnyarnino)propyI)-9H-Quin-6-am ine 6B6 -fluo~ro-8-((3-iodo-5,6,7,8-tetmhlydronaphthalen-2-vi)methyl)-9-(3 ________911-purin-6-aniine 6B-8 S-((3-ethynyl-5,6,7,&-tetrahiydronaphthalen-2-yI)thio)-9-(3-(isopropylamino)propyl)-9H ________purin-6-armne 68-9 3-((6-amino-9-(3-<isopropylamino)propyl)-9H-purin-8-vl~thio)-5,6,7,8 _________tetrahydronapli thaiene-2-carbonitrile 68n-10 8-((3-(azetidin- I -vI)-5,6,7,8-tetrabydronaphthalen-2 -yI)rnethy])-2-fluoro-9-(2 ________(neopentylaniino)ethvl)-9H-pnini-6-amine 6B-l11 8-((3-iodo-5,6,7,8-tetrabydronaphthaen-2-yl)tho)-9-(-(isobutyamino)ethyl)91-purin-6 amnine i6B-12 6-(6-arnino-8-(3-(oxazol-2-yl)-5,6,7.8-tetrahydronaphtha len -2-vlthio)9H-puri n-9 yl)hexanamide 6B-13 I -(3-(2-(8-(3-(IH-pyraoi-3-yl)-5,6,7,S-terahydronaphhaen-2-ylthio)-6-amino-9H-pudn i9-ylethyI.)pip eridin- I-yiethanorcve________ 6B-14 1-(3-(2-(6-amino-S-(3-ethynly1-5,6,7,8-tetahydroaphthae-2-ylthio)-9H-purin-9 ________yl)ethyl)piperidin-1I -yl)ethanone 6B-15 1-(3-(2-(6-arnino-2-fltoro-8-((3-(5-methyfrra-2-yl)-56,7,S-tefrahydronaphthaien-2 _______vl)methyl)-9H-pnrin-9-yl)ethyl)piperidin-1-y)etlhanone 6B-16 N--(2-((2-(6-amino-8-((3-(ftnan-2-yI)-5,6,7,8-tetrahydronaphtb.alen-2-yl)zhioi)-9H-purin-9 ________ y)e thyI) a tin o) ethI) me than &ilt naid e 6B-17 3-((2-(6-amino-8-((3-(fumrn-2-yI>-5,6,7,8-tetrahydronaphthalen-2-yI)thio)-911punn-9 ________ v)ethyl)aniino)-N-hydrxypropana-nidec 6B-18 9-(3-aminopropyl)-8-((3-iodo-5,6,7,8-tetrahydronaplithaien-2-vi)thio)-9H-purin-6-ammne 6B-19 9-(3-(isopropylan,o)propyl)-8-((3-(oxazol-2-yl)-5,6.1,S-tetrahlvdronaphthalen-2-yl)thio) ________9H-purirz-6-aini e 6B-20 9-(3-(tcrt-butylamiine)propyl)-8-((3-iodo-5,6i7,8-tetrahydronaphhalen-2-yl)thio)-91 ________purin-6-ariine 6B-21 (2-(6l-amino-8-(3-(5-nmethvlfuran-2-y)-5,6,7,S-terahydonaphthaim-2-ylthio)-911- WO 2011/044394 PCT/US2OIO/051872 199 ________ purin-9-v1)ethylpiperidiin-i-yl)ethanone 6B-22 1-(3-(2-(6-amino-8-(.3-(oxao-2-y.-5,6,.8tetrahydronap1thnleii2-ylthio)-9H-purin-9 _________yl)ethyl)piperidin-I.-yI)ethanone 6B-23 8-((3-(dimetlhylatino)-5,6,7,8-Eetrahydronapithaien-2-yl)thio)y9-(2 (nieopentyiamino)ethyl)-9i--purin-6-arnine 6B-24 9-(2-(1 -(methylstlfonyl)piperidin-3-yl)ethy)-S-((3-(5-methyhthiazo-2-yl)-5,6,78 _______teirahydron aphthalen-2-yI)tliio)-9H-purin-6-aminc 6B3-25 DZA-52-N9 ________8-(3-iodonaphthalen-2-vL)thio)-9-(3-(isopropylanino)propl>9H-purin-6amine 6B3-26 84((3-dirnez.hy'amiro)raphthalen-2-yl)thio)-9-(2-(neopentylanino)ethyl)-9H-p,-in-&, amine 6B1-27 1 -(3-(2-(6-arnino-8-(3-(5-methylfiura-2-yl)naphth.alen-2-ylthio)-9H-purin-9 ________yljethyl)piperidi.n-i -yl)ethanone 6-28 9-(2-( 1-(metliylst.fony)pipedin-3-yl)ethyl)-8-((3-(5-methylthiazol-2-yl)naphthalen-2 ________yl)tio)-9-pwi-6-amine 6B-29 R-((3-ethynylnaphthalen-2-yflthio)-9-(34(isopropylaminio)propyfl-9H-pudin-6-amine 6Bl-30 R-((3-(ll-pyrazol-3-yl)napbthalen-2-yl)thio)-9-(3-(isopropylaro)propyl)-9H-puin-6-I amine 61-3 -(6-amino-S-((3-iodonapithalen-2-yl)thiio)-9H-pudin-9-yl)-3-jisopropylamino)propan-2 6B1-32 5-(6-amino-S-(3-etirsnylnaphthaien-2-yltbio)-9H-purin-9-yl)pentane-1- -sufonamide 6B1-33 9.