NZ616758B2 - Hsp90 inhibitors - Google Patents

Abstract

The disclosure relates to purine derivative compounds as inhibitors of Heat Shock Protein 90 (HSP90) of general Formula (IA) and (IB), wherein the substituents are as described in the specification. Compositions comprising an effective amount of a Compound of Formula (IA) or (IB), and methods to treat or prevent a condition, such as cancer which overexpresses Her-kinases, comprising administering to an patient in need thereof a therapeutically effective amount of a Compound of Formula (IA) or (IB) or a pharmaceutically acceptable salt thereof. The disclosure further relates to compounds of Formula (IA) and (IB) in which X2 is a leaving group such as trialkyl tin or SN(CH2CH2(CF2)5CF3)3 for introducing a radiolabeled atom, such as 124I or 131I, and to methods of using such compounds in the preparation of radiolabeled compounds, particularly for use in imaging. at or prevent a condition, such as cancer which overexpresses Her-kinases, comprising administering to an patient in need thereof a therapeutically effective amount of a Compound of Formula (IA) or (IB) or a pharmaceutically acceptable salt thereof. The disclosure further relates to compounds of Formula (IA) and (IB) in which X2 is a leaving group such as trialkyl tin or SN(CH2CH2(CF2)5CF3)3 for introducing a radiolabeled atom, such as 124I or 131I, and to methods of using such compounds in the preparation of radiolabeled compounds, particularly for use in imaging.

Description

HSP90 INHIBITORS This application claims the benefit of and priority from US provisional application no. 61/472,061, filed April 5, 2011, the contents of which are incorporated herein by reference. 1. BACKGROUND 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 U. and [3, Grp94 and Trap-l. Hsp90 a and B 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 ing of denatured or "unfolded" proteins. It has therefore been proposed to on 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 (Hsp60, Hsp90, Hsp70 and p23), forming a dosome" and ultimately the ATP- dependent release of the chaperones from the ed protein.

Hsp90 can 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 mediated suppression of the phenotypes of mutations that lead to protein unfolding.

Hsp90 is also necessary to the conformational maturation of several key ns involved in the growth response of the cell to extracellular factors. These include the steroid ors as well as certain kinases (122., Raf serine kinase, v-src and Her2). The ism whereby Hsp90 s these proteins is not fully understood, but appears to be r 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 n in concert with release of other chaperones and immunophilins and is required for high ty binding of the steroid to the receptor. Thus, Hsp90 could function as a physiologic regulator of signaling pathways, even in the absence of stress. 3O Hsp90 has been shown to be overexpressed in le tumor types and as a on of oncogenic transformation. Whether it plays a necessary role in maintaining transformation is unknown, but it could have at least three functions in this . 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 l 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, fimctionally—active mation 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 ly also require onal 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 ycin (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.

WO98/51702 ses 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 s to bifunctional molecules having two moieties which interact with the chaperone protein Hsp90, including in particular homo— and dimers of cin antibiotics. These bifunctional molecules act to promote degradation and/or inhibition of HER—family tyrosine kinases and are effective for treatment of cancers which press Her-kinases.

Exemplary small molecule therapeutics that bind to the same binding pocket ofHsp90 as ATP and the ansamycin otics are disclosed in PCT Publication Nos. W002/36075, W02006/084030, W02009/042646, W02009/065035, and /044394; US. Patent No. 7,834,181; and US. Patent Publication Nos. 2005/0113339, 2005/0004026, 2005/0049263, 2005/0256183, 2005/0119292, 2005/0113340, 2005/0107343, 2008/0096903, 2008/0234297, 2008/0234314, 2008/0253865, and 2009/0298857, all of which are incorporated herein by reference.

In ular, certain small molecule therapeutics that bind to the same binding pocket of Hsp90 can be described by the following general structural formula where Z1, Z2, and Z3 are selected from CH and N and the le substituents are ed from a number of options : NH; X2 Xd Z 1 \ Z\ ‘ A Y ,2 X3 X4 22 N i=2 / Xc Xb While these compounds can be active as inhibitors ostpQO, their level of ty is extremely variable with measured values for ECSO and ICSO being ed in anywhere from the micromolar to nanomolar ranges. 2. SUMMARY In one aspect of the disclosure, new compounds that inhibit Hsp90 are described.

Compounds of Formula (IA) or (1B) are herein sed: NH2 NH2 x2 fliyx2 Z Z \ Z1 \ 3* Xa A / )_Y X3 N \ Z N X0 X4 z2 \ 1X0 X4 2 \ , R Xb R Xb__Xd (1A) (“3) or a pharmaceutically acceptable salt thereof, wherein: (a) each of Z, Zz and 23 is independently CH or N; (b) Y is CH2, 0, or S; (c) Xa, Xb, X0 and Xd are independently selected from CH, CH2, 0, N, NH, S, carbonyl, fluoromethylene, and difluoromethylene selected so as to satisfy valence, wherein each bond to an X group is either a single bond or a double bond; ((1) X2 is halogen, aryl, alkynyl, or amino; (e) X4 is hydrogen or n; and (i) R is straight-chain— or branched— substituted or unsubstituted alkyl, straight-chain— or branched— substituted or unsubstituted alkenyl, straight~chain~ or branched— substituted or unsubstituted l, or substituted or unsubstituted cycloalkylwherein the R group is interrupted by 1, 2, or 3 groups selected from —S(O)N(RA)-, O)—, —SOzN(RA)-, -NRASOZ-, -C(O)N(RA)—, and «NRAC(O)—, and/or terminated by — S(O)NRARB, —NRAS(O)RB, ~302NRARB, ~NRASOZRE, —C(O)NRARB, or -NRAC(O)RB, wherein each RA and RE is independently selected from hydrogen, C1-C6 alkyl, C2-C5 alkenyl, C2-C6 alkynyl, lkyl, heteroalkyl, heterocyeloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl. 3. DETAILED DESCRIPTION The invention es the following: (1) A Compound ofFormula (IA) or (1B): NHZ NH2 X2 X2 Z1 \ 3 21 \ 23 A / >_YQ)? A / N)—Y X‘; X4 22 N C ‘XC X4 22 \ I R Xb—Xd R Xb (IA) (113) or a pharmaceutically acceptable salt f, wherein: (a) each of Zl, Z; and 23 is independently CH or N; (b) Y is CH2, 0, or S; (c) Xa, Xb, Xe and Xd are independently selected from CH, CH2, 0, N, NH, S, carbonyl, fluoromethylene, and difluorornethylene selected so as to satisfy valence, n each bond to an X group is either a single bond or a double bond; ((1) X2 is halogen, aryl, alkynyl, or amino; (e) X4 is hydrogen or halogen; and (t) R is straight-chain- or branched- substituted or unsubstituted alkyl, straight-chain- or branched— substituted or tituted alkenyl, straight—chain— or branched— substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by -S(O)N(RA)-, —NRAS(O)-, -SOZN(RA)-, -NRA802-, -C(O)N(RA)—, or - NRAC(O)-, and/or terminated by -S(O)NRARB, -NRAS(O)RB, -SOQNRARB, -NRA802RB, -C(O)NRARB, or -NRAC(O)RB, wherein each RA and RE is independently selected from hydrogen, C1-C6 alkyl, C2—C6 l, C2—C6 alkynyl, cycloalkyl, alkyl, heterocycloalkyl, aryl, heteroaryl, ryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl. (2) The compound as in the above (1) which is a Compound of Formula (1): xii/ilk:— x2 N \ N\ Y i 2 oj or a pharmaceutically acceptable salt thereof, wherein Y is CH2 or S. (3) The nd as in the above (1) which is 21 Compound of Formula (2): N H 2 X2 at fYNN \ \ . Xb or a phannaceutically acceptable salt thereof, wherein: one of Xa and Xb is O and the other is CH2; and Y is CH; or S. (4) The compound as in the above (1) which is a Compound of Formula (3): N H 2 X2 xl): >‘YNN \ \ X4 N N\ _ J - Xb or a pharmaceutically acceptable salt thereof, wherein: one of Xa and Xb is C(=O) and the other is CH2; and Y is CH2 or S. (5) The compound as in the above (1) which is a Compound ofFormula (4): )6]: \> x2 N “\ x4 N \R g, ‘xc (4) or a pharmaceutically acceptable salt thereof, wherein: Xa—Xc-Xb is CHz-CHz-CHZ, CHZ, or CHz-CH=CH; and Y is CH2 or S. (6) The compound as the above (1) which is a Compound of Formula (5): N H 2 X2 /l / >‘Y Xa V Xb or a pharmaceutically acceptable salt thereof, wherein at least one of Xa and Xb is CHF or CF; and the other is CHF, CF2, or CH2. (7) The compound as in the above (1) which is nd of Formula (6): H X2 N / \w X4 N N\ 3 1 5 R O or a pharmaceutically acceptable salt thereof, (8) The compound as in the above (1), wherein ZI is CH or Z; is CH or 23 is CH. (9) The compound as in the above (1), wherein 21 and 22 are each CH or 21 and Z; are each CH or Z; and Z; are each CH. (10) The compound as in the above (1), wherein 21, 22, and Z3 are each CH. (11) The compound as in the above (1) to (10), wherein R is interrupted by one or more - S(O)N(RA)-, ~NRAS(O)-, -SOzN(RA)-, —NRASOZ-, -C(O)N(R,\)-, or -NRAC(O)- groups. (12) The compound as in the above (1) to (11), wherein R is terminated by an -S(O)NRARB, -NRAS(O)RB, —SOZNRARB, -NRASOZRB, -C(O)NRARB, or —NRAC(O)RB group. (13) The compound as in one of the above (1) to (12), wherein R is nesulfonic acid isopropylamide, 2—ethanesu1fonic acid mide, 2-ethanesu1fonic acid methylamide, 2- ethanesulfonic acid amide, 2-ethanesu1fonic acid t—butylamide, nesulfonic acid isobutylamide, Z-ethanesulfonic acid cyclopropylamide, isopropanesulfonic acid 2-ethy1amide, ethanesulfonic acid 2—ethy1amide, N-2 ethyl methanesulfonamide, 2-methy1-propanesulfonic acid 2-ethy1amide, 2—methy1-propanesu1finic acid larnide, 2-methyl—propanesu1fonic acid 2-ethylamide, cyclopropanesufonic acid lamide, 3—propane—1—sulfonic acid isopropylamide, 3-propane—1—su1fonic acid ethylamide, 3-propanesulfonic acid methylamide, 3- propane—l-sulfonic acid amide, ane-1—sulfonic acid t—butylamide, 3-propanesu1fonic acid isobutylamide, 3-propane—1—su1fonic acid cyclopropylamide, propane-Z-sulfonic acid 3- propylamide, ethanesulfonic acid y1amide, Npropy1methanesulfonamide, y1- propane—2—su1fonic acid 3«propylamide, 2—methyl-propanesulfinic acid ylamide, 2-methy1- propane-l-sulfonic acid 3-propylamide, cyclopropanesulfonic acid 3-propy1arnide, 3-N-isopropy1 propionamide, 3—N-ethy1propionamide, 3—N—methy1 propionamide, 3—propionamide, 3-N-t-buty1 propionamide, 3—N—isobuty1 propionamide, 3—N—cyclopropy1propionamide, N—2-ethy1 isobutyramide, N—2—ethy1propionamide, N—Z-ethyl acetamide, N—Z-ethyl formamide, Nethy1 2,2- dimethyl-propionamide, N—Z—ethyl 3-methy1butyramide, or cyclopropane carboxylic acid 1- amide. (14) The compound as in one ofthe above (1) to (12), wherein R is cyclopropane carboxylic acid 3-propy1—amide, opy1 methy1—propionamide, N-propyl-Z-methylpropane —Z—sulfinamide, t—butanesulfonic acid 3—propy1amide, or cyclopropanesulfonic acid 3- propylamide. (15) The compound as in one ofthe above (1) to (14), wherein X4 is H or F. (16) The compound as in one of the above (1) to (15), wherein Y is S. (17) The compound as in one of the above (1) to (15), wherein Y is CH2. (18) The compound as in one of the above (1) to (17), wherein X2 is optionally substituted heteroaryl. (19) The compound as in one of the above (1) to (18), wherein X2 is furanyl, fuIanyl, -methylfuran—2—yl, 1H—pyrazol-2—yl, lH—pyrazol—3-yl, thiazol-Z—yl, 5-methylthiazol-2—yl, oxazol-Z— yl, or 5-methyloxazol-2—yl. (20) The compound as in one of the above ( ) to (17), wherein X2 is alkynyl. (21) The compound as in one of the above ( ) to (17) or (20), wherein X2 is ethynyl. (22) The compound as in one of the above ( ) to (17), wherein X2 is halo. (23) The compound as in one of the above (1) to (17) or (22), wherein X2 is I. (24) The compound as in one of the above (A) to (17), wherein X2 is amino. (25) The compound as in one of the above ( ) to (17) or (24), wherein X2 is dimethylamino. (26) The nd as in one of the above ( ) to (11) or (13) to (25), wherein Z1 is N or 22 is N or 23 is N. (27) The compound as in one of the above ( ) to (10) or (13) to (25), wherein Z and Z2 are each N or 21 and Z; are each N or Z2 and Z3 are each N. (28) A pharmaceutical composition sing the nd as in one of the above (1) to (27) and a ceutically able carrier. (29) A method for treating or preventing cancer or a neurodegenerative disorder, comprising administering to a patient in need thereof a therapeutically effective amountof a compound as in one ofthe above (1) to (27). (30) Use of a compound as in one of the above (1) to (27) in formulating a pharmaceutical composition for the treatment or prevention of cancer or a neurodegenerative disorder. (31) A method for the tion of Hsp90, comprising contacting Hsp90 with an Hsp90 function inhibiting amount of a compound as in one of the above (1) to (27). (32) Use of a compound as in one of the above (1) to (27) in formulating a ceutical composition for the inhibition of Hsp90. (34) A Compound of Formula (IA) or (TB): NH2 NH2 x2 x2 Z \ 2 Z1 \ Z1 3 \ Y Xa A / Y X3 A /| 22 N N)— ‘XC X4 ‘ X4 22 R XbXC i2 Xb~x'd (IA) (18) or a salt thereof, wherein: (a) each of Z, Zr; and 23 is independently CH or N; (b) Y is CH2, 0, or S; (c) Xa, Xb, Xc and Xd are independently selected from CH, CH2, 0, N, NH, S, carbonyl, fluoromethylene, and difluoromethylene selected so as to satisfy valence, wherein each bond to an X group is either a single bond or a double bond; (d) X2 is a leaving group for introduction of a a radiolabeled atom to the structure; (e) X4 is hydrogen or halogen; and (f) R is straight—chain- or branched- substituted or tituted alkyl, straight—chain- or branched- substituted or unsubstituted alkenyl, ht—chain— or ed— substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by one or more (RA)—, O)-, -SOZN(RA)—, - NRASOZ-, —C(O)N(RA)—, or —NRAC(O)- groups, and/or terminated by an -S(O)NRARB, - NRAS(O)RB, -SOZNRARB, —NRASOZRB, -C(O)NRARB, or -NRAC(O)RB group, wherein each RA and RE is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl. (35) A compound as in (34) above, or a salt thereof, wherein X2 is trialkyl tin 0}" —Sn(CH2CH2(CF2)5CF3)3. (36) Use of a compound as in (34) or (35) above, or a salt f, as a precursor for the ion of a radiolabeled compound.

A. Compounds of Formulae (1A) and (18) As stated above, the disclosure encompasses Compounds ofFormulae (IA) and (LB): NH2 NH2 x2 x2 z1 \ \ 23 A / Y )\(a A /2t N)—Yi X4 22 N X0 X4 Z2 \ , R Xb R Xb—Xd (IA) (H3) or a pharmaceutically acceptable salt thereof, wherein: (a) each of Z, Z; and Z; is independently CH or N; (b) Y is CH2, 0, or S; (c) Xa, Xb, Xc and Xd are independently selected from CH, CH2, 0, N, NH, S, yl, fluoromethylene, and difluoromethylene selected so as to satisfy e, wherein each bond to an X group is either a single bond or a double bond; (d) X; is halogen, aryl, alkynyl, or amino; (e) X4 is hydrogen or halogen; and (i) R is straight-chain— or branched— substituted or unsubstituted alkyl, straight-chain- or branched— substituted or unsubstituted alkenyl, ht-chain— or branched- substituted or unsubstituted alkynyl, or tuted or unsubstituted cycloalkylwherein the R group is interrupted by -S(O)N(RA)-, -NRAS(O)-, -SOZN(RA)—, -NRASOZ-, - C(O)N(RA)-, and -NRAC(O)—, and/or terminated by -S(O)NRARB, -NRAS(O)RB, - SOgNRARB, ~NRASOZRB, -C(O)NRARB, or -NRAC(O)RB, n each RA and RE is independently selected from hydrogen, Cl—C6 alkyl, C2-C5 alkenyl, C2-C6 alkynyl, lkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, kyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl.

In certain embodiments, there may be 1, 2 or 3 upting and/or terminating groups, which may be the same or different. In general, the R groups of these compounds can be described as sulfonamido groups, sulfinamido groups, or amido groups.

In certain embodiments, specific R groups include Without limitation: 2-ethanesulfonic acid iscpropylamide, 2—ethanesulfonic acid ethylamide, Z—ethanesulfonic acid methylamide, 2- ethanesulfonic acid amide, 2-ethanesulfonic acid t—butylamide, 2-ethanesulfonic acid isobutylamide, 2-ethanesulfonic acid cyclopropylamide, isopropanesulfonic acid 2-ethylamide, ethanesulfonic acid 2-ethylamide, N-2 ethyl methanesulfonamide, y1-pr0pane-2—sulfonic acid 2-ethylamide, 2-methyl-propane—Z—sulfinic acid 2-ethylamide, 2—methyl-propane—l—sulfonic acid Z-ethylamide, cyclopropanesufonic acid 2-ethylamide, 3-pr0pane-l-sulfonic acid isopropylamide, 3—propane—l-sulfonic acid mide, 3-propane-l-sulfonic acid methylamide, 3- propane-l-sulfonic acid amide, 3-propane-l-sulfonic acid lamide, 3—propane—l-sulfonic acid isobutylamide, 3~propane—l-sulfonic acid cyclopropylamide, e—2-sulfonic acid 3— propylamide, ethanesulfonic acid 3—propylamide, Npropyl methanesulfonamide, 2-methyl- propane-Z-sulfonic acid 3-propylamide, 2~methyl—propanesulfinic acid 3<propylamide, 2—methyl— propane-l-sulfonic acid 3—propy1amide, cyclopropanesulfonic acid 3—propylamide, 3—N—isopropyl propionamide, 3—N—ethyl propionamide, 3-N-methyl propionamide, 3—propionamide, 3—N—t—butyl propionamide, 3-N—isobutyl propionamide, 3—N-cyclopropyl propionamide, N—Z-ethyl isobutyramide, N-Z-ethyl propionamide, N—2-ethyl acetamide, N—2-ethyl formamide, N-Z—ethyl 2,2— dimethyl-propionamide, N—2—ethyl 3-methylbutyramide, and cyclopropane ylic acid 2—ethyl- amide.

In n embodiments, c R groups include without limitation: cyclopropane carboxylic acid 3—propyl-amide, Npropyl 2,2-dimethyl—propionamide, N—propyl-Z-methyl- propane-Z-sulfinamide, t—butanesulfonic acid 3—propylamide, and cyclopropanesulfonic acid 3- propylamide.

In another embodiment, 21 is CH. In another embodiment, Z2 is CH. In another embodiment, 23 is CH. In another embodiment, Z1 is N. In another embodiment, Z; is N. In another embodiment, 23 is N.

In another embodiment, Z and 2,2 are each CH. In r embodiment, 21 and Z3 are each CH. In another embodiment, Z; and Z; are each CH. In another embodiment, 21 and Z; are each N. In another embodiment, 21 and Z3 are each N. In another ment, Z1 and 23 are each N.

In another embodiment, 21 and Z; are each CH and Z3 is N. In another embodiment, 21 and Z; are each CH and Z2 is N. In another embodiment, Z; and Z; are each CH and Z1 is N. In another embodiment, 21 and Z2 are each N and Z3 is CH. In another embodiment, Z1 and Z3 are each N and Z: is CH. In another embodiment, Zz and 23 are each N and Z; is CH. In r embodiment, Z1, 24, and 23 are each CH. In another embodiment, Zl, Z2, and Z3 are each N.

In the structures set forth in Formulae (l) through (6) below, embodiments are provided in which Z}, 22, and Z; are each N. These ments are intended as exemplary, and are not intended to e the above embodiments in which one, two, or three of 21, 22, and Z3 is CH with the same substituents or other substituent combinations within the scope of Formulae (IA) and (IB) as set forth above. In ular, embodiments in which 24 or 23 are each CH are ered to be Within the scope of this disclosure.

B. ions As used in connection with the present disclosure, the terms used herein have the following meaning: The terms ”alkyl" and "substituted alkyl“ are interchangeable unless otherwise specifically noted and refer to substituted and unsubstituted C1—C1.) straight-chain saturated tic hydrocarbon groups, i. e., groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, and substituted and tituted C3-Cm ed saturated aliphatic hydrocarbon groups, i.e., groups having 3, 4, , 6, 7, 8, 9, or 10 carbon atoms. For example, "alkyl" es but is not limited to: methyl (Me), ethyl (Et), propyl (Pr), isopropyl, butyl (Bu), tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like. In one embodiment, an alkyl is a C1-C5 alkyl, i.e., a group having 1, 2, 3, 4, 5, or 6 carbon atoms. An alkyl can be substituted with 1, 2, or 3 tuents or optionally substituted with l, 2, or 3 substituents. Illustrative examples of substituted C1—C6 alkyl groups include ~CHZOH, - CFZOH, —CH2C(CH3)2C(O)OCH3, -CF3, —C(O)CF3, -C(O)CH3, —(CH2)4SCH3, — CH(C(O)OH)CH2CH2C(O)N(CH3)2, -(CH2)5NHC(O)NH2, -CH2CH2-(4—fluorophenyl), - CH(OCH3)CH2CH3, —CHZSOzNH2, and *CH(CH3)CH2CH20C(O)CH3.

The terms "alkeny " and "substituted aikenyi" are interchangeable unless otherwise specifically noted and refer to substituted and unsubstituted C2-C1.) straight-chain aiiphatic hydrocarbon groups having 1, 2, or 3 carbon-carbon double bonds, i.e., groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, and substituted and tituted Cg-Cw branched aliphatic hydrocarbon groups having 1, 2, or 3 carbon—carbon double bonds, i.e., groups having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. For exampIe, "alkenyl" includes but is not limited to: ethenyl, -lenyl , —Z-enyl, 2—prop—l—eny1, 3-eny1, 2-pentenyl, 1-heXenyl, 1-hept—7-eny1, l-oct- 8-eny1, and the like. In one embodiment, an alkenyl is a C2-C5 l, i.e., a group having 2, 3, 4, , or 6 carbon atoms and 1 or 2 carbon-carbon double bonds. An alkenyl can be substituted with 1, 2, or 3 substituents or optionally substituted with 1, 2, or 3 substituents. Illustrative examples of substituted C2-C6 alkenyl groups include -C(H)=CHCHZOH, —C(H)=CF2, — CH2C(H)=CH(CH2)2CFZOH, ~CH1C(=CH2)C(O)OCH3, —C(H)=CHCF3, - CH2CH2C(H)=CHC(O)CH3, -C(H)=C(CH3)SCH3, -C(H):CHC(H):C(CH3)C(O)OCH3, and — C(H)=C=CHOC(O)CH3.

The terms "alkyny " and "substituted alkyny " are interchangeable unless otherwise specifically noted and refer to substituted and unsubstituted C2-C3“) straight—chain aliphatic hydrocarbon groups having 1, 2, or 3 carbon—carbon triple bonds, i.e., groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, and substituted and unsubstituted C3-C10 branched aliphatic arbon groups having 1, 2, or 3 carbon-carbon triple bonds, i.e., groups having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. For example, "alkynyl" includes but is not limited to: ethynyl, 1-prop yny1, 1-propyny1, -1—yny1, 3-prop—1—ynyl, l—but~3—yny1, 2-pent-2—ynyl, 6—yny1, l— heptynyl, 1-0ct-8ynyl, and the like. In one ment, an alkynyl is a C2—C5 alkynyl, i. e., a group having 2, 3, 4, 5, or 6 carbon atoms and l or 2 carbon-carbon triple bonds. An alkynyl can be substituted with 1, 2, or 3 substituents or optionally substituted with 1, 2, or 3 substituents.

Illustrative es of substituted C2—C6 alkynyl groups include -CECCHZOH, -CECF, - CHZCEC(CH2)2CFZOH, -CECCH2C(O)OCH3, -CH2C'="CCF3, -CH2CH2CECC(O)CH3, ~CECSCH3, and -CECC(O)OC(O)CH3.

The terms "cycloalkyl" and "substituted cycloalkyl" are interchangeable unless otherwise specifically noted and refer to a mono- or multi-ringed carbocycle wherein each ring contains 3, 4, , 6, 7, 8, 9, or 10 carbon atoms, and wherein any ring can contain 1, 2, or 3 carbon—carbon double “ includes but is not limited to: or triple bonds. For example, "cycloalky cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl, cycloalkynyl, and cycloheptyl. A cycloalkyl can be tuted with l, 2, or 3 substituents or optionally substituted with 1, 2, or 3 substituents.

The term "amino" refers to the group -NR|R2, wherein R1 and R2 are each independently H, C1-C6 alkyl, C2—C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, eteroaryl, heteroarylalkyl, or alkylheteroarylalkyl.

Optionally the amino group can be protonated to provide a compound in salt form. A protonated amino group, being positively charged, is usually associated with an anion known to those in the art, such as OH', Cl", Br‘, CH3C(O)O‘, H2P04', or HSO4‘.

The terms "aryl" and "substituted aryl" are interchangeable unless otherwise specifically noted and refer to a monocyclic, polycyclic, biaryl aromatic groups covalently attached at any ring position capable of g a stable covalent bond, certain preferred points of attachment being apparent to those in the art (e.g, 3-phenyl, 4—naphthyl, and the like). An aryl can be substituted with l, 2, or 3 substituents or optionally tuted with l, 2, or 3 substituents. The definition of "ary " includes but is not limited to heteroaryl. Illustrative examples of aryl groups include phenyl, biphenyl, yl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, anthracenyl, pyridyl, pyrimidyl, zinyl, thiadiazolyl, and the like.

The term "heteroalkyl" refers to an alkyl group where one or more of the carbon atoms or hydrogen atoms present is replaced, independently, with a nitrogen, oxygen, sulfur, or halogen atorn. If the heteroatom does not have the same number of e sites as the carbon atom it replaces, the number of hydrogens bonded to the replacement heteroatom may need to be increased or decreased to match the number of valence sites of the heteroatom. For example, if a carbon atom (with a e of four) is replaced by a nitrogen atom (valence of , one of the hydrogen atoms ly attached to the replaced carbon is deleted. Likewise, if a carbon atom is replaced by a halogen atom (valence of one), three of the hydrogen atoms ly attached to the replaced carbon is deleted. The term oalkyl" also refers to (1) an alkyl group where at least one of the hydrogen atoms attached to a carbon or (2) to a heteroalkyl group where at least one of the hydrogen atoms attached to a heteroatom of the heteroalkyl can be substituted with at least one of the following: alkyl, aryl, and alkyl.

The terms "heteroaryl" and “substituted heteroaryl" are interchangeable unless otherwise specifically noted and the terms "heterocyclo" and "substituted heterocyclo" are interchangeable unless otherwise specifically noted and these terms refer to a monovalent unsaturated group having a single ring or multiple condensed rings, from 1 to 8 carbon atoms, and from 1 to 4 heteroatoms within the ring, each heteroatom being independently selected from nitrogen, , or oxygen. In either heteroaryl or cyclo, the point of attachment to the molecule can be at a heteroatom or elsewhere within the ring. A heteroaryl or heterocyclo can be substituted with l, 2, or 3 substituents or optionally substituted with l, 2, or 3 substituents.

Illustrative examples of heteroaryl groups include thienyl, hienyl, isobenzothienyl, 2,3—dihydrobenzothienyl, furyl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, yl, pyrrol—3—yl, pyrrol-l-yl, l, isoindolyl, 3H—indolyl, indolinyl, indolizinyl, indazolyl, imidazolyl, imidazol-4—yl, dazolinyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, pyrimidin—Z-yl, nyl, quinolyl, isoquinolyl, 4H—quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, hiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, pyrazolyl, pyrazol—3—yl, triazolyl, 1,2,4—triazol-l -yl, tetrazolyl, tetrazol-l-yl, thiazolyl, thiazol—4-yl, isothiazolyl, benzthiazolyl, oxazolyl, oxazol-Z-yl, olyl, isoxazol—3 —yl, benzoxazolyl, oxadiazolyl, 1,2,4—oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazin—2~yl, thiophen—Z—yl, furan—2- yl, pyridin—Z-yl, pyridinyl, pyrimidin—Z-yl, and the like.

When any group is substituted with l, 2, 0r 3 substituents or optionally substituted with l, 2, or 3 substituents, each substituent is independently selected from the group sing halo, — OH, -SH, —CN, -N01,-NH2, trihalomethyl, pentahaloethyl, C1—Cmalkyl, Cmalkyl, C0- CloalkyloxyCo—Cmalkyl, CloalkyloxyCO-Cmalkyl, lkylthioCo-Cloalkyl, arleo- CloalkylthioCO-Cmalkyl, C0-C1oalkylaminoCo-Cwalkyl, arleo—CloalkylanrinOC0«C10alkyl, N—aryl-N— Co-CloalkylaminoCO-Cwalkyl, C,-Cmalkylcarbony1C0-C1oalkyl, arle1~C1oalkylcarbonleO-Cloalkyl, C1-C10alkylcarboxyCo—C1Dalkyl, arle1-C1oalkylcarboxyCo—Cmalkyl, C1-C10alkylcarbonylarninoCo- Cloalkyl, arleI«CloalkylcarbonylarninoCO—Cloalkyl, 0alkle(O)ORx, and -Co— Cloalkle(O)NRsz wherein RX, RY and R1 are independently selected from hydrogen, alkyl, and aryl or RY and RZ are taken together with the nitrogen to which they are attached to form a saturated cyclic or unsaturated cyclic system having 3, 4, 5, 6, 7, or 8 carbon atoms with at least one substituent as defined above. A “Coalkyl,” as in C0—C10alkyl, is a covalent bond.

The term "Co-C10alkyloxy" refers to an alkyl group having the indicated number of carbon atoms and attached to the molecule through an oxygen atom. In one embodiment, a C0-Cloalkyloxy is a lkyloxy, i.e., a group having 1, 2, 3, 4, 5, or 6 carbon atoms. Illustrative examples of alkyloxy groups include methoxy, , n—propyloxy, and pyloxy. Thus, the term "Co- CmalkyloxyCO-Cloalkyl" refers to a C0-C10alkyloxy attached through an oxygen atom to a C0- Cmalkyl which is attached to the molecule. Likewise, the term "arleo-CloalkylouyCmCmalkyl" refers to a C0—C10alkyloxy, which is substituted by aryl, ed through an oxygen atom to a C0— Cwalkyl which is attached to the molecule. A "Cualkyloxy" is -OH.

The term oalkylthio" refers to an alkyl group having the indicated number of carbon atoms and attached to the molecule through a sulfur atom. In one embodiment, a C0—Cloalkylthio is a lkylthio, i. e., a group having 1, 2, 3, 4, 5, or 6 carbon atoms. Illustrative examples of alkyloxy groups include methylthio, hio, n-propylthio, and isopropylthio. Thus, the term "Co- CwallcylthioCo-Cmalkyl" refers to a C0-Cmalkylthio attached through a sulfur atom to a C0-C10alkyl which is attached to the molecule. Likewise, the term "arleo-CmalkylthioCo-Cloalky " refers to a lkylthio, which is substituted by aryl, attached through a sulfur atom to a C0-Cwalkyl which is attached to the molecule. A"C0alky1thio" is —SH.

The term "C1—C10a1kylcarbony1" refers to an alkyl group having the indicated number of carbon atoms and ed to the molecule through the carbon atom of a carbonyl group. In one embodiment, a C1-Cmalkylcarbonyl is a lkylcarbonyl, i.e., a group having 1, 2, 3, 4, 5, or 6 carbon atoms, including the carbonyl carbon atom. Thus, the term "Cl-Cloalkylcarbonleo- Cloalkyl" refers to a C1-Cmalky1carbonyl attached through the carbon atom of a carbonyl group to a C0—C10alkyl which is attached to the molecule. se, the term "arle1-C10alkylcarbonleo- Cloalkyl" refers to a C1-Cmalky1carbonyl, which is substituted by aryl, attached through the carbon atom of a carbonyl group to a C0—C10alkyl which is attached to the molecule.

The term "CrCloalkylcarboxy" refers to an alkyl group having the indicated number of carbon atoms, including the carboxy's carbon atom, and attached to the molecule through the carboxy group, wherein the carboxy group has either a -C(=O)-O- or a -O-C(=O)- orientation. In one embodiment, a C1-C10a1kylcarboxy is a C1-C5alkylcarboxy, 122., a group having 2, 3, 4, 5, or 6 carbon atoms, including the carboxy's carbon atom. Thus, the term 0alkylcarboxyCo- Cloalkyl" refers to a C1—C10alky1carboxy attached through the y group to a alkyl which is attached to the molecule. Likewise, the term "arle1-C10alky1carboxyC0-C1oalkyl" refers to a C1- Cwalkylcarboxy, which is substituted by aryl, attached through the carboxy group to a C0-Cmalkyl which is attached to the molecule.

The term "Co-Cloalkylamino" refers to an alkyl group having the indicated number of carbon atoms and attached to the molecule through the nitrogen atom of the amino group —N(Rw)—, wherein Rw is H, C1-C6alkyl, or aryl. A "Coalkylamino" is -NHRW. In one embodiment, a C0- Cloalkylamino is a C1-C6alky1amino, i. a, a group having 1, 2, 3, 4, 5, or 6 carbon atoms in the alkyl group and 0, 1, 2, 3, 4, 5, or 6 carbon atoms in the RW group. Thus, the term "Co—CloalkylaminoCo- Cmalkyl" refers to a C0—C10alkylamino ed through the nitrogen atom of an amino group to a C0-Cmalkyl which is attached to the le. Likewise, the term ”arleO-CwalkylaminoCo- Cloalkyl" refers to a C0—C10alkylamino, which is substituted by aryl, attached through the nitrogen atom of an amino group to a C0—Cwalky1 which is attached to the molecule. The term “N—aryl—N— C0-C1oalkylaminoCo—Cmalkyl" refers to an amine nitrogen atom substituted by aryl and lkyl, that nitrogen atom being further attached to a C0—C10alkyl which is attached to the molecule.

The term “C1—C10alkylcarbonylamino" refers to an alkyl group having the indicated number of carbon atoms, including the ylamino's (i.e., amide‘s) carbon atom, and attached to the molecule through the amide, group, wherein the amide group has either a -C(=O)N(RV)— or a — N(RV)C(=O)- orientation and wherein RV is H or C1-C6alkyl. In one embodiment, a C1- Cmalkylcarbonylamino is a C1-C5alkylcarbony1amino, i.e., a group having 2, 3, 4, 5, or 6 carbon atoms, including the amide's carbon atom, in the alkyl group and O, 1, 2, 3, 4, 5, or 6 carbon atoms in the RV group. Thus, the term "Cl—C10alkylcarbonylaminoCo-Cloalkyl" refers to a C,- Cmalkylcarbonylamino attached h the amide group to a C0-Cwa1kyl which is attached to the molecule. Likewise, the term "arle1-C1oalkylcarbonylaminoC0-Cmalkyl“ refers to a C1— Cloalkylcarbonylamino, which is tuted by aryl, attached through the amide group to a C0- Cloalkyl which is attached to the molecule.

The term "alkylary " refers to an aryl group as defined above that is tuted with 1, 2, or 3 alkyl groups as defined above; a tolyl group is an exemplary alkylaryl. In one embodiment, an alkylaryl group is a "lower alkylaryl" group having 1, 2, or 3 alkyl groups attached to an aryl group, each alkyl group having, independently, 1, 2, 3, 4, 5, or 6 carbon atoms.

The term "arylalkyl" refers to an alkyl group as defined above that is substituted With 1, 2, or 3 aryl groups as defined above; a benzyl group is an exemplary arylalkyl. In one embodiment, an arylalkyl group is a "lower arylalkyl“ group having 1, 2, or 3 aryl groups ed to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms.

The term "heterocycloalkyl" refers to an alkyl group as defined above that is tuted with 1, 2, or 3 heterocyclo groups as defined above. In one embodiment, a heterocycloalkyl group is a "lower heterocycloalkyl" group having 1, 2, or 3 heterocyclo groups attached to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms.

The term "alkylheteroaryl" refers to a heteroaryl group as defined above that is substituted with 1, 2, or 3 alkyl groups as defined above. In one embodiment, a alkylheteroaryl group is a "lower alkylheteroaryl" group having 1, 2, or 3 alkyl groups attached to a heteroaryl group, each alkyl group having, independently, 1, 2, 3, 4, 5, or 6 carbon atoms.

The term "heteroarylalkyl" refers to an alkyl group as defined above that is substituted with 1, 2, or 3 aryl groups as defined above. In one embodiment, a arylalkyl group is a "lower heteroarylalkyl" group having 1, 2, or 3 aryl groups attached to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms.

The term "alkylheteroarylalkyl" refers to a heteroarylalkyl group as defined above that is substituted with 1, 2, or 3 alkyl groups as defined above. In one embodiment, an alkylheteroarylalkyl group is a "lower alkylheteroarylalkyl" group with each alkyl portion having, independently, l, 2, 3, 4, 5, or 6 carbon atoms.

The terms "halogen" and "halo" refer to fluorine, chlorine, bromine, and iodine.

An R group disclosed to be " interrupted by -S(O)N(RA)-, -NRAS(O)—, -SO;N(RA)-, - NRASOZ-, -C(O)N(RA)-, and —NRAC(O)—, and/or ated by —S(O)NRARB, —NRAS(O)RB, - SOgNRARB, —NRASOZRB, RARB, or —NRAC(O)RB", means said R group is (1) interrupted by one or more (for examplel, 2, or 3) —S(O)N(RA)—, -NRAS(O)-, -SOZN(RA)-, —NRASOZ-, - C(O)N(RA)—, or ~NRAC(O)— groups, (2) terminated by —S(O)NRARB, -NRAS(O)RB, -SOZNRARB, - NRASOZRB, -C(O)N'RARB, or -NRAC(O)RB groups, or (3) interrupted by one or more (for e 1, 2, or 3) -S(O)N(RA)—, -NRAS(O)-, RA)-, -NRA802-, -C(O)N(RA)-, or -NRAC(O)- groups and terminated by an -S(O)NRARB, —NRAS(O)RB, -SOZNRARB, —NRASOZRB, -C(O)NRARB, or -NRAC(O)RB group. In one embodiment, there are two uptions and no terminations of an alkyl R group as described above. In another ment, there is one interruption and no terminations of an alkyl R group as described above. In another embodiment, there is no interruption and a ation of an alkyl R group as described above. In another embodiment, there is one interruption and a termination of an alkyl R group as bed above.

Should there be doubt as to the agreement of a depicted chemical structure and a chemical name, the ed chemical structure governs.

The term "pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of the "free" compounds of Formulae (1A) and (18). A pharmaceutically acceptable salt can be ed from the reaction of the free base of a Compound ofFormulae (IA) or ([B) with an inorganic acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or an organic acid, for example, sulfonic acid, carboxylic acid, organic phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, salicylic acid, lactic acid, tartaric acid (e.g., (+)—tartaric acid or (-)-tartaric acid or mixtures thereof), and the like. Certain compounds of Formulae (IA) and (IB) have acidic substituents and can exist as pharmaceutically acceptable salts with pharmaceutically acceptable bases. The present disclosure includes such salts. Examples of such salts include metal counterion salts, such as sodium, potassium, lithium, magnesium, calcium, iron, copper, zinc, tin, silver, or aluminum salts, and organic amine salts, such as methylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, ylarnine, 2-propylamine, or dimethylisopropylamine salts, and the like. The term aceutically acceptable salt" includes mono-salts and nds in which a plurality of salts is present, e.g., di—salts and/or tri—salts. Pharmaceutically able salts can be prepared by methods known to those in the art.