-(3-(tert-butylanro)propv1)-8-((3-iodonaphthaen-2-v)tio)-91-puxrin-6-amine 6Bi-34 8-((3-(5-inethyloxazoi-2-yl)naphthalen-2-yl)thio)-9-(2-( -(methylsulfonyl)piperidin-3 I ______ylbethyl)>9H-purnq-6-aniine 6B-35 2-fkoro-S.((3-iodonaphthalen-2-vl)methyl)-9- 2-(isobutyIarnino)ethy1 -91*-purin,-6-amine 6B-3 I (3-(-(6amio-8-3-(ziriin- -y)npiithalen-2-ylzhio)-9H-puin-9-yi)ethvl)piperidin- I1 6B8-37 6-(6-aiino-8-(3-(5-methyloxazol-2-yI)-5,6,7,8-tetrahydronaphthaleni-2-ylthio)-9H-purin * ~~ I-v)exanamide 6B1-38 6-(6-amino-843-iodo-5,6,7,8-tctrahydronaphthalen-2-ylthio)-9H-pundiv9-ylhexanamide 6B1-39 j 5 -(6-arnino-S-(3 -iodo-5,6,7,8-tetrahydronaphta'en-2-yltio)-91-purin-9-y)pentane- I 1stilfonanlide 601-40 j1-36ain--3id-,,8ttayrnptae2yti)9Hpi- ______ yI)propyi)pyrrlidin-3-onc Table 7A No. iNa me 7A-1 S-, (2ehml-5-mehoxyphcnylthio)-9-(3-(isopropylamino)propyl)-9H-puin-6-amine I 7A-1 9 3(sorplamnino)propyl)-8-(5-methoxy-2-(prop-1-ynyl)plrnylthio)-9H-prin-6-amine 7A-3 9-{3-( sopropylamino)propyil)-S-(5-niethoxy-2-4phenylethynyl)phen.ylthio)-9H-purin-6 amIne 7A-4 18 (2-thyniyl-5-methoxyphenylthio)-9-(2-(isobutylamlino)cthy)-9H-purin-6-aminre 7A-5 1-(4-(2-( 6-a-ino-8-(2-ethynyl-5-methox3,phenvlthi&)-9H-purin-9-yl)ethy1)piperddin-1 YI'etharone 7A-6 4-(2-(6-amimo.8-(2-ethynyl-5-methoxypbenylthio)-9H-purIdn-9-yl)ethyl)piperidine-1 ______Icarbaldehyde WO 2011/044394 PCT/US2OIO/051872 200 7A-7 :1 14-4-(2-(6-arnino-8-(2-cthynyl-5-methoxybenzyl)-2-fiuoro9H-purin-9-y)cthyl)pipeidin 1-yl)etha~m-n 7A 7 8 4-(2-(6-aino-8-(2-ethvnyl-5-methoxybenzvl)-2-fluoro-9H-purtn-9-y)etbyl)piperidine-1 carbaldehyde 7A-9 1-(4-(2-(6-arniuno-2-ehloro-8-(2-etliynyl-5-methioxybenzyl)9H-purin-9-yl)ethyl)pperdi-I N 1-yl)elhanone 7A-10 4A 2-(-anino-2-chloro-8-(2-ethyniyl-5-methoxybenzy)-9H-purin-9-y)ethyl)piperidie-, carbaldeliyde 7A-i1 N-(2-(2-(6-arino-S-(2-ethvny-5-methoxyphenylthio)-9H-puhin-9 yI)ethylarnino)ethyl )sulfamide 7A-12 3-(2-(6-armno-S-(2-ethynyl-5-methoxyphenylthio)-9H-puhin-9-ylfrthylanino)hydroxypropan ari de 7A-13 8-(5-ethoxy-2-ethyyphenyithio)-9-(3(ioprpylarno)propyl)-9{-pnnin-6-armle 7A-14 1 -(6-amino-8-(2-ctlinyI-5-rnetfiox ,henythio)-9H-purin-9-y)-3-(isopropylamino)propa.l 2-ol 17A-15 8-(2-ethynyl-5-methoxyphenylthrio)-9-(2-Q. -(methylsalfonyl)pipeidin-3-yl)ethyl)-91 I7A-16 N-(3-(6-amino-8-(2-ethynyvl-5-m-ethoxypheiylthio)-9H-purin9 I _______yl)propyl)methanesulfonanide 7A-17 2-(3-(6-amir*,o-842-ethynyl-5-rnethoxyphenyrhio.)