Certain compounds of Formulae (IA) and (TB) and/or their pharmaceutically acceptable salts can exist in more than one l form and the present disclosure encompasses each crystal form and mixtures thereof. These l forms can be prepared by methods known to those in the art.

The term "solvate" refers to a x or aggregate formed by one or more molecules of a solute, e.g., a Compound of Formulae (IA) or (TB) or its pharmaceutically acceptable salt, and one or more molecules of a solvent, which is present in stoichiometric or non—stoichiometric amount.

Suitable solvents include but are not limited to water, acetic acid, ethanol, methanol, isopropanol, and n-propanol. Where the solvent is water, the e is a hydrate, Exemplary hydrates include but are not limited to a hemihydrate, a monohydrate, a dihydrate, a tn'hydrate, and a tetrahydrate.

In one embodiment, the solvent is pharmaceutically acceptable. In another embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a noncrystalline form. The present disclosure encompasses each solvate and mixtures thereof.

These solvates can be prepared by methods known to those in the art.

Certain compounds of ae (IA) and (IE) may exist in different tautomeric forms or as different geometric isomers, and the present disclosure includes each tautomer and/or geometric isomer of compounds of Formulae (IA) and (TB) and mixtures thereof.

Certain compounds of Formulae (IA) and (B) may contain one or more chiral centers and exist in different optically active forms, and the present sure includes each optically active form of compounds ofFormulae (IA) and (1B) and mixtures f When compounds of Formulae (IA) and (TB) contain one chiral center, the compounds exist in two enantiomeric forms and the present disclosure includes both enantiomers and es of enantiomers, such as c es. The enantiomers may be resolved by methods known to the art, for example, by formation of diastereoisomeric salts which may be separated, e,g. or liquid , by llization chromatography. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, ates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation. When 3 Compound of Formulae (IA) or (113) contains more than one chiral center, it may exist in reoisomeric forms. The diastereoisomeric compounds may be separated by s known to the art, for example, by chromatography or crystallization, and the individual enantiomers may be separated as described above. The present disclosure includes each diastereoisomer of compounds ofFormulae (IA) and (IE) and mixtures thereof.

The term "isotopically enriched" refers to a Compound of Formulae (IA) or (B) that contains an unnatural tion of an isotope at one or more of the atoms constituting the compound, and the present disclosure includes each isotopically enriched form of compounds of Formulae (IA) and (TB) and mixtures thereof. In certain embodiments, an isotopically enriched compound contains ral proportions of one or more isotopes, ing but not limited to hydrogen (1H), deuterium (2H), tritium (3H), —ll (”C), carbon-12 (12C), carbon—l3 (BC), carbon—l4 (14C), nitrogen—l3 (UN), nitrogen-l4 (14 , en-15 (LIN), oxygen—14 ('40), oxygen— (‘50), oxygen—l6 (160), oxygen-l7 (170), oxygen-18 (180), fluorine—l7 (17F), fluorine-18 (‘81:), sulfur-32 (32$), sulfur-33 (33S), sulfur-34 (34$), sulfur-35 (”8), sulfur-36 (36S), chlorine—35 (35cm, chlorine-36 (36cm, chlorine-37 (37cm, bromine-79 (7913i), bromine-81 (3113:), iodine-123 (”31), iodine-125 (”51), iodine—127 (”71), iodine—129 (”991), and iodine—131 (ml). In another embodiment, an isotopically enriched compound contains unnatural proportions of one or more isotopes, including but not limited to 1H, 2H, 12C, 13C, ”N, 15N, 16O, 17O, 13O, 17F, ”S, 33S, 3"S, 368, 35Cl, ”Cl, 79Br, 81Br, and 127I.

In another embodiment, an isotopically enriched compound is ctive. In another embodiment, an isotopically enriched compound contains ral proportions of one or more isotopes, including but not limited to 3H, 11C, 4C, 13N, 140, [50, 18F, 35S, 3éCl, 123], 1251, 129I, and 131I. In another embodiment, an isotopically enriched compound contains unnatural proportions of 123I, 124I, or 1311 and another isotope selected from 3H, 11C, 4C, 13N, 14O, 150, 18F, 358, and 36Cl. In r embodiment, an ically enriched compound contains an unnatural proportion of mi, 1241, and/or 1311. In another embodiment, an isotopically enriched compound contains an unnatural tion of 123I. In another embodiment, an isotopically enriched compound ns an unnatural proportion of 124I. In another ment, an isotopically enriched compound contains an unnatural proportion of 1le The term pically enriched" refers to the percentage of incorporation of a less prevalent isotope (8g, deuterium for hydrogen) of an element at a given location in a molecule in place of a more prevalent isotope (e.g., 1H for hydrogen) of that element. When an atom at a 3O particular location in a molecule is designated as a ular less prevalent isotope, it is understood that the abundance of that isotope at that location is substantially greater than its natural abundance.

The term "therapeutically effective amount" refers to an amount of a Compound of Formulae (IA) or (IE) or a combination of two or more such compounds that inhibits, totally or partially, the progression of the treated ion or alleviates, at least partially, one or more ms of the ion. A therapeutically ive amount can also be an amount which is prophylactically effective. The amount which is therapeutically effective s on the patient's gender and size, the condition to be treated, the condition's severity, and the result sought. For a given patient, a therapeutically effective amount can be determined by methods known to those in the art.

The term "patient" refers to an animal, including but not limited to a mammal, a primate (e.g., a human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.

The term "cancer" or ”neoplastic disorder" refers to a tumor ing from abnormal or uncontrolled cellular growth. Examples of cancers include but are not limited to breast s, colon cancers, colorectal cancers, prostate cancers, ovarian cancers, pancreatic cancers, lung cancers, gastric cancers, esophageal cancers, glioma cancers, and hematologic ancies.

Examples of stic disorders include but are not limited to hematopoietic disorders, such as the roliferative disorders, ial thrombocytosis, thrombocythemia, angiogenic myeloid metaplasia, polycythemia vera, myelofibrosis, myelofibrosis with myeloid metaplasia, chronic idiopathic myelofibrosis, the cytopenias, and pre—malignant myelodysplastic mes.

The term "hematologic ancy" refers to cancer of the bone marrow and lymphatic tissue - body's blood-forming and immune system. Examples ofhematological malignancies include but are not limited to ysplasia, lymphomas, leukemias, lymphomas (non-Hodgkin's lymphoma), Hodgkin's disease (also known as Hodgkin‘s lymphoma), and myeloma, such as acute lymphocytic leukemia (ALL), adult T-cell ALL, acute myeloid leukemia (AML), AlVIL with trilineage myelodysplasia, acute promyelocytic leukemia, acute erentiated leukemia, stic large—cell ma, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic neutrophilic leukemia, juvenile myelomonocyctic ia, mixed lineage leukemia, roliferative ers, ysplastic syndromes, multiple myeloma, and prolymphocytic leukemia.

The term "leukemia" refers to malignant neoplasms of the blood-forming tissues including but not limited to aCute lymphoblastic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, chronic lymphocytic ia, and chronic myelocytic leukemia. The leukemia can be relapsed, refractory, or resistant to conventional therapy.

The term "neurodegenerative disorder" refers to a disorder in which progressive loss of neurons occurs either in the peripheral nervous system or in the central nervous system. Examples of neurodegenerative disorders include but are not limited to chronic neurodegenerative diseases such as diabetic peripheral athy, Alzheimer's disease, Pick‘s disease, diffuse Lewy body disease, progressive supranuclear palsy (Steel—Richardson syndrome), multisystem degeneration (Shy-Drager syndrome), motor neuron diseases including amyotrophic lateral sclerosis ("ALS"), degenerative ataxias, cortical basal degeneration, ALS-Parkinson's-Dementia complex of Guam, te sing panencephalitis, Huntington's disease, Parkinson‘s disease, multiple sclerosis, einopathies, primary progressive aphasia, striatonigral degeneration, Machado-Joseph disease/spinocerebellar ataxia type 3 and olivopontocerebellar degenerations, Gilles De La te's disease, bulbar and pseudobulbar palsy, spinal and spinobulbar muscular atrophy (Kennedy's e), primary lateral sclerosis, familial spastic paraplegia, e-Korsakoffs related dementia (alcohol induced dementia), Werdnig-Hoffrnann disease, erg-Welander disease, Tay—Sach's disease, Sandhoff e, familial spastic disease, Wohifart—Kugelberg— Welander disease, spastic paraparesis, progressive multifocal leukoencephalopathy, and prion diseases (including Creutzfeldt-Jakob, Gerstmann—Straussler-Scheinker disease, Kuru and fatal familial ia). Other conditions also included within the s of the present disclosure include age-related dementia and other dementias, and conditions with memory loss including vascular dementia, diffuse white matter disease (Binswanger’s disease), dementia of endocrine or metabolic origin, ia of head trauma and diffuse brain damage, dementia pugilistica, and frontal lobe dementia. Also other neurodegenerative disorders resulting from cerebral ia or infarction including embolic occlusion and thrombotic occlusion as well as intracranial hemorrhage of any type (including but not limited to epidural, subdural, subarachnoid, and intracerebral), and intracranial and intravertebral lesions (including but not limited to ion, penetration, shear, compression, and laceration). Thus, the term ”neurodegenerative disorder" also encompasses acute neurodegenerative disorders such as those involving stroke, tic brain injury, schizophrenia, peripheral nerve damage, hypoglycemia, spinal cord injury, epilepsy, , and a.

In certain embodiments, the neurodegenerative disorder is selected from mer's disease, Parkinson's disease, amyotrophic lateral sclerosis, age-related memory loss, senility, and age ed dementia. In another embodiment, the neurodegenerative disorder is Alzheimer's disease, also terized as an amyloidosis. Thus, other embodiments of the disclosure relate to the treatment or tion of other amyloidosis disorders which share features, includin, but not limited to, hereditary cerebral angiopathy, normeuropathic hereditary amyloid, Down's syndrome, macroglobulinemia, secondary familial Mediterranean fever, Muckle—Wells syndrome, multiple myeloma, pancreatic- and cardiac-related amyloidosis, chronic hemodialysis arthropathy, Finnish amyloidosis, and Iowa amyloidosis.

The term "pharmaceutically acceptable carrier" refers to a pharmaceutically—acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being ible with the other ingredients of a pharmaceutical ation, and suitable for use in t with the tissue or an organ of a patient without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable carriers are known in the art; see, e.g., Pharmaceutical Preformulation and Formulation (Gibson, ed., 2nd Ed, CRC Press, Boca Raton, FL, 2009); Handbook ofPharmaceutical Additives (Ash and Ash, eds, 3rd Ed., Gower Publishing Co., Aldershot, UK, 2007); Remington’s Pharmaceutical Sciences ro, ed., 19m Ed., Mack Publishing, Easton, PA, 1995); and Handbook ofPharmaceutical Excipients (Amer.

Pharmaceutical Ass'n, Washington, DC, 1986).

C. Compounds ula (IA) in Which Xa and X1) are Each 0 In accordance with an embodiment of the disclosure, the nds are of Formula (IA) in which Xa and Xb are each 0 and Xc is CH2. In certain embodiments, the compounds of this embodiment can be represented by Formula (1): XiflN:— ‘Q3X2N \ N\\ Y or a pharmaceutically acceptable salt thereof, wherein: Y is CH; or S; X4 is hydrogen or halogen; R is a is straight-chain— or branched- substituted or unsubstituted alkyl, straight—chain- or branched— substituted or unsubstituted alkenyl, straight—chain- or ed- tuted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl n the R group ”is interrupted by —S(O)N(RA)-, -NRAS(O)—, -SOZN(RA)—, -NRASOZ-, -C(O)N(RA)-, or -NRAC(O)—, and/or terminated by -S(O)NRARB, -NRAS(O)RB, -SOZNRARB, —NRASOZRB, -C(O)NRARB, or - NRAC(O)RB, n each RA and RE is independently selected from hydrogen, C1-C6 alkyl, C2—C6 alkenyl, C2—C6 alkynyl, cycloalkyl, alkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, arylalkyl, and alkylheteroarylalkyl; and X2 is as disclosed below.

C-I. In some embodiments ofthe disclosure, X2 is halogen. Table 1A lists specific examples of compounds within this embodiment. In each of the structures as drawn, X2 is I and X4 is H. However, corresponding structures in which X2 is F or Br are within the scope of the , C1, disclosure. In each of the structures in Table 1A, Y is S. However, corresponding structures in which Y is CH2 and/or X4 is F, Cl, Br, or I are also within the scope of the disclosure. Additionally, in connection with each of the structures in Table 1A, corresponding structures in which X; is F, C1, or Br and Y is CH; are also Within the scope of the disclosure.

Table 1A Compound N0. Structure _] Name NHZ fi’ys I O 2-[6—Aminm8—(6-iodo- N/ N A benzo[1,3]dioxol—5- 1A-1 O ylsulfanyl)—purin—9~yl]— ethanesulfonic acid HN’ isopropylamide NH2 I \ N 2-[6—Amino-8—(6-iodo— N/ 3—st benzo[1,3]di0xol-5— 1A-2 o ylsulfanyl)—purin—9-yl]- sulfonic acid HNI802 ethylamide NHZ I \ N 2-[6—Amino(6-iodo— r‘lL / IJ>‘S 0 benzo[1,3]dioxol—5— 1A-3 0) ylsulfany1)-purin—9-yl]- ethanesulfonic acid III/502 methylamide NH2 I \ 2-[6-Amino(6—iodo— 1A_4 tN/ 3—st 1,3]dioxol 8 0 ylsulfanyl)-purin—9-yl]— 302 ethanesulfonic acid amide NH2H2N I ”iflhg—S O 2-[6-Amjnc—8—(6—iodo— N/ N J benzo[1,3]dioxol—5~ lA—S 8 0 ylsulfanyl)—purin—9-yl]— ethanesulfonic acid tert- HN’ butylamide NH2 I ”l /\ VS 0 2-[6—Amino(6-iodc- N N OJ benzo[l,3]dioxol 1A-6 anyl)—purin—9-yl]— ,802 ethanesulfonic acid :2 J isobutyl-amide Com ound N0. Name 2-[6-Amino(6-iodo- N benzo[1,3]dioxol 1A—7 ? O ylsulfanyl)—purin-9—y1]— [302 ethanesulfonic acid ”N cyclopropylarnide NN/ $ng\ \ Propanesulfonic acid amino(6-iodo- lA—S 8 0 benzo[1,3]dioxol—5— (NH anyl)-purinyl]— 023 ethyl}«amide EH2 I N \ N\ Ethanesulfonic acid {2—[6- K / N%5 0 amino-S-(é-iodo- 1A—9 8 0J benzo[1,3]dioxol ylsulfanyl)—purin—9—yl]~ 02§\_ ethyl}—amide NH2 I \ N\ N-{2-[6-Amino(6-iodo— / N>‘S 0 benzo[1,3]dioxol 1A-10 3 o) ylsulfanyl)—purinyl]- ethyl}- NH methanesulfonamide NH; , \ 2-Methy1—propane—2- NN’ NfSQj sulfonic acid {2-[6-amino- 1A-11 g 0 8—(6-iodo- [NH benzo[1,3]diox01 02S ylsulfanyl)—purin—9—y1]— N ethyl} -amide \2 I N 2-Methy1—propane—2- [l / N\>‘3 o sulfinic acid {2-[6-amino- N O) 8-(6-iodo- 1A_12 2 benzo[1,3]dioxol OSINH ylsulfanyi)—purin—9—y1]~ )T ethy1}-amide NH2 .

\ N y1—propane-1— \ \>“8 o sulfonic acid {2-[6-amino- N N 1A—13 O) odo- benzo[1,3]dioxol 03 ylsuifanyI)- urin—9-p y1]— 2 L< ethy1}—amide NH2 , \ Cyclopropanesulfonic acid NN/ HQB {2-[6-amin0(6-iodo— 1A—14 benzo[1,3]dioxol—5— ylsulfanyl)—purin—9-y1]— ethyl} ~amide Compound No. Name 3-[6-Amjno(6-iodo- benzo[1,3]diox01—5— 1A-15 ylsulfanyl)-purin—9-y1]— propane-1 nic acid isopropylamjde min0-8—(6-iodo- benzo[ 1 ,3]diox01—5- 1A-16 ylsulfany1)—purinyl]— propane-1 -su1fonic acid mide 3-[6-Amino—8—(6-iodo- benzo[ 1,3]diox01 1A-17 ylsulfanyD-purinyl} propane«1 —sulfonic acid amide 3—[6-Amino—8—(6—iodo— benzo[1,3]dioxol-5 - 1A-18 ylsulfanyl)—purin—9—y1]— propane—1 —sulfonic acid amide 3-[6—Amino—8—(6-iodo— benzo[1,3]dioxol-5— 1A—19 ylsulfany1)—purin—9—y1] — propane—l—sulfonic acid tert-butylamide 3-[6-Amino(6-iodo- benzo[1,3]dioxol—5— 1A—20 ylsulfanyl)—purin—9—yl]— propane-1 -sulfonic acid isobutyl-amide 3-[6-Amino-8—(6—iodo— benzo[1,3]dioxol—5- 1A—21 y1su1fany1)—purin-9—y1]— propans-1 ~su1fonic acid cyclopropylamide Compound No. Structure Name “151,2?stNH2 I Propane-Z-sulfonic acid N {3—[6—amino(6-iodo- 1A—22 i benzo[1,3]dioxol—5- ylsulfanyl)-purin—9—yl]— ”NS02 propyl} -arnide NH2 I NiN/ Nfs‘Qj\ Ethanesulfonic acid {3-[6- amino(6-iodo— 1A-23 O 1,3]dioxol-5— anyl)-purin—9—yl]— ”N302 propyl}-amide SEEKS I \ N \ Q j N—{3-[6-Amino—8—(6-iodo— benzo[1,3]dioxol—S— 1A-24 O ylsflfanyl)-purin—9-y1]- prowl}- HNISO esulfonamide NH2 I “if 3‘ng\ 2-Methyl-propane sulfonic acid {3—[6-amino- 1A-25 8-(6-iodo— benzo[1,3]dioxol HNI y1su1fany1)—purin—9-yl]- 302 propyl}~amide NH2 I “if 3“st\ N 2-Methy1-propane—2- sulfinic acid {3—[6—amino- 1 A—26 8-(6—i0do- benzo[1,3]dioxol HNI ylsulfanyl)-pm'in—9—yl]— so propy1}—amide NHQ I “if 3—8ng 2-Methyl-propane sulfonic acid {3-[6—amino- 1A—27 odo— benzo[1,3]di0X01—5— HNI yIsulfanyl)-purin—9-y1]— $02 propy1}-amide NH; I In : ysQo Cyclopropanesulfonic acid N N O) {3-[6-amino(6-iodo— 1A-28 benzo[1,3]dioxol ylsulfany1)-purin—9-y1]- propyl} -amide Compound N0. Structure Name NH2 I “P “\ - k / N>—5 ‘ o 3—[6-Am1no(6-1od0- 1A-29 <1 OJ 1,3]dioxol ylsulfanyl)—purin—9-yl]-N— isopropyl-propionalnide fig—8&0I 3-[6—Amino(6-iodo— N/ N 1A-3O J benzo[1,3]dioxol ylsulfanyl)—purin—9-yl]—N— 0 ethyl-propionamide NHQ I 1\ “\>_SQO 3—[6—Amino(6-iodo- N/ N 1A-31 J benzo[1,3]dioxol ylsulfanyl)—purin—9—yl]—N- o -propionamide MHZ,“3 I \ 3-[6—Amino—8-(6-iodo- 1A-32 {LIN%SQ3 benzo[1,3]dioxol~5- O ylsulfanyl)—purin—9—yl]— O propionamide NH?“ , M \ N\ k / N>—S . . o 3-[6-Annno—8-(6~1odo- 1M3 i: O) benzo[1,3]diox01-5— ylsulfanyl)-purin—9-y1]-N— HN tert—butyl—propionamide NH2 I [‘1 \ N\ .

L , NFS . o 3—[6-Arn1no—8-(6-10do— 1M4 é: o) benzo[l,3]di0X01—5- ylsulfanyl)-purinyl]—N— HNLO< isobutyl-propionamide {ENVSQOIN 3-[6-Amino—8-(6—iodo- 1A-35 é: OJ benzo[1,3]dioxol anyl)—purinyl]-N- HN cyclopropyl—propionanfide NH2 I t / N‘HQS N-{Z—[6—Am1no-8—(6—1od0-. 1A-36 2 o benzo[1,3]diox01—5- ylsulfanyl)—purin—9—yl]— ethyl}-isobutyramide Comgound No. ure Name NH2 I NI \ “(HQ N—{Z-{6-Amino(6-iodo— N/ N 1A 37 benzo[1,3]dioxol ' 2 O ylsulfany1)-purin—9-y1]- NH ethy1}-propionamide NH;— I NI \ kS‘QO N—{2-[6-Amino(6-iodo~ N/ N 1A 38 A benzo[1,3]dioxol-5— - 2 O ylsulfanyl)~purin—9-y1]— NH ethyl}-acetamide NH2 I N \ N\ N—{Z—[6«Amjno—8-(6-iodo— “\N/ 8“st benzo[1,3]dioon—5— 1A-39 O yl ' su1fanyl -purm—9-y1] - NH ethyl} -2,2-dimethyl- 03$? propionamide NH2 I \ N-{Z—[6-Amin0(6-iodo- H/ NH‘QE benzo[1,3]diox01 1A-40 g 0 ylsulfanyl)—purin~9—y1]— NH ethy1}-3—methy1~ 0 butyramide NH2 I ”Jiflfs Cyclopropanecarboxylic kN/ N acid {2-[6-amino(6— 1A-41 8 O iodo—benzo[1,3]diox01—5— NH ylsulfanyl)—purin—9—y1]— 03$ ethyl}-amide ””2 1 Vivi N-{2—[6—Amino—8—(6—iodo— 1A 42 lN/ N%s benzo[1,3]dioxol—5— 2 0 anyl)—puriny1]— NH ethyl}-formamide NH; I “(Edy-s o N—(3—(6—amino((6— N oJ 1A 43 nzo[d][1,3]dioxol -5—y1)thio)—9H—purin—9— 0 y1)propy1)piva1amide NH2 I “C NHQE N—(3-(6-Amino-8—((6— N N 1A-44 iodobenzo[d][1,3]dioxol y1)thio)—9H—purin—9- yl)propy1)isobutyramide nd No. Structure Name N—3—(6—amino—8-((6~ iodobenzo[d][l,3]dioxol 1A—45 i —5-y1)thio)-9H-purin—9- NH yl)propy1)cyclopropane 0;» carboxamide t 1‘ N‘>~s Q N—(3«(6-Arnino—8—((6— k” 0 N o) 1 A-46 it“ iodobenzo[d][1,3]dioxol thio)—9H—purin—9— 0 DH yl)propyl)isobutyramide “\“1 ' N 1-((3-(6—Arnino((6- Nu, ‘)—S o iodobenzo[d][1,3]dioxol N N J . . 0 —5-y1)thio)—9H—pur1n lA—47 yl)propyl)arnino)—2- 0a)?,Ac methyl—l—oxopropan—Z- yl acetate NH2 , NI \ NVSQO N-(3-(6—Amino-8—((6— N” N O) nzo[d][l,3]dioxol 1A-48 i -5—y1)thio)—9H—purin—9— NH yl)propyl)—2—hydroxy—2- ()on methylpropanamide NH2 I Mp NHQ N—(3-(6—amino—8-((2— N/ N iodo—S— 1A-49 methoxyphenyl)thio)— HN 9H—purin—9— 0 yl)propyl)pivalamide NH2 l H/ 9—5 o) 6—(6—arnino—8—((6- iodobenzo[d][1,3]dioxol 1A~50 —5-y1)thio)-9H—purin-9— yl)hexanamide Table 4A lists specific examples in which X2 is halogen and X4 is halogen. In each of the structures as drawn, X2 is I and X4 is F. However, corresponding structures in which X4 is H, Cl, Br, or I are within the scope of the sure. In each of the structures in Table 4A, Y is CH2, However, corresponding structures in which Y is S and]or X; is F, C1, or Br are also within the scope of the disclosure. Additionally, in connection with each of the ures in Table 4A, corresponding structures in which X4 is H, Cl, Br, or I and Y is S are also within the scope of the disclosure.

Table 4A Compound No. Structure Name NH2 I jfj'i. 2-(6-aufinofluoro-8—((6- F N/ N J iodobenzo[d][1,3]diox01—5— 4A-1 g 0 y1)methyl)-9H—purin—9-y1)- 802 N—isopropyl— HN ethanesulfonamide NH2 I i: VQON 2-(6-aminofluor9fl6- F N N ) 10d0benzo[d][1,3]d10xol—5— 4A-2 g 0 hyl)-9H-puriny1)- 302 N—ethylethanesulfonamide \ N\ 2-(6-aminofluoro((6- F)LN/ N iodobenzo[d][1,3]diox01 4A-3 8 o) y1)methy1)—9H-purin«9-y1)- HN’SOZ methylethanesulfonamide NH2 , \ N\ I 2-(6-aminofluoro-S-((6- FkN/ O 4A—4 J iodobenzo[d][1,3]diox01—5— g 0 y1)methy1)-9H-purin yl)ethanesulfonamide NH22 , )LJEN O ‘2—(6—aminofluor9«8-((6- F N N A 10d0benzo[d][1,3]dxox01—5- 4A-5 8 O y1)methy1)-9H-puriny1)- 802 N-(tert- HN/ buty1)ethanesu1fonamide NHZ ' l / \ O 2-(6-aminofluoro((6- F N N O) iodobenzo[d][1,3]dioxol—5— 4A—6 g hyl)«9H-purin—9—yl)— §02 N- :‘2 isobutylethanesulfonamide NH2 l iiNVQO 2—(6—amino-2—fluoro—8—((6— F N N ) i0d0benzo[d][1,3]dioxol 4A—7 g 0 y1)methyl)-9H—purinyl)- (302 N—cyclopropyl— HN ethanesulfonamide Comggund No. Structure Name NH2 I \ N\ 6—aminofluoro—8— F1 /N N j’ «6— 4M 2 O nzo[d][1,3]diox01—5— y1)methyl)-9H—purin {NH yl)ethyl)propane 02% sulfonamide NHZ | FXN/N \ N\ N-(Z—(6-aminofluoro-8— N ((6' 4A-9 )0 o iodobenzo[d][1,3]dioxol—5— yI)methy1)—9H—purin—9— yl)ethy1)ethanesulfonamide 0 SN”2 NH2 I N—(2«(6-ammoflu0ro-8—_ i / “Q0\ ((6- F N N 4A‘10 J iodobenzo[d][1,3]dioxol—5— 2 O y1)methyl)-9H-purin NH y1)ethy1)methane- 028' sulfonamide NH2 I \ N-(Z-(6-amino—2-fluoro—8— FAN/ \ ((6- N j . 4A—11 8 0 iodobenzo[d][1,3]d1ox01—5— yl)methy1)—9H~purin-9— ,NH yl)ethyl)methy1propane— 025’ 2-su1fonamide NHZ I \ N\ N-(Z—(6-amino—2—fluoro A / 0 N (<6- F N 4A-12 g OJ iodobenzo[d][1,3]diox01—5— yl)methyl)-9H-purin—9- ,NH y1)ethy1)—2-methy1propane— 08; 2—sulfinamide “HEN I 6-amino—2—fluoro-8— A / 0 ((6- F N N 4M3 2 O) iodobenzo[d][1,3]dioxol—5- yl)methy1)—9H—purin—9- ,NH y1)ethy1)—2-methylpropane— 028 1-su1fonamide NH2 I H \ N\ N—(2—(6-aminofluoro—8- FAN/ N j ((6- 4A—14 2 0 i0dobenzo[d][1,3]dioxol—5— yl)methy1)—9H-purin-9~ y1)ethy1)cyclopropane— sulfonamide W ure Name WWI;—I N \ “Iv/Q )L / 0 3-(6-aminofluoro—8—((6— F N N g O) i0d0benzo[d][1,3]dioxol-5— 4A-1 5 hy1)~9H—purin—9-y1)- N—isopropylpropane-l - O2stH sulfonamide NHZ I \ NWQO i 3«(6—amino-2—fluoro—8-((6— F N/ N J iodobenzo[d][1,3]dioxol—5— 4A-16 é O y1)methy1)-9H-purinyl)- N—ethylpropane-l- 023‘ sulfonamide NH2 I i\ ”\on 3-(6-aminofluoro((6- F N/ N J iodobenzo[d][1,3]dioxol-S- 4A-17 g 0 yl)methy1)—9H—purin—9—y1)— N—methylpropane—l— 025‘ sulfonamide NHZ ”“ A / we 3—(6—amino—2~fluoro—8-((6— F N N 4A~18 O) iodobenzo[d][1,3]diox01-5— y1)methyI)-9H-purin—9— y1)propanesu1fonamide o 52 ‘NHZ NH; I A\ N‘Vflo 3-(6-arrfinofluor0((6— F N/ N J iodobenzo[d][1,3]diox01-5— 4A-19 é O yl)methy1)—9H—puIinyl)- N—(tert—butyl)propane—1— 023‘ sulfonamide NH2 I A / ‘ o m1no—2—fluoro-8—((6— F NJTNWQN N O) iodobenzo[d][1,3]dioxol—5— 4A-20 é y1)methy1)-9H-purin—9—y1)« N—isobutylpropane-l - 025 sulfonamide Com ound No. Structure Name NH2 I \ N\ 3-(6-aminofluoro—8—((6- FAN/I O N A iodobenzo[d][1,3]dioxol 4A-21 0 yl)methy1)~9H—purin—9—y1)— N—cyclopropylpropane—l — sulfonamide NH2 —<]I A\ NYQO N-(3—(6—amino—2—fluoro—8— F N/ N J ((6- O 10dobenzo[d][1,3]d10xol. . 4A-22 y1)methy1)—9H—pufin HN y1)pr0py1)pr0pane \SOZ sulfonamide NHZj—I \ N\ N—(3—(6-amin0fluoro FAN/| o ((6“ N I . . 4A-23 O 10d0benzo[d][1,3]d10x01—5- yl)methyl)-9H-pufin y1)propy1)ethane- HNSOZ sulfonamide NH2 I II \ N\ 6-amino-2—fluoro—8— FAN/ O (<6_ N I . 4A—24 O 10'dobenzo[d][1,3]d10xol hyl)-9H-purin-9— y1)propyl)methane— HN‘SOZ sulfonamide NH2 I \ N\ N-(3-(6-amino—2—fluoro—8- A / O ((6- F N N O) iodobenzo[d][1,3]dioxol 4A—25 é y1)methyl)—9H-purin—9- y1)pr0py1)—2- HNISO methylpropane-Z- 2 sulfonamide NH2 I N \ N-(3-(6—anfino—2—fluoro A / o ((6- F N N J iodobenzo[d][1,3]dioon 4A-26 yl)methy1)—9H—purin—9- py1) methylpropane—Z- sulfinamjde nd No. I Structure Name I JEN I N-(3-(6-amin0fluoro—8— FlN/ 3 «6- N _ ‘ 0 1odobenzo[d][1,3]d1oon 4A-27 g y1)methy1)—9H~purin y1)pr0py1)-2— HMSO methylpropane-l— > 2 / sulfonamide NH2 I N‘ \ NWQO 6-aminofluoro F N/ N J ((5— 4A—28 iodobenzo[d][1,3]dioxol yl)methy1)—9H-purin HN y1)propy1)cyclopropane~ <r‘sog sulfonamide NH2 | N‘ \ ”i / 0 N 3-(6-amm0—2~fluoro—8-((6- F N 4A_29 g: O) iodobenzo[d][1,3]dioon-5— y1)methyl)-9H-purin—9-y1)- O N—isopropylpropanamide NJ I )NL\ $430 3-(6—amino-2—fluoro((6— F N/ N 4A—30 J iodobenzo[d][1,3]di0on hyl)—9H-puriny1)- o N—ethylpropanamide NHQ I it Nyflo 3—(6—aminofluoro((6- F N N 4A—31 /1 iodobenzo[d][1,3]dioxol-5— yl)methy1)—9H—purin—9-yl)- o N—methylpropanamide NH2 I hf \ N\ 3-(6-aminoflu0ro((6- 4A_32 FKN/ N A iodobenzo[d][1,3]diox01~5— 0 y1)methy1)-9H-purin—9— O y1)propanamide NH2 I \ N\ A / O 3-(6-anuno—2-fluoro((6-.

F N N J 4M3 i0dobenzo[d][1,3]dioxol—5— yl)methy1)-9H—purin—9-y1)- N-(tert—butyl)pr0panamide Compound N0. Name 3—(6-amino-2—fluor0—8-((6- 4A-34 iodobenzo[d][1,3]diox01 y1)methy1)-9H—purinyl)— N-isobutylpropanamide 3-(6-amino—2—fluoro-8—((6— iodobenzo[d][1,3]diox01—5- 4A-35 y1)methy1)—9H—purin—9-y1)— cyclopropylpropanamide N—(Z-(6-aminofluoro—8— ((6- 4A—36 iodobenzo[d][1,3]dioxol—5— yl)methy1)-9H—purin—9- y1)ethy1)isobutyramide N—(2-(6-amino—2—fluoro-8— ((6- 4A-37 iodobenzo[d][1,3]diox01 yl)methyl)-9H-purin—9— y1)ethyl)propionarnide N—(Z-(6~amino~2—fluoro ((6- 4A—3 8 iodobenzo[d][1,3]diox01—5- yl)methyl)—9H—purin yl)ethy1)acetamide G-amino-Z-fluoro-S- ((6- 4A-39 iodobenzo[d][1,3]dioxol—5- hyl)—9H—purin—9— y1)ethyl)formamide N—(2—(6—aminofluoro ((6- 4A-40 iodobenzo[d][1,3]di0x01—5— yl)methy1)—9H—purin~9— yl)ethyl)pivalamide Compound No. I Structure Name N—(2—(6-aminofluoro-8~ A /N/EN N‘ o ((6- F N 4A-41 8 OJ iodobenzo[d][1,3]dioxol yl)methy1)—9H—purin—9— NH y1)ethy1)—3- O methylbutanamide ”JEN I N—(2—(6-amino—2—fluoro-8— FAN/ N 3 ((6- ? 10dobenzo[d][1,3]dicx01. . 4A-42 o yl)methy1)-9H-purln—9- NH y1)ethyl)cycloprppane- O33> carboxamide {HEN I N—{3-[6-Aminofluoro— FAN/ N 3 8-(6-iodo- 4A—43 g benzo[1,3]dioon ' ylmethyl)—purin—9—yl]— i210H propy1}—2,2—dimethy1— namide NH2 , FfiWo 6-Aminofluoro- N 2 OJ 8—(6—10do— 4A-44 benzo[1,3]di0xol—5- ylmethyl)—purin—9—y1]— HN i . to propyl}-1sobutyranude “JEEN\ I Cyclopropanecarboxylic FAN/ N 3 acid {3-[6—amin0—2-fluoro- 4A—45 § 8—(6-iodo— benzo[1,3]di0X01 NH ylmethyl)—purin—9-yl]— 0% propyl} -amide NH; I \ N-{3-[6—Aminofluoro- FJLN/ N j 8-(6-iodo— 4A-46 i O benzo[1,3]dioxol ylmethyl)—purin-9—yl]— NH propyl}hydroxy- 0474». propionamide NH2 1 B1 \ Ii Acetic acid 6—amino— FAN/ N 03 ro—8—(6-iodo— 4A—47 benzo[1,3]dioxol-5— ylmethyl)—purin—9-yl] - propylcarbamoyl} methyl—ethyl ester Compound No. Structure Name ”AI \ I N-{3—[6-Amino—2-fluoro— FAN/ N 03 8-(6-iodo— 4A'48 3 benzo[l,3]dioxol ylmethyl)—purin—9-yl]- NH propyl}hydroxy-2— 0 OH methyl-propionamide Hsp90 binding results are presented for Compounds 1A«5. lA—IO, lA-l l, lA-lZ, lA-15, 1A-.9, lAfi22 , lA—24, lA-25 tolA—28, lA—43 to lA-SO, 4A-26, 4A—28, 4A-43, and 4A-45in Table 12 below. As can be noted therefrom, all compounds showed a high level of binding affinity. (3-11. In some embodiments ofthe disclosure, X2 is an optionally substituted aryl. Table lC lists specific examples of compounds Within this ment. In each of the structures as drawn therein, X2 is a en-containing aryl group, specifically a pyrazolyl group, and X4 is H. Corresponding structures in which X; is a different nitrogen-containing optionally substituted aryl group are within the scope of the disclosure. In each of the structures in Table 1C, Y is S and X4 is H. However, corresponding structures in which Y is CH2 and/or X4 is F, Cl, Br, or I are also Within the scope of the disclosure. Additionally, in tion with each of the structures in Table 1C, corresponding ures in which X; is a nitrogen—containing optionally substituted aryl group different from optionally substituted pyrazolyl, Y is CH2, and/or X4 is F, Cl, Br, 01‘ I are also Within the scope of the disclosure.

Table 1C Compound No. Structure Name HN \ NH2 N~ N 2-{6—Amino—8-[6—(1H- Nik\ VS 0 pyrazol—S-yl)- N/ N 101 J benzo[l,3]dioxol-5— O ylsulfanyl] -purin-9 -yl} — ethanesulfonic acid HN’ pylamide HN \ NH2 N‘ ”61ng 2-{6-Arnino—8—[6—(1H- \ N pyrazol-3—yl)— 102 j l,3]dioxol-5— o ylsulfanyl]-purin—9—yl}- ethanesulfonic acid HN/SOQ ethylamide Compound No. Structure Name HN \ NH2 N‘ 2-{6—Amino-8—[6—(1H- \ N pyrazol—3—yl)- 1c 3' “(1ng benzo[1,3]diox01—5— N )0 0 ylsulfanyl]-purin—9—y1} - ethanesulfonic acid HNISOZ methylamide HN \ ”H2 N‘ 2-{6-Amino-8—[6-(1H- '1“ N>'\ V pyrazc1 S y1)- -4 j benzo[1,3]diox01-5— g 0 ylsulfany1]—purin~9-y1}— cthanesulfonic acid amide , 2 HN \ NH2 5p 2-{6—Ammo[6-(1H—.

NI \ \>WS o pyrazol-Si—yl} N/ N 1C5 J 1,3]diox01—5* — 2 O ylsulfany1]-purin—9-yl} - ethanesulfonic acid tert- HN’ butylamide HN \ NH2 N‘ \ N 2-{6—Amino—8-[6-(1H- '1 / N\>‘S 0 pyrazol—3-y1)- 1C 6 o) benzo[1,3]dioxol—5- ylsulfanyl] -purin-9—yl} — [$02 ethanesulfonic acid “N isobutyl—amide HN \ NH2 N“ .

\ N mmo—8—[6—(1H— "i \>—s 0 pyrazoIy1)- N/ N 1C 7 J benzo[1,3]dioxol - 8 O ylsulfany1]—puriny1}- sulfonic acid cyclopropylamide Propane-Z-sulfonic acid (2— {6-amino[6-(1H— pyrazoly1)- benzo[1,3]dioxol-5— ylsulfany1]—puriny1} — cthy1)—amide Compound No. Structure Name I Hh‘l \ NHz N“ Ethanesulfomc amd (2-{6-A .