-9H-purn-9-y)popy)nyoidine-I ________carbaldehyde 7A-l8 8-(2-ethvnt-5-me-thoxybenzyi)-2-fliaoro-9-(3.-(ispropylarTino)propvl)-9H-pnrin-6-anine 7A-19 i-(3-(6-axin-o-g-(2-ethyn-yl-5-rnethoxyphenylthio)-9H-puin-9-yl)propyl)pyrolidin.-3-one 7A-20 PU-WS31 ________8-((2-ethMvl-5-mthoxypeny)thio)-9-(2-(neopentylamino)ethy)-9H-purin-6-arniw Table 7B NO. Name 7B-1 2-((6-amino- -fluoro-9-(3-(isopropylamino)propyl)-9H-purin--yi)netvl)-4 _______ rnthoxybenritrile 7B-2 2-(6-aio9k-iopoyamioropy)-9H-p ri--lthio)-4-methoxybenzonitrile 7B-3 2-(2-(6-amaino-9-(3-(isopropylainino)propyi)-9H-pmin-8-ythio)4 _________methoxyphenylhacetonitrile 78-4 2-(2-ff6-arnino-2-fluoro-9-(2-(isobntyla.nino)ethyl)-9H-purin-8-yI)trethyl)-4 methioxyphenyfl)acetonitrile '7B-5 2-C9(2-(ac1pj perdin4-v1)ethyl)-6-an~ho9Hpurn-8yltio)4-ethoxybenzonitdle 7R-6 2-((6-amino-2-flnoro-9-(2-(I -forryipperidin4-y)ethyl)-91I-pmin-8-yl)niethy>-4' ________ ,nthoxybenzonitrile 7B-'1 2-((94(2-(1-acetylpiperidinA-yl)ethyl)-6-arnino-2-chloro-9H-purin-8-yl)rnethyl)A methoxybenzonitrile 7B-8 2-(2-(6-amino-9-(2-(1 -formylpiperidiii4-yI)etliyl)-9H-pain-8-ylthio)-4 ________medioxyphenylhacetontl 7B-9 2-(2-((9-(2-(I -acetylpipedidinA-yI)etIhyI)-6-aniino-2-flLioro-9H-pnrin-8-yi)metli inethoxyphenyl)acetonitrile 7B-10 2-((6-aw-ino-2-fluoro-9-(3-(isopropylarnino)propyl)-9H-purin-8-yl)methyl) ethoxybenzonitrilc WO 2011/044394 PCT/US2OIO/051872 201 L47B11 N}.2(-nio.&(2-cyano-5-methox~vhevthio)-9H-prnlin-9 Iyl)ethylamino)ethl)meffthineslfoniaride 7B1-12 3-(2-(6-antno-8-(2-cyauo-5-methox y-phenylthio)-9H-purin-9-yl)ethylamino)-N ihydroxypropanamide Table 7C No. Name 7C-1 -8-(2-(fumrn-2-yl)-5-methoxyphenylthio)-9-(3-(isopropylamino)propyl)-9H-puin-6-anine 7C-2 9-(3-(isopropylarnino)propyl)-S-(5-mcthoxy-2-(5-methylfara-2-yl)phenylthio)-91H-pnrin ________6-armine 7C-3 9-(3-(isopropylamidno)propyl)-8-(2-(isoxazolA-yl)-5-tnethoxyphienylthio>-9H-pnrin-6 amnel F7C-4 S-(2-(5-(aminomethyl)furan-2-yI)-5-methoxvitenvlthio)-9-(3-(isopropylarnino)propl) 93-punn-6-amine 7C->5 2-fluoro-8-(2-(furan-2-v1)-5-meLhoxybezy)4$-(-(isobuLylarmino)ethy1)-9H-purin-6 7C-6 2-fluoro,-8-(2-(ftwi-3-y1)-5-rnetfrobenzy)-9-(2-(isobutvianino)ethiyl)-9H-purin-6 7C-7 2-fluoro-9-(2-(isobityafino)ty)-8-(5-nethoxy-2-(5-mnethytfinan-.-y)benz-yl)-9H ________purin-6-amine 7C-8 [2-f uoro-942(isobtyinino)ethyIV8-(2(isoxa7i--y1)-5-nethoxyhen7 i)-9H-pu~nr-6 amine 7C-9 -- 2(-afioehlf 2y)5.