\ N hi / \>‘s o amino—8—[6—(1H—pyrazol 109 N N ) yl)—benzo[1,3]dioxol—5— 8 0 yIsulfanyl]—purin—9-y1}- [NH -amide HN \ NH\2 N N N-(2-{6-Amino-8—[6-(1H— t / \>—S o pyrazol-S-yl)— lC-IO N N 2 O) benzo[1,3]dioxol ylsulfany1]-puxin-9—y1}- [NH ethy1)—methanesu1fonamide ozs\ HN \ NHz :‘w N \ N\ 2-Methyl-propane K / O sulfonic acid amin0- 1011 N “1%8 J 8—[6—(1H—pyrazolyl)- benzo[1,3]diox01—5- ylsulfany1]-purin—9-y1} — ethyI)-amide y1—propane—2- sulfinic acid amino- 1C 12 8—[6-(1H-pyrazolyl)— benzo[l,3]dioon-5— ylsulfanyl]-puriny1} - ethy1)-amide thl \ NH2 N~ 2-Methy1—propane—1- fl \ \>—S sulfonic acid (2-{6—arm'no— N/ N 1013 A 8-[6-(1H—pyrazol-3—y1)— g 0 benzo[1,3]diox01 NH ylsulfanyl]-purin—9—yl} - 023’ ethyl)*—amide HN \ \2 N‘ N Cyclopropanesulfonic acid "i / \>—s 0 (2-{6-am1'n0—8—[6-(1H— N N 1014 ) pyrazol—S-y1)- 2 0 benzo[1,3]dioxol [NH ylsulfanyl]-pu1in-9—yl} - 028 ethy1)-amide Compound No. ure Name HN \ NHz N\ 1)): VS\ N 3-{6-Amino-8—[6-(1H— 0 pyrazoly1)- N N 1015 O) benzo[1,3]dioxol ylsulfany1]—puriny1} - propane—1 -sulfonic acid 0 s - - \NH lsopropylamlde Hbll \ ”H2 N‘ 3—{6~Amino[6—(1H— "1 \kN/ N}\ S pyrazol—3-y1)— 101 6 )0 benzo[1,3]dioxol—5« O ylsulfany1]~puriny1}- e—1 -su1fonic acid 023‘ ethylamide HN \ ”HZ “a 3-{6-Arm'no[6-(1H- hi\ N \>—s O l—S—y1)- N/ N 1017 J benzo[1,3]dioxol O ylsulfany1]-purin—9—y1}— propane— 1 ~su1fonic acid 023 methylamide HN \ ”“2 N“ 3—{6—Amino[6—(1H- \ pyrazo1—3—y1)— 1018 KN/ N>_S j 1,3]dioxol O ylsulfanyl] -puriny1} - propane—1 —su1fonic acid amide ‘NHZ HN \ “”2 N‘ 3—{6—Amino—8-[6—(1H— K ys O pyrazoI-3—y1)- N/ N 1019 A benzo[1,3]dioxol-S~ O ylsulfany1]-puIin—9-y1} — propane-1 -sulfonic acid 023‘ tert-butylamide HN \ NHz ‘N~ N \ 3-{6-Amlno[6-(1H- m / \>‘3 O pyrazolyl)— N N 1020 O) benzo[1,3]dioon ylsulfany1]—purin-9—yl} - propane-1 -sulfonic acid isobutyl-amide Compound No. Structure Name HN \ JEN N‘ mino[6-(1H— 151/ hf\ pyrazo1.3—y1)- ~ \ s 1021 )0 benZO[1,3]dioxol—5— O ylsulfanyl]—pufin-9.y1}_ propane-1 -su1fonic acid cyclopropylalnide e—Z-sulfonic acid (3 {6-amino[6-(1H- pyrazol—3 —yl)— benzo[1,3]diox01-5— ylsulfanyl]—purin—9-yl} - propyl)—amide Ethanesulfonic acid (3—{6— amino—8—[6—(1H—pyrazol—3 nzo[1,3]dioxol ylsulfany1]—purin-9—y1} - propyl)—amide N-(3-{6—Amino-8—[6—(1H- pyrazol—3—y1)— benzo[1,3]di0X01 ylsulfany1]-pminy1} — prowl)— methanesulfonamide 2—Methyl-propane—2— sulfonic acid (3—{6—am1'no- 8-[6-(1H-pyrazol-3—y1)— benzo[1,3]dioxol ylsulfanyl] —purinyl} - propyl)—amide Compound N0. Structure Name Hh‘I \ NHz N“ \ N y1-propane—2— fl / >‘5 o sulfinic acid (3-{6-amino— N N 1C-26 é 0) 8—[6-(1H-pyrazolyl)— benzo[1,3]dioxol ylsulfanyl]—purin-9«yl} — HN‘so )-arnide Hh‘l \ NH2 NH \ N 2-MethyI—propane—1- [l / gfs O sulfonic acid (3—{6—amino- 1027 é O) 8-[6-(1H—pyrazol—3-yl)— benzo[1,3]dioon ylsulfanyl] -purin—9~y1} - HNSO propy1)—amide >4 2 H” \ NHZ N* 1/ Cyclopropanesulfonic acid NVS o (3-{6-amino-8—[6—(1H— -28 o) pyrazoly1)- benzo[1,3]dioxol .g ylsulfany1]-purinyl} - HN\SOZ propyl)—amide HN \ NH2 N‘ hi /\ N 3-{6-Am1no-8—[6-(1H— N\>'S o pyrazolyl)- 1c-29 N g: OJ benzo[1,3]dioxol—5— ylsulfanyl] -puriny1} ~N— HN isopropprropionamide Hl\‘| \ “”2 N‘ 3—{6-Amino—8—[6—(1H— "i: N V8 0 pyrazol-S-yl)— 1C-30 N N O) 1,3]dioxol HN§:0 ylsulfanyl] -puriny1} -N- propionamide HN \ ““2 N“ 3-{6—Amino—8—[6—(1H— ‘ N\>_S o pyrazoly1)— 1C-31 N/ N J benzo[1,3]di0X01—5— ylsulfanyl]-purin—9-yl}-N- methyl—propionamide Compound N0. Structure Name HN \ NH2 N‘ 1113—3 3-{6—Amino[6-(1H- \ pyrazoI~3—y1)— 1032 j’ benzo[1,3]dioxol-5— o ylsulfanyl]-puriny1} - o propionamide Hh‘l \ NHZ N‘ 3—{6-Am1no-8—[6—(1H—‘ \ N / V3 o pyrazol-3—yl)— 1C-33 N é: OJ benzo[1,3]diox01—5- ' ylsulfanyl]—purin—9-yl} ~N— HN ten-butyl-propionamide HN \ NH2 N‘ \ N 3-{6—Ammo—8—[6-(1H- NL/ \>—5 0 l-3—y1)— -34 N N é: OJ benzo[1,3]dioxol—5- ylsulfanyl] -puriny1} —N— HN yl—propionamide ___1 H51 \ NH? N‘ {inrfs 3{6A ' - — - — \ N mmo-8[6(1H- 0 pyrazolyl)— —35 N g: O) benzo[1,3]dioxol ylsulfanyl]~purin—9~y1}-N- HNBO cyclopropyl-propionamide HN \ NHZ N“ N \ N-(Z-{6—Ammo-8—[6—(1H— { / N\>—S o pyrazol-3—yl)~ 1036 N 2 OJ benzo[1,3]di0X01—5- ylsulfanyl] -purinyl} - 0 ethy1)—isobutyramide HN \ “”2 N‘ N—(2-{6—Amino-8—[6-(1H— l\ N\>¥S o pyrazol—3-y1)- 1C—37 N/ N o) benzo[1,3]diox01 2 anyl] —purin—9-y1} - NH ethy1)-propionamide thl \ ““2 N‘ N-(Z-{6-Amino-8—[6-(1H— N‘K\ N\%S o ly1)- 1C-38 N/ N benzo[1,3]diox01 ylsulfany1]—purin—9-yl} - ethy1)—acetamide I nd N0. Structure Name HN \ NH2 Rh N—(2-{6-Amino—8-[6—(1H- \ N pyrazol—3—yl)— 1039 H/ h?“ 03 benzo[1,3]dioxol—S- g anyl] -puriny1} - NH ethyl)-formamide HN \ NH? N“ N—(2—{6-Amino—8—[6—(1H— N \ N\ pyrazol-3—yl)— H/ f3 1c 40 j’ benzo[1,3]dioxol _ 2 O ylsulfanyl] —pu1‘iny1} - NH ethy1)-2,2-dimethy1- O namide Hh‘l \ N“? N“ N—(Z—{6—Amino—8—[6—(1H- \ 1.3-y1)— lN/ N>—S benzo[1,3]dioxol—5- 1041 )0 2 O ylsulfany1]—purin—9 -y1} — NH ethy1)-3—methyl- 0 butyramide erg \ “”2 N‘ ”SEN‘H‘ Cyclopropanecarboxylic acid (2~{6-amino—8-[6- N/ N 1042 CA (1H—pyrazoly1)— 2 benzo[1,3]dioxol NH ylsulfanyl] —purin—9—y1} - 04B ethyl)—amide HN \ ””2 N“ N N-(3-{6-Amino[6-(1H— l / \)—s o pyrazol—3—y1)- N benzo[1,3]dioxol 1C 43 o) ylsulfanyl]-purinyl} — propy1)-2,2-dimethyl- propionamide N—(3—{6~Amino-8—[6—(1H— pyrazol-3 —y1)- 1C-44 benzo[1,3]diox01—5- ylsulfanyl] -purinyl} - propyl)-isobutyramide Compound No. Structure Name Hh‘l \ NH ~ \2 N Cyclopropanecarboxylic "i/ \ s 0 acid (3-{6-amino[6- N N 1045 i O) (1H-pyrazolyl)- benzo[l,3]dioxol—5- NH ylsulfanyl] -purin—9—y1} — o propyl)—armde Hh‘I \ ””2 N‘ N N—(3—{6—Amino[6-(1H— 'l /\ ‘>-5 o pyrazoly1)- N N 1 C-46 i O) benzo[l,3]dioxol ylsulfanyl]—purinyl} — NH prepy1)72-hy<i_r§xy- O propionaml e Hts‘l \ ”H2 ‘ Acetic acid 1-(3—{6—amino- “I j \)—s j 8-[6-(lH—pyrazol—3-yl)- N N c 1047 o benzo[1 ,3]d10X01—5— ylsulfanyl] -purinyl} — propylcarbamoyl)—l — methyl—ethyl ester N-(3-{6-Amino[6-(1H- pyrazol-3 —yl)- benzo[ l ,3]dioxol—5 — ylsulfanyl] -purin—9-yl} - propyl)hydroxy methyl-propionamide N—(3—(6—amino—8—((5— methoxy-Z—(lH—pyrazol—3- lC—49 yl)phenyl)thio)—9H—purin— 9—yl)propyl)pivalamide Table 1D lists c es of additional compounds within this embodiment. In each of the structures as drawn therein, X2 is a nitrogen and oxygen—containing aryl group, specifically an oxazolyl group, and X4 is H. Corresponding ures in which X2 is a different nitrogen and -containing optionally substituted aryl group are within the scope of the disclosure, In each of the structures in Table 1D, Y is S and X4 is H. However, corresponding structures in which Y is CH2 and/or X4 is F, Cl, Br, or I are also within the scope of the disclosure.

Additionally, in connection with each of the structures in Table 1D, corresponding structures in which X; is a en and —containing optionally substituted aryl group different from optionally substituted oxazolyl, Y is CH2, and/or X4 is F, Cl, Br, or I are also within the scope of the disclosure.

Com ound Nor Name 2-(6-arrfino-8—((6-(oxazol- 2-yl)benzo[d] [l ,3]dioxol— lD-l 2 o 5~yl)thio)—9H—purin—9-yl)- N—isopropyl- HN/SOZ ethanesulfonamide NH: @N N \ 2-(6-amino—8-((6—(oxazol- 113-2 “\N/ 3—353 2-yl)benzo[d][l,3]dioxol— g o 5—y1)thio)—9H—purin—9—yl)- N—ethylethanesulfonamide , 2 HN\_ NH2 0(7N .

N 2~(6—annno—8—((6-(oxazol- "it \>_S o 2-yl)benzo[d][l,3]dioxol- lD—3 N Ng O) 5-yl)thio)-9H—purinyl)- ,soz methylethanesulfonamide NH; (7“ N \ 2-(6-amino((6—(oxazol- I 9—5 0 / 2—ylbenzo (1 1,3 dioxol- lD-4 N N 8 OJ hio)—9H—purin—9— yl)ethanesu1fonamide HZN’ NHz @N \ N 2~(6—amino—8—((6-(oxazol— / N\>_S 0 2-yl)benzo[d][l,3]dioxol— lD-S 8 o) 5-yl)thio)—9H-purin—9-yl)- N-(tert— so2 butyl)ethanesulfonamide Compound No. ure Name NH2 OK?N N| \ N\>—s 2-(6—amino((6-(oxazol— kN’ O N J 2-y1)benzo[d][1,3]diox01~ 1D—6 O 5—yl)thio)—9H—purin—9-y1)— HN' isobutylethanesulfonamide NH: O(\’N N \ N\>w 2—(6—anfino—8—((6~(oxazol- KN/ S N j enzo[d][1,3]diox01— 1D—7 2 o 5-y1)thio)—9H-purin—9-yl)— N-cyclopropyl— HN’ ethanesulfonamide NH2 0%)“ N-(Z-(6-am1no-8—((6-. “(Thifs (oxazol-Z- N/ N 1D-8 A yl)benzo[d][1,3]dioxol 2 O y1)thio)—9H—purin-9— [NH y1)ethyl)propane-2— 023 sulfonamide NHz OK: N-(2-(6-a1nino-8—((6- N \(I 9‘s (oxazol-Z— 1D—9 yl)benzo[d][1,3]dioxol~5- N N J g o y1)thio)—9H—purin yl)ethy1)ethane 023' sulfonamide NH; 0C” N-(Z—(6—amino((6- \ N\ (oxazol—Z- 1D—10 tN/ N>‘S )0 yl)benzo[d][1,3]dioxol—5— 2 O yl)thio)-9H—purin—9— yl)ethy1)methane 023’ amjde NH2 0%)“ N-(2-(6-am1n0—8-((6—. ’ >—S (oxazol-Z- kN/ :2 113-11 j’ yl)benzo[d][1,3]diox01 yl)thio)—9H-purin—9— yl)ethyl)—2-methylpropane— 2-su1fonamide Comflund No. Structure Name NH2 f)": N-(2-(6—ammo—8-((6—- l\N’ (oxazol~2- 1D-12 2j%\o o) y1)benzo[d][1,3]dioxol—5- g yl)thio)-9H-purin—9— NH y1)ethy1)—2—methylpropane— 2-su1finamide MHZ (O N-(2-(6—am1no—8—((6-.

N'K\ Kfsbo (oxazol—Z- N/ N 1D-13 2 0) yl)benzo[d][1,3]dioon-5— - o)—9H-purin ’NH yl)ethyl)—2—methy1propane- 028L< 1-su1fonam1'de NH2 f}! N—(Z—(6-am1no((6-, N \ N\ b K / S 0 (OXazol-Z— N N ~ 1D-14 0) y1)benzo[d][1,3]d10x01 g yl)thio)-9H—purin [NH y1)ethy1)cyclopropane— OISE sulfonamide NH2 0(7N \ N\ 3-(6-am1'n0-8—((6~(oxazol- {N’ K35)" 2-y1)benzo[d][1,3]di0xol— 1D-15 O hio)-9H-purin—9~yl)- N—isopropylpropane 023‘ sulfonamide NH2 of7N N \ 3-(6-amino—8—((6-(oxazol- m / N\>-S o 2-y1)benzo[d][1,3]dioxol— 1D-16 N g OJ 5—y1)thio)—9H-purin—9—y1)— N-ethylpropane-l - sulfonamide |_— __/NH NH2 0??"1 \ N 3—(6-amino((6—(oxazol— ‘k / >-8 2-yl)benzo[d][1,3]diox01- 1D-17 3 —y1)thio)-9H—purin—9—yl)— N—methylpropane- 1- sulfonamide Compound N0. Structure Name NH2 0(7N N \ N\ 3-(6-anfino((6—(oxazol- 1mg KN/ 8—35)" enzo[d][1,3]dioxol- 0 5—y1)thio)—9H—purin—9— yl)propane-1 —su1fonamidc ozs\ NH; 0(7N N \ 3—(6—amino((6-(oxazol— m / NVS o 2-yl)benzo[d][1,3]dioxol— 113—19 N O) 5-y1)thio)-9H—puriny1)— N-(ten-butyl)propane— 1 — ' sulfonamide ogs\HNA< NH2 0(7N N \ N\ 3—(6—amino((6—(oxazol— KN/ 3—353 2-y1)benzo[d][1,3]dioxol— 1D—20 0 5—yl)thio)-9H-pUIinyl)— N-isobutylpropane— 1 - 02$ sulfonarrfide HN3— NH @N N 3-(6-amin0—8-((6-(oxazol— N \2 / ‘>—s 0 enzo[d][1,3]dioxol- 1D—21 N N O) 5-y1)thi0)-9H—purin-9—y1)- N—cyclopropylpropane—l- sulfonamide 2H‘N<] NH2 6“ N N—(3—(6-am1no—8—((6— t / \>—S o (oxazol—Z- N N 1D-22 O) y1)benzp[d][1,3]dipx01 yl)th1o)—9H—pur1n—9- HN y1)propyl)propane 3302 sulfonarmde ”H2 KEN 0 N-(3-(6-amino—8-((6- N'K: N \>—s o (oxazol-Z: 1D—23 N N ) y1)benzo[d][1,3]d10x01 y1)thio)-9H—purin-9— y1)pr0pyl)ethane— sulfonamide nd No. Structure Name NH @N . 2 N-(3-(6-am1no—8-((6~ N'K: N\>._s o (oxazol-Z: N N ) yl)benzo[d][1,3]d10x01-5— 1D—24 0 yI)thio)—9H—purin~9— y1)propy1)methane ”N sulfonamide /soz NHZ 0%)“ . ”“33:qu N—(3-(6-armno((6- (oxazol-Z— N/ N J zo[d][1,3]dioxol—5— 1D-25 é y1)thio)-9H—purin—9- y1)pr0py1) “N‘s methylpropane—Z- 7< sulfonamide “Hz 0(7 N—(3—(6—amino—8-((6- N \'JNINHN\ (oxazol—Z- j’ yl)benzo[d][1,3]dioxol 1D-26 0 o)—9H—purin—9- y1)pr0py1) HN\ methylpropane-Z- 750 mide "Hz ’ 0 N—(3-(6-amino((6- NJjj‘i (oxazol-Z- Kr N>_S j y1)benzo[d][l,3]dioxol—5- 1D—27 O yl)thio)-9H—purin-9~ y1)pr0py1) HN‘ methylpropane-l - >430: sulfonamide NHz If)“ N N—(S-(6-amino((6— / N\>—S o (oxazol—Z- N O) yl)benzo[d][1,3]dioxol—5— 1D-28 é y1)thio)—9H—purin-9~ HN yl)pr0py1)cyclopropane- ‘so2 sulfonamlde 0(7N/ NH2 NI \ N\>_S 3-(6-arnino((6-(oxazol KN/ o 1D-29 J yl)benzo[d][1,3]dioxol 0 yI)thio)—9H—purin—9-y1)-N— 0 isopropylpropanamide Compound No. Structure Name NH2 f7“; N/%:N\ 3—(6—amjno—8—((6—(oxazol— 'N/ N>“S j) 2-y1)benzo[d][1,3]d1'ox01—5- 1D—30 0 y1)thio)-9H-purina9—y1)—N— ethylpropanamide NHZ Q“ [HEN 3-(6-amino-8—((6-(oxazol- \>—s - 1D—31 [N/ N )0 2-y1)benzo[d][1,3]d10x01— o 5—y1)thi0)—9H—purin~9—y1)~ N-methylpropanamide ‘l NH (\IN . o 3-(6—ammo—8—((6—(oxazol— 1D 32_ | Jib! ‘ s y , 2— l)benzo[d][13]diox01— N’ N)— D 3 hio)-9H—purin—9- pionamide NH2 0(7N N'k\ N\>_S o 3—(6-amino-8—((6—(0)'cazol- N 2 yl)benzo[d][1 3]d10x01' ' 1D—33 N J a O 5-y1)thio)-9H-purin—9-y1)— 0 N—(tert—butyl)propanamide HN)L NH2 ’N [Rik—s o 3-(6-amin0-8—((6-(0)I(azol- 1D—34 N N J 2-y1)benzo[d][1,3]d10xol- O 5-y1)thio)-9H-puriny1)— o N—isobutylpropanamide HN\_< , NH2 OK)“ «\INy—s 3-(6—amino((6—(oxazol—2— N/ N 1D-35 ) yl)benzo[d][1,3]diox01 yl)thio)—9H-purin—9-yl)-N- 0 cyclopropylpropanamjde Com ound No. Name N \ N—(Z-(6—amino—8-((6- & / N‘ (oxazol-Z— 1D—36 N 2 o y1)benz0[d][1,3]dioxol—5- y1)thi0)-9H-purin 02;: y1)ethy1)isobutyranfide NH2 6N 6-ammo-8—((6-. ”1.: N \)—s o l—Z-t 1D—37 N N J y1)benzo[d][1,3]d10xol ’ 8 O y1)thio)—9H—purin—9- NH y1)ethy1)propi0namide ”H2 ’ 0 N—(Z-(6-amino—8-((6- N|\ N \)~s o (oxazol—Z— 1D-38 N/ N J yl)benzo[d][1,3]dioxol 2 O y1)thi0)-9H-pufin NH y1)ethy1)acetamide NH2 0CN N—(2—(6—amin0—8—((6— N \ (oxazol-Z- 113—39 lN/ ,P‘S j zo[d][1,3]dioxol 8 0 yl)thio)—9H-purin—9- NH yl)ethy1)formamide NH2 6N N—(Z-(6-am1n0~8-((6-. “(\INyS O (oxazol-Z- 1D-40 N’ N ; yl)benzo[d][1,3]dioxol-5— 2 O yl)thio)-9H—purin—9— NH yl)ethy1)pivalamjde “”2 DON N—(2—(6—amino—8-((6— NI \ N\>_S (oxazol—Z- N/ N 1D—41 J yl)benzo[d][1,3]dioon 8 0 yl)thio)-9H-purin NH YDSthYD-3' Oi< methylbutanamide Compound No. Name N-(Z-(6—amino-8—((6— (oxazol-Z— “3'42 2 O y1)benzo[d][1 ,3]dioxol—5- o)—9H-purin NH yl)ethy1)cyclopropane— Ox carboxamide W K“ .

N-{3-[6-Amm0(6- hi / ‘9—5 0 oxazol-Z-yl- 1D-43 o) benzo[1,3]dioxol ylsulfanyl)-purinyl]— propyl} imethyl- o propionamide Nsz /N “filly—5&3o\ N N-{3-[6-Amino—8-(6- oxazol—Z-yl— 1D-44 O benzo[1,3]dioxol—5- ylsulfanyl)—purin—9-y1]- H N propyl} —isobutyramide NH2 Q/IN Cyclopropanecarboxyhc. N 'iL /\ \)—s 0 acid {3-[6—amino—8-(6- N N 1D-45 i o) oxazol-Z-yl- benzo[1,3]dioxol NH ylsulfanyl)-purin—9-y1]— 0%» propyl}—amide NH; //N N-{3-[6-Am1no(6-. ll /\ N\)—s o oxazol-Z-yl- N N i benzo[1,3]dioxol-5— 1D—46 ylsulfanyl)—purin—9~yl]- NH propyl} hydroxy- DJIOH propionamide NH2 O//N Acetlc acld 1-{3-[6-ammo—. 4 . hi / \)—s o xazol—2—yl- N N 1D-47 i O) benzo[1,3]dioxol—5— ylsulfanyl)-puriny1]- NH carbamoyl} 0%,Ac methyl-ethyl ester Compound No. I Structure Name ””2 / N N—{3—[6—Arnino(6- ”it \>—-s o oxazol-Z-yl- N N 1D—48 KL o) benzo[1,3]dioxol ylsulfanyl)—purin—9-y1]' NH propyl} —2—hydroxy WW methyl—propionarnlde (IQ—SbNH2 I N—(3-(6-armno—8-((5—. lD—49 é 0/ ,, 7: methoxy—Z-(oxazol-Z- " yl)Pheny1)thiO)—9H-purin- 9-yl)propyl)pivalamide Table 1E lists specific examples of additional compounds within this embodiment. In each of the structures as drawn therein, X2 is a nitrogen and sulfur-containing heteroaryl group, specifically a thiazolyl group, and X4 is H. ponding structures in which X2 is a different nitrogen and sulfur-containing optionally substituted aryl group are Within the scope of the disclosure. In each of the structures in Table 1E, Y is S and X4 is H. However, corresponding ures in which Y is CH; and/or X4 is F, Cl, Br, or I are also Within the scope of the disclosure.

Additionally, in connection with each of the structures in Table 1E, corresponding structures in which X; is a nitrogen and sulfur-containing optionally substituted aryl group different from optionally substituted thiazolyl, Y is CH2, and/or X4 is F, Cl, Br, or I are also within the scope of the disclosure.

Table 113 Compound N0. ure Name f‘N ’1 NH2 / Nfi My, 0 mino—8-((6-(thiazol-2— N/ N lE—l ) yl)benzo[d][1,3]dioxol g 0 o)—9H—purinyl)-N- [302 isopropylethanesulfonamide NH2 QN ,}>‘S:§}jN N \ mino-8—((6-(thiazol— 113-2 {N/ 2—yl)benzo[d][l,3]dioxol- O 5—y1)thio)—9H—purin—9—yl)— N-ethylethanesulfonamide ,302 Compound No. Structure Name “Hz I 8 . .

N xmno((6-(th1azol- NI: \>_s O 2-yl)benzo[d][1,3]dioxol- 1E-3 N N J 5-y1)thio)-9H-purin—9-y1)— HN,502 methylethanesulfonarnide NH: 0 2-(6—ammo—8—((6—(th1azol-. . 1E-4 { , N‘>—S o 2—yl)benzo[d][1,3]dioxol— N OJ 5—yl)thio)—9H-purin—9— yl)ethanesu1fonamide HNISOZ2 mg 57“ N)\IN 2-(6-amino((6-(thiazol- / N‘>—S o 2—y1)benzo[d][1,3]dioxol- 1E-5 2 oJ hio)—9H-purin—9—y1)— N—(tert— HN'SOZ butyl)ethanesu1fonamide NH2 5(7N N \ N mino-8—((6-(thiazol- Kr N>~S:22\3 2-y1)benzo[d][1,3]dioxol— 1E-6 2 0 5-y1)thio)-9H-puriny1)- HN isobutylethanesulfonamide NH: ’N N \ N\ 2—(6-amino—8-((6—(thiazol- mN/ N>—3 3 2-yl)benzo[d][1,3]dioxol- 1E—7 2 o 5-y1)thio)-9H-purin—9-yl)- N-cyclopropyl— HN‘ ethanesulfonamide NH2 6N N-(2-(6-am1no((6-.

NU ksbo (thiazol—ZN / N 1E—8 J y1)benzo[d][1,3]d10xol y1)thio)—9H-purin—9— yl)ethy1)propane—2— sulfonamide Compound No. Structure Name 1 NHz SK: N—(Z-(G-amino-S-((6— N \ (thiazol—2« 113—9 KN/ N\>‘S j zo[d][1,3]dioon—5— 2 O yl)thi0)—9H-purin—9- y1)ethyl)ethane—2- (3sz sulfonamide NH2 IN 3 N—(2—(6—amino—8—((6— N \ N\ (thiazol-Z- 1B“) 'kN/ N>‘S j) y1)benzo[d}[1,3]dioxol-S- 2 O o)-9H-purin—9- NH y1)ethy1)methane~2— 025; sulfonamide NH2 g)“ N—(2-(6-am1no((6~. "it N \)—s 0 (thiazol-Z-I N N lE—ll 8 0) yl)benzo[d][1,3]d10xol—5- y1)thio)-9H-purin—9— [NH yl)ethyl)—2-methy1propane- 02$ 2-su1fonamide NH2 6N N—(Z—(6-am1no—8—((6—- N'k: N\>‘S 0 (thiazol—Z: N N 1E-12 o) yl)benzo[d][1,3]d10X01-5— 2 yl)thio)—9H—purin—9- ,NH yl)ethy1)—2-methylpropane- 0% 2-sulfinamide NH2 g7,”/ N-(Z-(6—am1no—8—((6-‘ N‘K: N\>_S 0 (thiazol-Z: N N 1E—13 o) yl)benzo[d][1,3]d10xol 2 yl)thio)—9H—purin—9- [NH yl)—2—methy1propane- Ozs\_< 1-su1fonamide ””2 //N NR1 \>_s N—(2-(6—amino-8—((6— O (thiazol-Z: 11344 N? O) y1)benzo[d][1,3]d10x01 yl)thi0)—9H-purin—9- N y1)ethyl)cyclopropane- sulfonamide Compound N0. Structure Name NH2 @N MENtN’ N>_5 3—(6—amino((6-(thiazol- )0 2-y1)benzo[d][1,3]dioxol— 1E-15 0 5—yl)thio)—9H-purin—9—yl)— ropylpropane 025‘ sulfonamide m; :‘>—8 3-(6-amino-8—((6-(thiazol— 2-y1)benzo[d][1,3]dioxol~ 1E—16 5—y1)thio)—9H—purinyl)— N-ethylpropane-l - sulfonamide 3-(6-amino((6-(thiazol- mN, :‘>‘S 2—y1)benzo[d][1,3]dioxol- 1E-17 5—y1)thio)-9H-purin—9-y1)- N—methylpropane—l — sulfonamide /‘NH NH2 /N NI)\IN‘>—S 3-(6-am1'no-8—((6-(thiazol- 1E-18 N/ N j 2-y1)benzo[d][1,3]dioxol- 0 5—y1)thio)—9H—purin—9- y1)propane-1 -su1fonamide NH2 6N N \ mino((6-(thiazol- I “IFS o / 2-yl)benzo[d][1,3]dioxol- 113-19 oJ 5-y1)thio)—9H-purin—9—y1)— N—(tert-butyl)propane— 1 — sulfonamide 02$H‘NA< SK7N/ NH: N \ N\ mino((6-(thiazol— “\N’ 3-8233) 2-y1)benzo[d][l,3]dioxol— 1E-20 5—y1)thio)—9H—puIiny1)- N—isobutylpropane-l - sulfonamide Compound No. Structure Name NH2 SK:N 3-(6-am1no—8-((6-(th1azol-. . i \>—3 o / 2—y1)benzo[d][1,3]d10xol—. 1E-21 N N é O) 5-y1)thio)—9H-purin—9-y1)- N-cyclopropylpropane-l- sulfonamide ZH‘NA “Hz 0 N N-<3 (6— —a1m'no—8—<<6— le: V550 ol—Z— N N 1E—22 o) yl)benz§)[d][1,3]dif)xol«5— yl)th1o)-9Hupunn-9— yl)propy1)propane ‘802 sulfonamide s(\/N/ NH2 N—(3—(6—am1no-8—((6—‘ ”ti: \>_SN 0 (thiazol—Z- N/ N 1E-23 J yl)benzo[d][l,3]di0x01~5- y1)thio)-9H-purin y1)propyl)ethane—2— HN\ sulfonamjde n/sog NH2 QN N—(3-(6—am1no-8—((6-.

N'K\ N)—s o (thiazol—Z- N” N 1E—24 J y1)benzo[d][1,3]dioxol—5— yI)thio)-9H-purin y1)propyl)methane—2- HN\ sulfonamide /soz NH2 if:N .

“Hi: \>_S N-(3-(6—ammo—8-((6- o (thiazoI—Z- N/ N J yl)benzo[d][1,3]dioxol 1E—25 g 0 o)-9H-purin~9— y1)pr0py1) HN‘ methypropane—Z- amide ”“2 (7N S N-(3-(6-amino((6— N \ N\ (thiazol-Z— Kr N>‘S j yl)benzo[d][1,3]dioxol 113—26 y1)thi0)—9H—purin-9« y1)pr0py1)~2- methypropane-Z— sulfinamide Compound No. Structure Name :"E 3 N—(3-(6-amino((6— N \ N\ (thiazol-Z- 'N’ r?s j” y1)benzo[d][1,3]dioxol 113—27 g 0 yl)thio)—9H-purin—9— y1)pr0py1) ropane-l— P302 sulfonamide NH2 @N N \ N—(3—(6—anfino((6— K 1 9—550 (thiazol 1328 g OJ y1)benzo[d][1,3]dioxol—5- yl)thio)-9H-purin—9~ HN y1)propy1)cyclopropane— <60; sulfonamide NH; S(\’N ”fix-s 3—(6-amjno—8-((6-(thiazol~ N/ N 1E-29 J 2—y1)benzo[d][1,3]diox01- 0 5-y1)thio)—9H—puriny1)- o ropylpropanamide NH2 @N N \ N\ 3-(6-amino((6—(thiazol— 1330 ILN/ N>—S J0 2-y1)benzo[d][1,3]dioxol- 0 5-yl)thio)-9H—puriny1)— N—ethylpropanamide HN\_ NH2 8(7N N \ N\ 3~(6-amino—8-((6-(thiazol— 1331 KN/ Nfs 3 2-y1)benzo[d][1,3]dioxol— 0 5-y1)thi0)—9H—purinyl)- o N—methylpropanamide ”“2 SON 3 (6 amino 8 ((6 (thi- — — — - 1 NlN: N ‘azo— 1E—32 N\>_S 2-y1)benzo[d][1,3]d10xol— Jo 5-y1)thio)—9H—purin-9— yl)propanamide Compound No. Structure Name NH2 it“! hit “*5 o 3~(6-amino—8—((6-(thliazol- N N J 2 y1)benzo[d][1 3]d10x01- - 11333 , O 5—y1)thio)-9H-purin—9-yl)— o t-butyl)propanamide HN)L 3N/ NH2 N'k: “{>_S O 3—(6—amino((6-(th_iazol- N 2 y1)benzo[d][1 3]d10x01‘ ‘ 1334 N J a o 5-y1)thio)-9H—purin—9—y1)— o N—isobutylpropanamide HN\_< Sr:N/ NH2 N \ 3—(6-amino—8-((6—(thiazol- , 0 2-y1)benzo[d][1,3]di0x01— N N‘>—S 113—35 Q oJ 5-y1)thio)—9H—purin—9—y1)— HN cyclopropylpropanannde NH2 /N N N—(Z—(6—amino((6- N'k/ 3—is\ oI-Z- 1E—36 N 2 O) y1)benzo[d][1,3]dioxol—5— y1)thi0)-9H-purin-9— 0 yl)ethyl)isobutyramide NH2 /N S N—(Z-(6—ammo—8—((6-. "1\ N \)—s o (thiazol-Z- 1E-37 N/ N ) y1)benzo[d][1,3]diox01—5- 2 o o)—9H-purin NH yl)ethy1)propionamide “”2 6N N-(Z (6 amino 8 ((6- . _ _ _ N‘ \ \)—s o (thiazol—Z- 1E—38 N/ N 0) y1)benzo[d][1,3]diox01—5- 2 yl)thio)-9H—purin—9— 04H yl)ethy1)acetamide NH: 8(7 N-(2-(6-amino—8-((6— N \ N\ (thiazol-Z— 1E-39 lN/ NH 3 yl)benzo[d][1,3]dioxol y1)thio)—9H—purin—9— y1)ethy1)formamide Coulpound No. —l Structure Name ”H2 mS N-(2-(6-amino—8-((6- ”t: Nys o (thiazol-Z- 1E-40 N N J y1)benzo[d][1,3]diox01. g 0 yl)thio)—9H—purin NH y1)ethyl)p1'valamide fig: 3 N-(2—(6-amino—8-((6- N \ N\ N>—3 (thiazol-Z- 113—41 Kr j y1)benzo[d][1,3]dioxol—5— g 0 yl)thio)~9H—purin—9- NH y1) Oi< methylbutanamide NH (\IN 2 S N—(Z-(6-amino~8-((6- N \ N\ 'L / >—s o zo1—2— N N 1E-42 8 o) y1)benzo[d][1,3]dioxol—S- yl)thio)-9H—purin—9— O yl)ethyl)cyclopropane- carboxamide m [— NH2 I N-{3-[6-Ammo—8-(6—. N 'iL /\ \)~s o thiazol-Z-yl- N ,N 1E 43— o) benzo[l,3]dioxol-5— ylsulfanyI)—puriny1]- HN propyl} -2,2-dimethy1— o propionamide ‘l / NH2 /N {fifsbgj8\ N 6—Amjno(6- thiazol-Z—yl- 1E-44 benzo[1,3]dioxol—5— ylsulfanyI)-puxinyl]- :szo propyl}—isobutyramide NH2 6N Cyclopropanecarboxyhc‘ N “1k /\ \>—s 0 acid {3—[6-a1m'no—8-(6- N N 1E-45 O) thiazol-Z—yl- benzo[1,3]d10xol.

NH ylsulfany1)-puriny1]— 0 propy1}-amide Compound N0. Structure Name C“ —| ””2 S 'fljj: \>_3N N-{3-[6-Amino(6- o thiazol-Z-yl— N N 1E-46 i o) 1,3]djoxol ylsulfanyl)-purinyl]— NH propyl}—2—hydroxy- 04>.0H propionamide NH2 //N Acetic acid 1—{3-[6-amino- Hp j \>—s o 8-(6—thiazolyl- N N lE-47 % o) benzo[l,3]dioxol—5- anyl)—purin—9-yl]- NH propylcarbamoyl}-l- '_l methyl—ethyl ester . (aw/Ac ””2 S hip/'1 \>—sN N—{3-[6-Amino—8—(6- o thiazol-2—yl— N N IE-48 % O) benzo[l,3]dioxol-5— ylsulfanyl)—purin—9-yl]— propyl}-2—hydroxy-2— methyl-propionamide {ff/[$55NH2 I N—(3—(6-amino—8—((5~ 113.49 < O methoxy-Z-(thiazol-Z- yl)phenyl)thio)-9H—purin— 9-yl)propyl)pivalamide Table 1F lists specific examples of onal compounds within this embodiment. In each ofthe structures as drawn therein, X2 is an oxygen—containing heteroaryl group, specifically a furanyl group, and X4 is H. Corresponding structures in which X2 is a different oxygen-containing optionally substituted aryl group are within the scope of the disclosure. In each of the structures in Table 1F, Y is S and X4 is H. However, corresponding structures in which Y is CH; and/or X4 is F, Cl, Br, or I are also within the scope of the disclosure. Additionally, in connection with each of the structures in Table 1F, onding structures in which X2 is an oxygen—containing optionally substituted aryl group ent from optionally substituted furanyl, Y is CH2, and/or X4 is F, Cl, or I are also within the scope of the disclosure.