-h~yb~l--ioo9(-iouyari~~y) 9H-purip,>&a mine 7C-10 I -(3-(6-arnino-8-(5-methoxy-2-(5-methylfuiran-2-yl)phcnylthio)-9H-prin-9 _________yl)propyl)pyrrolidin-3-one 70e y1-9Hpudn--arrn '7C-12 5-(6-amino-8-(5-niethoxy-2-(oxazol-2-yI)phenylthio)-9H-purin-9-yl)pentane- - sulfonamide 7C-13 Tf-V-138 _______ j8-2-(ftiran-2-yl)-5-methoxyphenylthio)-9-(2-neopentylanmino)ethy)-9H-purin-6-aniine XC-14 j -(2-(furan-3-yl)-5-methioxyphenyithio)-9-(2-(neopentylamino)ethyl)-9H-purin-6-anine 7C-15 8-(5-medioxy-2-(5-methylfuran-2-yl)phenvltbio)-9-(2-(neopent-ylamino)ethyl)-9H-purin-&) tamille 7C-16 8-(Zl(isoxaol-4-vi)-5-methoxvphenylthio)-9-(2-(neoper.,tyhnin)ethyl)-9H-purin-6 747-1- -(3-(atno--(5-methoxy-24oxazol--ylh p nyhio)-9-pur )-9l)hylpie I -- anoine 7C1 1-(3-(46-anT~ho-2-too--(5-r.e'oxy-2-ox-2-2hbenzI)-9H-pxin9 ________yl~thv1)piperidin-1-y1)ethanonc ________ l)etbyinipdine-I -carbaldehyde 7C-22 1-(3-(2-(6-anmino-8-(5-methoxy-2-(5-mcthylfuran-2-yl)phenylthio)-9H-pamin-9- WO 2011/044394 PCT/US2OIO/051872 202 ?C7-23 1-(4-(2-(6-anino-2-tiuoro-8-(5-rnethoxy-2-(5-medyfran-2-y)bcnzy1)-9H-purir-9 _______yi)ethyl)pipendin-1-yI)ethanone 7C7-24 1-(3-(6-ainino-8-(5-,tethoxy-2-(thiazo-2-yhphenylthio)-9H-purin-9-y)propy)pyrolidini Vote 7C7-25 9-(3-arninopropyl)-8-(5-rnetboy--5-nmethylfura-2-yI)phenylthio)-9H-purin-6-anmine N7C7-26 9-(3-4isoprooylarnino)propyl)-8-(5-inethoxv-2-(oxazol-2-y)phenyltbio)-914-ourin-6-am .ine 7C7-27 1 <4-(2-(6-arnino-8-(2-(5-(am ninomethyl)fiian-2-y1)-5-nrthoxyphenylthio)-9H-purin-9P 7C2 i-(4-(2-(6-antno--(2-(5-(aminomethyl)fmar-2-y)-5-methoxybnyl)-2-lur-9H-purn ________9-yI)ethyl)pipedidip-1 -yI)e-hanone X4-29 I 4-(2-(6-arnino-8-(2-(isoxzol-4-i)-5-mehoyphnyr1liio)-9B-puirvii9-yl)ethy)piperidiie I _______I l-oarbaldehvde 7C7-30 ~4-(2-(6-arino-2-ehloro-S -(2-(isoxazo1 4-y)-5 -netoxybenzyI)-9H-purin-9 _______ IvbcthyI)pipeld ne- I -cabaldehvdc ,C2-31 N-(2 (2-(6-amino-8-(2-(hran-2 -yI)-5 -inethoxyphenylthio)-91I-purin-9 I _______ yI)ethyiamino)etliyl)sulfaniide 7C7-32 (2,(6an 8(2(fran2y)5metoxyphenylti>9Hpsin9y)eyam-tio)>Th I7C-33 I8-(5-ethoxv-2-(fra-2-yi)penythio)-9-(3-(isoproyaino~hzopyh)-9H-purin-6-amine 7C7-34 ___l isup________ , lmio pt- In- 7C2-35 I9-(3-(tt-butylamixo)propyl)-8-(2-(fura-2-yi)-5-tnethoxyphenytltfo)-9H-puin-6-anine rahle 70 No. Name 71 W(-ioroyaonopoy -gn - noehtxo 7D-2 2-fluoro-9-(2-(isobutylamino)ethyl)-8-(5-methoxv-2-(thiophen-2-yl)benl)-9H-pain-6-amine 70-3 TT-N-139 _______8-(5-methoxy-24thiophen-2-yl)phieyltio)-9-(2-(nopentyaroiro)ethyD-9H-puin-6anine 7D-4 9-3(sppyaio~rpl-- (h 7D-5 N-(346-antino-8-(5- etoxy-2-(tfizo-2-I)imylthio)-9H-pti-9-y1)propyI)methanernlfonaide 7D-6 8 (5-metboxy-2-(zhiophen-3-vipIenytho-92(entylam-.o)ethyl)-9H-pin n6-amine 1)7 14-(2-(6-amino-8(-ehx--tiphn2y hn~ho-9H-puirin-9-yl)ethwyl)pipridin-1 _________ l)effian one 7D-8 4-(2-(6-arnino-8-(5-methoxy-2-(thicphen-2-yl)phenylthio)-9H-purin-9-yl)ethyl)pipedidine- _______carbaldehyde 7D- 9 1 (4-(2-(6-amino-2-tluoro-8-(5-methoxy-2-thiophen-2-yl)ezyl)-911-puin-9-y)etyl)piperidin- ________yI)cthanone 7D- 10 1 (6-anino-8-(5-rnethoxy-2-(thiophen-2-yl)phenylthio)-911-purin9-yl)-3-(isopropylamino)propani-2 911-puin-6-amine 7D-12 N-(2-(2-(6-ano- 8-(5-inethoxy-2-(thi'ophen-2-yl)pheniylthio)-9H-pnrin-9 yl~ethylamino)ethyl)sulfamide 7D-13 3-(2-(6-amino-g-(5-rnethoxy-2-(tbiophen-2-yl)plienvlthio)-9H-purin-9-ybethyamino)-N- __ _ _ _ hydroxypropanamide---------------- 7D-14 &-5e~x--ti~e--lbnzl--lo 9(_(sbjl S7D-15 9-(3-arninopropyfl4--(5-methoxy-2-(thioph.en2-y)phenyltbio)-9H-pnrn-6-amine I7D-16 9-(3-(isopropylamino)prcpyl)-8-(5-mcthoxy-2-(thiazol-2-yl)phenythio)-QH-puin-6amine WO 2011/044394 PCT/US2OIO/051872 203 Table 7E No. [Name 7E-1 9-(3-(isopropylamaino)propyl)-S-(5-methoxy-2-(1H-pyraol-4-yl)phenylthio)-9H-puin-6 ammo 7E-2 9-(3-(isopropylamino)propyl)-S4(5-methoxy-2-( lH-pyrazoi-3-yl)phenylthio)-9H-purin-6 amine 7E-3 2-fluoro-9-(2-(isoblitylamino)ethyl)-S-(5-methoxy-2-(11l-pyrazol-4-yI)benzv)-9HI-purn ________6-amine 71>4 2-fur-9-(2-(isobutylamiino)ethyl)-8-(5-methoxy-2-(IH-pyraol-3-yl)benzyl)-9H-puin ______I6-amn 7E-5 1 -(3-(2-(6-amino-8-(5-methoxy-2-( tH-pyrazol-3-yl)phenylthio)-914-purin-9 _________yl)ethyl)pyrolidin-l -yflethanone 7E-6 TT-V-140 S-(5-rncthoxv-24 IH-pyrazobl3-yl)phcenylthio)-9-(2-(nen tylain.,o)ethyl)-9H-purii-6 "F 1-4-(2(6-amno-8(5-methoxy-241I-pyao-3-yl)phenylthio)-9-T-pudn-9 _________yiethylJpiperidin-1 -vl)ethanone 7E-8 4-(2-(6-amaino-8-(5-tnethoxy--(1H-pyrazo-3-y)phenylthio)-9H-purin-9 ________ yllethyl)piperidine-1 -carbaldehyde 7E-9 1-4(--aioSfuo-(-mhxy2(Ipvac3-Ibni)-9H-parin-9 ylbethvl)Tpidin- 1 -vbiethanone 7E-10 4-(2-(6-aino-2 -fluoro-8-(5-methoxy-2-( I fI-pyrazol-3-y!benzyl)-911-pminn-9 _L1)eihyI)pipeide-.-caldatebydie 7E-11 1-(4-(2-(6-amino-2-chloro-8-(5-melhoxy-2-(l11-p-yraol-3-yl)benzyl)-9H-purin-9 jl~etbl)piperidin-. -y)etbanone __________________ 7E-12 4-(2-(6-aniino-8-(5-methoxy-2-( 1H--prazo-4-y1)phenylthio)-9H-puiriin-9 yl)ethylpiperidine-I -arbaldehyde 7E-13 I -(6-atnino-8-(5-methoxy-2}(IH-pyrazol-3-yl)phenylthio)-9H-puin-9-yI)-3 _________ isopropylarnino)propa-2-ol 7E-14 N-(2-(2-(6-amino-S-(5-methoxy-2-(IH-pyrazol-3-yl)phenylthio)-9H-pmin-9 yl)ethylamino)ethyflsulfamide 7E-15 3-(2-(6-amino-8-(5-methoxy-2-(1H-pyrazol-3-y)phenylthio)-DH-purin-9-yl)ethylanino) N-hydroxypropanamide 7E-16 8-(5-ethoxy-2-(1H-pyvol-3-yl)phenytltho)-9-(3-(,isopropylamino)propyl)-91-purin-6 amine 7E417 84(5-ethoxy-2-( l--pyrazol-3-yl)benzyi)-2-fluero-9-(2-(isofrityanino)ethyl)-91-purin-6 amne 7E-14 9-(3-arniniopropvl)-8-(5-rnethoxv-2 -(IHi-yaZol-3-yl)phenvthio)-9H-nuin-6-amine 7E-20 8-(5-rnethoxy-2-(1 H-pyrazol-3-yl)phenyltiio)-9-(2-(1 4methylsulfonyP)piperidin-3 __________yl)ethyl)-9H-puin-6-amine ________________________ 7E-21 N-(3-(6-amino-S-(5-me~hoxy-2-(I{l-pyrazol-3-yi:)phienylthio)-9H-purin-9 yl)propyl)methanesulfonamnde 712 9-(3-(isopropylarino)propy!)