Table 1F [ ndNo. l Structure Name Compound N0. Structure Name NH2 / “,qu 2-(6-amino—8-((6—(fi1ran—2- mN/ N>*S o yl)benzo[d][1,3]dioxol-5— lF-l o yl)thio)—9H—purin—9—y1)—N— isopropyl- HN§02 ethanesulfonamide NH2 / \ N 2-(6-amino((6-(furan-2~ 1R2 KN/ 3‘5 j yl)benzo[d][l,3]dioxol—5— 2 O yl)thi0)—9H—purinyl)-N- ethylethanesulfonanfide NH2 0/ N 2-(6—amino—8—((6—(furan 1E3 'kN/ N\>‘S 3 zo[d][1,3]di0x01—5— 2 o yl)thio)—9H—purin—9-y1)-N- methylethanesulfonamide NH2 / N \ 2-(6-amino((6-(fi1ran—2- 1F-4 K / N‘>—S 0 yl)benzo[d][1,3]dioxol 8 OJ y1)thio)—9H—purin anesulfonamide ,soz NH; / N \ N\ 2—(6-amino-8—((6—(furan lN, N>—S o y1)benzo[d][1,3]dioxol—5— 1115 2 o) y1)thio)—9H-purinyl)—N— (tert- HN/SOZ butyl)ethanesulfonamide NH2 0/ | o / 2-(6-amin0—8-((6—(furan-2— N N‘>—s 1R6 2 0) y1)benzo[d][1,3]dioxol y1)thio)-9H—purin—9-y1)—N- So2 isobutylethanesulfonanfide nd No. I Structure Name NH2 / \ N\ 2-(6-anfino-8—((6—(furan~2- mN/ N>—S o y1)benzo[d][l,3]diox01—5— 1F-7 8 o yl)thio)-9H-pufin—9—yl)—N— cyclopropyl- HN’ ethanesulfonamide “H2 // 0 N—(2-(6-amino—8—((6— Hr| N>_\ s .2- 1F 8 y1)benzo[d][1,3]dioxol ' )0 2 ° y1)thio)—9H—pmin [NH y1)ethyl)propane—2- 025>__ sulfonamide NH: ’ 0 N—(2-(6—amino((6- N \ (furan—Z— 1m 'N/ NVS j y1)benzo[d][1,3]diox01—5« 2 O yl)thio)—9H—purin—9- NH yl)ethy1)ethane OQS\__ sulfonalmde NH2 / 0 N—(2—(6—amino((6- N \ (furan~2- lF—IO lN/ 3'3 3 yl)benzo[d][1,3]dioxol—5— 8 O yl)thio)—9H-purin y1)ethy1)methane NH . 023’ sulfonamlde __L._ \ NH2 / \ N N-(2-(6—am1'no((6— K / 0 N N\>_S (furan-Z- lF-ll 8 O) yl)benzo[d][1,3]dioxol—5- o)—9H—purin~9— 0 81“” y1)ethyl)—2-methy1propane— )V 2-su1fonamide “H2 // 0 N-(2-(6-amino—8-((6- “i\ N \)—s 0 (furan—Z- N/ N 11112 J yl)benzo[d][1,3]dioxol 8 0 yl)thio)—9H—purin—9- NH y1)ethyl)methy1propane— OS}V 2-su1finamide Compound No. Structure Name “”2 / N—(2—(6—amino—8-((6— NI \ NV—s o (finan—2—_ N/ N 11:43 yl)benzo[d][1,3]d10xol—5— 2 o y1)th1'o)—9H—purin—9- [NH y1)ethy1)—2-methy1pr0pane— OZSL< 1—su1fonamide ””2 0 6-amino—8-((6- NI \ N\>_s o (furan—Z— N/ N 1F-14 o) y1)benzo[d][1,3]diox01-5— 2 yl)thi0)-9H-purin ,NH yl)ethyl)cyc10propane- 023$ sulfonamide NH; / N x$1,?”N\ 3-(6-amino—8—((6—(fi1ran—2— yl)benzo[d][1,3]dioxol—5- 113.15 0 yl)thio)—9H—purin—9-y1)—N- isopropylpropane-l- 023‘ sulfonamide NH: / N \ N\ 3~(6—amino((6-(furan—2— / N>“S o yl)benzo[d][1,3]dioxol—5- 1F-16 g OJ yl)thio)—9H—purin—9-y1)-N- ethylpropane—l- sulfonamide 028‘ _/NH NH2 / N \ N 3-(6-amino-8—((6-(furan—2- t / N‘>*S o yl)benzo[d][1,3]diox01 1F-17 é OJ o)-9H-purin—9—y1)-N- methylpropane-l- sulfonamide 028‘ NH2 / \ N\ mino—8—((6-(furan-2— 11118 H” NH 3 y1)benzo[d][l,3]dioxol—S— é 0 yl)thio)—9H-purin—9- yl)propanesu1fonamide 025‘ Comgound No. Structure Name NH2 / NJEN 3~(6—amin0((6—(furan—2— m / N‘>‘S o y1)benzo[d][1,3]dioxol 1F-19 g OJ yl)thio)—9H-puriny1)—N— (tert-butyl)propane sulfonamide 02$H‘NA< NH2 / \ N\)—s 3—(6-amino—8-((6-(furan I 0 N/ N ) y1)benzo[d][1,3]diox01—5- 1F-20 é O yl)thio)-9H—purin-9~yl)-N- ylpropane-l- OZS‘N sulfonamide NH2 0 \ N 3-(6-amin0((6-(fi1ran—2- 1/ \)—s O yl)benzo[d][1,3]dioxol 1F—21 N N g O) y1)thio)-9H—purin—9-yl)-N— cyclopropylpropane— 1 - sulfonamide 2H‘N—<] NH2 0/ “fie—S N(3 (6 ' N - — —am1no—8((6< — o (furan-Z- N yl)benzo[d][1,3]dioxol-5~ 1F-22 é o) y1)thi0)—9H-purin«9- yl)propy1)propane~2— *{302 sulfonamide N”? 0 N—(3—(6—amino—8—((6— le\ N\>_S o (furan—Z— N/ N 1F<23 O) y1)benzo[d][1,3]dioxol—5— g yl)thio)—9H-purin y1)propy1)ethane—2— HN‘ amide _/so2 ”“2 // 0 6-arnino—8-((6~ l\ N\>_S (furan—Z— N/ N 11344 O) y1)benzo[d][1,3]dioxol g y1)thio)-9H-purin—9- y1)propy1)methane-2— HN\ sulfonarnide /soz Compound No. Structure Name ““2 / 0 N—(3-(6-amino-8—((6- | N>_\ s (furan—Z- kN” )0 y1)benzo[d][1,3]dioxol—5— 1F-25 y1)thio)—9H-purin-9— y1)pr0py1) HN\ methylpropane—Z- sulfonannde.

NH; / N N-(3-(6-amino((6- lk / ‘>—5 o (furan—Z— N N 113—26 é O) y1)benzo[d][1,3]dioxol y1)thio)-9H-purin yl)propy1)propane 7&0 sulfinamide NH2 / 0 N-(3-(6—amino—8—((6— \ (furan-Z- mN/ N>_S j yl)benzo[d][1,3]dioxol 1F-27 O yl)thio)—9H-purin—9— y1)pr0py1)2— HN\ methylpropane—l- >_/S°2 sulfonamide NH2 / \ N N-(3-(6-amino-8—((6- [ / N\>—S 0 —Z- N J zo[d][1,3]di0xol—5- 1F-28 g yl)thi0)—9H—purin—9- HN yl)propyl)cyclopropane- <(‘SOZ sulfonamide NH2 / Nl \ N>_S 3-(6-amino((6-(furan KN/ O 1329 ) zo[d][1,3]dioxol—5- 0 y1)thio)-9H-purin—9—y1)-N— o isopropylpropanamide NH: / \ N 3-(6—amino-8—((6—(furan—2- 0 1)benzo[d][1,3]dioon 1F 30_ N y N oJ yl)thio)—9H—purin—9-y1)-N- ethylpropanamide Compound No. Structure Name NH: / \ N\ 3-(6-amino-8—((6-(furan 1331 ILN/ N>—S y1)benzo[d][1,3]dioxol—5- o y1)thio)—9H-purin—9-y1)—N— methylpropanamide ““2 // 0 3—(6—amino—8~((6—(furan—2~ N>_\ | S Y1)benzo[d][13]diox01«5— W 32 j a N/ yl)thio)-9H-pu1in g: 0 panamjde NH: 0/ \ 3—(6-amin0—8—((6-(furan-2— I “9‘s 0 N/ N 11:33 J yl)benzo[d][1,3]dioxol O yl)thio)—9H—purin—9—yl)-N- o (tert-butyl)propanamide HN)L NH2 / “(MlNrs\ N \ 3-(6-amin0-8—((6—(furan—2— 112-34 j yl)benzo[d][1,3]dioxol-5— ° yl)thio)—9H-purinyl)-N- o isobutylpropanamide HN\_< NH2 0/ 1 N\>_S O 3-(6-amino-8—((6-(furan—2- N/ N 1F—35 J zo[d][1,3]dioxol—5— y1)thio)—9H-purin—9-y1)—N— O cyclopropylpropanamide NH2 0/ N(2(6 ' N ~ — —am1no—8((6— - le: N\>“S o (furan-Z— 1F—36 N 2 OJ y1)benzo[d][1,3]dioxol yl)thio)-9H-purin 03$“: yl)ethy1)isobutyramide ””2 / 0 N—(2—(6—amin0((6- l\ N \>—s 0 (furan-Z- 1F-37 zo[d] [1 ,3]diox01—5— y1)thio)-9H-purin—9- yl)ethyl)propanamide Comgound N0. Structure Name ":2 0 N—(2-(6-amino((6- N'K / \)~s o (furan—Z- 1F—38 N N y1)benzo[d][1,3]dioxol-5— 2 0 y1)thi0)-9H—purin-9— NH yl)ethy1)acetamide NH2 / 0 I 6-amino((6- NI \ N\>—s (finan—Z- 11139 0 N/ N yl)benzo[d][1,3]dioxol~5~ 2 0 y1)thio)—9H—purin~9— yl)ethy1)formamide 0_JNH ““2 / 0 N—(2—(6-amjno-8—((6— N'K\ N \>_5 (furan 11140 N’ N ) y1)benzo[d][1,3]diox01—5— 2 ° y1)thio)-9H—purin—9- NH yl)ethy1)piva1amide o? J “”2 / 0 N—(2-(6-amino—8-((6- hi\ N\>_S (furan—Z- N/ N 11341 J yl)benzo[d][1,3]dioxol g 0 yl)thio)-9H-purin—9~ NH yl) O methylbutanamide ”\“2 0 N-(Z-(6-amino—8-((6- “m / \)——s o (furan-Z- N N 1F—42 0 y1)benzo[d][1,3]diox01—5- 2 o)—9H—purin—9— NH y1)ethy1)cyclopropane- carboxamide “H2 / 0 2—(6—amino((6-(5- “i\ N\>_S o methylfuran—ZN ’ N y1)benzo[d][l,3]dioxol ”43 2 O y1)thio)—9H—puri11—9—y1)—N— (so: isopropyl— HN ethanesulfonamide Compound No. Structure Name NH2 l 0 . 2-(6-am1no-8—((6~(5- NIL, \)—s o methylfijran-Z— 1F-44 N N O) yl)benzo[d][1,3]dioxol 3 , yl)thio)-9H-puriny1)-N- ,502 ethylethanesulfonamide HN\_ NH2 / 2—(6-am1n0—8-((6-(5-_ t / s o furan—Z- 1F-45 N N 0) zo[d][1,3]diox01 g » yl)thio)—9H—purin—9—y1)—N- [$02 methylethanesulfonanfide ”H2 / NIJEENV‘S 2-(6-aInino-8—((6-(5- methylfuran—2- 1F-46 KN/ o N J y1)benzo[d][1,3]dioxol«5— 2 0 yl)thio)-9H-pun'n yl)ethanesu1fonamide H N5022 NH2 0 2-(6—am1no—8-((6—(5—. “it \)—sN o methylfurantz- N N o) yl)benzo[d][1,3]d10x01—5- 1F—47 2 y1)thio)-9H—pur1'n—9-y1)-N- '30; (tert— HN buty1)ethanesulfonamide NH2 / NI \/ N\>_S 2-(6-amino((6-(5- N N J methylfuran—Z- 11748 2 O y1)benzo[d][1 ,3]diox01—5— [302 yl)thi0)~9H—purin-9—y1)-N— HN isobutylethanesulfonanfide NH2 / 0 2—(6-armno-8—((6-(S—. l: \>-s o methylfuran-Z- N N 11:49 0) yl)benzo[d][1,3]di0xol 2 yl)thio)—9H—purin—9-yl)-N- ,802 cyclopropyl- HN ethanesulfonamide Compound No. Structure Name ““2 / ° N-(2-(6-amino((6—(5- "\\ N\ s o methylfuran—Z- N/ N 1F-50 O) yl)benzo[d][1,3]dioxol—5- 2 yl)thio)~9H-purin—9— [NH y1)ethy1)pr0pane 028 sulfonamide NH2 / 0 N-(Z-(6-amino((6-(5- N \ methylfuran-Z- 11151 {N/ 3‘3 3 y1)benzo[d][1,3]dioxol 2 O y1)thio)-9H—purin-9— NH yl)ethy1)ethane—2— 023L- sulfonamide NH2 / 0 N—(2—(6-amino—8-((6—(5— \ N\ methylfuran-Z- 1F-52 lN/ N )0 y1)benzo[d][1,3]dioxol 2 o y1)thi0)—9H—purin yl)ethy1)methane—2‘ sulfonamlde.

NH2 / N \ N\ N—(2-(6—amino-8—((6—(5— K / N>_S 0 methylfuran—Z— 1F—53 8 0J yl)benzo[d][1,3]dioxol o)-9H—purin—9— ozs’NH y1)ethy1)~2—methylpropane- )T 2—su1fonamide l___._____.._ NH2 / N—(2-(6-a1mno—8—((6—(5—. “i\ N \ s o methylfuran—Z— N/ N 115—54 O; zo[d][1,3]dioxol«5- 2 y1)thio)-9H-purin [NH yl)—2-methy1propane- 0% 2-su1finamide NH2 0 N-(Z—(6—armno—8—((6-(5-.

N|\ N \>_3 O methylfuran-Z- N/ N 1F—55 0) y1)benzo[d][1,3]dioxol—5- yl)thio)-9H—purin—9— NH yl)ethyl)methy1propane- 1-su1fonamide nd N0. Structure Name ‘ “”2 / 0 N—(2-(6-amino((6-(5- ”it N \>—s o methylfuran-IZ- N N y1)benzo[d][1,3]d1oxol—5— 1F-56 2 O) y1)thio)—9H-purin~9- ,NH y1)ethyl)cyclopropane— 025 sulfonamide NH2 // NIKE/[3‘5\ N 3-(6—amino((6-(5— 0 methylfuran-Z- N 0J yl)benzo[d][1,3]dioxol-5— 1F-57 y1)thio)-9H—purin—9—yl)~N— isopropylpropane-l — ozs .

‘NH sulfonamlde ”H2 / O 3-(6-amino-8—((6-(5— “f\ N \>—s O methylfuran—Z- N/ N 1F-58 J yl)benzo[d][1,3]dioxol y1)thio)—9H—purin—9-yl)—N— ethylpropane—l — 025‘ sulfonamide ”H2 / 0 3-(6-amino-8—((6-(5- l: N\%S O methylfuran-‘Z- N N 1F—59 o) yl)benzo[d][1,3]d1oxol-5— yl)thio)t-§I§-purinyl)-N-me ypropane-l- 023‘ sulfonamide NH / \2 O N 3—(6—amino—8—((6—(5— I ‘>—S o / furan—Z- 1F-60 N N O) yl)benzo[d][1,3]dioxol yl)thio)—9H-purin—9- yl)propanesulfonanfide ””2 / 0 3—(6-amino-8—((6-(5— N|\ N \>——s o furan—2- N/ N yl)benzo[d][1,3]dioxol 1F‘61 0 yl)thio)-9H—pun'n—9-y1)—N- (tert—buty1)propane-1 - 028 sulfonamide Compound No. Structure Name NH2 0/ “fie—S ' N 3(6- '31’111110-8((6(5- - - 0 filran-Z- 1F~62 é 0 y1)benzo[d][1,3]dioxol-5— y1)thio)-9H—purin-9«y1)—N- isobutylpropane-l — H‘N‘>V sulfonamide NH2 0/ 3-(6-amino—8-((6—(5- 1\ N\ s methylfuran—Z- 1F-63 N/ N y1)benzo[d][1,3]dioxol g 0 y1)thi0)—9H—purin-9—y1)—N— ropylpropane—l - 02:\N__<] sulfonamlde NH2 / ”JEN N—(3-(6—amino((6-(5- I S / N‘ o methylfuran—Z- 1F-64 é 0 yl)benzo[d][1,3]dioxol—5— y1)thio)—9H—purin—9— yl)propy1)propane #502 sulfonamide “H2 // N—(3-(6-amino((6-(5— le\ N \)—s o methylfuran—Z— N/ N 11:65 O) y1)benzo[d][1,3]dioxol—5- yl)thio)—9H-purin—9— pyl)ethane—2~ HN\ sulfonamide #302 ”“2 // 0 N—(3-(6-amino((6-(5- “i\ N\>_s o methylfuran-Z— N/ N 1F—66 o) y1)benzo[d][1,3]di0xol—5- é y1)thio)-9H-purin—9- yl)propyl)methane—2- HN\ sulfonamide “”2 0/ ”<6ij N-(3—(6—amino—8-((6-(5- methylfuran—Z— N’ N J y1)benzo[d][1,3]di0X01—5- 1F-67 O yl)thio)—9H-purin y1)pr013y1) HN‘soz propane—Z— sulfonamide Comgound N0. Structure Name NH: / \ N N—(3-(6—amino((6-(5— r‘li / o methylfuran—Z— N N\>_S INS é o y1)benzo[d][1,3]dioxol y1)thio)-9H-purin y1)propyl)propane 7&0 sulfinamide ““2 / 0 N—(3—(6-amino-8—((6~(5- N \ N)“\ methylfuran-Z- H/ s j’ yl)benzo[d][1,3]dioxol—5— 1F—69 O y1)thio)—9H-purin—9- y1)pr0py1)2- H N‘ methylpropane >_/SO? amide NH2 / \ N\ N—(S-(6-amino-8—((6~(5- K , N>‘5 O methylfuran—Z— 1F-70 y1)benzp[d][1,3]dif)x01—5- yl)th10)-9H—pur1n—9— HN yl)propy1)cyc10propane- <f‘so2 sulfonamide NH2 / \ N 3—(6—amino—8—((6—(5— N'k/ N\>‘S 0 methylfuran-Z— 113—71 N é: O) yl)benzo[d][1,3]dioxol y1)thio)—9H—putin-9—y1)—N— HM): isopropylpropanamide NH2 / 0 3-(6-ammo-8—((6—(5-. ”l \ s o methylfilran—Z— 1F-72 N/ N y1)benzo[d][1,3]diox01—5— o)-9H-purin—9-y1)—N— 0 ropanamide NH2 / 0 3—(6-am1no—8-((6—(5—.

\ N “l \ s o methylfuran—Z- 1F-73 N” N y1)benzo[d][1,3]dioxol yl)thio)-9H—puriny1)—N- 0 methylpropanamide Compound No. Structure Name NH2 0 N 3-(6—amino—8-((6-(5- t / S o methylfuran—Z- 1F-74 N N g: 0) yl)benzo[d][l,3]diox01~5- yl)thio)-9H-purin—9- o yl)propanam1de‘ ”H2 / N 3 <6— ~amino(<6- 5-< let N\>—S o methylfuran—Z- 11:45 N €10 O) yl)benzo[d][1,3]dioxol—5- yl)thio)—9H~purin—9—y1?—N- (tert—butyl)propanam1de HN)L "Hz 0/ 3(6 ‘ - -am1no-8((6 (5— - - NI \/ N N\>—5 0 methylfuran—Z- 1F-76 N <10 0) yl)benzo[d][1,3]dioxol y1)thio)-9H-purin—9—yl)«N« isobutylpropanarnide HN\_< NH: / \ N mino—8—((6-(5— K / N\ S 0 methylfuran—Z- 1F—77 L0 O) yl)benzo[d][1,3]dioxol yI)thio)-9H-puriny1)_-N- HN cyclopropylpropanam1de NH: / N 6-amino—8—((6-(5- [ / N\>—5 o methylfuran-Z- 1F-78 N 2 o) y1)benzo[d][1,3]dioxol-5— yl)thio)-9H—puxin ’ (fig: yl)ethy1)isobutyramide NHZ // 0 N—(Z—(6~amino-8—((6-(5— l: N \>_3 o methylfuran-Z— 1F-79 N J y1)benzo[d][1,3]diox01-5— y1)thio)-9H-purin-9— yl)ethyl)propanamide Compound N0. Structure Name ”H2 / N N-(Z-(6—amino((6—(5— l\ \>_3 o methylfuran—Z- lF-SO N/ N o) yl)benzo[d][1,3]dioxol 2 yl)thio)-9H—purin NH y)1 ethy)1 acetamide NH: / 0 N-(2-(6—amino—8~((6-(5- \ N\)—s methylfuran—Z— 1F-81 'N/ N j zo[d][1,3]diox01—5— 2 0 y1)thio)-9H-purin NH yl)ethy1)formamide NH; / N \ N\ N-(2—(6-amino((6-(5~ tN’ N>—S J0 methylfuran—2— 1F-82 2 0 zo[d][1,3]diox01—5— NH 0)-9H-purin-9— 0 yl)ethy1)pivalamjde “”2 // 0 N—(2—(6-amino-8—((6—(5- N‘ \ N\>_5 methylfuran—Z— N/ o 11:83 ) yl)benzo[d][1,3]di0xol—5- g 0 y1)thio)-9H-pun'n NH y1)ethy1) 0 methylbutanamide “”2 // f‘fj: \N N—(2—(6—amino((6-(5- s o methylfuran-Z— N N 1F-84 2 o) y1)benzo[d][1,3]dioxol—5- yl)thi0)-9H-purin—9- yl)ethy1)cyclopropane- carboxamide N—(3—{6-Amino[6-(5- methyl-hran—Z-yl} lF-SS benzo[1,3]dioxol-5— ylsulfanyl]-purin—9—y1} — propyl)—2,2-dimethy1— propionamide Compound No. Name N—(3- {6-Amino—8—[6—(5— methyl—furan-Z-y1)— 1F-86 benzo[1,3]dioxol ylsulfanyl] —9—y1} - propyl)—isobutyramide Cyclopropanecarboxylic acid (3-{6-am1'no[6-(5- -furan—Z—yl)— 1F—87 benzo[1,3]dioxol ylsulfanyl]-purin—9-yl} - propy1)-amide N—(3- {6-Amino—8—[6-(5- methyl-furan—Z-yl)— benzo[1,3]dioxol-5— 1F-88 ylsulfanyl]—purin—9-y1} — propyI)hydroxy— propionamide Acetic acid 1-(3—{6-amjno— -methyl—furan—2-y1)- benzo[1,3]dioxol 1F-89 ylsulfany1]—puriny1} - propylcarbamoyl)-l - methyl-ethyl ester N~(3-{6-Amin0[6-(5- methyl-furan—Z-y1)- benzo[1,3]diox01—5— 1F-90 ylsulfanyl] —purin—9 -y1} — propy1)hydroxy methyl-propionamide N-(3-(6-amino-8—((5— methoxy-Z—(S— 1F-91 methylfuran—Z— y1)phenyl)thi0)-9H—purin~ 9-y1)propyl)pivalamide C-HI. In some embodiments of the disclosure, X2 is an alkynyl group, e.g., ethynyl, 1- prop—l-ynyl, and 3-prop~1—ynyl. Table 1B lists c examples of compounds within this embodiment. In each of the structures as drawn, X2 is ethynyl and X4 is H, However, corresponding structures in which X; is another alkynyl group, including specifically for example propynyl or butynyl, are within the scope of the sure. In each of the structures in Table 1B, Y is S. However, corresponding structures in which Y is CH; and/or X4 is F, Cl, Br, or I are also within the scope of the disclosure Additionally, in connection with each of the structures in Table 1B, corresponding structures in which X; is another alkynyl group, including specifically for example propynyl or butynyl, and Y is CH; are also within the scope of the disclosure.

Table 1B Corn ound No. ure Name NH2 \< “Hill 2-[6—Amino(6-ethyny1- l >_S 0 N/ benzo[l,3]dioxol lB-l > O ylsulfanyl)—purin—9—yl]— ethanesulfonic acid HN’ isopropylamide NH2 \ 2—[6—Annno—8—(6—ethyny1-. N ”t /\ \>—s o benzo[1,3]dioxol-5— 113.2 N N ? OJ ylsulfanyl)—purin—9-yl]— ethanesulfonic acid W302 ethylamide NHZ \ \ N 2-[6—Amino—8-(6-ethyny1— blk , \>—s o benzo[l,3]dioxol-5— N N 1B-3 OJ ylsulfanyl)-purin~9—yl]- ethanesulfonic acid HN/SOZ amide NH2 \ 2-[6-Amino(6-ethynyl- [\1 \ N\ 1B-4 KN/ N>fls )0 1,3]dioxol 8 O ylsulfany1)—purin—9—yl]— ethanesulfonic acid amide , 2 NH; \ N \ N\ 2-[6-Amino—8-(6—ethynyl— KN/ N%8 j benzo[1,3]dioxol—5- lB-S 8 0 ylsulfanyl)-purinyl]— sulfonic acid tert- HN’ butylamide Compound N0. Structure Name NH2 \\ .

NU Nys O 2-[6—Amino—8-(6—ethyny1- N N o) benzo[1,3]d10xol«5- 1B-6 ylsulfanyl)-purin—9-yl]- (802 sulfonic acid HN isobutyl-amide NH; \ N \ 2-[6—Amino-8—(6—ethyny1- Kr N\>iS 03 benzo[1,3]dioxol 1B-7 ylsulfany1)-purin-9—y1]— ethanesulfonic acid HN;D cyclopropylamide NH; \ \ N ”KN/ Propane-Z-sulfonic acid \>—S )0 {2—[6—amino—8—(6—ethynyl‘ lB—S > 0 1,3]dioxol~5: NH ylsulfany1)-puriny1]- 023’ -amide NH: \\ Ethanesulfomc ac1d {2-[6-, , l / \>—S 0 ~ amino-S-(G-ethynyl- 113.9 N 2 OJ benzo[1,3]dioxol ylsulfanyl)—purin—9—yl]~ 0281”” ethyl}-amide NHz \ \ N N—{Z-[6-Am1no—8—(6— hi / \>*8 o ethynyl-benzo[1,3]dioxol— 1B-10 N N 2 o) 5-y1su1fany1)—purinyl]— ethyl}— ozs’NH methanesulfonamide NH2 \ N \ N\ 2-Methy1-propane—2- {N/ s N )0 sulfonic acid {2-[6—amin0— 1B-11 g 0 8-(6—ethynyl— NH benzo[1,3]di0XOI ' 023’ ylsulfanyl)-purinyl]— )V ethy1}—amide NH2 \ 2—Methy1-propane—2— N'K: N \>~s sulfinic acid {2-[6—amino— 1B-12 > 05) 8-(6-ethyl'nyl- benzo[1,3]d10x01—5- ,NH ylsulfanyl)—purin—9—yl]— ethy1}-amide '7 Compound No. Structure Name NH2 \ 2-Methyl-propane m : y—s sulfonic acid {2-[6-amino- N N O) 8—(6-ethyny1— 1B-13 8 benzo[1,3]dioxol—5— ,NH ylsulfanyl)—purin—9-y1]— Ozsx < ethy1}-amide NHz \ N \ N\ Cyclopropanesulfonic acid I >_S N/ )0 {2-[6—amino(6-ethyny1- 18—14 > 0 benzo[1,3]dioxol NH ylsulfany1)-puriny1]— 023%> ethy1}-amidc NHg \ fjks O mino(6-ethyny1— N N o) benzo[1,3]diox01—5- 13—15 g ylsulfanyl)—purin—9—yl]— e-1 —su1fonic acid 028“ isopropylamide NH2 \ [if 3-[6-Amino(6-ethyny1— 3—3 j benzo[1,3]dioxol 1B-16 g 0 ylsulfanyl)—purin—9—yl]— propane-l-sulfonic acid 02% ethylamide NH: \ \ N 3-[6-Amino(6-ethyny1— lN/ N\%S j) benzo[1,3]diox01—5— 1B—17 < 0 ylsulfany1)—purin—9—yl]— propane—l—sulfonic acid 028‘ amide "(INVSR)0NH2 \ \ N 3-[6-Ami110—8—(6—ethyny1— benzo[1,3]dioxol 1B-1 8 oJ ylsulfany1)—purin—9—y1] - propane— 1 -su1fonic acid amide 025‘ NHz \§ N \REF?” mino—8—(6—ethynyl- 3 benzo[1,3]dioxol 1B-19 0 ylsulfanyl)—purinyl]— propane-1 -su1f0nic acid tert-butylamide Com ound No. Name 3—[6—Amino—8—(6—ethyny1— benzo[1,3]dioxol—5- ylsulfany1)—purin—9-yl]- propane-1 -su1fonic acid yl-amide 3—[6-Amino(6-ethyny1- benzo[1,3]dioxol—5— 1B—21 o ylsulfanyl)-purin—9-yl]- e- 1 —su1fonic acid 023 cyclopropylamide H‘N—Q NHz —\\ "Ii: N\>_S o Propanefl—sulfonic acid N N J {3-[6-am1n0-8—(6—ethynyl- 1B-22 benzo[1,3]dioxol any1)-purin—9-yl]— :2302 propy1}-amide NHz \ N \ N\ Ethanesulfonic acid {3-[6- N/ N%S j amino—S—(G—ethynyl— 1B—23 0 benzo[1,3]dioxol—5— ylsulfanyl)-purin—9-y1]- HN\ propyl}—amide NHz \ N N—{3-[6—Am1'no-8—(6— KN/ Q‘s )0 l-benzo[1,3]dioxol— 1B-24 O 5-ylsu1fany1)-puriny1]- prowl}- HN\ methanesulfonamide NHz \ N \ 2—Methy1-propane K / N\>_s 0 sulfonic acid {3-[6—amino— N CA 8-(6—ethyny1- 1B—25 benzo[1,3]dioxol HN\ ylsulfanyl)—purinyl]- S02 propyl} ~amide NHz \ WJXN‘ 2—Methyl-propane-2— k / 0 sulfinic acid {3—[6-amino— N N%8 0) 8 6 h 1 1B-26 é ‘( ‘et yny ‘ benzo[1,3]dioxol ylsulfanyl)-purin—9-y1]— propyl} -amide Compound No, 4 Structure Name NH: \ ”JEN 2—Methy1—propane— 1 - k / N>~S o sulfonic acid {3—[6—amino- N o) 13-27 8-(6-ethynyl— benzo[1,3]dioxol—5- HN anyI)-purinyl]— ‘soz propy1}—amide NH2 \ “it N\>_S o Cyclopropanesul-fonic acid N N o) {3-[6-amino-8—(6—ethynyl- 1B-28 < benzo[1,3]diox01—5- HN ylsulfanyl)-pufiu—9-yl]— <f‘soz propyl}—amlde NH2 \ N‘k: Nys o mino—8-(6-ethynyl- 1B-29 0) benzo[1,3]dioxol~5- ylsulfanyl)-purin—9-y1]—N— 0 isopropyl-propionamide NHg \ N \ N\ 3-[6—Am1'no(6-ethyny1— “330 H/ W5 3 benzo[1,3]dioxol O ylsulfany1)—purin—9-yl]-N- 0 ethyl—propionamide NH2 \ N \ N\ N>_S 3-[6-Amino-8—(6-ethyny1— 1B-31 KN/ j benzo[1,3]dioxol 0 ylsulfanyl)—purinyl]—N— o methyl-propionamide NHZ \ IN/\ N 3-[6-Anfiuo(6—ethyny1— 11332 N\>~s j benzo[1,3]diox01 O ylsulfany1)—puriny1]- o namide _H2N NHg \ _l t: N\ s o 3-[6—Amino-8—(6-ethynyl- N N 113-33 benzo[1,3]dioxol ylsulfany1)-purin-9—y1]-N- 0 tert—butyl-propiouamide Compound No. Name 3—[6-Amino—8-(6—ethynyl- benzo[l,3]dioxol—5- 1B-34 ylsulfanyl)—purin-9 -yl] -N- isobutyl-propionamjde 3-[6-Amin0(6-ethynyl- 1B-35 benzo[1,3]di0xol ylsulfanyl)—purin—9-yl]-N- cyclopropyl-propionanfide N—{2-[6-Amino—8-(6- ethynyl—benzo[1,3]dioxol— -ylsulfanyl)-pun'n—9—yl]— ethyl} -isobutyramide N—{Z—[6—Amino-8—(6— l-benzo[1,3]dioxol— -ylsulfanyl)-purin—9-yl]- ethyl} —propionamide N— {2-[6-Amino(6- ethynyl-benzo[1,3]dioxol- ~ylsulfanyl)-purin-9—yl]- ethyl} -acetamide N— {2-[6-Am1'n0(6- ethynyl-benzofl ,3]dioxol— —ylsulfanyl)~purinyl]— ethyl} -formamide N— Amino(6— l-benzo[ 1 ,3]dioxol- 113—40 5-ylsulfanyl)-puxinyl]— ethyl}-2,2-dimethylpropionamide 1— Compound No. Structure NH2 \\ \ N “if N-{2-[6-Amino-8—(6- \>_S )0 l—benzo[1,3]dioxol— 1B-41 > O 5~ylsulfanyl)—purin—9—y1]— NH —3-methy1- 0—1 butyramide NH: \ N \ Cyclopmpanecarboxylic lN/ 3‘3 3 acid {2-[6-amino—8-(6- 1B-42 2 0 ethynyl-benzo[1,3]dioxol- NH 5-ylsulfanyl)-purin-9—yl]- OX ethyl} -amide NH; \\ 1\ N\ 5 O N-{3-[6-Amino(6— N/ o) ethynyl—benzo[1,3]dioxol- 1B—43 g 5-ylsulfany1)-puriny1]- } ~2,2 ~dimethyl— 1?:0 propionamide NHz \\ ”His—s\ N 3 N—{3-[6-Amino—8-(6- o ethynyl—benzo[1,3]dioxol— 1B_44 -ylsulfany1)~purin—9-y1]— HN propyl}-isobutyramide NH2 \ “Hibiys ropanegarboxylic N N j aCld {3—[6—amlno(6— 113—45 i O ethynyl-benzo[l,3]dioxol- -ylsu1fany1)-purinyl]- 0% propy1}—amide NH; \\ N \ N\ |\N/I N>—s 2:2 N-{3—[6—Amino~8—(6— )0 ethynyl-benzo[1,3]diox01— 1B—46 fl 0 -ylsu1fanyl)—purin—9-yl]— propyl} -2 -hydroxy- NH propionamide 0 OH NHz \\ Acetic acid 1- 3-[6-amino- N \(1&8 { 3 8-(6-ethyny1— benzo[l,3]diox01—5- 13—47 ylsulfanyl)—purin-9«y1]— propylcarbamoyl } ~1- methyl-ethyl ester L nd No. Structure Name NH2 \\ “Hi \N . s N—{3—[6—Amino—8—(6— KN/ N>~‘ 03 ethynyl-benzo[l,3]dioxol— 1B-48 fl 5«ylsulfanyl)-purin—9—yl]- propyl}hydroxy-2— methyl-propionamide OffOH NHZ \\ ”Rib—s N—(3-(6—amino—8—((2~ N N ethynyl-S- lB-49 g 0 methoxyphenyl)thio)—9H— purin—9- 1%0 y1)propyl)pivalamide Hsp90 binding results are ted for Compounds lB-ZS. lB-43, and lB-45 in Table 12 below. As can be noted therefrom, all compounds showed a high level of binding affinity.

C—IV. In some embodiments of the disclosure, X2 is an amino group, i.e., —NR1R2, wherein R1 and R2 are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2—C5 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, or alkylheteroarylalkyl. Table 1G lists specific examples of compounds Within this embodiment.

In each of the structures as drawn, X2 is dimethylamino and X4 is H. However, corresponding ures in which X; is another amino group, including specifically for example diethylamino, methylethylamino or ropylamino, are within the scope of the disclosure In each of the structures in Table 1G, Y is S. r, corresponding structures in which Y is CH2 and/or X4 is F, Cl, Br, or I are also within the scope of the disclosure. Additionally, in connection with each of the structures in Table 16, corresponding structures in which X2 is another amino group, including specifically for example diethylamino, methylethylamino or cyclopropylamino, and Y is CH2 are also within the scope of the sure.

Table 1G Compound No. Structure i Name NH2 N “fl” 2—(6—amino—8-((6- r / N‘HQO hylamino)benzo[d] lG-l N 8 0) [1,3]dioxolyl)thio)—9H- purin—9-yl)-N—isopropyl— ethanesulfonamide Com ound No. ure NH2 \N 2-(6-amino—8—((6~ “‘1: yngoN (dime‘thylamino)b§nzo[d] 1G—2 N N ) 10x01—5-y1)th10)—9H- purmyl)-N-. [802 ethylethanesulfonamide HN\__ NHz 5N m1no((6-.

NI \ NVS‘QO (dimethylanfino)benzo[d] 1G-3 N/ N J [1,3]d1'oxol—5—y1)thio)~9H- purm—9~y1)-N—. [502 methylethanesulfonamide NH - 2 ‘N 2-(6—am1n0-8—((6- NI \ N\)—s (dimefl1y1amino)benzo[d] 1G—4 KN/ o N J [1,3]dioxol—5—yl)thio)-9H— O purin-Q- 502 yl)ethanesu1fonanfide HZN' NH2 \N/ N \ 2-(6-amino—8—((6- m / o (dimethylamino)benzo[d] N N‘>—S 1G-5 0) [1,3]dioxolyl)thio)-9H- purin—9—y1)-N—(tert— HN,302 butyl)ethanesu1fonamjde NH2 \N/ N \'11,“?ng"i 2-(6-amino((6- (dimethylamino)benzo[d] 1G—6 2 0 [1,3]dioxoly1)thio)—9H- 302 purin—9-yl)—N- :12 isobutylethanesulfonamide NH2 xN/ N \ N\ 2-(6-amino((6- / N>‘S O (dimethylamino)benzo[d] lG-7 2 o [1,3]dioxolyl)thio)—9H- purin-9~y1)-N—cyclopropy1- HN§02 ethanesulfonamide Compound N0. Structure Name NH2 \N/ N \ N—(2—(6-amino-8—((6- { / o (dimethylanfino)benzo[d] lG-S N N\>_S 2 OJ [1,3]dioxol—5-y1)thio)—9H— purin-Q-yl)ethyl)propane- ozs’NH 2-sulfonamide NHz ‘N/ .

N N—(2-(6-ammo((6- hi \ VS‘Q‘O (dimethylamino)benzo[d] 1G-9 N/ N J [1,3]di0on—5-y1)thio)-9H- 2 O purin-9—yl)ethyl)ethane—2- [NH sulfonamide NH2 \N/ 6-an}1n0((6-. N K / \)—S o (d1methy1am1no)benzo[d] 1G—10 N N 8 O) [1,3]di0xol—5-y1)thi0)—9H— purin-Q-yl)ethyl)methane- ,NH 2—su1fonamide ozs\ ““2 “N/ N-(Z—(6-amino—8—((6— Nlk \ VS‘QO (d1methy1ammo)benzo[d]. . lG—ll N/ N J [l,3]dioxol—5-y1)thio)-9H— g 0 purin—9—y1)ethy])—2- NH methylpropane-Z- 023}V amide NH; \N/ N—(2-(6-am1n0((6-- Nt \ NVSQO (dimethylamino)benzo[d] 1G—12 N/ N J [1,3]dioxolyl)thio)—9H— 2 0 pmn-9—y1)ethy1)—2— NH methylpropane—Z- 03' sulflnamjde NH2 \N/ N-(2«(6—am1no—8-((6-' 'K N\>_S (dimethylamino)benzo[d] 1G—13 N/ N ) [1,3]dioxol—5—yl)thio)-9H- 8 O 9-yl)ethyl)— NH Zmethylpropane—L sulfonamide Com ound No. Name N—(2-(6-amjn0((6- (dimethylamino)benzo[d] 1GM o) [l,3]dioxol-§ -yl)thio)—9H— 2 punn—9- ,NH y1)cyc10propane- 023> sulfonamide NH2 \N/ _ N 3-(6—ammo—8—((6— m / \)—S 0 (dimethylamino)benzo[d] N N O [1,3]dioxoly1)thio)-9H— 1645 puriny1)-N- isopropylpropane—l - OZS‘NH sulfonamide NH2 \N/ EATNVSQO 3_(6 ammo 8 ((6-_ _ _ _ (dimethylanfino)benzo[d] N/ N 1G—16 J [1,3]dioxol—5—y1)thio)—9H— g O purin—9—y1)-N— ropane—l- 0255\NH sulfonamide NH? ‘N/ 3-(6—amino—8—((6— t\ N¥SQO (dimethylamino)benzo[d] N/ N J [1,3]dioxol—5-y1)thio)—9H— 1317 é O purin-Q—yl)-N- methylpropane-l - OZS‘NH sulfonamide NH2 ‘N/ N 3-(6-amino((6- u\ / ‘>-8 o (dimethylamino)benzo[d] 1G—18 N N g OJ [1,3]dioxol-5—yl)thio)—9H- purin-9—yl)propane-1 — sulfonamide NH2 \N/ 3-(6-am1no-8—((6—‘ “(ix—s (dimEthylanfino)benzo[d] N/ N 1G—19 [1,3]dioxoly1)thio)—9H— purinyl)—N-(tertbutyl ne— 1 — sulfonamide Compound No. Structure Name |“”2 \N/ .

N 3-(6—ammo—8—((6- t / “>-S o (dimethylamino)benzo[d] N N lG—ZO é O) ioxol—5-yl)thio)—9H— purin-9—yl)-N— isobutylpropane—l- 023,4} amide NH2 \N/ 3-(6—amino((6- N \ (dimethylamino)benzo[d] 1G_21 {113‘s ioxoly1)thio)—9H— 0 purin—9—yl)—N— cyclopropylpropane— 1 - 02g sulfonamide NH2 \N/ \ N\ N-(3-(6-amino—8-«6- lN/ N>‘S‘Q\)O (dimethylamino)benzo[d] 1G-22 é 0 [1,3]dioxoly1)thio)-9H— purin—9—y1)propy1)propane- HN\ 2-su1fonamide NH2 \N/ N \ItVSQo N-(3-(6—amino((6- (dimethylamino)benzo[d] N N 16-23 é o) [1,3]dioxoly1)thio)—9H~ purin—9-y1)propyl)ethane- 2-su1fonamide _/‘so2 NHz ‘N/ N—(3—(6—amjno((6- &\ N\)—SQ0 (dimethylamino)benzo[d] 1G-24 N/ o) [1,3]d10XOI-5'-y1)th10)-9H- g punn yl)propy1)methane HN\ sulfonamjde /soz ””2 \N/ .