-8-(5-mnethoxy- -(5-methyl-i H-pyaol-3-yl)phenylthxo) ____-22_ 9H-purin-6-anine Table 7F WO 2011/044394 PCT/US2OIO/051872 204 No. Nam 7F-1 9-(3-(isopropylant no)propy.)-8-(5-methtxy-2-( 1H-pyrrol-3-yl)pheniylthiQo)-9H _____purin-6-aniine 7F~-2 9-(3-(isopropylamino)propyl)-8-(5-methoxy-2-(IH-pyrol-2-yl)phenylthio)-9H purin-6-amine 7F-3 2-fluoro-9-(2-(isobutylarino)ethyl)-8-(5-methoxy-2-(1H-pyrrol3-yl)benzyl) 9H--pmin-6-amrine 7F-4 8-(5-methoxy-2-(1 H-pyrrot-3-yl)phenylthio)-9-(2-(1 -(methyisulfonyl)pyrrlidin .. 2:Y)othyIA-Hpurin6-anine. 7F-5 8-(5-rnethoxv-2-(1H-pyrrol-3-yl)phenykhio)-9-(2-(neopentylaiinorthyl)-9 ________purin-6-amine 7F-6 9-(3-(isopropylamino)propyl)-8-(5-methoxy-2-(5-methyl-1 H-pyrrol-3 ______________yl)phenylthio)-9H-purin-6-amine _____________ 7F-7 4-(V(6-aino-S-(5-methioxy-2-(iH-pyrol3'-y1phenyl&io)-9H-purin-9 ________________ )propyi)piperidinie-l-carbaidehyde 7F-8 4-(2--Q-amino-S-(5-nmezhoxy-2-( IH-pyrrcl-3 -yl)phienylthio)-9H-purin-9 ______________yl)ethyi)piperidine-i -carbaidehvde 7F-9 1-4(-6amn Hlor--5.e~oy2(l-pytrol-3-yl)benzyl)-9H-pnrin-9 7F-10 I 443-(6-an~ino-2-f~horo-S-(5-methoxy-2-(1H-pyrol-3.vi.)benzyl)-9H-purin-9 _______________ yI)propyl)piperidir -llethanone _______________ y)ethyl)piperidin- I -yI)ethanone 7F-12 N-(6(arnino-S-( 5-methoxy-2- 4lII-pyrrol-3 -yI)phenylt hio)-9H-puri n-9 yI)prolmethanesulfonamide ________ 7F-13 8-(5 -methoxy-2-(1 H-pyro1-3 -yI)phenylthio)-9-(2-(1 -(methylsulfonyI)piperidin ______________ ±!)efly-Ipun6amn 7F-14 N-(2-(2-(6-arniino-8-(5-rnethoxy-2-( 1H-pyrrol-3-yl)phenylthio)-9H-purin-9 ________________yi)ethylaniino)ethyl)sulfamide 7F-J 5 3-(2-(6-amino-8-(5-rncthoxy-2-(I H-pyrol-3-yl)phenyltio)-911-purin-9 ____ _________yl)ethylartino)-N-hvdroxroanid 7F-16 8-(5-ethoxy-2-(1H-pyrrol-3-yI)phenyltliio)-9-(3-(isopropylanilno)propyl)-9H ____________________purinl-6arnilne 7F-17 8-(5-ethoxy-2-(I H-pyrrol-3-yl)benzyi)-2-fluoro-9-(2-(isobutylamino)ethyl)-91{ ______________prnn-6-amine 7F-18 9-(3-(terv-butylarnno)pr-opy1)-8-(5-methoxy-2-( I H-pyrrol-3-yl)phenylthio)-9H _____________ purin-6-amine 7F-19 9-(3-aminopropyl)-8-(5-metlioxy-2-(1H-nynol-3-yl)phenylthiO)-9H-pnn-6 wF-20 1 -(6-arnino-8-(S-methoxy-2-(1 H-pyrro1-3 -y1)phenylthio)-9H-pmrin-9-yf03 _______________ (Sonropylanmino~propan-2-oi WO 2011/044394 PCT/US2010/051872 205 Table 8 Options for R. I R is hydrogen, a CT to C,. alkyl, alkeryl, alkynyl, or an alkoxvaiky group, optionally including neteroatoms 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, S(O), SO 2 , N(R 2 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 R210 B is a tinker; R... is selected from the group consisting of hydrogen, N(R2)COR 4 ,