\ N N~(3-(6—atmno—8—((6— l / VSQO (dimethylamino)benzo[d] N N J 1625 [1,3]dioxoly1)thio)-9H— purin—9-y1)propy1)—2- methylpropane-Q- sulfonamide Compound No. Structure Name NH2 HN/ N‘ N—(3-(6-amino—8—((6— l / N\>—S o (dimethylamin0)benzo[d] 1&6 g 0) [1,3]d1'oxoly1)thio)-9H— purin—9—y1)pr0py1)—2- methylpropane—Z— HN\SO sulfinarnide NH2 \N/ N N—(3-(6-amin0—8—((6— m / \>—s 0 hylarrfino)benzo[d] N N 1627 g 0) [1,3]dioxolyl)thio)-9H- 9-y1)propyl)—2— methylpropane—l — >:I:\SOZ sulfonamide NH2 \N/ N N—(3—(6—amino—8-((6— [ / 3—ng0 (dimethylamino)benzo[d] 1 G-28 é OJ [1,3]dioxolyl)thio)-9H- purin HN y1)propyl)cyclopropane- <r‘302 sulfonarmde NH2 RN/ N \ 3-(6—amino-8—((6— I ‘>—3 o / (dimethylamino)benzo[d] 1G-29 N N 0) [1,3]dioxol-5—yl)thio)-9H— purin-9—y1)—N— HN isopropylpropanamide ”H2 “N “(i \>—s 3-(6-amino((6— 0 (dimethylamino)benzo[d] 1G—30 N N [1,3]di0xol-5—y1)thio)-9H— Lo o 9—yl)—N— ethylpropanamide ””2 ‘N ”(g/[Nys 3-(6—amino—8—((6« o (dimethylamino)benzo[d] 1G-31 N” N O; [1,3]dioxoly1)thi0)—9H— purin-Q-yl)—N- methylpropanamide Compound No. Structure Name NH2 \N/ ' N 3-(6-ammo((6- I \>“5 o , (d1methy1amino)benzo[d]. 1G—32 N N é; O) [1,3]diox01y1)thjo)-9H- puriny1)propanamide NH2 \N/ \ N 3-(6-amino((6- I o / (dimethylamino)benzo[d] 1G-33 N N‘>—S L OJ ioxoly1)thio)—9H— purin—9~yl)—N—(tert- ”>40 butyl)propanamide NH2 \N/ \ N 3—(6-amino((6- / N\>—5 o (dimethylamino)benzo[d] 1G-34 N it O) [1,3]diox01—5-y1)thio)~9H— purin—9—y1)—N— HNLO< isobutylpropanamide NH2 \N/ I : N\>_S<Q\O 3—(6—amino-8—((6— N N J (dimethylamin0)benzo[d] 1G—35 [1,3]dioxolyl)thio)—9H- 0 purin-Q-yl)-N- HN cyclopropylpropanamide NH2 KN/ .

\ N N-(2—(6—am1n0—8-((6— { / N‘>—S‘Qo (dimethylamino)benzo[d] 1G—36 N 2 O) [1,3]dioxoly1)thio)—9H- purin—9— 02$”: y1)ethy1)isobutyrarrfide ‘N N-(2—(6—armn0-8—((6—. "i\ N \>—s 0 (dimethylamino)benzo[d] 16-37 M” N [1,3]dioxoly1)thio)—9H- 2 O) purin NH y)p1 to ep N—(2—(6—amino—8-((6~ (dimethylamino)benzo[d] 1G—38 [1,3]dioxol—5-y1)thio)-9H— pufin«9—y1)ethyl)acetamide Compound N0. Structure Name NH2 \N/ N \ N—(2-(6-amino-8—((6- l / y—SQO (dimethylamino)benzo[d] 1G—39 N N OJ ioxoly1)thio)-9H- plain-9— 0- y1)ethyl)formamide NH; \N’ NJEEN N—(2-(6-am1no((6—' K / N‘>—s o (dimethylamino)benzo[d] 1G~40 N 2 O [1,3]dioxolyl)thio)—9H- purin-Q- 0 y1)pivalamide NH2 \N/ N N N—(2-(6—amin0—8—((6- / VS‘QO (dimethylamino)benzo[d] 1G—41 N N O) [1,3]dioxol-5—y1)thio)-9H— purinyl)ethy1) 0 methylbutanamide r NH2 \N/ NJTN‘ N-(2—(6—an3jno—8-«6— “\N/ N>"S j (d1methy1ammo)benzo[d] 1G—42 8 o [1,3]dioxol—5—y1)thio)—9H— purin—9— 0Zfl> yl)ethy1)cyclopropane— carboxamide NHZ ‘ EJIKS‘SQ‘O\ N—{3-[6—Amino-8—(6- ylamino— 1643 2 oJ l,3]dioxol-5— ylsulfanyl)-purin—9-y1]— HN propy1}-2,2-dimethyl- A60 propionamide NH2 -N/ wasN N J dxmethylammo— 1G—44 g 0 benzo[1,3]dioxol ylsulfanyl)—pufin—9-y1]— HNi 0 propyl}—isobutyramide NH; -N/ JEN Cyclopropanecarboxylic ”i“ Ny—S‘Qo acid {3-[6-amino(6— 1 G-45 dlmethylammo- benzo[1,3]dioxol ylsulfanyl)—purin—9—y1]— propy1}—amide Compound No. Structur/e Name Jig \ ilk / N—{3-[6-Amino—8-(6— N :\>‘3 dimethylamjno- 1G_46 i oJ 1,3]dioxol ylsulfanyl)~purinyl]- NH propyl}hydroxy- ofi‘OH propionamide NH2 _N/_ O\ N Acetic acid l-{3-[6-amino- 8-(6—dimethylamino- N OJ 1647 i benzo[l,3]dioxol—5— ylsulfanyl)-purin—9-yl]— NH propylcarbamoyl} 0&0,A0 methyleethyl ester NHZ J “(Airy—350N N{— 3-[6—Amino—8 (6— - dimethylarnino- i oJ 1948 benzo[1,3]dioxol—5- anyl)—purin—9-yl]- NH p10py1}hydr0Xy 030,1 -propionamide NH2 \N/ ”billy—s N—(3-(6-amino-8—((2— N/ N 0/ (dimethylamino) lG—49 methoxyphenyl)thio)—9H— purin—9- HN y1)propyl)pivalamide Hsp90 binding results are presented for Compounds lG—ZS. lG—43, and lG—45 in Table 12 below. As can be noted therefrom, all compounds showed a high level of binding affinity.

D. Compounds of Formula (IA) in Which Xa or Xb is O In accordance with another embodiment of the disclosure, the compounds are of Formula (IA) in which one of Xa and Xb is O and X0 and the other ofXa and Xb is CH2. Thus, the compounds of this embodiment can be represented by Formula (2): NH2 X2 kaN/I xa or a pharmaceutically able salt thereof, wherein: one of Xa and Xb is O and the other is CH2; Y is CH2 or S; X4 is hydrogen or halogen; R is a is straight—chain— or branched— substituted or tituted alkyl, straight—chain— or branched- substituted or tituted alkenyl, ht—chain- or branched- substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by —S(O)N(RA)-, -NRAS(O)-, 'SOQN(RA)', -NRASOZ-, -C(O)N(RA)-, or -NRAC(O)-, and/or ated by -S(O)NRARB, -NRAS(O)RB, -SOZNRARB, -NRASOZRB, ;C(O)NRARB, or — NRAC(O)RB, wherein each RA and RE is independently selected from hydrogen, C1-C5 alkyl, C2-C5 alkenyl, C2—C6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl; and X2 is as disclosed below.

D-I. In some embodiments of the disclosure, X2 is halogens Table 2A lists c examples of compounds within this embodiment. In each of the structures as drawn, X2 is I and X4 is H. However, corresponding structures in which X2 is F, C1, or Br are within the scope of the disclosure. In each of the structures in Table 2A, Y is S. However, corresponding structures in which Y is CH2 and/or X4 is F, Cl, Br, or I are also within the scope of the disclosure. Additionally, in connection with each of the structures in Table 2A, corresponding structures in which X2 is F, C], or Br and Y is CH2 are also within the scope of the sure Table 2A Compound No. Structure Name Compound N0. ure Name NHz I “16:6?st 2-[§-Amino-8—(5-iodo-2,3- N N dihydro—benzofuran-é- 2A-1 O ylsulfanyl)—puxin—9-yl]- ethanesulfonic acid HN’ isopropylamide NH2 I N \ 2-[6—Amino(5-i0do-2,3- K / N\>_S dihydro-benzofilran—fi- 2A—2 o ylsulfanyl)—purin—9—y1]- ethanesulfonic acid HN’SOZ ethylamide NHz I \ N\ 2-[6—Amino—8-(5—iodo-2,3— ”\ / N>—s dihydro-benzofuran-é- 2A—3 o ylsulfanyi)-puxin—9-y1]— ethanesulfonic acid HN/SOZ methylamide NHZ I fiNVSQj Z-EfI-IAmino-S-(5-iodo-2,3- 2A-4 N N 1 ydro—benzofuran-6— O ylsulfanyl)—purm—9—yl]- ethanesulfonic acid amide NHSZN I N \H]: ys‘Qj 2-[6—Annno(5-10do. i N/ N dihydIo-benzofuran—é- ZA-S 2 0 ylsulfanyl)~purin—9—y1]- ethanesulfonic acid tert- HN/ butylamide NHz I N \it VS 2—[6—Amino-8—(5—iodo—2,3— N N O dihydro-benzofiiran-6— 2A—6 3 ylsulfanyl)—purin—9—y1]~ [502 ethanesulfonic acid H“) isobutyl—amide NHz I N \ 2-[§—Annno«8—(5~1odo—2,3—. .

I / xyst N N d1hydro—benzofuran-6— 2A-7 8 O ylsulfany1)-puriny1]- ethanesulfonic acid HN cyclopropylamide Compound No. Structure Name N H2 NIKEN\%S Propane—Z-sulfonic acid N/ N {2—[6-am1'no-8—(5-iodo—2,3— 2A-8 8 O o-benzofuran—G- NH ylsulfany1)-puriny1]— 028/ ethy1}—amide N H2 | Ethanesulfonic acid {2—[6— amino-8—(5-iodo-2,3- 2A'9 o dihydro-benzofuran-G- ylsulfanyl)—purin—9—yl]- IN” ethy1}—amide NHg I l xys N—(2-(6—Amino-8—(5—iodo- N/ N 2A 10' 2,3-dihydro—benzofu1'an—6- 8 0 ylsulfanyl)-purin—9—y1)— NH ethyl)—Inethanesulf0namide 025/ NH2 I N \ N\ 2-MethyI-propane—2- l / N>—S sulfonic acid {2-[6—amjno— 2A 11 o — 8 8-(5—iodo-2,3-dihydro— benzofuran-é-ylsulfanyl)- ,NH purin—9—y1]—ethyI}-amide NHZ I l N\>_s 2-Methy1-propane-2— N/ N sulfinic acid {2-[6-amino— 2A-12 g 0 8-(5-iodo-2,3-dihydro— NH lranylsulfany1} os’ purin—9—y1]—ethyl} —amide NHZ I "II \ “3.3 2-Methy1-propane—1- N/ N sulfonic acid {2-[6-amino- 2A-13 g 0 8~(5—iodo—2,3-dihydro- NH uran-6—y1su1fanyl)- 023’ purin—9-y1]-ethy1}~amide NH: I N'k \ N\>_s Cyclopropanesulfonic acid N/ N {2-[6-amino—8—(5-iodo-2,3— 2A—14 0 dihydro—benzofuran-6— ylsulfanyl)—purin-9—y1]— ethyl} -amide Compound N0. Structure Name NHz ‘ N \ N\ I %S / 3—[6-Amino -2,3- N N o-benzofilran-6— 2A-15 ylsulfany1)—purinyl]- propane-1 -su1fonic acid OZS\NH isopropylamide NH: I N \ Nye 3-[6-Amino(5—iodo-2,3— N/ N o-benzofuran—fi 2A—16 ylsulfanyl)—purinyl]— propane—1 -su1fonic acid 023‘ ethylarnide NH2 , NI \ N\>—S 3-[6-Amino(5-iodo-2,3— N/ N dihydro-benzofuran—G- 2A—17 ylsulfanyl)—purin—9—yl]— propane-l -su]fon1'c acid 02$ methylamide NHz | N: \ N\>—s 3-[6-Amino(5-iodo-2,3- N/ N dihydro—benzofuran-é- 2A-1 8 ylsulfany1)~purin—9 —y1]- propane~1 -su1fonic acid amide NH; I N \ N\>‘S 3-[6-Anfino-8—(5-iodo-2,3- N/ N dihydro—benzofilran 2A-19 ylsulfanyl)—purin—9—y1]— propane-1 -su1fonic acid 023‘ tert—butylamide NH; I N \ N\ K / N%S 3-[6-Amino(5-iodo—2,3- N dihydro-benzofuran—6- 2A-20 ylsulfanyl)—puriny1]- propane-1 -su1fonic acid 028 isobutyI-amide Comgound No. Structure r— Name NH2 I \ Nyngj I 3-[6_-Amino(5-iodo—2,3— N/ N d1hydIo-benzofuran 2A-2 1 ylsulfanyl)—purin—9 -y1] - e— 1 -su1fonic acid 023 cyclopropylamide H‘N—<] NH2 I t / VSCU Propanesulfonic acid N N {3-[6-amino(5-iodo— 2A-22 é 2,3,3a,7a—tetrahydro- lran—6—y1sulfanyl)— HNI 9-y1]—propy1}-amide NH2 I ll \ ’1}ng Ethanesulfonic acid {3—[6- N/ N amino-8—(5—iod0—2,3— 2A-23 dihydro-benzofi1ran ylsulfany1)—purinyl]- ”NI propy1}-amide NH2 I \ [3—st l N—{3-[6-Amino—8-(5-iod0— N/ N 2,3—dihydro—benzofi1ran—6- 2A-24 ylsulfany1)—puriny1]— prowl}- HNI methanesulfonamide NH2 | lk / VSQj Z—Methyl-propane-Z- N N sulfonic acid {3—[6-amino- 2A-25 8—(5-iodo-2,3-dihydxo- benzofuran-6~ylsulfanyl)- HN puriny1] —propyl} —amide MHZ I l / VS‘Qj 2-Methyl-pr0pane-2— N N sulfmic acid {3-[6-amino- 2A-26 8-(5—iodo-2,3-dihydrobenzofixran —6—y1sulfanyl} purin—9-y1]—propyl} -amide Compound No. Structure Name NH2 I N \ N\ t / N>_S 2-Methy1-propane-1— N sulfonic acid {3-[6-amin0— 2A-27 8-(5-i0do-2,3-dihydro- benzofiJran—6-ylsulfanyl)~ HNISOZ purin—9-yl]—propy1}-amide NHz I N \ N\ K / N%S Cyclopropanesulfonic acid 0 {3—[6-amino—8—(5-iodo-2,3— 2A-28 dihydro—benzofuran ylsulfanyl)—purin—9—y1]— HN‘SOZ propyl}-amide NHT‘ I N \{ts—S 3-[6—Annno(5—1odo—2,3-. I 2A-29 0 dihydro-benzofuran—6— ylsulfanyl)—purin—9-y1]—N- HN isopropyl-propionamide NHz I N'k: NH, 3—[§—Amino—s—(5—iodo-2,3- N N 2A-30 d1hydr0—benzofuran~6— ylsulfanyl)—purin—9-yl]—N— 0 ethyl—propionamide NH; I N‘k \ “(*3 3-[6-Amino-8—(5-iodo-2,3- N/ N 2A—31 dihydro—benzofuran—é— ylsulfanyl)—purin—9—y1]—N- o methyl-propionamide NH2 I N \ N mino—8—(5—iodo-2,3~ KN/\ \>—S 2A-32 N dihydro—benzofuran-é— O ylsulfanyl)-purin-9—yl]- o propionamide N I . . . l / NVS 3-[6-Am1no(5—lodo—2,3— 2A-33 é: o dihydro-benzofuran—G— any1)-purinyl]-N- HN tert—butyl—propionamide Compound No. Name I 3-[6—Amino-8—(5—iodo-2,3— 2A 34_ g: 0 o—benzofuran-6~ ylsulfanyl)-puriny1]-N— HN\_O< isobutyl—propionarrfide NH2 I ”(ifsN 3-[6-Amino-8~(5—iodo-2,3- 2A-35 o dihydro-benzofuran-G- ylsulfanyl)-purin—9—y1]—N- cyclopropyl-propionamide NH; I NC ks N—{2-[6-Amino—8—(5-iodo- N/ N 2A—36 2,3—dihydro-benzofuran-6— 2 O anyl)—purin—9—yl]— NH ethyl}-propionamide NH2 I {\INNWS N—{2-[6—Amino-8—(5-iodo— N/ N 2,3—dihydro—benzofi1ran—6— 2A-37 2 O ylsulfanyl)—purinyl]- NH ethyl}—propionamide NH2 , WEEKS N-{Z-[6-Amino(5-iodo- N/ N 2A—38 2,3—dihydro-benzofixran—6- 8 O ylsulfany1)—pufin-9—y1]- NH ethy1}—acetamide 2 | \ N IEN” N>——S\ 2:2 N—{Z-[6-Amino(5-iodo— 2,3-dihydro—benzofuran-6— 2A-39 2 O ylsulfany1)—purin-9—y1]— NH ethy1}-2,2-dimethy1— 0? propionamide NHz .

N|)\IN\>*S N—{Z—[G—Amino—S-(S-iodo- kN” N 2,3-dihydr0-benzofi1ran—6- 2A-40 8 O ylsulfany1)-purin—9-y1]— NH ethyl} ~3—methy1— 0 butyramide NHZ , “fli'ks Cyclopropanecarboxylic k,( N acid amino-8—(5- 2A-41 iodo—2,3—dihydrobenzofuran-6 ~ylsulfanyl)— purin-9—yl] —ethy1} —amide Compound No. Structure Name NH; I \ N\ N-{Z—[6-Amjno(5-iodo- 2A 42 N>—S - {N/ 2,3-dihydro-benzofi1ran 8 ylsulfany1)—purin—9-yl]- NH ethy1}-f0rmamide ‘1 NH; “161$.stI N—{3-[6—Amino—8-(5-iodo- N 2,3—dihydro-benzofi1ran—6- 2A-43 ylsulfanyl)—purin—9-yl]— H propy1}-2,2-d1'methy1- $0 propionamjde ”fix I kN/ N>_S N—{3-[6-Amino—8—(5-iodo- 2A 44' hydIo—benzofuran-6— ylsulfanyl)-purinyl]- H propyl} -isobutyramide “ff/[NysVQjI Cyclopropanecarboxylic N N acid {3-[6—amino(5- 2A-45 i ,3—dihydro- NH benzofuran-é-ylsulfanyl)- . . o purm—9-y1]-propyl}-am1de ”ki‘ I s N-{3-[6-Amino—8-(5-iodo- N N 2,3-dihydro-benzofuran—6— 2A-46 i ylsulfanyI)—purin—9-y1]- NH propy1}hydroxy- Dav‘oH namide 1??stI\ N Acetic acid 1-{3-[6-amino— 8-(5—iodo-2,3-dihydro- 2A-47 benzofilracylsulfanyl)- purm—9—y1]— NH propylcarbamoyl}—1— 0 0A" methyl—ethyl ester {1‘}stI N—{3-I6—Amino—8—(5-iodo- N N 213—d1hydro—benzofuran 2A-48 i anyl)—purin—9-yl]— NH propyl}hydroxy—2— 0&0“ methyl-proplonamlde. .

Table 5A lists specific examples in which X; is halogen and X4 is halogen. In each of the structures as drawn, X2 is I and X4 is F, However, corresponding structures in which X, is H, Cl, Br, or I are Within the scope of the disclosure. In each of the structures in Table 5A, Y is CH2.

However, corresponding ures in which Y is S and/0r X2 is F, C1, or Br are also within the scope of the disclosure. Additionally, in tion with each of the structures in Table 5A, corresponding structures in which X4 is H, Cl, Br, or I and Y is S are also Within the scope of the disclosure.

Table 5A Compound No. Structure Name NHg l N \ N\ 2—(6-aminofluoro-8—((5- )L / ionic—2,3— F N N 5A-1 2 o dihydrobenzoiuran-6— yl)methyl)-9H-purinyl)— ,302 N—isopropyl- sulfonamide NH2 I “JEN 2—(6—amino~2—fluoro((5- N i0d0—2,3— F)LN/ 5A-2 o dihydrobenzofuran—é— yl)1nethyl)-9H—purinyl)— HN’SOZ N—ethylethanesulfonamide NH; I .

N 2-(6-aminofluoro-8—((5- iod0—2,3—. A \ F N/ N 5A-3 obenzofuran-G- 2 O yl)methyl)-9H—purin—9-yl)— ,soz HN methylethanesulfonamide NH2 l N \ 2-(6-aminofluoro((5- A / iodo-2,3- F N N 5A-4 g O dihydrobenzofilran-G— yl)methyl)—9H—purin—9— /Soz yl)sulfonamide NH2 l N \ N\ 2-(6-aminofluoro((5- A / iodo-2,3- F N N 5A-5 g O dihydrobenzofiiran-G- yl)methyl)—9H-purin-9—y1)- ,302 N—(tert— HN butyl)ethanesulfonamide I CompoundNo, Structure Name NH; I NI \ N\>/\<:%j 2-(6-amin0fluoro—8—((5— F/kN/ N iOdO-2,3- 5A-6 2 dihydrobenzofilran—G- SO y1)methy1)~9H—pur1'n—9-y1)- HN’ N- isobutylethanesulfonanfide NH2 1 \ N\ 2—(6-amino—2-fluoro—8-((S— )L / N i0d0—2,3— F N o dihydrobenzofuran-é- 5A-7 g yl)methy1)-9H-purinyl)— HNISOZ N-cyclopropylt- \{> ethanesulfonamlde NH; I \ N N—(2-(6—aminofluoro )L / N‘ do-2,3- F N 5A_8 g o dihydrobenzofilran—6— yl)methyl)«9H—purin-9— ,NH yl)ethy1)propane—2— O28 sulfonamide NH2 1 N \ N\ N-(2-(6-aminofluoro-8— )L / NWQU ((5—iodo—2,3- F N 5A-9 2 o dihydrobenzofuran-6— yl)methyl)—9H—purin OZS'NH yl)ethy1)ethanesulfonamide 31%“! I N—(2-(6-amino—2—fluoro—8- )L / ij ((5-iodo-2,3- F N N 5A-10 obenzofuran g O yl)methy1)-9H-pu1in—9- [NH y1)ethy1)methane— ozs\ sulfonamide NH; ‘ \ N 6—amino—2—fluoro—8— )L / [$ij ((5—iodo—2,3- F N 5A“ 8 O dihydrobenzofuran y1)methy1)—9H-purin ,NH y1)ethy1)—2-methy1propane— 025 2-su1fonamide NH2 I \ N N-(Z-(6-aminofluoro AL / N‘ ((5-iodo-2,3- F N 5A-12 dihydrobenzofuran—6- yl)methy1)-9H—purin—9- yl)ethy1)~2-methy1propane— 2-su1finamide Compound No. Structure Name NH2 I \ N\ N—(Z-(6-amino—2-fluoro )L / ((5-iodo-2,3- N N 5A-13 g dihydrobenzofilran yl)methyl)-9H—purin—9— , yl)ethyl)—2~methy1pr0pane— O S,NH2 1-su1fonamide NHZ I \ j N—(2-(6—amino—2-fluoro N ((S—iodo-Z 3— N , 5A~14 dihydrobenzofilran—G— yl)methy1)—9H—purin—9- y1)ethy1)cyclopropane- o S,NH2 W> sulfonamide NHz I )fiiNv/Qj 3-(6-aminofluoro((5- N” N iodo—2,3— 5A-15 dihydrobenzofuran y1)methy1)—9H—puriny1)— 023‘ N-isopropylpropane—l- NH sulfonamide NH2 I \ N\ 3-(6-aminofluor0—8-((5— jL / iodo—2,3- N N 5A-16 { dihydrobenzofuran-G— hyl)—9H—purin—9—y1)— lpropane—l- o s2 ‘NH amide NH; I N \ N\ 3—(6-amino—2-fluoro((5- /l‘\ / iodo—2,3— N N 5A-17 g dihydrobenzofuran—6— y1)methyl)-9H-purin—9-y1)- N—methylpropane-l - 023W sulfonamide NH2 I j: \ 11% 3-(6-amino-2—flu0r0—8—((5~ N/ N iodo-2,3- 5A-18 g dihydrobenzofumn-G- yl)methy1)—9H—purin y1)propane— 1 -su1fonamide Compound No. Structure Name NHZ | NI \ N\ FXN/ 3-(6-ami1'10é2-élgoro—8~((5—10 o- - N , 5A-19 é o d1hydrobenzofuran yl)methy1)-9H—purin—9-y1)- N—(tert-buty1)propane« 1 - OZSN sulfonamide NH2 I J: \ N\>/\Qj F N/ N 3-(6-anfinoé2-fluoro«5-i0 o-2,3- 5A-20 dihydrobenzofur'an-6— y1)methy1)-9H—pur1n-9—yl)— 025‘ N—isobutylpropane-l- HN sulfonamide NHZ I N \ N\ A / 3~(6-anfi1}oé2-§1;oro-8~((5—10 o~ — F N N 5A-21 O dihydrobenzofuran—G— y1)methy1)-9H-purinyl)- N-cyclopropylpropane—l— 023N sulfonamide NHQ I NI \ "{ N-(3-(6-aminofluoro—8— FJ\N/ N ((5-i0d0-2,3- é ° yfiifiigzfiifgfgafii; HN\ y1)pr0py1)pr0pane 802 sulfonamide NH2 I )NL \ “{ij 6—am1'no—2—fluoro—8— / ((S—iod0—2,3- F N N 5A-23 é O obenzofuran—fiyl )methy1)-9H-purin yl)propyl)ethane- \ sulfonarnide NH: I U N—(3—(6-amino—2-fluoro-8— / ((5—iodo-2,3- F N N 5A—24 dihydrobenzofuran yl)methy1)-9H—purin—9- y1)propyl)methane— sulfonamide nd No. Structure Name ——‘ NH2 I \ N N-(3-(6-aminofluoro—8- )L / ((S-iodo-2,3- F N N‘ 0 dihydrobenzofilran-G— 5A-25 g yl)methy1)~9H—purin—9- py1) HN\SO methylpropane-Z- 7< sulfonamide NH2 I \> N N—(3-(6—aminofluoro-8— )L / N‘ ((5-i0do—2,3- F N o dihydrobenzofilran 5A-26 é yl)methy1)-9H—purin—9- y1)pr0py1) ”NSC methylpropane-Z- sulfinamide NHz I N \ N—(3-(6—amin0fluoro—8— /H\ / ((5-iodo—2,3- F N N‘ O dihydrobenzofuran—é- 5A-27 é yl)methyl)-9H—purin—9- y1)pI0py1) HN\SO methylpropane—1~ > 2 / sulfonamide NHZ I /H\ t N—(3-(6-a1uino—2-fluoro—8- F N N ((5-1odo-2,3- 5A-28 obenzomran—6- y1)methyl)—9H-purin-9— HNK yl)propy1)cyclopropane- <rsoz sulfonamide _L_.—______— NH2 I ij nfiuofluoro«5- F N N 10d0-2,3- 5A—29 dihydrobenzofuran—6— yl)methy1)—9H—purin—9~yl)- N—isopropylpropanamide 3—(6—amino—2-fluoro—8—((5~ iodo-Z,3 - dihydrobenzofuran—6- y1)methy1)-9H-puriny])— N—ethylpropanamide Compound No. I Name 3-(6-aminofluoro((5- iodo-2,3- F N 5A—31 dihydrobenzofin‘an-6— y1)methy1)—9H-purin—9—y1)— O N—methylpropanamide NH2 I N \ 3-(6—amino—2—fluoro—8—((5- A / \ iodo-2,3- 5A-32 F N obenzofuran y1)methyl)—9H-purin O yl)propanamide NHz I )NL \ \ 3-(6-aminofluoro((5— F N/ iodo—2,3— 5A—33 dihydrobenzofuran—é- O yl)methy1)-9H-puriny1)- H N—(tert-butyl)propanamide NH2 I NI \ N\ 3—(6—amino-2—fluoro—8—((5— I: N/ iOd0-2,3- 5A-34 dihydrobenzofilran y1)methy1)-9H—puriny1)- N-isobutylpropanarnide NH2 I )Nfij: \ 3-(6-aminofluoro-8—((5- F N/ ,3- 5A—35 dihydrobenzofuran—6- O y1)methyl)-9H—puriny1)— N—cyclopropylpropanamide NH2 I )NL \/ N\ N—(2—(6—an'1inofluoro—8— F N N d0-2,3- 5A-36 8 O dihydrobenzofuran-é- NH y1)methy1)-9H—purin—9— o y1)ethyl)isobutyramide NH2 I N \ N-(Z-(6—amino—2—fluoro—8- FJLN/ ((5—iodo—2,3— 5A-37 dihydrobenzofilran—6— yl)methy1)-9H—purin—9- y1)ethyl)propionamide I ndNo. Structure Name NH2 I )L\ NVQU/ N—(2-(6-amjnofluoro-8— ((5-iodo-2,3- F N N 5A-38 2 dihydrobenzofuran—6— yl)methyl)-9H—purin~9- NH yl)ethy1)acetamide NH2 I ND “\ N-(Z-(6—amino—2—fluoro ((5—iodo~2,3- 5A-39 FAN/ N dihydrobenzofuran—6- yl)methy1)-9H-pun'n—9- yl)ethy1)f0rmamide N—(Z—(6—amin0—2—f1uoro—8- ((5-10d0-2,3- dihydrobenzofuran—fi- yl)methy1)—9H-purin y1)ethy1)piva1amjde N—(Z—(6—amino—2-fluoro—8— ((5-iod0-2,3- obenzofuran—6— yl)methyl)-9H-pufin—9- y1)ethy1)-3— methylbutanamide N-(2—(6—aminofluoro ((5—iodo—2,3- dihydrobenzofuran—6— hyI)-9H-purin yl)ethy1)cyclopropane- carboxamide N—{3-[6—Amino—2-fluoro- 8-(5-iodo—2,3 -dihydro- benzofuran-6—ylmethy1)~ purin—9—y1] -pr0py1} —2,2- yl-propionalnide N—{3—[6—Amino—2—fluoro 8-(5—i0do-2,3-dihydrobenzofilran-é-ylmethyl purin-9—yl] -propy1} - isobutyramide Compound No. Structure Name flirtbI\ N Cyclopropanecarboxylic.

F N acrd {3—[6—am1nofluoro— 5A—45 i 8-(5—iodo—2,3-dihydro— L NH benzofuran—6—ylmethyl)- 0%» purin—9-yl]-propyl} -amide ”F72— I fiwN N—{3—[l6-Aminofluoro- F N i 8-(5—10do—2,3-d1hydro- 5A-46 benzofuran—6—ylmethyl)— NH purin—9-yl] l} —2- 093A»! hydroxy-propionamide NH; I N\ Acetic acid l-{3-[6-amino- FAN/hi \ N 2-fluoro-8—(5—iodo—2,3- 5A—47 fl 0 dihydro-benzofuran-G— ylmethyl)—purinyl]— N H propylcarbamoyl} -1 - J 04><YAC methyl-ethyl ester NH2 , N-{3-[6—Aminofluoro- FAN/’iJiEN‘ a 8—(5-iodo—2,3—dihydro— 5A—48 benzofuran—6—ylmethyl)- purinyl] l} -2 — NH y-Z—methyl— 03m propionamide In each of the structures Xb is O and Xa is CH2. However, corresponding structures in which Xb is CH; and Xa is O are also within the scope of the disclosure.

Hsp90 binding results are presented for Compounds 2A-11, 2A—12, 2A~26 and 2A-45 in Table 12 below. As can be noted therefrom, the compounds showed a high level of binding affinity.

D—H. In some embodiments of the disclosure, X2 is an optionally substituted aryl.

Specific examples of compounds within the scope of this aspect of the disclosure correspond to the compounds disclosed in Tables 2A and 5A, or variations thereof as described in A. and D-I. above, in which X; is an optionally tuted aryl, including but not limited to pyrazolyl, azol-3— yl, oxazolyl, oxazol-Z-yl, thiazolyl, thiazol-Z-yl, furanyl, furan—Z—yl, and 5-methylfuran—2—yl.

D—IH. In some embodiments of the disclosure, X2 is an alkynyl group, e.g., ethynyl, 1— prop-l—ynyl, and 3—prop-l-ynyl. c examples of compounds Within the scope of this aspect of the sure correspond to the compounds disclosed in Tables 2A and 5A, or variations thereof as described in A. and D-L above, in which X2 is an alkynyl group.

D-IV. In some embodiments ofthe disclosure, X2 is an amino group, i.e., , wherein R1 and R2 are each independently H, C1-C5 alkyl, C2—C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heteroallcyl, heterocycloalkyl, aryl, heteroaryl, ryl, kyl, alkylheteroaryl, heteroarylalkyl, or alkylheteroarylalkyl. Specific examples of compounds within the scope of this aspect of the disclosure correspond to the compounds disclosed in Tables 2A and 5A, or variations thereof as described in A. and D—I. above, in which X2 is an amino group.

E. Compounds of Formula (IA) in Which Xa or Xb is C(=O) In ance with another embodiment of the disclosure, the compounds are of a (IA) in which one of Xa and Xb is C(:O) and KC and the other of Xa and Xb is CH2. Thus, the compounds of this embodiment can be represented by Formula (3): NH2 X2 Xi’kN/It \>_Y Xa . x5) (3) or a pharrnaceutically acceptable salt thereof, wherein: one of Xa and Xb is a carbonyl group, i.e., C(=O), and the other is CH2; Y is CH; or S; X. is hydrogen or n; R is a is straight-chain- or branched— substituted or unsubstituted alkyl, straight—chain— or branched— tuted or tituted alkenyl, straight-chain— or branched- substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by -S(O)N(RA)-, -NRAS(O)-, -SOZN(RA)-, —NRASOZ~, -C(O)N(RA)—, or —NRAC(O)-, and/or terminated by -S(O)NR,\RB, -NRAS(O)RB, «SOZNRARB, -NRASOZRB, -C(O)NRARB, or — NRAC(O)RB, wherein each RA and RE is independently selected from hydrogen, C1-C6 alkyl, CTC5 alkenyl, C2-C5 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, aryl, ryl, arylalkyl, alkylheteroaryi, arylalkyl, and alkylheteroarylalkyl; and X2 is as sed below.

E-I. In some embodiments of the disclosure, X2 is n. Table 7A lists specific examples of compounds within this embodiment. In each of the structures as drawn, X2 is I and X4 is H. However, corresponding structures in which X2 is F, C1, or Br are Within the scope of the disclosure. In each of the structures in Table 7A, Y is S. However, corresponding structures in which Y is CH; and/or X4 is F, Cl, Br, or I are also within the scope of the disclosure. In each of the structures in Table 7A, Xb is C(=O) and Xa is CH2. However, corresponding structures where Xa is C(=O) and Xb is CH2 are also within the scope of the disclosure. Additionally, in connection with each of the structures in Table 7A, corresponding structures in which X2 is F, C1, or Br, Y is CH2, Xa is C(:O), and XI) is CH2 are also Within the scope of the disclosure.

Table 7A Com ound No. Structure Name NH2 I NEENVS 2-(6—amino-8—((6-iodo—3- N/ N oxo—2,3-dihydro-1H—inden- 7A-1 2 5—yl)thio)-9H—purinyl)— Hp;— isopropylethanesulfonamide NH2 I “EEC \>_sN 2-(6-amino—8—((6-iodo—3- N/ N 7A-2 Dim-2,3-dihydro-1H—inden- 2 5—y1)thio)-9H-purin—9-yl)— [502 N—ethylethanesulfonamide NH2 I le \ \>—s 2—(6-amino—8—((6-iodo N/ N 7A—3 oxo-2,3—dihydro—IH-inden- g 5-yl)thio)—9H—purin—9-yl)— [502 N—methylethanesulfonamide NH2 | l Nys 2—(6-amino((6-iodo 7A-4 N/ N oxo—2,3—dihydro-1H—inden— 8 5—y1)thio)-9H—purin-9— O yl)ethanesulfonamide [302 Compound No. Structure Name NH2 I NIJiNys mino—8-((6-iodo-3— N/ N axe—2,3-dihydro—1H-inden— 7A—5 g 5-y1)thio)—9H—purin—9—y1)- so N-(tert— HN’ buty1)ethanesulfonamide NHZ ‘ N \ N\ m / >—S 2—(6-amino((6—iodo—3- N N mic—2,3~dihydro—1H—inden— 7A-6 2 hio)~9H—puriny1)— [302 N- :‘2 isobutylethanesulfonamide NH2 I “I‘L\ N \>—s 2-(6—amino—8-((6—iodo—3— N/ N axe-2,3-dihydro-1H—inden— 7A-7 g 5~y1)thio)-9H—puriny1)- 802 N—cyclopropyl— HN’ ethanesulfonamide NHZ I Nl\ N \>_s N—(Z-(6—amino((6-iodo— n” N 3-oxo-2,3-dihydro-1H- 7A-8 2 inden-S—y1)thio)—9H-purin— NH 9-y1)ethy1)propane-2— 023' sulfonamide NH2 1 N \ N\>_S N—(2—(6—amino—8—((6-iodo- KN/ N 3-oxo—2,3—dihydro-1H- 7A—9 2 inden—S—y1)thio)—9H—purin~ < 9_ 'NH yl)ethy1)ethanesulfonamide O S2 NHg I N \ N\>_S N—(Z-(6—amino—8-((6—iodo- KN/ N 3—oxo—2,3-dihydro—1H- 7A-10 2 S—yl)thio)—9H-purin- 9—y1)ethyl)methane- sulfonamide Compound No. Structure Name NH2 , \ N—(Z—(6—amino((6-iodo— K / N>—S 3-0x0—2,3—dihydro-1H— 7A41 inden-S-y1)thio)-9H-pun'n- O 9—y1)ethy1)—2- ’NH methylpropane—Z- 0:5 sulfonamide NHZ ‘ \>—3 N—2—(6—amino((6—iodo— kN/I N 3—oxo—2,3-dihydro—1H* 7A-12 inden—S-y1)thio)-9H-purin- O 9-yl)ethyl)—2- [NH methylpropane-Z- 03V sulfinamide NH2 | N \ 6-anfino—8—((6—iodo- IL / N\>_S 3—0X0~2,3-dihydro-1H— 7A-13 2 S-y1)thio)—9H—purin— o 9—y1)ethy1) ’NH methylpropane—l- 023‘ < sulfonamide NH; I N \ . “\ / \>—s N—(Z—(6—annno—8-((6-1odo—.