N(R

2 )CON(i,)R 4 , N(R 2

)COOR

4 , N(R2)S(O)aR 3 , N(R2)S(O),NR 3

)R

4 ; where i, and i are independently selected from hydrogen, aliphatic or substituted aliphatic; R. is selected from the group consisting of: aryi, substituted aryl, heteroarvi, substituted heteroaryl, heterocyclic, substituted heterocyclic, cyloalkyl, substituted cycloaiky[, cycloalkenyl, substituted cycloalkenyi, and substituted or unsubstituted -Ci-CG alkyl, -C-C alkenyl, or -Cr Cc alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from 0, 5 or N; n is 1 or 2; Mi is absent or selected from substituted or unsubstituted -Ci-C 6 aikyl, -- Cr Ce alkenyl, or -CrC6 alkynyl, aryl, substituted aryl, heteroaryt, substituted heteroaryl; M2 is absent, 0, 5,50, 502, N(R 2 ) or CO; M, is absent, 0, 5, 50, SO2, N(R,), CO, Ci-C alkyl, Cr-Cs alkenyl, C 2 CG alkynyi, cycloalkyl, heterocyclic, aryl, or heteroaryl;

M

4 is hydrogen, NR 5

R

6 , CF 3 , OR, halogen, substituted or unsubstituted -C,- C 6 alkyl, -Q-C 6 alkenyl, or CQalkynyl, cyciaalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl or substituted heteroaryl; where Rs and R, are independently selected from the group consisting of hydrogen, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl or substituted cycloalkyl; provided that -R and -Mi-MrMr

M

4 cannot be both hydrogen.

WO 2011/044394 PCT/US2010/051872 206 Table 8 cont'd 3. Ris N 32 R wherein Rk is (a) hydro; (b) Cr-C alkyl optionally substituted with 1, 2, 3, 4, or 5 substituents each independently chosen from the group of halo, hydroxyl, amino, cyano, and -C(=O)R wherein R 3 I is amino; (c) -C(=O)R, wherein R 3 _ is selected from the group consisting of: (1) hydro, (2) C,-C, 0 (e.g., CrC-) 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) C-C 6 haloaikyl (e.g., trifluoromethyl), (F) C, Cs alkoxy (e.g., methoxy) optionally substituted with C-C 6 alkoxy (e.g., methoxy), (G) C-amido, (H) N-amido, (1) sulfonyl, (J) -N(R" )(R'2) wherein R 2 1 and R 2 are independently hydro, Cr CG alkyl, sulfonyl, and C-carboxy, (3) C,-Cr cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents each independently chosen from the group of halo, hydroxyl, amino, cyano, and C-Cs haloalkyl (e.g., trifluoromethy), and (4) C,-C 6 alkoxy optionally substituted with 1, 2, 3, 4, or 5 substituents each independently chosen from halo, hydroxyl, amino, cyano, and C-ec haloalkyl (e.g., trifluoromethyl), (f) heterocycie or heterocyclylalkyi, optionally substituted with 1, 2, 3, 4, or 5 substituents independently chosen from halo, hydroxyl, amino, cyano, trihalomethyl, and CC 4 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently chosen from halo, hydroxyl, amino, cyano, C-C haloalkyi (e.g., trifluoromethyl) (e.g., tetrazole-5-y! optionally substituted with 1, 2. 3, or 4 CrC- alkyI); (g) sulfonyl; and () optionally substituted heteroaryl Table 8, cont'd 4. R is -Rs 4 -R" wherein WO 2011/044394 PCT/US2010/051872 207 R" is -(CHN,- wherein n=0-3, -C{O), -C(S), -SOr, or -SO 2 N-; and R3 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, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, -Ns, -SRs, -0 Rs -CN, -CO 2 R", NO2, or -N R"Rs', R"* is hydrogen, lower alkyl, lower aryl, or -C(O) R"; R" is lower alkyl, lower aryl, lower heteroaryl, -N R 0

R

0 or-O ; R" is independently hydrogen or lower alkyl; and RsI 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 araalkyi, optionally substituted aryloxyalkyl, optionally substituted alkoxyalkyl, alkylamimoalkyl, alkylcarbonylaminoalkyl, alkylcarbonyoxylalkyl, optionally substituted heterocyclic, hydroxyaikyl, haloalkyl, perhaloalkyl, C(O)Re, S(O)2R, C(O)NHR 2 and C(O)OR; where R" is 6. R is H, SRv;, SOR7,, SO2R 7 i, ORn. COOR 71 , CONR 1 R-p, --CN, C_ alky[, C 2 s alkenyl, C>, alkynyl, -OR0R, -RANRm, --RANRV Re, -- R7ASRm, --RkASOR or -RASO 2 RB, cycloalkyl, heteroalkyl, heterocycioalkyl. aryl, heteroaryi, alkyiaryl, arylalkyl, alkylheteroaryl. heteroarylalkyl, NRvRn, --OSO,N(RIc), --N(R 7 c)S02OH, -N(R'c)SO2R 7 c, --RTAOSO 2