N N 2,3—dihydro—1H— 7A-14 2 indeny1)thio)—9H—purin- NH 9—y1)ethy1)cyclgpropane- 025%> sulfonarmde NH2 I i / N\>—s 3-(6-amino—8-((6-iodo 0X0-2,3~dihydro—1H—inden— 7A-15 O 5—y1)thio)-9H-purin—9-y1)- N-isopropylpropane-l - 028‘ sulfonamide NH2 I ”(i xysN 3—(6-amino—8—((6—iodo N/ N 0X0-2,3-dih dro—lH-inden—Y 7A-16 5—yl)thio)—9H-purin—9-y1)— N-ethylpropane-l - sulfonamide Compound No. Structure Name NH2 I fix—3% mino—8—((6-iodo—3— N/ N oxo-2,3-dihydro-1H—inden— 7A-17 5—y1)thio)-9H—purin—9—yl)~ O N—methylpropane—l- sulfonamide 023‘ NH; 1 m / \>—S 3-(6—amino-8—((6-iodo-3— N N g oxo—2,3-dihydro—lH—inden- 0 5-y1)thio)—9H-purin y1)pr0panesulfonamide 023‘ NHZ I h(ND:N%S\ N\ 3-[6-Amino—8—(6—iodo oxo-indan-S-ylsulfany1)— 7A-19 g purin—9—y1]—propane—1— sulfonic acid tert— 02$ butylamide NH2 ""'—’——‘ N \<1ng 3-[6-Amino(6-iodo oxo-indan—S-ylsulfanyl)— 7A-20 O puriny1]—propane~1- 023M sulfonic acid isobutyl-amide NH2 I II \ N\>—s 3-[6-Amino(6-iodo-3— N/ N oxo—mdan-S-ylsulfanyl)— 7A—21 g pun'n—9—yl] —propane—1 — 0 sulfonic acid ozsI cyclopropylamide HNvfl 2 | N \Kit/[II%S Propane-Z-sulfonic acid {3- no-8—(6-iodooxo- 7A-22 O indan-S-ylsu1fany1)-purin HNI302 y1]-propy1}—amide NH2 """ l / Vsfi Ethanesulfonic acid {3-[6- N N . . 7A-23 é . annno-S-(6-10d007so- o 1ndan—5-ylsu1fanyl)-pur1n—9- HN y1]-propyl}-amide Comgound No. Structure Name 2 I fiflH N- {3-[6-Amino—8—(6-iodo— 7A—24 3-oxo—Iindan-5—ylsulfanyl)— o punn—9-y1]-pr0py1} - methanesulfonamide )so2 (i \ I s y1—pr0pane N N ic acid amino- 7A-25 g o 8-(6-i0d00xo-indan ylsulfany1)—purin—9-yl]~ HN . ‘802 propyl} -am1de “Kitifs 2-Methy1—pr0pane—2— N N sulfinic acid {3-[6-amino—8— 7A—26 0 (6-iodo—3-oxo-indan—5- ylsulfany1)~pur1'n—9-y1]— HN . ‘30 propyl}-am1de NHz ‘ hi / N\>_S 2~Methy1—propane~1- N sulfonic acid {3—[6—amino- 7A-27 O 8-(6-iod00x0-indan—5— ylsulfanyl)—puriny1]— HN - \SOZ propyl} armde_ NH: 3 I \/ ‘>—S _ _ N N Cyclopropanesulfomc amd 7A 28 {3-[6-amino(6—iodo _ . o oxo—indan—S—ylsulfany1)- HN\ purin—9—yl]~propy1} ~amide <{SOZ NH2 I N \ N\ l / *3 3—[6-Amino(6-iodo-3— N N . 7A-29 oxo_—1ndan—5-ylsulfanyl)— O purm-9—y1]—N—isopropyl- O propionamide NH2 I “it VsN 3—[6—Amino(6-iodo—3— N N oxo—indan—S-ylsulfany1)— 7A-3O purin—9-y1]-N—ethyl- propionamide Compound No. Structure Name NH; “ft \fs 1 N 3-[6—Amino—8—(6—iodo—3- N/ N 7A-31 dan-S-ylsulfany1)- purin-9—yl]—N—methy1— O propionamide NH2 I "l/ \>-6 3—[6-Amino—8—(6—iodo—3- 7A—32 N €: oxo-indan—S—ylsulfanyl)- 0 puriny1]—propi0namide NH2 1 “P “x k / 3—[6—Amino—8—(6—iodo—3- N Nfs 7A-33 g: 0X0—indan-5—y1su1fany1)— o purin—9—y1]—N—tert-buty1— 0 propionamide NH2 Z—“‘“_I N \ N\ N “ks 3-[6-Amino(6-iodo 7A-34 é: oxo—indan-S-ylsulfanyl)— o purin—9-y1]—N-isobuty1— 0 propionamide NHz I “P “x kN/ Nfs 3—[6-Amino—8-(6-iodo—3— oxo-indan-S—ylsulfany1)— 7A-35 O purinyl]-N—cyclopropyl- O propionamide NH2 I N \ N\ l / “ks 6-Amino-8—(6—iodo- N 3-oxo-indan—5 fanyl)- 7A-36 8 O purin—9—y1]—ethy1}— NH isobutyramide NH; | fl\ N \>—s N-{Z—[6—Amino-8—(6—iodo— N/ N 7A-37 3—0x0—1'ndanylsulfany1)— 8 purin—9-y1] —ethy1} - NH propionamide Compound No. ure T Name NH2 I '1\ ”9—5 N—{2-[6—Amino-8—(6-iodo— N/ N 7A-38 3-oxo-indan—5—ylsulfanyl)— 8 purin—9—yl] ~ethyl} — NH acetamide r NH2 I t / N‘>—S N-{Z-[6-Amino—8—(6—iodo— 7A—39 8 3-oxo—indanylsulfanyl)— 9-yl]—ethyl}—2,2- NH dimethyl-propionamide NH2 I N—{2-[6-Amino-8—(6-iodo— 7A-40 g indan—5-ylsulfanyl)- purin—Q—yl] ~ethyl} -3 - 04W -butyramide NH2 I p we;3 Cyclopropanecarboxylic acid {2-[6—amino—8—(6~iodo- 7A—41 3—oxo-indan-5—ylsulfanyl)- NH purin~9—yl]—ethyl} -an1ide NHZ I “@ng N— {2-[6—Amino(6-iodo— 3—oxo-indan-5 -ylsulfanyl)— 7A-42 i... purinyl] —ethyl} — formamide Qfi I_ Table 9A lists specific examples in which X; is halogen and X4 is halogen. In each of the structures as drawn, X2 is I and X4 is F. However, corresponding structures in which X; is H, Cl, Br, or I are within the scope of the disclosure. In each of the structures in Table 9A, Y is CH2.

However, corresponding structures in which Y is S and/or X2 is F, C1, or Br are also within the scope of the disclosure. In each of the structures in Table 9A, Xb is C(=O) and Xa is CH2.

However, corresponding structures Where Xa is C(:O) and Xb is CH2 are also Within the scope of the disclosure. However, corresponding structures in which Y is S are also within the scope of the disclosure. Additionally, in connection with each of the structures in Table 9A, corresponding structures in which X; is H, Cl, Br, or I, Y is S, X8. is C(=O), and Xb is CH2 are also within the scope of the disclosure.

Table 9A Compound No. Structure Name NH; | JNL\ N \ 2-(6-aminofluoro((6- F N/ N i0dooxo-2,3-dihydro—1H— 9A-1 g inden-S-yl)methy1)-9H- 302 purin—9—y1)—N- HN’ isopropylethanesulfonamide NH2 I WEEK 2-(6-amin0fluoro—8-((6— F )LN/ N —oxo-2,3-dihydIo-1H- 9A-2 inden—S-yl)methy1)-9H— o puriny1)—N— HN’SOE ethylethanesulfonamide \__.

NH2 I N)\IN\ 2-(6—amino—2—fluoro—8—((6— FJLN/ N iodooxo-2,3-dihydro—1H— 9A—3 inden—S-yl)methy1)—9H- O purin-9—y1)—N- HN,502 methylethanesulfonamide NH2 I N \ 2-(6—aminofluoro((6- A / N\ iodo—3—oxo—2,3—dihydro—1H— 9A—4 F N 2 S-yl)methyl)—9H— O pUIiIl-g- ISOZ anesu1fonamide NH2 I 1%“: 2—(6~amino—2-fluor0—8—((6— F N/ N i0dooxo-2,3-dihydro—1H— 9A-5 2 inden—S-yl)methyl)—9H- 502 puriny1)—N-(telt— HIX— butyl)ethanesulfonamide NH2 I N \ N\ A / 2-(6-amino—2—fluoro-8—((6- F N N iodo—3~0x0—2,3-dihydro—1H— 9A-6 8 O inden—S-y1)methyl)~9H— ISO2 purinyl)—N— HN isobutylethanesulfonamide Compound N0. Structure Name NH2 I :JEEN 2-(6-aminofluoro-8—((6« F N/ N iodooxo-2,3-dihydro-1H— 9A—7 inden—S—y1)methyl)—9H- 502 purin—9-y1)—N—cyclopropyl- HN1I> ethanesulfonamide NH2 I Jlfiibi N-(Z-(6—amino—2-fluoro—8— F N/ N ((6—iodo—3-0xo-2,3-dihydro- 9A-8 2 1H-inden—5-y1)methyl)-9H- NH purin~9—y1)ethy1)propane-2— 023/)— sulfonamide NH2 | N/‘\j:N\ N-(Z-(G-amino-Z-fluoro—S- FJLN/ N ((6-iodooxo-2,3-dihydro- 9A-9 2 1H—inden—S-y1)methyl)-9H— purin-9— OZS’NH yl)ethanesulfonamide \___ NH2 I NJEN N—(2-(6-aminofluoro F)LN/ N ((6—iodoox0-2,3-dihydro— 9A-10 g 1H—inden—S-yl)methy1)-9H— 9—y1)ethy1)methane— ,NH sulfonamide NH2 I ”JEN N—(Z-(G—amino-Z—fluoro—S- A / N ((6-iodo—3-oxo—2,3-dihydro- F N 9A-11 2 1H—inden—5-y1)methyl)—9H— pLu'in-9—yl)ethyl) ,NH mathylpropane—Z- 025 sulfonamide NH2 I 6—arr11'n0—2-fluoro~8- )L /Nfifl‘N ((6-iodooxo-2,3—dihydro— F N 9A” 2 1H-inden—5-yl)methy1)-9H— purin—9-yl)ethyl)—2- OS,NH methylpropane-Z- sulfinamide Compound No. Structure Name NH; | JEN 6—amino—2—fluoro~8- )L / ((6—iodo—3—oxo-2,3—dihydro— F N N\ en—S-y1)methyl)—9H— 9M3 2 o purin—9-y1)ethy1)—2- ,NH methylpropane—l- on\__< sulfonamide NH2 I “Kg/[Ti N-(Z—(6—amino—2—fluoro—8- )L / N ((6—iodo0xo—Z,3—dihydro— F N lH—inden—S-yl)methyl)—9H- 9A-14 8 ‘ O purln ,NH yl)ethy1)cyclopropane- 0235 sulfonamide NHz .

”HER 3-(6-aminofluoro((6- FXN/ N iod0—3-oxo—2,3-dihydro—1H— inden-S-y1)methy1)~9H— 9A“ 0 puriny1)-N— 02$ isopropylpropane-l- _{\IH sulfonamide NH2 I jiiN‘ 3—(6—amjnofluoro((6- F N/ N iodooxo-2,3-dihydro-1H- 9A-16 S—yl)methy1)—9H— puriny1)—N—ethy1propane- 025‘ 1—su1fonamide NH2 __l_________ N \ 3—(6—amin0flu0ro((6- /l|\ / N\ iodo—3-oxo-2,3-dihydm-1H- F N inden-S-yl)methyl)—9H- 9A_17 0 purin—9-y1)—N— methylpropane-l - OzstH sulfonamide NH2 | NJ\I\ 3-(6-amino—2—fluoro—8—((6— FJLN/ N iodo0xo-2,3-dihydro—1H— 9A-1 8 inden—S—y1)methy1)—9H— O pun'ny1)p1'opane-1 - sulfonamide O S2 Compound No. l__ Structure Name NH2 , N \ N\ 3-(6-amino—2-fluor0((6- JL / N iodo—3-0X0-2,3—dihydro—1H- F N 9A_19 inden—S-yl)methy1)—9H- purin-Q—yl)-N-(tert— buty1)propane 02:\NA< sulfonamide NH2 | NI \ N\ FAN/ 3—(6-aminofluor0-8—((6- N iodo-3—oxo—2,3-dihydro-1H- 9A-20 g inden—S-y1)methy1)-9H- purin—9—yl)-N— 02$ isobutylpropane-l- H\N—>, sulfonamide NH2 1 N \ I3-(6-amino-2—flu‘oro—8—((6- )L / \ lodeoxo-2,3-d1hydro-1H— F N N 9A_21 inden—S—y1)methy1)-9H- purin-Q—y1)-N— cyclopropylpropane-l- o S2 \ sulfonamide HN—<] NH2 | N \ N\ JL / 6-am1no-2—fluoro-8—_ F N N ((6—iodo-3—oxo-2,3-dihydro— 9A-22 1H—inden—S-yl)methyl)-9H— purin-9—yl)propy1)propane- HN\ 2-sulf0namide NH2 l JNL \ N\ N—(3-(6-anfinofluoro-8— F N’ N ((6-iodo—3—oxo-2,3-dihydro- 9A-23 lH—inden—S-yl)methyl)-9H- purin-9—y1)propyl)ethane- HN amide ‘soz _._/ NH2 I NI \ Nx N-(3—(6-amino-2—flu0ro F N/ N ((6-i0do—3~0xo-2,3-dihydro— 9A-24 lH-inden—S-y1)methy1)-9H- 9-y1)propy1)methane— HN sulfonamide '— /‘so2 I Compound No. Structure Name NH; I ”(JEN N~(3-(6-amino—2-fluoro F N N 6-iodooxo—2,3—dih dro—Y 9A—25 en—S-yl)methy1)-9H« puriny1)propyl)—2— HN propane-Z- \Soz sulfonamide NH2 I NIJj:N\ N-(3—(6-aminofluoro—8— FkN/ N ((6—iodo—3-oxo-2,3-dihydro- 1H-inden—5-yl)methyl)—9H- 9A-26 puriny1)propyl)—2— HN methylpropane—Z— 7<80 sulfinamide NH2 I N! \ N—(3—(6—aminofluoro—8- FXN/ N ((6-iodo—3—0xo—2,3—dihydro- 9A 27_ g 1H—inden—5«y1)methyl)—9H— purinyl)propyl)—2- HN methylpropane-l — ‘802 : L sulfonamide NH2 I 1/531 N-(3—(6-amin0—2-fluoro—8- F N/ N ((6—iodo—3—oxo-2,3-dihydro- 9A-28 1H-inden—5-y1)methy1)—9H- purin—9— HN‘ yl)propyl)cyclopropane- <{502 sulfonamide NH2 I ESE“: 3-(6—amino—2-fluoro—8—((6- F N/ N iodooxo—2,3-dihydro-1H— 9A-29 inden—S-yl)methyl)—9H- O 9—yl)-N- HN isopropylpropananfide NH2 1 Nfifl 3-(6-aminofluoro—8-{(6- FJLN/ N iodo-3~oxo—2,3-dihydro-1H- 9A—30 inden—S—y1)methy1)-9H— purin—9-yl)—N— ethylpropanamide nd No. Structure J Name NHZ I N \ N\ 3-(6-anfino—2-fluoro((6- FJLN/ N iodo-3—oxo—2,3—dihydro-1H— 9A—3 1 inden-S-yl)methy1)—9H- purin-9~yl)—N— 0 methylpropan—amide NH2 I N! \ N\ minofluoro—8-((6— 9A-32 FAN/ N iodo—3—oxo-2,3-dihydIo-1H- inden—S—y1)methy1)-9H— o puriny1)propanamide NH2 I JNLJEEN 3-(6-amino—2-fluoro((6— F N/ N iodo—3—oxo—2,3-dihydro-1H- 9A-33 S-yl)methyl)—9H— o purinyl)-N—(tert- HN)[_ buty1)propanamide NH2 I j‘fiit‘i 3-(6-amino-2—fluoro—8—((6- F N/ N iodooxo—2,3-dihydro—1H— 9A-34 inden-S-yl)methyl)—9H- o puriny1)-N— HN : isobutylpropanamide NH; | l \ N\ 3-(6—aminofluoro—8—((6- F N/ N iodo-3—0X0-2,3-dihydro-1H— 9A-35 inden—S—yl)methyl)—9H— o purin-9—y1)—N— HNI> cyclopropylpropanarrfide NH2 I 1 \ N\ N-(Z-(6—amino—2-fluoro F N/ N ((6-iodo0X0-2,3-dihydro— 9A—36 2 lH-inden-S—yl)methy1)-9H- NH purin—9— 0:37 y1)ethy1)isobutyramide NH2 I N \ N\ N-(Z-(6-amino—2—fluoro FJLN/ N ((6-i0do—3voxo-2,3-dihydro- 9A—37 2 1H—i11den—5-y1)methyl)—9H— purin—9- yl)ethyl)propionamide Compound No. Structure Name NH: I 1%N\ N—(2-(6-aminofluoro—8- F N’ N ((6-iodo—3—oxo-2,3-dihydro- 9A-38 2 en-S-yl)methyl)—9H- NH purin—9-yl)ethyl)acetamide F’J\N/NHEEN N—(Z—(6—amino-2—fluoro—8— 9A—39 N ((6'i0d0OXO—2,3-dihydro— 1H—inden—S-yl)rnethyl)-9H- 0 purin—9-yl)ethyl)formamide NH2 I N \ N\ )L / 6-aminofluoro F N N 9A_40 2 ((6-iodo—3—oxo-2,3-dihydro— o lH-inden—S-yl)methyl)-9H- 023'“: purinyl)ethyl)pivalamide NH2 1 )NL\ N\ N—(Z—(G—amino-Z-fluoro—S- F N/ N ((6—iodo—3~oxo-2,3-dihydro— 9A-41 2 1H—inden—5-yl)methyl)-9H— NH purin—9-yl)ethyl)—3- o:<_< methylbutanamide NH2 I N \ N\ N—(Z-(fi-amino—Z-fluoro—S- ((6-iodooxo—2,3-dihydro— FiN/ N 9A-42 2 lH—inden—S-yl)methyl)—9H— O — NH yl)ethyl)cyclopropane- L carboxamide E—II. In some embodiments of the disclosure, X2 is an optionally substituted aryl.

Specific es of nds within the scope of this aspect of the disclosure correspond to the compounds disclosed in Tables 7A and 9A, or variations thereof as described in A. and E-I. above, in which X2 is an optionally tuted aryl, including but not limited to pyrazolyl, lH—pyrazol yl, oxazolyl, oxazol-Z-yl, thiazolyl, thiazol-Z—yl, furanyl, filran-Z—yl, and 5—methy1fi1ran—2—yl.

E—IH. In some embodiments of the disclosure, X2 is an l group, eig. l- , ethynyl, prop-l-ynyl, and 3-propynyl. Specific examples of compounds within the scope of this aspect of the disclosure correspond to the compounds disclosed in Tables 7A and 9A, or variations thereof as described in A. and EL above, in which X2 is an alkynyl group.

EN. In some embodiments of the disclosure, X2 is an amino group, i.e., ~NR1R2, wherein R, and R2 are each independently H, C1-C6 alkyl, C2—C6 alkenyl, C2-C5 alkynyl, lkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, arylalkyl, or alkylheteroarylalkyl. Specific examples of compounds within the scope of this aspect of the sure correspond to the compounds disclosed in Tables 7A and 9A, or variations thereof as described in A. and BI. above, in which X; is an amino group.

F. Compounds ofFormula (IA) in Which Xa and Xb Each se Hydrocarbon In accordance with another embodiment of the disclosure, the compounds are of Formula (IA) in which Xa, Xb and X0 all comprise hydrocarbon and are connected by two single bonds or one single bond and one double bond. Thus, the compounds of this embodiment can be represented by Formula (4): H\> x2 x4 N N\ VJXC or a pharmaceutically able salt f, wherein: Xa-Xc-Xb is CHZ-CHz—CHZ, CH:CH-CH2, or CH2-CH=CH; Y is CH; or S; X4 is hydrogen or halogen; R is a is straight—chain— or branched— substituted or unsubstituted alkyl, straight-chain- or branched— substituted or tituted alkenyl, straight-chain- or branched— substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by -S(O)N(RA)—, ~NRAS(O)-, -SOZN(RA)-, -NRASOz-, -C(O)N(RA)-, or -NRAC(O)-, and/or terminated by -S(O)NRARB, —NRAS(O)RB, -SOZNRARE, -NRASOZRB, -C(O)NRARB, or - NRAC(O)RB, wherein each RA and RB is independently selected from hydrogen, C1-C5 alkyl, C2-C6 alkenyl, C2—C6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, ryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl; and X2 is as disclosed below.

F-I. In some embodiments of the disclosure, X2 is n. Table 3A lists specific examples of nds within this embodiment. In each of the structures as drawn, X2 is I and X4 is H. However, corresponding structures in which X2 is F, C1, or Br are within the scope ofthe disclosure. In each of the structures in Table 3A, Y is S. However, corresponding structures in which Y is CH; and/or XI is F, Cl, Br, orI are also within the scope of the disclosure. Additionally, in connection with each of the structures in Table 3A, corresponding structures in which X2 is F, Cl, or Br and Y is CH2 are also within the scope of the disclosure.

Table 3A [—Compound No. Structure Name NHz I \ '1 k / N>—S 2-[6-Amino(6-iodo-indan- 3M 5-ylsulfanyl)—purinyl]— ethanesulfonic acid HN’SOQ pylamide NH2 1 “i\ N ys 2-[6-Amino~8—(6—iodo—indan— N/ N 3A—2 5-ylsulfanyl)—pu1inyl]- ethanesulfonic acid 502 ethylamide NH2 I . i .

K / \fs 2-[6—Am1no—8—(6—1odo-1ndan— N N 3A-3 5-ylsulfanyl)-purin—9-yl]- ethanesulfonic acid [502 amide NH2 I 'k , \>~S 2-[6-Amino-8—(6—iodo-indan— 3A-4 N N —ylsulfanyl)-purinyl]— ethanesulfonic acid amide H NISO2 NH22 I / 2-[6-Amino—8-(6~iodo-indan— N N‘>‘S 3A_5 ‘ 5-ylsulfanyl)—purin—9-yl]— ethanesulfonic acid tert- HN,302 mide NH: I Q ‘%S N’ . . .

N 2—[6~Annno(6-10do—1ndan~ 3A-6 g 5—ylsulfanyl)-purinyl]- sulfonic acid isobutyl— HN’ amide ound No. Structure Name k / NVS 2—[6-Amino-8—(6—iodo-indan— 3A-7 5-ylsu1fanyl)-puriny1]— ethanesulfonic acid HNSOZ cyclopropylamide NH2 I N \(IN\%S Propane-Z-sulfonic acid {2- 3A—8 8 [6-amino(6-iodo-indan—5- ylsulfany1)~purin—9-y1]— ethy1}—amide O S/NH2 NH2 I N \El \>—s Ethgnesulfodic acid {2-[6—i .

N N ammo-8—(6-1odo—mdan—5- 3A-9 8 ylsulfany1)-purin-9—yl]— NH ethyl} «amide 028’ NH2 I K / \>#s 'N—{2-[6—Amm0(6-19d0-.

N N 3A-10 5—ylsu1fany1)—purin—9— 2 yl]—ethyl}— NH methanesulfonamide ozs’\ NH;a I N N 2—Methy1—propanesulfomc 3A-11 8 acid {2-[6-amino(6—iod0— NH indan—S-ylsulfany1)-purin 025/ yl] -ethyl} -amide NH2 I l / N\%S 2-Methyl-propane—2—sulfmic 3A_12 2 acid {2-[6-am1'no—8—(6-iodo— indan—S—ylsulfanyl)—purin—9- OS/N H yl] —ethy1} —amide NH; , l / N\>“S Z-Methyl-propane-l-su1fonic 3M3 8 acid {2-[6-amino—8-(6—iodo- indan-S-ylsu1fany1)—purin—9- yl]-ethyl}-am.ide o éNH2 Compound N0. Structure Name Cyclopropanesulfonic acid 3A-14 8 {2-[6-amino(6-iodo— indan-S~ylsu1fany1)-purin—9- NH ' (Es/b yl] ethyl} amlde_ _ W I N \ N\ KN/ if%s 3-[6—Amino-8—(6-iodo-indan— 3A-15 5-ylsulfany1)-purin—9-yl]- propane-1 -su1fonic acid 02% pylamide NH2 I k / NVS 3-[6—Amino(6-iodo-indan— 3A—16 5-ylsu1fanyl)—purin—9-yl]- propane-l-sulfonic acid ethylamide 023‘ NHz I l / 3-[6-Amino-8—(6-iodo—indan— N NVS 3A-17 5-ylsu1fanyl)-purin-9—y1]— propane- 1-sulfonic acid methylamide ozs\ NH2 3 m : VS 3-[6-Amino(6-iodo—indan- N N 3A_18 1fanyI)-purinyl]- propane-1 -su1fonic acid amide 023‘ NH2 1 K / N\>_S 3-[6-Amino(6—iodo-indan— 3A-19 5-ylsulfanyl)-pufin—9—y1]— propane-1 ~suifonic acid tert- butylamide I Compound No. Structure Name NH2 I I \>—8 N/ N min0—8—(6-iodo—indan- —ylsu1fany1)-purin—9-yl]- 3A 20_ propane-l-sulfonic acid 023 isobutyl—amide NH: I . . . u / \>—S 3-[6-Ammo(6-10do-1ndan- N N 5-ylsulfanyl)-purinyl]- 3A—21 propane-1 ~su1f0nic acid cyclopropylamide 2H‘N NH2 I t / Q‘S‘Cb Propane-Z-sulfonic acid {3- N [6-amino(6-iodo- 3A—22 2,3,3a,7a-tetrahydro-1H— ’ inden-S—y1su1fanyl)—purin-9~ H ”IS y1]-p1‘opyl} —amide NH2 I / NVS Ethanesulfonic acid {3-[6- N amino(6-i0do-indan 3A—23 anyl)—puriny1]— propyl}-amide NH2 I N [IVS N—{3-[6—Amino—8-(6-iodo— indan—S-ylsu1fany1)—purin 3A-24 é y1]-pr0py1}- methanesulfonamide ‘302 MHZ I u / Vs .

N N 2-Methy1—propanesu1f0n1c acid {3-[6-amino(6-iodo- 3A—25 indan-S—ylsu1fany1)-purin—9- HN yll-pr0py1}-amide Compound No. Structure Name 2-Methy1—propane—2—su1finic 3A-26 é acid {3—[6-amino(6—iodoindan —S -ylsulfanyl)-pun'n-9— yl] -propy1} -amide yl-propanesulfonic acid {3—[6—amino-8—(6-iodo— 3A‘27 indan—S-ylsu1fany1)-pufin—9— HN y1]-propy1} -amide ‘802 MHZ I N: \ >—8 N/ N Cyclopropanesulfonic acid 3A 28_ g {3—[6-amino—8—(6—i0do— indan-S-ylsu1fanyl)—purin—9- HN yl]-propy1} ~amide <f‘so2 NHz .

NJEENlN/ 8—8 3~[6—Amino—8-(6-iodo-indan— 3A-29 5—ylsu1fany1)-purin—9-yl]-N- o isopropyl-propionamide NH2 I le / y‘SQ N N 3-[6-Amino—8—(6-iodo-indan— 3A—30 5-ylsu1fany1)-purin—9-y1]-N- ethyl—propionamide N“ HQ] N N 3-[6-Amino-8—(6—iodo-indan— 3A-31 5—ylsu1fanyl)—purin—9-yl]—N— -propionamide 3-[6-Amino(6-iodo-indan— 3A-32 @Mfib N N -ylsu1fany1)—purin—9—y1] — propionamide Compound No. ure Name NH2 I 'C N‘H N/ N 3-[6-Anfino-8—(6—iod0—indan— 3A-33 S-ylsulfany1)-purinyl]—N— o ten-butyl-propionamide NHQ ‘ C N‘H N/ N 3-[6-Amino(6-iodo-indan— 3A-34 5-ylsulfanyl)-purinyl]-N— O isobutyl-propionamide HN : NH; I w : \>~s N N 3—[6-Amino—8-(6-iodo-indan— 3A—35 5-ylsu1fanyl)—purinyl]—N— O cyclopropyl-propionamide HNW> NHZ l {N/ NVSQ N—{2—[6—Amino(6-iodo— 3A-36 2 indan—S-ylsu1fanyl)-purin-9— y1]-ethy1}—propionamide NH2 1 mN/ NVSQ N-{2-[6-Amino(6—iodo- 3A-37 2 indan—S-ylsu1fany1)-purin yl]-ethyl}-propionamide 04NH NHZ I N \<1:ng N-{Z-[6-Amino—8—(6—1'odo— 3A—38 8 S-ylsu1fany1)-purin y1]-ethy1} -acetamide NHZ I k / N‘>‘S N—{2-[6—Amino(6-1'odo- 3A_39 8 indan-S—y1sulfany1)~purin—9- yl]-ethy1} -2,2-dimethy1- ofi: propionamide I CompoundNo. I Structure Name NH2 I t / VS‘Q N N N—{2-[6-Anfino-8—(6—iodo— . . 3A-40 8 1ndanylsu1fany1)-punn yl]-ethy1}-3 -methyl- NH butyramide NH2 I K / N\>~S Cyclopropanecarboxylic acid 3A_41 2 {2—[6-amino-8—(6—iodo— indan-S—ylsu1fanyI)—purin—9- 0:3": yl]-ethy1}-amide NH2 ‘ N—{Z-[G—Ammo—S-(é-xodo-. . k / VSQ 3A—42 N N 8 indan—S~ylsu1fany1)-purin—9« yl] -ethy1}—formamide _CL—/NH NHZ \ N'k: N Vs 6-Amino-8—(6- N N 3A-43 g ethynyl-indan—S—ylsulfanyl)- purin—9—y1]—propyl} - methanesulfonamide MHz—L “END:VSQ.\ N N—{3—[6—Amino(6-iodo- 3A-44 3 indan—S—y1su1fanyl)-purin yl] -propy1} -2 ,Z-dimethyl- H propionamide NH2 —I 1: ‘HQN N N N-{3-[6—Am1no—8—(6—1odo-- - 3A-45 g indan—S-y1su1fanyl)—purin—9— yl] 1} -isobutyramide NHg I “1\ Ny—S KN/ . .

N Cyclopropanecarboxyhc a01d 3A-46 2 amino-8—(6-iodo- indan—5-ylsu1fany1)-pun'n NH yl] —p1'opy1} -amide Compound No. Structure Name will; I \ 5% 6-Amino(6-iodo- 3A-47 indan-S~ylsulfanyl)—purin-9— yl] —propyl} hydroxy- NH propionamide [ ”CW“ KAINy—«s , Acetic acid 1- {3—[6—amino—8— N (6-iodo-‘mdan-5—ylsulfany1)— 3A—48 purin-Q-yl} NH propylcarbamoyl} -1 -methyl— _l GAE),Ac ethyl ester 6-Amino(6—iodo— 3A—49 indan—S-ylsulfanyl)-purin—9- yl] —propyl} «2—hydroxy methyl-propionamide Table 6A lists specific examples in which X; is halogen and X4 is halogen. In each of the structures as drawn, X2 is I and X4 is F. However, corresponding structures in which X4 is H, Cl, Br, or Iare within the scope of the sure. In each of the structures in Table 6A, Y is CH2.

However, corresponding ures in which Y is S and/or X2 is F, Cl, or Br are also Within the scope of the disclosure. Additionally, in connection with each of the ures in Table 6A, corresponding structures in which X4 is H, Cl, Br, or I and Y is S are also within the scope of the disc.osure.

Table 6A Compound No. Structure Name NH2 I j‘fijfi 2-(6-arrfino—2-flucro—8-((6- F N/ N iodo—2,3-dihydro—lH-inden— 6A-l g 5—yl)methyl)-9H—purin—9-yl)— HN’ isopropylethanesulfonamide NH2 I IEN\ _l 2-(6-amino—2—fluoro((6- F N/ N 6A-2 iodo-2,3-djh dro—lH—inden- g 3’ -yl)methyl)-9H-purin—9-yl)— [802 N—ehtylethanesulfonamide Cmund No‘ Structure Name NH; I liww% 2-(6-amino-2—fluoro—8-((6« F N N 6A—3 iodo-2,3-dihydro—1H~inden— g 5-y1)methy1)-9H-purin—9—y1)— I302 N—methylethanesulfonanfide NH2 | NI/‘i'i 2—(6—aminofluoro-8—((6- 6M FXN/ N iodo—2,3—dihydro—1H-inden- 8 5-y1)methy1)—9H—purin-9— yl)ethanesulfonamide [502 NHz | J‘jjhg/{b minofluoro-8—((6— F N/ N iodo—2,3-dihydro-1H-inden- 6A—5 2 ethyI)-9H—purin-9—y1)- $02 N-(tert— HN’ butyl)ethanesulfonamide NH2 I i / WQ 2-(6-amino—2—fluoro—8—((6- F N N iodo-2,3-dihydro-1H-inden- 6A-6 g 5—y1)methy1)—9H—pminyl)- [802 N- H“; isobutylethanesulfonamide NH2 | i\ “1% 2-(6-aminofluoro—8-((6— F N/ N iodo-2,3-dihydro-1H—inden- 6A-7 2 5—y1)methyl)-9H—purin—9-y1)- 302 opropyl— HN/W> ethanesulfonamide NH2 | N-(2—(6—amino—2-fluoro-8— FAfiNyACb N” N ((6—iodo—2,3—dihydro—1H— 6A—8 g inden—5~y1)methy1)—9H— NH puriny1)ethyl)propane-2— 023’ sulfonamide NHg I [HEN N-(Z—(6-amino-2—fluoro—8— )L / N ((6-iodo-2,3-dihydro-1H- F N 6A—9 2 inden—S-yl)methy1)-9H- purin-9— NH yl)ethy1)ethanesulfonamide Compound N04 Structure Name NHZ I \ N\ 6—amino-2—fluoro F JLN/ N ((6-iodo-2,3-dihydro-1H— 6A-1O 8 inden-S—yl)methy1)—9H— purin—9— .

NH y1)ethy1)methanesulfonamide NH2 I \ N N—(2-(6-aminofluoro A , I; ((6—iodo~2,3—dihydro-1H- F N 6A_11 ? inden—S-yl)methy1)—9H— purin-9—y1)ethyl)—2 - ,NH methylpropane-Z— 025 sulfonamide NHz I l / N—(Z-(6—amino—2-fluoro—8— N‘ ((6-iodo-2,3-djhydro-1H— F N 6A_12 8 inden—S—yl)methy1)—9H— purin—9—yl)ethyI) ,NH methylpropane"2~ sulfinamide NH; I N \ N\ N—(Z-(6—amino—2-fluoro )L / N do-2,3—dihydro—1H- F N 6M3 g inden—S-yl)methy1)—9H— 9-yl)ethyl)—2- ,N H methylpropane 02$ sulfonamide NHQ I \ N\ N-(2—(6—aminofluoro-8— F 1N/ N ((6-iodo—2,3-dihydro-1H— 6A—l4 2 Inden-S-ylfinethyD-QH- purln—9— ozs'NH yl)ethy1)cyclogropane- I> sulfonannde NH2 I )L / %% 3-(6—amino—2—fluor0-8—((6- F N N iodo—2,3—dihydro—1H—inden- 6A-15 5—y1)methy1)-9H-purin—9-y1)— N—isopropylpropane— 1 - sulfonamide nd No‘ Structure Name NH2 I AflNy/Q 3-(6—aminofluoro—8—((6— F N/ N iodo—2,3~dihydro—1H—inden- 6A—16 ethyl)—9H—purin—9—yl)- N—ethylptopane- 1- 023‘ sulfonamide NH2 I \ “1% l 3-(6-amino—2-fluoro-8—((6— F N/ N iodo-2,3-dihydro—1H—inden— 6A—17 5-yl)methy1)—9H-puriny1)- N—methylpropans-1 - 023 sulfonamide NH; 1 /j|\ / WCb 3-(6—anfin0fluoro((6- F N N 6A_18 é i0do-2,3«dihydro-1H—inden— -y1)methyl)—9H—purin—9—y1)— N—propanesulfonamide 028‘ NHZ I \ “lg/Q A 3~(6-aminofluoro((6— F N/ N iodo-2,3-dihydro—1H—inden— 6A-19 5-y1)methy1)-9H-purin—9-yl)— N-(tert-butyl)propane-1 - 025‘ sulfonamide NHz I /H\ / 3-(6-amino-2—fluoro—8-((6- F N N\>/\<% iodo—2,3-dihydro-1H-inden- 6A-20 é 5-y1)methy1)-9H-purin—9~yl)~ utylpropane-l - 023‘ sulfonamide NH2 I Ni \ “1% 3-(6-amin0—2-flu0ro-8—((6— FAN/ N iodo—2,3—dihydro—1H-inden- 6A—21 5-y1)methy1)-9H—pufin—9—y1)— N-cyclopropylpropane-l- sulfonamide Compfllpd No. Name N72 I N \ N\ A / N—(3—(6—aminofluoro F N N ((6-iodo-2,3-dihydro-1H- 6A-22 g inden—S—yl)methy1)-9H— purinyl)propy1)pr0pane—2- ”NSC amide NH2 I \ N\ /H\ N-(3-(6-amino-2—fluoro—8- F N/ N ((6—iodo-2,3-dihydro—1H~ 6A-23 S-y1)methyl)—9H~ purin—9- HN y1)propyl)ethanesulfonamide \soz NHZ I )NL \ N\ N—(3-(6-amino-2—fluoro—8— F N/ N ((6—iodo—2,3—dihydro-1H- 6A—24 inden—S—yl)methy1)—9H— purin—9-y1)propy1)methane— HN sulfonamide ‘302 NHZ I \ N\ [ N-(3-(6-amino—2-fluoro FAN/ N ((6-iodo—2,3—dihydro-1H- 6A‘25 é inden-S-y1)methyl)—9H— purinyl)propyI)-2— HN propane-Z— 7502 sulfonamide NH2 I \ N\ l N—(3~(6—anfino—2-fluoro-8— F N/ N ((6-iodo-2,3—dihydIo-1H- 6A‘26 g inden-S-yl)methy1)—9H— purinyl)propy1) HN methylpropane-2« 750 sulfinamide NH2 | N-(3—(6—aminofluor0—8- ((6—iodo-2,3—dihydro—1H- inden—S—y1)methyl)~9H- 6A—27 puriny1)propyl)-2— methylpropane-l- sulfonamide [ Compound No‘ ure Name NH2 l Ji\ N\ N—(3—(6-aminofluoro F N/ N ((6—iodo—2,3—dihydro-1H- 6A-28 é inden—S-yl)fnethy1)-9H- punn—9- HM py1)cyclopropane- <{502 sulfonamide NH2 I N \ N\ )L / N 3-(6-aminofluoro—8-((6- F N 6A-29 L iodo-Z,3-dihydro—1H-inden— -y1)methy1)—9H—purin—9—y1)- 0 N—isopropylpropanamide NH2 1 )NL: N \ 3—(6—anfinp—2-fluoro-g-«6- F N N 6A-30 iodo-2,3—d1hydro-1H-mden- -y1)methy1)-9H—purin-9—y1)- O N-ethylpropanamide NHZ I ”itN\ 3-(6—aminofluoro-8—((6— F N/ N 6A_31 iodo-2,3-dihydro-lH-inden-S- y1)methy1)—9H-pur1'n—9-y1)-N— O methylpropanamide NH2 I NI \ N\ 3-(6-amino—2-fluoro—8-((6- 6A-32 F/kN/ iodo-2,3-dihydro—1H—inden- -y1)methy1)—9H—purin—9-y1)- N—propanamide NH2 I F N N\ 3-(6-amin0—2-fluoro((6- 6M3 : iodo—2,3-dihydro-1H—inden- -y1)methyl)—9H~purin—9—y1)— 0 N—(tex’c-butyl)propanamide NH; I / N\ 3—(6—amino—2-fluoro—8—((6- F N 6A-34 g: iodo~2,3-dihydI0—1H-inden- -y1)methy1)—9H—purin—9—y1)— 0 N-isobutylpropanamide HN / Compound N0. Structure Name NH2 I )L / 3-(6-amino—2-fluoro-8—((6- F N N\ 6A_35 L ,3-dihydro-1H—inden— —yl)methy1)-9H—purin—9-yl)- O N—cyclopropylpropanamide NH; , )L / J—(Z-(6—amino—2-flu0ro((6- F N N‘ 6A-36 2 Odo—2,3—dihydro-1H<inden y1)methy1)—9H—purin—9— NH yl)ethyl)isobutyramide NHZ I N \ N\ N~(2—(6-amino—2-fluoro )L / N ((6—iodo—2,3-dihydro-1H- F N 6A-37 g inden—S—y1)methyl)—9H- purin—9— 04”” yl)ethy1)propionamide NH; l )L: ”\wa N—(Z-(S-amino-Z—fluoro—8- F N N 6A-38 ((6-iodo—2,3—dihydro-1H— 2 inden-S—yl)methyl)—9H— NH purin—9—y1)ethy1)acetamide NHQfio I \ N\ N—(2—(6—aminofluoro—8- 6A_39 FXN/l N ((6—iodo-2,3-dihydro-1H- ? inden-S-y1)methy1)—9H- puriny1)ethy1)f0rmamide NH; I )L / NVQ N—(Z—(é—arninofluoro F N 6A_40 g ((6-iodo-2,3—dihydro-1H— inden-S thy1)—9H— NH ‘ ' ‘ 0% purm 9 yl)ethy1)p1valam1de NH2 I \ “1% i N-(2-(6-amino—2-flu0r0 F N/ N do—2,3-dihydro-1H- 6A-41 2 inden-S-yl)methyI)-9H- NH purinyl)ethyl) o methylbutanamide .CompoundNo. [ Structure Name NHz I N \ N\ N-(Z—(é—amino—Z-fluoro-S- A / N ((6-iodo-2,3—dihydro—1H— F N 6A-42 2 inden—S—yl)methyl)—9H— purin NH yl)ethyl)cyclopropane— O:fi> carboxamide Hsp90 binding results are presented for Compounds 3A-10, 3A—1 1, 3A-12, 3A—24 and 3A- 26 in Table 12 below. As can be noted therefrom, all compounds showed a high level of g affinity.

F-H. In some embodiments of the disclosure, X2 is an optionally substituted aryl.

Specific examples of compounds within the scope of this aspect of the disclosure pond to the compounds disclosed in Tables 3A and 6A, or variations thereof as described in A. and F-I. above, in which X2 is an ally substituted aryl, including but not limited to pyrazolyl, lH—pyrazol yl, oxazolyl, -2~yl, thiazolyl,thiazoly1, furanyl, furan—Z-yl, and 5-methylfuran—2—yl.

F-Ill. In some embodiments ofthe disclosure, X2 is an alkynyl group, e.g. 1- , ethynyl, prop-l-ynyl, and 3-prop—l—ynyl. Specific examples of compounds within the scope of this aspect of the disclosure correspond to the compounds disclosed in Tables 3A and 6A, or variations f as described in A. and FL above, in which X2 is an alkynyl group. Hsp90 binding results are presented for Compound 3A—43 in Table 12 below. As can be noted therefrom, the compound showed a high level of binding y.

F-IV. In some embodiments of the disclosure, X2 is an amino group, i. e., -NR1R2, wherein R1 and R2 are each independently H, C1-C5 alkyl, C2-C6 alkenyl, C2—C5 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, or eteroarylalkyl. Specific es of compounds within the scope of this aspect of the disclosure correspond to the compounds disclosed in Tables 3A and 6A, or variations thereof as described in A. and F-I. above, in which X2 is an amino group.

G. nds of Formula (1A) in Which at Least one ofXa and Xb is CHF or CF; In accordance with another embodiment of the disclosure, the compounds are of Formula (1A) in which at least one of Xa and Xb is CHF or CFz, the other of Xa and Xb is CHF, CFz, or CH2, and Xc is CH2. Thus,ithe compounds of this embodiment can be represented by Formula (5): NH2 )<2 kaN/Nl/i\iN\>mY Xa or a pharmaceutically acceptable salt thereof, wherein: at least one of Xa and Xb is CHF or CFZ and the other is CHF, CFZ, or CH2; Y is CH2, 0, or S; X4 is hydrogen or halogen; R is a is straight-chain— or branched- substituted or unsubstituted alkyl, ht—chain— branched- substituted or unsubstituted alkenyl, straight-chain— or branched— substituted unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by -S(O)N(RA)-, -NRAS(O)-, —SOZN(RA)-, Z-, -C(O)N(RA)—, or —NRAC(O)-, and/or ated by -S(O)NRARB, -NRAS(O)RB, -SOZNRARB, -NRASOZRB, —C(O)NRARB, or - NRAC(O)RB, wherein each RA and RE is ndently selected from hydrogen, C1-C6 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, kyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl; and X2 is as disclosed below.

In one embodiment, Y is O.

In another embodiment, Y is OH; or O In r embodiment, Y is CH; or S.

In another embodiment, Y is O or S.

G—I. In some embodiments of the disclosure, X2 is halogen. Table 8A lists specific examples of compounds within this embodiment. In each of the structures as drawn, X2 is I and X4 is H. However, corresponding structures in which X; is F , C1, or Br are within the scope of the disclosure. In each of the structures in Table 8A, Y is S. However, corresponding structures in which Y is OH; or O and/or X4 is F, Cl, Br, or I are also within the scope of the disclosure. In each of the ures in Table 8A, Xb is CHF and Xa is CH2. r, corresponding structures in which Xa is CHF and Xb is CH;, Xa is CF; and Xb is CH;, Xb is CF; and X21 is CH;, Xa is CHF and Xb is CF;, Xb is CHF and Xa is CF;, Xa is CHF and Xb is CHF, or Xa is CF; and Xb is CF; are also Within the scope of the disclosure. Additionally, in connection with each of the structures in Table 8A, ponding structures in which X; is F, C1, or Br, Y is CH; or O, and Xa is CHF and Xb is CH;, Xa is CF; and Xb is CH;, Xb is CF; and Xa is CH;, Xa is CHF and Xb is CF;, Xb is CHF and Xa is CF;, Xa is CHF and Xb is CHF, 0r Xa is CF; and X1) is CF; are also within the scope of the disclosure.

Table 8A Compound No. [ Structure Name NH; I ”*1“l / 2-[6—Amino—8-(3—fluoro N Nfs 8A_ 1 iodo-indan-S-ylsulfanyl)- F purinyl]-ethanesulfonic HN’SOZ acid isopropylamide L NHz—Z: I m / \fs 2—[6—Annno—8-(3-fluoro N N 8A-2 10do—1ndan—5—ylsulfanyl)- purinyl]-ethanesulfonic acid ethylamide I502 NH; I J \>—s 2-[6-Am1no-8—(3-fluoro—6— N N 8A-3 iodo—indan-S—ylsulfanyl)- 9—yl] esu1fonic acid methylamide (502 NH2 1 NJiN%S 2-[6-Amino~8—(3~fluoro-6— 8A_4 KN/ iodo-indan—S-ylsulfanyl)— purin—9—yl] -ethanesulfonic F acid amide NH; I l / N\>—S 2-[6-Amino—8-(3-fluoro 8A-5 iodo—indan—S—ylsu1fany1)— F purin-Q-yl]-ethanesulf0nic HN’SOQ acid tert-butylamide nd No. I Structure Name ”13%\ N .

N N 2-[6-Am1n0-8—(3-fluoro—6— 8A_6 2 iodo-indan-S-ylsulfany1)- puriny1]-ethanesu1fonic L HN’ acid isobutyl—amide {INVS . \ N min0(3-fluoro—6- 8A-7 iodo-indan-S—y1sulfanyl)- F purin—9—yl]-ethanesu1fonic HN’SOZ acid cyclopropylamide NH2 | \ N\ 'L / N N>_S Propane—Z—sulfouic acid {2- 8A-8 2 [6-amino-8—(3-fluoroi0do— F indan—S-ylsulfany1)-purin—9- ,NH Y] e1 — th3’} mm1 — ‘de B NH2 I . A l / \fs Ethanesulfomc acid {2—[6— N N 8A-9 amino—8-(3—fluoroiodo— 2 F indan—S-ylsulfanyl)-purin NH y1]-ethyl}-amide NH2 I L / \>—s N—{2-[6—Am1no-8—(3-fluoro- N N 8A-10 6-iodo—indan-5—ylsu1fany1)- 2 F purin—Q—y1]«ethyl}-.

NH methanesulfonamide 023’ NH2 I “ijys 2-Methyl-propanesu1fonic N/ N acid {2-[6-amino(3- 8A-1 1 8 fluoro—6-iodo—indan—5— NH ylsulfanyl)—purin—9—y1]- 023’ ethyl} -amide _NH2 K| “1k \ N\>_S 2-Methyl-propanesulfinic N/ N acid {2—[6-amino-8—(3- 8A-12 8 fluoro-6—iodo-indan—5— ylsulfanyl)—purin—9—y1] - ethyl} -amide Compound No. I Structure Name “fix/[N94 | 2-Methy1-propane-l-su1fonic N/ N acid {2-[6-amin0-8—(3- 8A-13 8 fluoro—6-iodo-indan-5— NH ylsulfany1)~purin—9-y1]- 023’ ethy1}-amide NH; 1J1§fs | \ N Cyclopropanesulfonic acid 8A-14 8 {2—[6-amino(3-fluoro F iodo—indan-S -ylsu1fanyl)— ,NH purin—9—y1]—ethyl} -amide ()sz NHQ I big\ N>‘ 4%\ 3 3-[6-Amino—8—(3-fluoro—6— 8A-15 iodo-indan-S-ylsulfanyl)— F purin—9-yl]-propane sulfonic acid isopropylamide 025‘ 1 /\ N “P‘s 3—[6—Amino(3-fluoro 8A46 ndan—5-y1su1fany1)— pufin-9—yl]-propane-1 — sulfonic acid mide /: 2\/ 2/2W]: 3-[6-Amino—8—(3-fluoro 8A-17 iodo—indan—S-ylsu1fanyi)- purm-9—y1]—propane. sulfonic acid methylamide O S2 ”(I \>—s\ N mino(3-fluoro-6— N N 8A—18 é iodo-indan-S-ylsulfanyl)- puriny1]-propane sulfonic acid amide o s2 \NHZ Compound No. Structure Name NH2 ' ‘s\ N 3-[6-Amino(3—fluoro—6- 8A-19 iodo—indan—5-ylsu1fany1)- F purin—9-y1]—propane sulfonic acid tert—butylamide O s2H\NA< NH2 I [if N>_\ s 3—[6—Amino(3~flu0Io—6— iodo-indan—S -ylsu1fany1)- 8A-20 F purin—9-y1]-propane-l - sulfonic acid isobutyl—amjde NH2 , N . [1 : Vs 3—[6—Amm0—8—(3—fluoro-6— N N 10d0—1ndan—5~ylsu1fanyl)— 8A—21 purinyl]-propane F ic acid 028 cyclopropylamide “it we\ N . .

N N Propane—Z-sulfomc ac1d {3- 8A 22 [6-arnino—8—(3-fluoro—6—iodo— _ g F indan-S-ylsulfanyl)-purin HN yl]-propy1}-amide \soz mi ——I N \ N\ 'L / f8 Ethanesulfonic acid {3-[6- N N . . 8A-23 armno—S—(3-fluoro—6—1odo— F indan-S-ylsulfany1)-purin-9— yl] —propy1} -amide ‘soz QFI2 I t / N‘FS N—{3—[6-Amino(3—fluoro- 6—iodo—indan—5 fanyl)- 8A-24 g F puriny1] -propy1} - methanesulfonamide ‘so2 I_ Compound No. I Structure Name NH2 I \ N\ fl / >_S 2-Methy1—propane—2-su1f0n1c.

N N acid {3-[6—amino-8~(3— 8A—25 F fluoro-é-iodo-indan—S- any1)-purin-9—y1]- HN .

I502 propyl} amlde_ NH2 I [l /\ N\>“S 2~Methy1—propanesulfirfic N N acid {3-[6-amino—8—(3- 8A—26 F fluoroiod0—indan anyl)-purin—9-yl]— HNISO }—amide NHZ I \ N\ l / >‘S Z-Methyl-propane—l-su1fonlc.

N N acid {3—[6—amino-8—(3- 8A-27 F fluoro1'odo-1'ndan-5— ylsulfanyl)—purin—9—yl]- HN\so propyl}-amide NHg I W \kN” N>—\ 8 Cyclopropanesulfonic acid 8A—28 {3-[6-amino—8-(3-fluoro-6— iodo—indan—S-ylsulfanyl)— HN pun'n—9-yl] ~propy1} -amjde NH2 I “1 \ “x k / N>—S 3-[6-Amino-8—(3-fluoro 8A—29 iodo—indan—S—ylsulfanyl)- . .

F punnyl]—N«1sopropy1— 0 propionamide NH2 I Wk \>_s 3-[6-Ammo—8-(3-fluoro.

N/ N 8A 30' iodo—indan—S-ylsu1fany1)— puriny1]-N—ethy1- o propionamide I ComEound No. Structure Name NH2 I K \>—s 3—[6—Ammo—8-(3-fluoro—6— N/ N 8A—31 iodo—indan—S-y1su1fany1)- purin—9-yl]~N—methy1- O propionamide NHQ I ”1 \ “x k / >—S 3—[6-AImno(3—fluoro—6-4 8A—32 N N g: iodo—indan—S-ylsu1fanyl)- F purin-Q-yl]-propionamide NH2 I \ N\ / Ifs 3—[6—AInino—8-(3-fluoro 8A_33 g: iodo-indan-S-ylsulfanyl)— F purin—9-y]]—N—tefi-buty1— 0 propionamide NH2 I N \ "i l / N>“S 3-[6-Amino(3-flu0ro—6— 8A-34 L ndan-S-ylsulfanyl)- F purin—9—y1]-N—isobutyl- 0 propionamide L HN NH2 | 3—[6-Amino-8—(3-fluoro 8A-35 iodo-indan—5-ylsulfany1)— F purinyl]-N-cyclopropy1— propionamide NHz I N \thVS N—{2-[6-Amino-8—(3—fluoro- —indan—5 -ylsu1fany1)- 8A—36 2 F purin—9—y11—ethy1} - NH isobutyramide NH; it x)_s | \ N N-{2—[6—Am1no~8-(3-fluoro-.

N/ N 8M7 0—indan-5—ylsu1fany1)- 2 purin—9—y1]—ethyl}- NH propionamide Compound No. Structure Name NH2 I ilk / N\>“S N-{2-[6—Amino~8—(3-fluoro- 8A-38 2 6-iodo-indan—5—ylsu1fanyl)— F 9-yl] —ethyl} ~acetamide NH2 | “t \ N\ N Nfs N—{2—[6—Amino—8—(3-fluor0- 8A-39 8 6—i0do-indan-5—ylsulfanyl)- F purin-9—yl] -ethy1} -2,2- NH dimethyl—propionarnide NH2 l i \ ”x N Nfs N-{2-[6—Amino—8-(3—fluoro— M40 8 6-iodo—indan—5~ylsulfanyl)- F 9-yl]—ethyl}methy1- NH butyramide N '__2 'l \ ”\ l\ / “1%8 Cyclopropanecarboxylic acid 8A—41 {2-[6—amino—8—(3—fluoro F iodo-indan—S—ylsulfanyl)— NH purinyl]-ethyl}-amide NH2 3 “if “1%S\ N-{2-[6—Amino-8—(3—fluoro- 8A—42 6—iodo-indanylsulfanyl)— g purin—9-yl] -ethyl} - F formamide Table 10A lists specific examples in which X; is halogen and X4 is halogen. In each of the structures as drawn, X; is I and X4 is F. However, corresponding structures in which X; is H, Cl, Br, or I are within the scope of the disclosure. In each of the structures in Table 10A, Y is CH; However, corresponding structures in which Y is S or O and/or X; is F, C1, or Br are also within the scope ofthe disclosure. In each of the structure in Table 10A, Xb is CHF and X3 is CH;~ However, corresponding ures in which Xa is CHF and Xb is CH;, Xa is CF; and Xb is CH;, Xb is CF; and Xa is CH;, Xa is CHF and Xb is CF;, Xb is CHF and X3 is CF2, Xa is CHF and Xb is CHF, or Xa is CF; and Xb is CF; are also within the scope'of the disclosure. Additionally, in tion with each of the structures in Table 10A, corresponding structures in which X4 is H, Cl, Br, or I, Y is S or O, and Xa is CHF and Xb is CH;, Xa is CF; and Xb is CH;, Xb is CF; and X3 is CH2, Xa is CHF and Xb is CFZ, Xb is CHF and Xa is CFz, Xa is CHF and Xb is CHF, 0r Xa is CF; and Xb is CFZ are also Within the scope of the disclosure.

Table 10A Compound No. Structure Name NH2 I N \ Nx JL mino—2-fluoro—8-((3- F N/ N fluoro—6—i0do-2,3—dihyd1‘o— 10A-1 en-S-yl)methyl)—9H— 802 purinyl)—N- HN’ isopropylethanesulfonanfide NHZ | N/ljj‘l 2-(6-amino—2-fluoro-8—((3- F)LN/ N fluoroiodo—2,3-dihydro— 10A-2 lH-inden-S-yl)methyl)—9H- F purin—9-yl)-N- HN,SO2 ethylethanesulfonamide NHZ | ”Hill 2-(6—amino—2-fluoro-8—((3- F)LN/ N fluoro—6-iodo—2,3~dihydr0- 10A-3 en-S—yl)methyl)—9H— F purinyl)-N- HNISOZ methylethanesulfonaxrfide NH2 I N \ N\ 2-(6—ami1io—2-fluorQ—8-((3- )L / fluoro-é-1odo-2,3—d1hydro- IDA-4 F N N lH—inden-S-yl)methyl)—9H— F purin—9- [802 yl)ethanesulfonamide NH2 I JNIji'i 2-(6-aminofluoro-8—((3- F N/ N fluoro—6-iodo-2,3—dihydro~ 10A-5 8 lH—inden-S-yl)methyl)-9H- purin—9—yl)—N—(tert- HN' butyl)ethanesulfonamide NH2 I JL / \ 2-(6-amino-2—fluoro-8—((3- F N N fluoro-6—iodo-2,3—dihydro— 10A-6 2 F lH-inden-S-yl)methyl)-9H~ [$02 purin—9-yl)-N- :Nz isobutylethanesulfonamide I Compound No. Name 2-(6-amino—2—fluoro-8—((3- fluoro-é—iodo—Z,3-dihydro- 1H-inden—S-y1)methy1)-9H— ,302 purinyl)—N—cyclopropy1— HNI> ethanesulfonamjde NH2 I N \ N\ 6—amino—2-fluoro-8— )L / ((3—fluoro—6—iodo—2,3— F N N 2 dihydro—lH—inden-S— F yl)methy1)—9H—purin—9— S,NH y1)ethy1)propane sulfonamide N—(2-(6—aminofluoro—8- ((3-flu0ro-6—iodo-2,3- dihydro—lH—inden—S- yl)methy1)—9H—purin—9— yl)ethyl)ethanesulfonamide NH2 | NJE N-(2-(6—amino—2-fluoro—8— oroiodo-2,3— F)LN/ dihydro—lH-inden-S— F y1)methy1)—9H-purin—9— ,NH yl)ethyl)methanesulfonamide ozs\ NHZ | N \ N—(2-(6—amino—2—fluoro—8— )L / \ ((3-fluoroiodo—2,3- F N N - - 1 OA—ll 2 o—IH-mdeII-S- F yl)methy1)—9H—pur1n—9— ,NH yl)ethy1)—2-methy1propane—2— 02% sulfonamide NH2 I N)\/I:N NN-(2-(6-amin0—2—fluoro—8— )L / N\ ((3-fluor0iodo—2,3- F N 10A—12 2 dihydro—lH—inden-S- F y1)methy1)—9H-purin-9— ,NH y1)ethyl)-2—methy1propane—2— OS)? sulfinamide NH2 I “HEN N—(2-(6-aminofluoro JL / N‘ ((3-fluoroiodo-2,3- F N 10A~13 2 dihydro-lH-inden—S— F y1)methy1)—9H—purin—9— ,NH yl)ethy1)—2-methy1propane—1- 023 : sulfonamide _.—.1__.—___i Compound N0. Structure Name NHZ | NJTN‘ N-(2—(6-aminofluoro-8— FAN/ N ((3—fluoroiodo—2,3- 10A—14 o-lH—inden—S- F yl)methyl)<9H—purin—9« ,NH y1)ethy1)cyclopr0pane- 028$ sulfonamide NH2 I jng“ 3-(6-amino—2-fluor0-8—((3- F N/ N fluoro—6—iodo-2,3-dihydro— 10A‘15 g 1H—inden—5-y1)methy1)-9H~ F purin—9-y1)-N- 025 isopropylpropane-l— \NH sulfonamide NH2 I JNL\ "i 3-(6—amino—2—fluoro—8—((3- I: N/ N fluoro—6-iodo-2,3—dihydro- 10A-16 1H—inden—S—y1)methyl)—9H— purin—9—y1)-N-ethylpropane— 028 l-sulfonamide NH2 I N \ N\ 3-(6—aminofluoro((3— )L / N fluoroiodo-2,3—dihydro— F N 10A—17 g 1H—inden—5-y1)methy1)-9H- purin«9—yl)-N— methylpropane—l — OZS‘NH sulfonamide 1" / NH2 I N \ N\ 3-(6-aminofluoro-8—((3— FJLN/ N fluoroiodo—2,3-dihydro- 10A-1 8 g 1H—inden—5«y1)methy1)-9H- F purin—9-y1)propane—1- sulfonamide 028‘ NH2 I )Iijy/Q mino—2-fluoro((3— F N/ N fluorogé-iodo-2,3-dihydro- IDA-19 en—5-y1)methy1)—9H- purin-9—y1)-N—(tert— 025 buty1)propane-l -su1f0nam1'de Compound No. Structure Name NH2 I j 3—(6—aminofluoro-8—((3- fluoroiodo-2,3-dihydro— 10A-20 1H-inden—5-yl)methy1)-9H- F purin—9-y1)-N— isobutylpropane~1 — sulfonamide 3-(6-am1'no-2—flu0ro—8—((3- fluor0iodo—2,3—dihyd1‘o— 10A-21 1H-inden-S-y1)methyl)-9H- purin—9-y1)—N— cyclopropylpropane— 1 - sulfonamide 6—aminofluoro—8— ((3 —fluoroiodo-2,3— 1 OA-22 dihydro—lH—inden—S- y1)methy1)-9H~purin—9— yl)propy1)propane-2— sulfonamide N—(3—(6-aminofluoro-8— ((3-fluoro-6—iodo—2,3- 1 0A—23 dihydro-lH—inden—S— yl)methyl)-9H-purin yl)propyl)ethanesu1fonamide N—(3-(6-amino-2—fluoro-8— ((3-fluor0-6—iodo-2,3— 10A-24 dihydIo—lH-inden-S — y1)methyl)—9H-purin pyl)methane- sulfonamide N-(3-(6-amino—2-fluoro-8— ((3-fluoroiodo-2,3— lOA—25 dihydro—lH-inden—S- yl)methy1)—9H—purin—9—, y1)propy1)~2—methylpropane- 2—sulfonamide Compound No. Name N—(3-(6-amino—2«fluoro~8- ((3-fluoro-6~iodo-2,3- 10A-26 dihydro- lH-inden-S- yl)methyl)-9H—purin yl)propy1)~2-methylpr0pane- 2-su1finamide N—(3—(6—aminofluoro ((3-fluoro—6—iodo—2,3- 10A—27 dihydro- lH-inden-S- y1)methyl)-9H-purin—9— y1)propy1)methylpropane- 1-su1fonamide N—(3-(6-amino—2-fluoro-8— ((3-fluoro—6—iod0—2,3- IDA—28 dihydro-lH-inden—S- yl)methy1)—9H-purin—9- y1)propy1)cyclopropane- sulfonamide 3-(6-amino—2—fluoro~8—((3- fluoroiodo—2,3-dihydro— 1 OA-29 1H—inden—5-y1)methy1)-9H— purin—Q-y1)—N— isopropylpropanamide 3-(6-amino~2—fluoro-8—((3- 6-iodo-2,3-dihydr0— 10A<30 1H—inden—S—y1)methy1)-9H— purin—9—yl)—N— ethylpropanamide 3-(6-aminofluor0-8—((3- 6-iodo-2,3—dihydro— 10A-31 1H—inden—S-y1)methy1)-9H- purin—Q-yl)—N— methylpropanamide I CompoundNo. Structure Name NH2 I “flirt 3-(6-aminofluor0—8—((3— 10A82 FAN/ N fluoro-6—iodo-2,3-dihydrolH —inden-S-y1)methy1)—9H— F purin—9-yl)propanamjde NH2 I JNL\ N\ 3-(6-amin0—2-fluoro—8—((3— F N/ N fluoroiodo-2,3-dihydro— 10A—33 1H—inden—5-y1)methy1)-9H— 0 purin—9-yl)—N-(t§rt- Hy buty1)propanam1de NH2 I J‘L\ N\ 3~(6—amino—2-fluoro—8—((3- F N/ N fluoroiodo—Z,3-dihydro— 10A-34 lH-inden—S—y1)methy1)-9H- o purin-Q-y1)-N- HN ylpropanamide NH2 I Ji\ N\ 3-(6—aminofluoro—8—((3— F N/ N fluoroi0do-2,3-dihydro~ 10A-35 1H-indeny1)methy1)—9H- F . 0 —yl)-N- HNI> cyclopropylpropanamide NH2 I JL\ N\ N—(2—(6-amino—2-fluoro—8- F N/ N ((3-fluoroiodo—2,3- 10A—36 2 dihydro—lH—inden—S- NH yl)methy1)—9H—purin-9— oi y1)ethyl)isobutyramide NH2 I Viki N—(Z—(6—amino—2—fluoro—8— FAN/ N ((3-fluoro—6—iodo-2,3— 10A-37 dihydro-lH—inderbS— F yl)methyl)—9H—purin—9- NH y)e1 thly)prop10nam1‘ 'de NH2 I “Jib: N-(2-(6—aminofluoro ((3—flu0ro—6-iodo-2,3- FiN/ N 10A—38 o—lH—inden—S— F yl)methyl)—9H—purin NH yl)ethy1)acetamide Compound No, Structure Name N \2 N N—(2—(6—amino—2«fluoro-8— JL / \ ((3—fluoro—6-iodo—2,3— 10A—39 F N N 2 o—lH—inden—S- F hyl)-9H—purin—9- _/NH yl)forrnamide NH? | JNL \ “1% N—(2-(6—amino-2—fluoro—8- F N/ N ((3-fluoro—6—iodo-2,3— 10A—40 2 dihydro-lH—inden-S- NH yl)methyl)-9H-purin—9- O yl)ethyl)pivalamide NH2 ‘ N \ N«(2-(6-amino—2—fluoro—8— )L / N\ ((3—fluoro—6-iod0—2,3- F N 10A-41 8 dihydro-lH-inden—S- F yl)niethyl)—9H—purin NH yl)ethyl)—3- O:<_< methylbutanarnide NH2 | N/ij:N\ N—(2—(6-aminofluoro-8— A , N ((3-fluoro—6-iodo-2,3- F N 10A-42 2 dihydro—lH—inden-S- F yl)methyl)-9H-purin NH yl)ethyl)cyclopropane— ox carboxamide G—lI. In some embodiments of the disclosure, X2 is an optionally substituted aryl.

Specific examples of compounds within the scope of this aspect of the disclosure correspond to the compounds disclosed in Tables 8A and 10A, or variations thereof as described in A., G. and G—I. above, in which X2 is an optionally substituted aryl, including but not limited to pyrazolyl, 1H— pyrazol—3—yl, oxazolyl, oxazol-Z-yl, thiazolyl, thiazol—Z-yl, furanyl, furan-Z—yl, and 5— methylfuran—Z—yl.

G-Hl. In some embodiments of the disclosure, X2 is an alkynyl group, e.g, ethynyl, 1- -ynyl, and 3-prop-l-3myl. Specific es of compounds within the scope of this aspect of the disclosure correspond to the compounds disclosed in Tables 8A and 10A, or ions thereof as described in A., G. and G—I. above, in which X2 is an alkynyl group.

G—IV. In some embodiments ofthe disclosure, X2 is an amino group, i.e., -NR1R2, wherein R1 and R2 are each independently H, C1-C6 alkyl, C2—C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, eteroaryl, heteroarylalkyl, or alkylheteroarylalkyl. c examples of compounds within the scope of this aspect of the disclosure correspond to the compounds disclosed in Tables 8A and 10A, or variations thereof as described in A., G. and G-I. above, in which X2 is an amino group.

H. Compounds of a (1B) in which Xa and Xb are Each 0 In ance with another embodiment of the disclosure, the compounds are of Formula (TB) in which each ofXa and Xb are 0 and each of X0 and Xd are CH2. Thus, the compounds of this embodiment can be represented by Formula (6): x41:N?“Y : _O>X2N \ N\ R O or a ceutically acceptable salt thereof, wherein: Y is CH2, 0, or S; X; is hydrogen or halogen; R is a is straight-chain- or branched- substituted or unsubstituted alkyl, straight-chain- or branched- substituted or unsubstituted alkenyl, straight—chain— or branched— substituted or unsubstituted alkynyl, or substituted or tituted cycloalkyl wherein the R group is interrupted by —S(O)N(RA)~, -NRAS(O)-, RA)—, «NRASOT, —C(O)N(RA)-, or -NRAC(O)-, and/or terminated by -S(O)NRARE, -NRAS(O)RB, —SO2NRARB, -NRASO2RB, -C(O)NRARB, or - NRAC(O)RB, wherein each RA and R3 is independently selected from hydrogen, C1~C5 alkyl, C2—C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, ryl, arylalkyl, alkylheteroaryl, arylalkyl, and alkylheteroarylalkyl; and X2 is as disclosed below.

In one embodiment, Y is O.

In another embodiment, Y is CH2 or O In another embodiment, Y is CH2 or S.

In another ment, Y is O or S.

H—I. In some embodiments of the disclosure, X2 is halogen. Table 11A lists specific examples of compounds within this embodiment, In each of the structures as drawn, X2 is Iand X4 is H. r, corresponding structures in which X; is F, C1, or Br are within the scope of the sure. In each of the structures in Table 11A, Y is S. r, corresponding structures in which Y is CH2 or O and/or X4 is F, Cl, Br, or I are also within the scope of the disclosure.

Additionally, in connection With each of the structures in Table 11A, corresponding structures in which X; is F, C1, or Br and Y is CH2 or O are also Within the scope of the disclosure.

Table 11A Comgound No. Structure Name NH; I \ N\ 'L / N>“S o 2-(6-amino((7-iodo—2,3- 11A_I OJ dihydrobenzo[b][1,4]dioxin- 6-yl)thio)—9H—purin—9-yl)-N— HN’SOZ isopropylethanesulfonamide NH2 l . . l VSQO 2—(6—annno—8—((7—1odo-2,3- N/ N 11A_2 J dihydrobenzo[b][1,4]dioxin— g 0 6—yl)thio)-9H-purinyl)-N- HN’802 ethylethanesulfonamide NH2 I . . "I fl / ysQO 2—(6—am1no—8~((7-1odo-2,3- N N 11A-3 OJ dihydrobenzo[b][1,4]dioxin- g 6-yl)thio)—9H—purin—9~yl)-N— [302 methylethanesulfonamide NH2 I NI \ N\>—S 2-(6-amino—8—((7~iodo—2,3— 11A 4 Km N j dihydrobenzo[b][1,4]dioxin— 0 6—yl)thio)—9H—purin yl)ethanesulfonamide H N’SOZ NHZL I / “IVS o 2-(6-amino—8—((7—iodo-2,3- 11A-5 OJ dihydrobenzo[b][l,4]dioxin— hio)—9H-purin—9-yl)—N- HN’SOZ (tert-buty1)ethanesulfonamide NH2 I N \ N\ tN/ N>_ Q3s 2-(6-amino((7-iodo-2,3- 11A 6' dihydrobenzo[b][1,4]dioxin— so 6-y1)thio)—9H-purin—9—yl)—N- HN’ isobutylethanesulfonamide CompoundNo. F— Structure Name NH; I . . l ¥SQ0 2—(6—am1n0—8-((7—1odo-2,3- N/ N dihydrobenzo[b] [ 1 ,4]dioxin- 1 1A—7 6-y1)thio)—9H-purin—9-y1)‘N— 302 cyclopropyl- HN’W> ethanesulfonamide NH2 I \ N N—(Z-(G-amino—S-((7-iodo- N / NNSQO 2,3— 11A_8 8 OJ dihydrobenzo[b][1,4]dioxin— 6-y1)thio)—9H—purin—9— ,NH yl)ethy1)propane—2- 023 sulfonamide NH2 I Nl \ MysQ N—(Z-(6-amino((7-iodo- / 0 2 3- N N , 11A—9 8 OJ obenzo[b][1,4]dioxin— 6-y1)thio)-9H-purin—9- yl)ethyl)ethanesu1fonamide O SNH2 NH2 , \ N N— 2— 6-amino( —M ( &/ NN‘SQO 2,3— 1 lA-I 0 2 OJ dihydrobenzo[b] [1 ,4] dioxin- 6—y1)thio)-9H—purin—9— yl)ethyl)methanesulfonamide o s’NH2 NHZ I \ Nfs‘Qo l N-(2-(6—amino—8-((7-iodo- N/ N 2,3- 11A—11 8 DJ obenzo[b][l,4]dioxin— NH 6—y1)thio)-9H-pun'n 025/ yl)ethy1)—2~methy1propane-2— N sulfonamide NH2 | N \ N-(Z-(6-amino((7-iodo- l / hfS‘QO 2,3- 11A-12 2 OJ dihydrobenzo[b][1,4]dioxin— 6-y1)thio)-9H-purin ,NH y1)ethy1)methy1propane sulfinamide NHz [ \ N N-(2—(6—an'1ino—8-((7-iodo- / VS‘QO 2,3- N J 11A-13 dihydIobenzo[b][1,4]dioxin— 6—yl)thio)—9H-purin-9— y1)ethy1)—2-methy1propane sulfonamide Compound No. Structure Name NH2 I N(- 2- 6—amin( N [\P—S‘QON 238- -((7—iodo- 11A-14 2 OJ dihydrobenzo[b][1,4]dioxin— 6-y1)thio)-9H-purin y1)ethy1)cyclopropane- 0 SN”2 sulfonamide NHz I l / VSQO 3-(6-amino((7—iodo—2,3— N N OJ dihydrobenzo[b][1,4]dioxin— 1 1A-15 é 6—y1)thio)—9H-purin—9 -yl)~N— isopropylpropane 023 sulfonamide «{‘H NHz | t*1“/ o 3—(6-amino-8~((7-iod0—2,3- N N‘>*S 1 1A_16 OJ dihydrobenzo[b][1,4]dioxin- 6-y1)thio)—9H-purin—9-yl)—N— ropane-l —su1fonamide 023‘ NH2 I ‘l l / N‘fs o 3—(6-amino-8—((7-iodo~2,3- 11A—17 g OJ dihydrobenzo[b][1,4]dioxin— 6-y1)thio)-9H—purin—9-yl)—N- methylpropane— 1 -sulfonamide 028‘ NH2 I Ni: ysQoN 3-(6-amino-8—((7-iodo-2,3— N N 11A—18 g OJ dihydrobenzo[b][1,4]dioxin— 6-y1)thio)-9H-pun'n-9— pane—1—sulf0namide 023‘ NHg I K\ “i SQ” 3-(6-amino—8—((7—iodo—2,3- N/ N J dihydrobenzo[b][1,4]dioxin— 11A—19 0 6-y1)thio)-9H-puriny1)-N— (tert-butyl)propane sulfonamide nd No. uxe Name NHZ I u\ / VSQO 3—(6—amino((7-iodo-2,3- N N OJ dihydrobenzo[b][1,4]dioxin— 1 1A—20 6—y1)thio)—9H—purin-9—y1)-N— isobutylpropane-l- 025\ sulfonamide NH: | NJEQKN/ “1%s 3—(6—amino-8—((7-iodo-2 3-, :3) dihydrobenzo[b][1,4]dioxin- 1 1A-21 0 6—yl)thio)—9H—purin—9~y1)—N- cyclopropylpropane— 1 - sulfonamide O s2 HN—<]\ NH2 | \ “i N-(3-(6-amino—8-((7—iodo- [ , >‘3 o N N J 2,3— 11A-22 dihydrobenzo[b][1,4]dioxin— 6-y1)thi0)-9H—purin-9— HN y1)propyl)propane—2- \SOZ amide NHZ I “i\ N\>_S o N—(3~(6—amino—8-((7-iodo— N/ N J 2,3- 1 1A-23 O dihydrobenzo[b][1,4]dioxin— 6-y1)thio)-9H—purin—9~ HN\ y1)propyl)ethanesulfonamidc NH2 I N \ “ifs N—(3—(6-amino—8—((7-i0do— t / 0 2,3- N N OJ dihydrobenzo[b][1,4]di0X1'n— 1 1A-24 é 6-y1)thio)-9H-purin y1)propy1)methane- “N sulfonamide NH2 I \ N\ N-(3-(6-amino((7-iodo— [ , >*5 o N N J 2,3- d1hydrobenzo[b][1,4]d10xm— 11A-25 6-y1)thio)—9H—purin—9- y1)propyl)—2—methy1propane- 2-su1fonamide Comgound No. Structure Name N—(3-(6-amino((7-iodo- 2,3- ““6 g dihydrobenzo[b][ 1 ,4] dioxin- 6—yl)thio)—9H—purin—9- ”N y1)propy1)—2~methylpropane- so 2-sulfinamide NH; I l\ Nys N-(3-(6-amino((7—iodo- N/ N J 2,3- 11A-27 dihydrobenzo[b][1,4]dioxin- hio)—9H—purin—9— HN y1)pr0pyl)-2—methy1propane— \802 1-su1fonamide NH2 , \ N . .

K \>—s o N-(3-(6—am1no—8-((7-1odo— N/ N 2,3- 11A—28 dihydrobenzo[b][1,4]dioxin- 6—y1)thio)-9H—purin—9- HN\ yl)propy1)cyclopropane~ <r$02 amide NH2 I w \ ”\ L / Nys o 3—(6-amino((7-iodo-2,3- 11M9 g: OJ dihydrobenzo[b][1,4]dioxin- 6—y1)thio)-9H—purin—9—yl)-N— 0 isopropylpropanamide NH2 I “i: N\>-SQ0 3-(6-amino-8—((7-iodo-2,3- N N 11A-30 OJ dihydrobenzo[b][1,4]dioxin~ 6—yl)thio)—9H—purin—9—y1)-N— o ethylpropanamide NHQ I \>—s 3—(6-anuno-8—((7-10do-2,3-. . t / o N N 11A-31 OJ dihydrobenzo[b][1,4]di0xin~ 6-yl)thio)—9H-puriny1)—N- 0 methylpropanamide NH2 l N! \ N>_S mino—8-((7-iodo-2,3- 11A—32 kN/ N J dihydrobenzo[b][1,4]dioxin— 0 6-yl)thio)—9H—purin-9— y1)propanamide {—____ HZN Compound N0. Structure Name NHz , / N‘fsflo 3-(6-amino((7-iod0—2,3- 11A—33 é: OJ dihydrobenzo[b][1,4]di0xin— 6-y1)thio)-9H-puriI1yl)—N- 0 buty1)propanamide NH; 1 / NVSQO 3-(6-amino—8-((7-iodo—2,3- 11A_34 OJ dihydrobenzo[b][1,4]dioxin— 6-y1)thio)-9H—puriny1)-N- 0 isobutylpropanamide NH2 | kN/ Q‘SQ‘OOJ 3-(6—amino—8-((7—iodo-2,3- 11A-35 dihydrobenzo[b][1,4]dioxin- 6-y1)thio)—9H—purin—9—yl)—N- 0 cyclopropylpropanamide NH2 I l: N . . \>_S O N—(Z-(6—annno—8—((7-1odo- N N J 2,3- 11A—36 8 0 obenzo[b][1,4]dioxin— NH 6-y1)thio)-9H-pun'n O y1)ethy1)isobutyramide NHZ I &: N¥S~Qo N-(2—(6—am;n§:8-((7-iodo- N N a 11A-37 8 OJ dihydrobenzo[b][1,4]dioxin- 6-yl)thio)-9H—purin 04W y1)ethy1)propionamide NHZ | .

N‘ \ N\>_S N-(Z-(6—amino—8—((7—iodo- kN/ 0 N 2,3— 1 1A-38 8 OJ dihydrobenzo[b][1,4]dioxin- 6-yl)thio)—9H—purin—9- NH2:/\ yl)ethyl)acetam1de‘ \>—s N—(2 m / 0 -( -ammo-6 8-((7' d-10 o- N N J 2,3- 1 1A-39 g 0 obenzo[b][1,4]dioxin— NH 6—y1)thio)—9H—purin o y1)ethy1)pivalamide Com ound Not Structure Name NFig i {\IN>‘SQO 6-amino—8-((7-iodo- N/ N DJ 2,3- 11A—40 2 dihydrobenzo[b][1,4]dioxin- NH 6-yl)thio)—9H-purin—9- o . yl)ethyl)—3-methylbutanarnide NH2 i N \ N—(Z-(6—amino((7-iodo- 11A-41 dihydrobenzo[b][l,4]dioxin— 6-yl)thio)—9H-purin—9— NH y1)cyclopropane- O23> carboxarmde.

NHz , i “1%S N—(Z—(6—amén3o-8—(U-iodo-" N : O / llA-42 kN g oj dihydrobenzo[b][1,4]dioxin— 6—yl)thio)-9H-purin—9- _/NH yl)ethyl)forrnamide H-H. In some embodiments of the disclosure, X2 is an optionally substituted aryl.

Specific examples of compounds within the scope of this aspect of the disclosure correspond to the compounds sed in Table 11A, or variations thereof as described in A., H. and H—1. above, in which X; is an optionally tuted aryl, including but not limited to pyrazolyl, lH—pyrazol—3 ~yl, oxazolyl, oxazol-Z-yl, thiazolyl, thiazol—Z-yl, furanyl, furan-Z—yl, and 5—methylfuran—2-yl.

H-H]. In some embodiments ofthe disclosure, X2 is an alkynyl group, e.g., ethynyl, l- prop-l-ynyl, and 3-prop-l-ynyl. Specific examples of compounds within the scope of this aspect of the disclosure pond to the compounds disclosed in Tablel 1A, or variations thereof as described in A, H. and H-1. above, in which X2 is an alkynyl group.