N(R

7 c)2, or -R-N(Rc)OSOR7c;

R

7 1 and R 2 are independently selected from the group consisting of H, COOR7B, CON(R7c) 2 CjA alkyl, C2 6 alkenyl, C 6 aikynyl, -RAORB-, -- RANRC, --RANR7IR,, --RASR, -RASOD or -ASOZRa cycloalkyl, heteroalkyl, heterocycloalkcyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl. and heteroarylaikyl; each RA is independently C14 alkyl, C2- alkenyl, C2 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl. heteroatyl, alkylaryl, arylalkyl. alkylheteroaryl, alkylheteroarylalkyl, or heteroarylalkyl; and each Rs is independently H1, C> 6 alkyl, C 2 .6 alkenyl, C,.r alkynyt, cycloalkyl, heteroalky1, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl. alkylheteroaryl, heteroarylalkyl, --SO20H, -SO2N(R 7 A)2, --SO2NHRA or --SO 2 NH2; and each R.sub.C is independently H, C,.

6 alkyl, C 2 < alkenyl, C2 6 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 intermpted or terminated by 0, S, S(O), SO 2 , N(Rss), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic; substituted or unsubstituted cycloalkyl; where Rs, is hydrogen, acyl, aliphatic or substituted aliphatic. 7B. R is -M1-M2-M3-M4, where Mi is absent, CrC 6 alkyl, CrC alkenyl, C-C alkynyl, aryl or heteroaryl; M2 is absent, 0, S, SO, SO 2 , N(Rs), or C=O; M is absent, C=O, 0, S, SO, S02 or N(Rs); and M is hydrogen, halogen, CN, N, hydroxy, substituted hydroxy, amino, substituted amino, CF 3 , C,-C6 alkyi, C-C 6 alkenyl, C-C 6 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl.

Claims

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

24. A compound of the formula: NH 2 X2 Z 1 N Z 3 >Y X~c x 4 z 2 N IXc R Xb-Xd wherein (a) each of Z 1 , Z 2 and Z 3 is independently CH or N; (b) Xa and Xb are 0, and Xc and Xd are CH 2 ; (c) Y is -CH 2 -, -0- or -S-; (d) X 4 is hydrogen or halogen; and (e) X 2 and R are a combination selected from: (i) X 2 is halogen or cyano and R is suitably a primary amino alkyl, a secondary or tertiary alkyl-amino-alkyl, a trialkylammonioalkyl group, an aryl-alkyl, or a nonaromatic heterocycle-alkyl, with the proviso that R does not include a piperidino moiety; or (ii) X 2 is selected from the group consisting of an aryl, an alkynyl, a cycloalkyl and an cycloalkenyl and R is: (a) hydrogen; or (b) a straight-chain- or branched- C 1 to Cio alkyl, C 2 to C 6 alkenyl, or C 2 to C 6 alkynyl, which is unsubstituted or substituted; or (c) aryl, heteroaryl, heterocyclic, cycloalkyl, alkylaryl, or arylalkyl, which is unsubstituted or substituted; or (d) -SR71, -S(O)R 7 1 , -SO 2 R 7 1, -OR 7 1 , -COOR 71 , -CONR 7 1 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, -R 7 AOSO2N(R 7 c)2, or -R7AN(R7c)OS02R7c, wherein each R 7 1 and R 72 is independently selected from the group consisting of hydrogen, COOR7B, CON(R 7 c) 2 , C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, -R7AOR7B, -R7ANR7B, -R7ASR7B, R7AS(O)R7B, -R7ASO2R7B, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, and heteroarylalkyl, 230 each R7A IS independently C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl, and each R7B is independently hydrogen, C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, -SO 2 OH, SO2N(R7A)2, -SO2NHR7A, or -SO 2 NH 2 ; and each R 7 c is independently hydrogen, C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, or heteroarylalkyl; or (e) -Mi-M 2 -M 3 -M 4 , wherein: Mi is absent, C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, aryl, or heteroaryl, M 2 is absent, 0, S, S(O), SO 2 , N(Rss), or C(=0), M 3 is absent, C(=O), 0, S, S(O), SO 2 , or N(Rss), and M 4 is hydrogen, halogen, CN, N 3 , hydroxy, amino, substituted amino, CF 3 , C1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein Rss is hydrogen, aliphatic, substituted aliphatic, or acyl.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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