H—IV. In some embodiments of the disclosure, X2 is an amino group, 119., -NR1RZ, wherein R1 and R2 are each independently H, C1-C6 alkyl, C2—C5 alkenyl, C1-C5 alkynyl, cycloalkyl, alkyl, heterocycloalkyl, aryl, heteroaryl, ryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, or alkylheteroarylalkyl. Specific examples of compounds within the scope of this aspect of the disclosure pond to the compounds disclosed in Table 11A, or variations thereof as described in A., H. and H—1. above, in which X; is an amino group.

J. Additional Embodiments Each of the following embodiments relates to the compounds of Formulae (IA) and (IB) and, particularly, to each of the appropriate embodiments 01 through H—IV of the compounds of Formulae (1) through (6).

In one embodiment, Y is CH2. In another embodiment, Y is S.

In another embodiment, X4 is H. In another embodiment, X4 is halogen. In another embodiment, X4 is F, C1, or Br. In another embodiment, X4 is F, C1, or I. In another embodiment, X4 is F, Br, or I. In another embodiment, X4 is Cl, Br, or I. In r embodiment, X4 is F or I. In another embodiment, X4 is F or Br. In another ment, X4 is F or Cl. In another embodiment, X4 is Cl or I. In another embodiment, X4 is C1 or Br. In another embodiment, X4 is Br or I. In another embodiment, X4 is F. In another embodiment, X4 is C1. In another embodiment, X4 is Br.

In another ment, X4 is I. In r embodiment, X4 is H, F, Cl, or Br. In another embodiment, X4 is H, F, C1, or I. In another embodiment, X4 is H, F, Br, or I. In another embodiment, X4 is H, Cl, Br, or I. In another ment, X4 is H, F, or I. In another ment, X4 is H, F, or Br. In r embodiment, X4 is H, F, or Cl. In another embodiment, X4 is H, Cl, or I. In another embodiment, X4 is H, C1, or Br. In another embodiment, X4 is H, Br, or I. In another embodiment, X4 is H or F. In another embodiment, X4 is H or C1. In another embodiment, X4 is H or Br. In another embodiment, X4 is H or I.

In another embodiment, X2 is halogen, aryl, or alkynyl. In another embodiment, X2 is n, aryl, or amino. In r ment, X2 is halogen, alkynyl, or amino. In another embodiment, X2 is aryl, alkynyl, or amino. In another embodiment, X2 is halogen or amino. In another embodiment, X2 is halogen or alkynyl. In another embodiment, X2 is halogen or aryl. In another embodiment, X2 is halogen. In another embodiment, X2 is aryl. In r ment, X2 is alkynyl. In another embodiment, X2 is amino. In another embodiment, X2 is halogen, heteroaryl, alkynyl, or amino. In another embodiment, X2 is halogen, aryl, or alkynyl. In another embodiment, X2 is halogen, heteroaryl, or amino. In another embodiment, X2 is heteroaryl, alkynyl, or amino. In another embodiment, X2 is halogen or heteroaryl. In another embodiment, X2 is heteroaryl. In another embodiment, X2 is alkyl-substituted heteroaryl. In another embodiment, X2 is C1-C5 alkyl-substituted heteroaryl. In another ment, X2 is -, ethyl-, n—propyl—, or isopropyl—substituted aryl. In another embodiment, X2 is methyl- or ethyl-substituted heteroaryl. In another embodiment, X2 is methyl-substituted heteroaryl. In another embodiment, X2 is ethyl-substituted heteroaryl.

In r embodiment, X2 is F, Cl, or Br. In another embodiment, X2 is F, C1, or I. In another embodiment, X2 is F, Br, or I. In another embodiment, X2 is Cl, Br, or I. In another embodiment, X2 is F or I. In another embodiment, X2 is F or Br. In another embodiment, X2 is F or C1. In another embodiment, X2 is C1 or I. In r embodiment, X2 is C1 or Br. In another embodiment, X2 is Br or I. In another embodiment, X2 is F. In r embodiment, X2 is C1. In another embodiment, X2 is Br. In r embodiment, X2 is I.

In another embodiment, X2 is optionally substituted heteroaryl. In another embodiment, X2 is unsubstituted heteroaryl. In another embodiment, X2 is furan-Z -y1, furan—3-y1, 5-methy1furan—2- yl, azol—Z-yl, azol—S-yl, thiazol—Z-yl, 5-methy1thiazol-2—yl, -Z-yl, 5— methyloxazoI-Z-yl, thiophene-Z-yl, thiopheneyl, lH-imidazo-Z—yl, 1H—imidazo—4—y1, or 1H- imidazo—S—yl. In another embodiment, X2 is furan-Z-yl, furany1, 5«methylfurany1, 1H- l—Z—yl, 1H—pyrazol—3—yl, thiazoI—Z-yl, 5-methylthiazoly1, oxazoi—Z—yl, or 5—methyloxazoI—2— yl. In another embodiment, X2 is furan-Z-yl, furan-S-yl, or 5-methy1furan—2-yl. In another embodiment, X2 is 1H—pyrazoi—2 -y1 or 1H—pyrazoI-3 -y1. In another embodiment, X2 is thiazol—Z-yl or 5-methylthiazolyl. In another embodiment, X2 is oxazol-Z-yl or 5-methyloxazol—2—y1. In another embodiment, X2 is thiophene-Z-yl, thiophene-S-yl, 1H—imidazoyl, dazo-4—yl, or 1H—imidazo-5 ~y1. In another embodiment, X2 is thiophene—Z—yl or thiophene—3 —y1. In another embodiment, X2 is lH-imidazo—Z—yl, 1H—imidazo—4—y1, or IH-imidazo—S-yl.

In another ment, X2 is ethynyi, propynyi, or butynyl. In another embodiment, X2 is ethynyl or propynyl. In another embodiment, X2 is l or butynyl. In r embodiment, X2 is propynyl or butynyl. In another embodiment, X2 is ethynyi. In another embodiment, X2 is propynyl. In another embodiment, X2 is butynyl.

In another embodiment, X2 is dimethylamino, diethylamino, ethylarnino, or cyclopropylamino, In another embodiment, X2 is dimethylamino, diethylamino, or methylethylamino. In another embodiment, X2 is dimethylamino, diethylamino, or cyclopropylamino. In another embodiment, X2 is dimethylamino, methylethylamino, or cyclopropylamino. In another embodiment, X2 is diethylamino, methylethylamino, or cyclopropylamino. In another embodiment, X2 is dimethylarnino or diethylamino. In another embodiment, X2 is dimethylamino or methylethylamino, In another ment, X2 is ylamino or cyclopropylamino. In another embodiment, X2 is diethylamino or methylethylamino. In r embodiment, X2 is diethylamino or cyclopropylamino, In another embodiment, X2 is methylethylamino or cyclopropyiamino. In another embodiment, X2 is dimethylamino. In another embodiment, X2 is diethylamino. In another embodiment, X2 is methylethyiamino. In another embodiment, X2 is cyclopropylamino.

In another embodiment, X2 is Br, I, furan—Z-yl, furan—3-y1, 5-methy1furan—2-yl, lH—pyrazol— 2—y1, 1H-pyrazoly1, thiazol—Z-yl, 5~methy1thiazoI—2-y1, oxazol—Z-yi, 5-methyloxazolyl, ethynyl, propynyl, dimethylamino, diethylamino, or methylethylamino. In another embodiment, X2 is I, furan-Z—yl, furan—3—yl, yIfuran—2-y1, ethynyl, ylamino, diethylamino, or methylethylamino. In r embodiment, X2 is Br, Z-yl, furan—B—yl, 5—methylfuranyl, ethynyl, ylamino, diethylamino, or methylethylamino. In another embodiment, X2 is I, furan—Z-yl, furan~3—yl, 5-methylfuran—2-yl, ethynyl, or dimethylamino. In another embodiment, X2 is Br, 2-yl, furan—3—yl, ylfi1ran—2—yl, ethynyl, or dimethylamino. In another embodiment, X2 is I, 1H-pyrazol-2—yl, lH—pyrazolyl, ethynyl, dimethylamino, diethylamino, or methylethylamino. In another embodiment, X2 is Br, 1H-pyrazol—2-yl, lH-pyrazol-S-yl, ethynyl, dimethylamino, diethylamino, or methylethylamino. In another embodiment, X2 is I, 1H-pyrazol—2- yl, lH-pyrazolyl, ethynyl, or dimethylamino. In another embodiment, X2 is Br, lH-pyrazol~2—yl, 1H-pyrazolyl, ethynyl, or dimethylamino. In another embodiment, X2 is I, l~2~y1, 5— methylthiazol-Z-yl, ethynyl, dimethylamino, diethylamino, or methylethylamino. In another embodiment, X2 is Br, thiazol-Z—yl, 5-methy1thiazolyl, l, dimethylamino, diethylamino, or methylethylamino. In another embodiment, X2 is I, thiazol—Z-yl, 5—methylthiazol—2-yl, ethynyl, or dimethylamino. In another embodiment, X2 is Br, thiazol—Z—yl, ylthiazolyl, ethynyl, or ylamino. In another embodiment, X2 is I, oxazol—Z -y1, 5-methyloxazolyl, ethynyl, dimethylamino, lamino, or methylethylamino. In another embodiment, X2 is Br, oxazol—Z-yl, -methyloxazolyl, ethynyl, dimethylamino, diethylamino, or methylethylamino. In r embodiment, X2 is I, oxazol-Z—yl, yloxazol—2-yl, ethynyl, or dimethylamino. In another embodiment, X2 is Br, oxazol—Z-yl, 5-methyloxazol—2-yl, ethynyl, or dimethylamino.

In another embodiment, X2 is halogen, aryl, or alkynyl and Y is S. In another embodiment, X2 is halogen, aryl, or amino and Y is S. In another embodiment, X2 is halogen, alkynyl, or amino and Y is S. In another ment, X2 is aryl, alkynyl, or amino and Y is S. In another embodiment, X2 is halogen or amino and Y is S. In another embodiment, X2 is halogen or alkynyl and Y is S. In another embodiment, X2 is halogen or aryl and Y is S. In another embodiment, X2 is n and Y is S. In another ment, X2 is aryl and Y is S. In another embodiment, X2 is alkynyl and Y is S. In another embodiment, X2 is amino and Y is S. In another embodiment, X2 is halogen, heteroaryl, l, or amino and Y is S. In another embodiment, X2 is n, aryl, or alkynyl and Y is S. In another embodiment, X2 is halogen, heteroaryl, or amino and Y is S. In another embodiment, X2 is heteroaryl, alkynyl, or amino and Y is S. In another embodiment, X2 is halogen or aryl and Y is S. In another embodiment, X2 is heteroaryl and Y is S. In another embodiment, X2 is alkyl-substituted heteroaryl and Y is S. In another ment, X2 is C1—C6 alkyl—substituted heteroaryl and Y is S. In another embodiment, X2 is methyl-, ethyl—, n—propyl-, or isopropyl-substituted heteroaryl and Y is S. In another embodiment, X2 is methyl- or ethyl-substituted heteroaryl and Y is S. In another embodiment, X2 is methyl— substituted heteroaryl and Y is S. In another embodiment, X2 is ethyl—substituted heteroaryl and Y is S. In another embodiment, X2 is Br, I, furan—Z-yl, furan-3—yl, 5-methy1fi1ran—2-yl, lH-pyrazol-Z- yl, 1H—pyrazol—3—yl, thiazol—Z-yl, 5-methylthiazol—2-yl, oxazol—Z-yl, 5-methyloxazol—2-yl, ethynyl, propynyl, ylamino, diethylamino, or methylethylamino and Y is S. In r embodiment, X2 is I, Z-yl, furanyl, 5—methylfurany1, ethynyl, dimethylamino, diethylamino, or methylethylamino and Y is S. In another embodiment, X2 is Br, furan—2-yl, furan—3—yl, 5- furan-Z-yl, ethynyl, dimethylamino, diethylamino, or methylethylamino and Y is S. In another embodiment, X2 is I, furan—Z-yl, furanyl, 5—methy1furan—2-yl, ethynyl, or dimethylamino and Y is S. In another embodiment, X2 is Br, furan-Z—yl, furan-S—yl, 5—methylfuran—2—y1, ethynyl, or dimethylamino and Y is S. In r embodiment, X2 is I, 1H—pyrazolyl, 1H-pyrazol-3—yl, ethynyl, dimethylamino, diethylamino, or ethylamino and Y is S. In another embodiment, X2 is Br, lH-pyrazolyl, lH—pyrazoly1, ethynyl, dimethylamino, diethylamino, or methylethylamino and Y is S. In another embodiment, X2 is I, azol-Z-yl, azol-S-yl, ethynyl, or dimethylamino and Y is S. In r embodiment, X2 is Br, lH—pyrazol—Z-yl, 1H- pyrazol-S-yl, ethynyl, or dimethylamino and Y is S. In another embodiment, X2 is I, l-Z-yl, -methylthiazol—2-yl, l, dimethylamino, diethylamino, or methylethylamino and Y is S. In another embodiment, X2 is Br, thiazol-Z—yl, 5-methylthiazolyl, ethynyl, dimethylamino, diethylamino, or methylethylamino and Y is S. In another embodiment, X2 is I, thiazol—Z—yl, 5- methylthiazol—Z—yl, l, or dimethylamino and Y is S. In another embodiment, X2 is Br, thiazol-Z-yl, 5—methylthiazol—2-yl, ethynyl, or dimethylamino and Y is S. In another embodiment, X2 is I, -Z—yl, 5-methyloxazolyl, ethynyl, dimethylamino, lamino, or methylethylamino and Y is S. In another embodiment, X2 is Br, oxazol-Z-yl, 5-methyloxazol—2—yl, ethynyl, dimethylamino, diethylamino, or methylethylamino and Y is S. In another embodiment, X2 is I, oxazol-Z—yl, 5-methyloxazol-2—yl, ethynyl, or dimethylamino and Y is S. In another embodiment, X2 is Br, oxazol-Z-yl, 5—methyloxazol—2—yl, ethynyl, or dimethylamino and Y is S.

In another embodiment, X2 is halogen, aryl, or alkynyl and Y is CH2. In another embodiment, X2 is halogen, aryl, or amino and Y is CH2. In another embodiment, X2 is halogen, alkynyl, or amino and Y is CH2. In another embodiment, X2 is aryl, alkynyl, or amino and Y is CH2. In another embodiment, X2 is halogen or amino and Y is CH2. In another embodiment, X2 is halogen or alkynyl and Y is CH2. In another ment, X2 is halogen or aryl and Y is CH2. In another embodiment, X2 is halogen and Y is CH2. In another embodiment, X2 is aryl and Y is CH2.

In another embodiment, X2 is alkynyl and Y is CH2. In another embodiment, X2 is airline and Y is CH2. In another embodiment, X2 is halogen, heteroaryl, alkynyl, or amino and Y is CH2. In r embodiment, X2 is halogen, heteroaryl, or alkynyl and Y is CH2. In another embodiment, X2 is halogen, heteroaryl, or amino and Y is CH2. In another embodiment, X2 is heteroaryl, alkynyl, or amino and Y is CH2. In another ment, X2 is halogen or heteroaryl and Y is CH2.

In another embodiment, X2 is heteroaryl and Y is CH2. In another embodiment, X2 is alkyl— substituted heteroaryl and Y is CH2. In another embodiment, X2 is C1—C6 alkyl-substituted aryl and Y is CH2. In another embodiment, X2 is methyl-, ethyl—, n-propyl-, or isopropyl~ substituted heteroaryl and Y is CH2. In another embodiment, X2 is methyl- or ethyl-substituted heteroaryl and Y is CH2. In another embodiment, X2 is methyl-substituted heteroaryl and Y is CH2.

In another ment, X2 is substituted heteroaryl and Y is CH2. In another embodiment, X2 is Br, I, furan—Z—yl, furan-3—yl, 5-methy1fi1ran—2-yl, lH-pyrazol-Z—yl, 1H—pyrazolyl, thiazoI—Z— yl, 5—methy1thiazol—2-y1, -Z-yl, 5-methyloxazoI—2-yl, ethynyl, yl, dimethyiamino, diethylamino, or methylethylamino and Y is CH2. In another embodiment, X2 is I, filran-Z-yi, furan—3—y1, ylfuran—2-y1, ethynyl, dimethylamino, diethylamino, or ethylamino and Y is CH2. In another ment, X2 is Br, furan-Z—yl, furan-B-yl, 5—methyifuran-2—yl, ethynyl, dimethylamino, diethylamino, or methylethylamino and Y is CH2. In another embodiment, X2 is I, furan-2—yl, furan—3-y1, 5—methy1furany1, ethynyl, or dimethylamino and Y is CH2. In r embodiment, X2 is Br, finan-Z-yl, furan-3—yi, 5-methy1furan—2-yl, ethynyl, or dimethylamino and Y is CH2. In another embodiment, X2 is I, azol-Z—yl, IH-pyrazoI—3—yl, ethynyl, dimethylamino, diethyiamino, or methylethylamino and Y is CH2. In another embodiment, X2 is Br, lH—pyrazoI-Z- yl, IH-pyrazol-S-yl, ethynyl, dimethylamino, diethylamino, or methylethylamino and Y is CH2. In another embodiment, X2 is I, IH—pyrazol-Z-yl, 1H—pyrazol—3-yl, ethynyl, or dimethylamino and Y is CH2. In another embodiment, X2 is Br, lH-pyrazol—Z-yl, lH—pyrazoI—S—yl, ethynyl, or dimethylamino and Y is CH2. In another embodiment, X2 is I, l—Z-yl, 5-methylthiazoI—2-yl, l, dimethylamino, diethylamino, or methylethylamino and Y is CH2. In another embodiment, X2 is Br, thiazol-Z-yl, 5—methy1thiazol—2—y1, ethynyl, dimethylamino, diethyiamino, 0r methylethylamino and Y is CH2. In another embodiment, X2 is I, thiazoI-Z-yl, 5—methylthiazoI yI, ethynyl, or dimethylamino and Y is CH2. In another embodiment, X2 is Br, thiazoI—Z—yl, 5- methylthiazol-Z-yl, ethynyl, or dimethylamino and Y is CH2. In another embodiment, X2 is I, —Z—yl, 5-methyloxazoly1, ethynyl, dimethyiamino, diethylamino, or methylethylamino and Y is CH2. In another embodiment, X2 is Br, oxazoI-Z—yl, 5—methyloxazoIyl, ethynyI, dimethylamino, diethylamino, or methylethylamino and Y is CH2. In another ment, X2 is I, oxazol—Z-yl, 5-methyloxazol-2—y1, ethynyl, or dimethylamino and Y is CH2. In another embodiment, X2 is Br, oxazol—2—yl, 5—methyloxazoly1, ethynyl, or dimethylamino and Y is CH2.

In another ment, X4 is H and Y is S. In another embodiment, X4 is halogen and Y is S. In another embodiment, X4 is F, C1, or Br and Y is S. In another embodiment, X4 is F, C1, or I and Y is S. In another embodiment, X4 is F, Br, or I and Y is S. In another embodiment, X4 is Cl, Br, or I and Y is S. In another embodiment, X4 is F or I and Y is S. In r ment, X4 is F or Br and Y is S. In r embodiment, X4 is F or C1 and Y is S. In another embodiment, X4 is C1 or I and Y is S. In another embodiment, X4 is Ci or Br and Y is S. In another embodiment, X4 is Br or I and Y is S. In another embodiment, X4 is F and Y is S. In another embodiment, X4 is C1 and Y is S. In another embodiment, X4 is Br and Y is S. In another embodiment, X4 is I and Y is In another ment, X4 is H, F, C1, or Br and Y is S. In another embodiment, X4 is H, F, C1, or I and Y is S. In another embodiment, X4 is H, F, Br, or I and Y is S. In another embodiment, X4 is H, Cl, Br, or I and Y is S. In another embodiment, X4 is H, F, or I and Y is S.

In another embodiment, X4 is H, F, or Br and Y is S. In another embodiment, X4 is H, F, or Cl and Y is S. In another embodiment, X4 is H, C1, or I and Y is S. In another embodiment, X4 is H, C1, or Br and Y is S. In r embodiment, X4 is H, Br, or I and Y is S. In another ment, X4 is H or F and Y is S. In r embodiment, X4 is H or Cl and Y is S. In r ment, X4 is H or Br and Y is S. In r embodiment, X4 is H or I and Y is S.

In another embodiment, X4 is H and Y is CH2. In r embodiment, X4 is halogen and Y is CH2. In another embodiment, X4 is F, C1, or Br and Y is CH2. In another embodiment, X4 is F, C1, or I and Y is CH2. In another embodiment, X4 is F, Br, or I and Y is CH2. In another embodiment, X4 is Cl, Br, or I and Y is CH2. In another embodiment, X4 is F or I and Y is CH2. In another embodiment, X4 is F or Br and Y is CH2. In another ment, X4 is F or C1 and Y is CH2. In another embodiment, X4 is C1 or I and Y is CH2. In another embodiment, X4 is C1 or Br and Y is CH2. In another embodiment, X4 is Br or I and Y is CH2. In another embodiment, X4 is F and Y is CH2. In another embodiment, X4 is C1 and Y is CH2. In another embodiment, X4 is Br and Y is CH2. In another embodiment, X4 is Iand Y is CH2.

In another embodiment, X4 is H, F, C1, or Br and Y is CH2. In another embodiment, X4 is H, F, C1, or I and Y is CH2. In another embodiment, X4 is H, F, Br, or I and Y is CH2. In another embodiment, X4 is H, Cl, Br, or I and Y is CH2. In another embodiment, X4 is H, F, or I and Y is CH2. In another embodiment, X4 is H, F, or Br and Y is CH2. In another embodiment, X4 is H, F, or Cl and Y is CH2. In another embodiment, X4 is H, C1, or I and Y is CH2. In r embodiment, X4 is H, C1, or Br and Y is CH2. In another embodiment, X4 is H, Br, or I and Y is CH2. In another embodiment, X4 is H or F and Y is CH2. In another embodiment, X4 is H or C1 and Y is CH2. In another embodiment, X4 is H or Br and Y is CH2. In another embodiment, X4 is H or I and Y is CH2.

In r embodiment, X2 is halogen, aryl, or alkynyl, X4 is H or F, and Y is S. In another embodiment, X2 is halogen, aryl, or amino, X4 is H or F, and Y is S. In another embodiment, X2 is halogen, alkynyl, or amino, X4 is H or F, and Y is S. In another embodiment, X2 is aryl, alkynyl, or amino, X4 is H or F, and Y is S. In another embodiment, X2 is halogen or amino, X4 is H or F, and Y is S. In another embodiment, X2 is halogen or alkynyl, X4 is H or F, and Y is S. In another embodiment, X2 is halogen or aryl, X4 is H or F, and Y is S. In another embodiment, X2 is halogen, X4 is H or F, and Y is S. In another embodiment, X2 is aryl, X4 is H or F, and Y is S. In another embodiment, X2 is alkynyl, X4 is H or F, and Y is S. In another embodiment, X2 is amino, X4 is H or F, and Y is S. In another embodiment, X2 is halogen, heteroaryl, alkynyl, or amino, X4 is H or F, and Y is S. In another embodiment, X2 is n, aryl, or alkynyl, X4 is H or F, and Y is S.

In another embodiment, X2 is n, heteroaryl, or amino, X4 is H or F, and Y is S. In another embodiment, X2 is heteroaryl, alkynyl, or amino, X4 is H or F, and Y is S. In another embodiment, X2 is halogen or heteroaryi, X4 is H or F, and Y is S. In another embodiment, X2 is heteroaryl, X4 is H or F, and Y is S. In r embodiment, X2 is alkyl—substituted heteroaryl, X4 is H or F, and Y is S. In another embodiment, X2 is Cl'Cé alkyl-substituted heteroaryl, X4 is H or F, and Y is S. In another embodiment, X2 is methyl-, ethyl-, n-propyl-, or isopropyl-substimted heteroaryl, X4 is H or F, and Y is S. In another embodiment, X2 is methyl- or ethyl-substituted heteroaryl, X4 is H or F, and Y is S. In another ment, X2 is methyl-substituted heteroaryl, X4 is H or F, and Y is S.

In another embodiment, X2 is ethyl—substituted heteroaryl, X4 is H or F, and Y is S. In another embodiment, X2 is Br, I, furan—Z—yl, fiiran—S—yl, y1furan—2—y1, IH—pyrazol—Z—yl, 1H-pyrazol yl, l-Z—yl, 5—methy1thiazol-2—yl, oxazol—Z—yl, yloxazoly1, ethynyl, yl, dimethylamino, diethylamino, or methylethylamino, X4 is H or F, and Y is S. In another ment, X2 is I, furan-Z-yl, 3-y1, ylfi1ranyi, ethynyl, dimethylamino, lamino, or methylethylamino, X4 is H or F, and Y is S. In another embodiment, X2 is Br, furan—Z-yl, furany1, 5—methy1furan—2-yl, ethynyl, dimethylamino, diethylamino, or methylethylamino, X4 is H or F, and Y is S. In another embodiment, X2 is I, furan—Z-yl, furan—3-yi, —methylfuran—2—y1, ethynyl, or dimethylamino, X4 is H or F, and Y is S. In another embodiment, X2 is Br, furan—Z-yl, furan—3—y1, y1fi1ran—2-yl, ethynyl, or dimethylamino, X4 is H or F, and Y is S. In another embodiment, X2 is I, lH-pyrazol-Z-yl, 1H—pyrazolyi, ethynyl, ylamino, diethylamino, or methylethyiamino, X4 is H or F, and Y is S. In another embodiment, X2 is Br, 1H- l-Z-yl, azol-S-yl, ethynyl, dimethylamino, diethylamino, or methylethylamino, X4 is H or F, and Y is S. In another embodiment, X2 is I, IH-pyrazol-Z-yl, 1H-pyrazoiy1, ethynyl, or dimethylamino, X4 is H or F, and Y is S. In another ment, X2 is Br, lH-pyrazol—Z-yl, 1H— pyrazol—3 -y1, ethynyl, or dimethylamino, X4 is H or F, and Y is S. In another embodiment, X2 is I, thiazol-Z-yl, 5-methy1thiazolyi, ethynyl, dimethylamino, diethylamino, or methylethylamino, X4 is H or F, and Y is S. In another embodiment, X2 is Br, thiazoI-Z-yl, 5-methy1thiazoly1, ethynyl, dimethylamino, diethylamino, or methylethylamino, X4 is H or F, and Y is S. In another embodiment, X2 is I, thiazol-Z-yl, 5-methy1thiazoiyl, l, or dimethylamino, X4 is H or F, and Y is S. In another embodiment, X2 is Br, thiazoI—2—y1, 5—methy1thiazoI—2—y1, ethynyl, or dimethylamino, X4 is H or F, and Y is S. In another embodiment, X2 is I, oxazol—Z—yl, 5— methyloxazol-Z-yl, ethynyl, dimethylamino, diethylamino, or methylethylarnino, X4 is H or F, and Y is S. In another embodiment, X2 is Br, oxazol—Z-yl, 5-methyioxazol—2-yi, ethynyl, dimethylamino, diethylamino, or methylethylamino, X4 is H or F, and Y is S. In another embodiment, X2 is I, oxazoI—Z—yl, 5—methyloxazoi—2 -y1, ethynyl, or dimethylamino, X4 is H or F, and Y is S. In another embodiment, X2 is Br, oxazol-Z-yl, 5-methyloxazoi—2-yl, ethynyl, or dimethylamino, X4 is H or F, and Y is S.

In another embodiment, X2 is n, aryl, or alkynyl, X4 is H or F, and Y is CH2. In another embodiment, X2 is halogen, aryl, or amino, X4 is H or F, and Y is CH2. In another embodiment, X2 is halogen, alkynyl, 0r amino, X4 is H or F, and Y is CH2. In another embodiment, X2 is aryl, alkynyl, or amino, X4 is H or F, and Y is CH2. In another embodiment, X2 is halogen or amino, X4 is H or F, and Y is CH2. In another embodiment, X2 is halogen or alkynyl, X4 is H or F, and Y is CH2. In another ment, X2 is n or aryl, X4 is H or F, and Y is CH2. In another embodiment, X2 is halogen, X4 is H or F, and Y is CH2. In r embodiment, X2 is aryl, X4 is H or F, and Y is CH2. In another embodiment, X2 is alkynyl, X4 is H or F, and Y is CH2. In r embodiment, X2 is amino, X4 is H or F, and Y is CH2. In another embodiment, X2 is n, heteroaryl, alkynyl, or amino, X4 is H or F, and Y is CH2. In another embodiment, X2 is halogen, heteroaryl, or l, X4 is H or F, and Y is CH2. In another embodiment, X2 is n, heteroaryl, or amino, X4 is H or F, and Y is CH2. In another embodiment, X2 is heteroaryl, alkynyl, or amino, X4 is H or F, and Y is CH2. In another embodiment, X2 is halogen or heteroaryl, X4 is H or F, and Y is CH2, In another embodiment, X2 is heteroaryl, X4 is H or F, and Y is CH2. In another ment, X2 is alkyl—substituted heteroaryl, X4 is H or F, and Y is CH2. In another embodiment, X2 is C1—C5 alkyl-substituted heteroaryl, X4 is H or F, and Y is CH2. In another embodiment, X2 is methyl-, ethyl—, n—propyl~, 0r isopropyl-substituted heteroaryl, X4 is H or F, and Y is CH2. In r embodiment, X2 is methyl- or ethyl-substituted heteroaryl, X4 is H or F, and Y is CH2. In another embodiment, X2 is -substituted heteroaryl, X4 is H or F, and Y is CH2. In another embodiment, X2 is ethyl—substituted heteroaryl, X4 is H or F, and Y is CH2. In another embodiment, X2 is Br, I, furan—Z-yl, furanyl, 5—methylfuran—2-yl, azol-Z—yl, lH—pyrazol—B— yl, thiazol-Z—yl, 5-methylthiazolyl, oxazol—Z-yl, 5-methyloxazolyl, ethynyl, propynyl, dimethylamino, diethylamino, or methylethylamino, X4 is H or F, and Y is CH2. In r embodiment, X2 is I, filran-Z-yl, B—yl, 5—methylfuran—2 -yl, ethynyl, dimethylamino, diethylamino, or methylethylamino, X4 is H or F, and Y is CH2. In r embodiment, X2 is Br, furan-Z-yl, furanyl, 5—methylfuran-2—yl, ethynyl, dimethylamino, diethylamino, or methylethylamino, X4 is H or F, and Y is CH2. In another embodiment, X2 is I, furan-Z-yl, furan—S— yl, 5-methylfuranyl, ethynyl, 0r dimethylamino, X4 is H or F, and Y is CH2. In another embodiment, X2 is Br, furan-Z-yl, furan—3 -yl, S—methylfuran-Z—yl, ethynyl, or dimethylamino, X4 is H or F, and Y is CH2. In another embodiment, X2 is I, lH-pyrazol—Z-yl, lH-pyrazol-S-yl, ethynyl, dimethylamino, diethylamino, or methylethylarnino, X4 is H or F, and Y is CH2. In another embodiment, X2 is Br, 1H—pyrazol-2—yl, lH-pyrazol-3—yl, ethynyl, dimethylamino, diethylamino, or methylethylamino, X4 is H or F, and Y is CH2. In another embodiment, X2 is I, 1H—pyrazol~2-yl, azol-B—yl, ethynyl, or dimethylamino, X4 is H or F, and Y is CH2. In another embodiment, X2 is Br, lH-pyrazol-Z-yl, lH—pyrazol-3—yl, ethynyl, or dimethylamino, X4 is H or F, and Y is CH2.

In another embodiment, X2 is I, thiazol-Z—yl, 5-methylthiazol-2—yl, ethynyl, ylamino, diethylamino, or methylethylamino, X4 is H or F, and Y is CH2. In another embodiment, X2 is Br, thiazol-Z-yl, 5-methylthiazolyl, ethynyl, dimethylamino, diethylamino, or methylethylamino, X4 is H or F, and Y is CH2. In another embodiment, X2 is I, thiazolyl, 5-methylthiazol—2—yl, ethynyl, or dimethylamino, X4 is H or F, and Y is CH2. In r ment, X2 is Br, thiazol-Z- yl, 5~methylthiazolyl, ethynyl, or dimethylamino, X4 is H or F, and Y is CH2. In another embodiment, X2 is I, —Z-yl, 5-methyloxazol—2—yl, ethynyl, dimethylamino, diethylamino, or methylethylamino, X4 is H or F, and Y is CH2. In another embodiment, X2 is Br, oxazol—Z-yl, 5— methyloxazol—Z—yl, ethynyl, dimethylamino, diethylamino, or methylethylamino, X4 is H or F, and Y is CH2. In another embodiment, X2 is I, oxazolyl, 5-methyloxazol~2—yl, ethynyl, or dimethylamino, X4 is H or F, and Y is CH2. In another embodiment, X2 is Br, oxazol-Z-yl, 5— methyloxazol—Z-yl, ethynyl, or dimethylamino, X4 is H or F, and Y is CH2.

In connection with each of the R groups ning a sulfonamide structure, the corresponding structure in which the sulfonamide has the reverse orientation or in which R contains a sulfinamide or an amide (each of either orientation) is within the scope of the disclosure as if each was cally disclosed herein. In connection with each of the R groups containing a sulfmamide structure, the corresponding structure in which the sulfinamide has the e orientation or in which R contains a sulfonarnide or an amide (each of either orientation) is within the scope of the disclosure as if each was specifically sed herein. In connection with each of the R groups containing an amide structure, the ponding structure in which the amide has the reverse orientation or in which R contains a amide or a sulfinamide (each of either orientation) is within the scope of the sure as if each was specifically disclosed herein. Thus, by way of example, in each instance the disclosure of a nd in which the R group contains an — SOZN(RA)— structure should also be considered as a disclosure of a compound in which the R group contains an —NRASOZ-, -S(O)N(RA)-, -NRAS(O)-, -C(O)N(RA)-, or —NRAC(O)— structure in place of the —SOZN(RA)- structure.

Specific R groups include without limitation: 2-ethanesulfonic acid isopropylamide, i.e., \ /ii cH3 ”RA/K0 nesulfonic acid ethylamide, i.e., 0 H \\ /N\/CH3 H/VKo Z-ethanesulfonic acid methylamide, i. e.

Z-ethanesulfonic acid amide, i. e‘ HH/V 2-ethanesu1fonic acid t-butylamide, 112., \\ /H CH3 fiLL/VS\\O CH3 2-ethanesulfonic acid isobutylamide, i.e., o\\s/“\J\CH3 ‘1. \\0 2-ethanesulfonic acid cyclopropylamide, i. 6., \\/N LEL/Vs\\o isopropanesulfonic acid 2-ethylamide, i.e., nW“\S/O O// YOH; sulfonic acid Z-ethylamide, i. e., maA/“\S//O CH3 c)// \/ N—2 ethyl methanesulfonamide, i. e., H //° ‘1;/\/ \s// \CH3 2-methyl—propane—2—su1f0nic acid 2-ethylamide, 112., “La/VESMWCH3 3 2-methy1-pr0pane—2—su1finic acid 2—ethy1amide, i‘e‘, ”HA/“WWW 0 CH3 2-methyl—propane—1—su1fonic acid 2—ethylamide, i.e., LHL/VN\ //0s o// WAC”; ropanesufonic acid Z—ethylamjde, i. e. , o u 3-propane-l —sulf0nic acid ethylamide, i. 9., EMS/ o// \NACHa 3 —propanesu1fonic acid methylamide, i. a “a /\/\3/ 1 CH3 O// \H/ 3-propane-1 -su1fonic acid amide, i. e. , 1/\/\s//O ‘1' // \NHZ anc—1 -su1fonic acid t-butylamide, tie‘, 3—propanesulfonic acid cyclopropylamide, 12a, EMS/O / \u propane-Z-sulfonic acid 3-propy1amjde, i.e., N—3-propy1 methanesulfonanfide, i. e. , y1—propane-2—su1finic acid 3—propylamide, i.e., fl CH3 EMfi/S\/kwa 2—methy1—propanesu1f0n1'c acid 3—propy1amide, Le. , cyclopropanesulfonic acid 3«propy1amjde, i.e., 3—N—isopropyl propionamide, 116., 3-N-ethy1 propionamide, i. e. , 3-N—methy1 propionamide, i. e. , “a MA 3—propionamjde, i.e., LEI/\JKNHz 3—N—t-buty1 propionamide, i. e. , 0 H30 “IRA/“\N)<0H3CH3H 3-N-isobutyl propionamide, i. e. , Mk CH3 .111. N/YH 3-N-cyc10propyl propionamide, z'. e. , ”EA/“NA N—2-ethy1 isobutyramide, i. e. , hyl propionamide, 115., N—2-ethy1 acetamide, i.e., N CH3 N—2-ethy1 formamide, 122., N H N-2~ethy1 2,2-dimethyl-propionamide i. e. , , ‘11L/\/ CH: N—2—ethy1 3-methy1butyramide, i. e. , NNWCH3 0 CH3 cyclopropane ylic acid 2-ethyl—amide, tie‘ , aNW/A cyclopropane carboxylic acid 3-propy1-amide, La, N-3—p1‘0py1 2,2-dimethyl-propionamide, i. e. , fWH\n)<CHaCH3 N-propylmethy1-propane—2-su]finamide, i.e., LLEL/\/\N/3 CHa CH3 and t-butanesulfonic acid 3-propylamide, 112., In connection with each of the X4 groups of the structures disclosed herein, a corresponding structure in which X4 is hydrogen, a fluoro group, or other halogen is within the scope of the disclosure as if each was specifically disclosed herein.

In a further aspect of the invention, each of the compounds described above can he made as a precursor compound in which X; is a leaving group which can be replaced by iodine for use as a abel, for example 124I or 1311 useful as g tools. Exemplary leaving groups include without limitation trialkyl tin, for example trimethyl, or tributyl tin, trialkyl silicon, trialkyl geranium, or fluorus analogs of trialkyl tin such as —Sn(CH2CH2(CF2)5CF3)3, aryl c acids, thalium trifluroacetates, triazines, and metallated arenes. Techniques for radioiodination are well known in the art, for example from Seevers, et al. Chem. Rev., 1982, 82 (6), pp 5757590 and McIntee et al., J. Org. Chem. 2008, 73, 8236—8243 wghich are incorporated herein by reference.

The precursor compound in which X; is a leaving group are provided as reagents or in kits for addition of a radiolabeled X2 substituent, for example 1241 or 1311 in the time immediately prior to use as an imaging marker. The precursor is readily d and stored prior to use since it is not itself radioactive, but it is readily converted to the labeled imaging marker.

In r embodiment, a pharmaceutical ition is formed from a Compound of Formulae (IA) or (IE) and a pharmaceutically acceptable r by a method known in the art.

Thus, another embodiment relates to a pharmaceutical composition comprising a Compound of Formulae (IA) or (1B) and a pharmaceutically acceptable carrier. Such a composition is useful for ng or ting cancer or a neurodegenerative disorder, e.g., in a patient in need thereof. r embodiment relates to a method for treating or preventing cancer or a neurodegenerative disorder, sing administering to a patient in need thereof a therapeutically effective amount of a Compound ofFormulae (IA) and/or (IE). Another embodiment relates to a method for treating or preventing cancer or a neurodegenerative disorder, sing administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a Compound ulae (IA) and/or (IE). Another embodiment relates to a method for ng cancer or a neurodegenerative disorder, sing administering to a patient in need thereof a therapeutically effective amount of a Compound of Formulae (IA) and/or (18). Another ment relates to a method for treating cancer or a egenerative disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition sing a Compound of Formulae (IA) and/or (IB). Another embodiment relates to a method for preventing cancer or a neurodegenerative disorder, comprising administering to a patient in need thereof a therapeutically effective amount of 21 Compound ofFormulae (IA) and/or (IE). Another embodiment relates to a method for preventing cancer or a neurodegenerative disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a Compound of Formulae (IA) and/or (IB). Another embodiment relates to the use of a Compound of ae (IA) or ([3) in the manufacture of a medicament useful for treating cancer or a neurodegenerative disorder or for preventing cancer or a neurodegenerative disorder.

Another embodiment relates to a method for the inhibition of Hsp90, comprising contacting Hsp90 with an Hsp90 function inhibiting amount of a Compound of ae (IA) or (IE). An exemplary determination of an Hsp90 on inhibiting amount is provided in the example below ed “Hsp90 Binding Assay." In one embodiment, the ICSO determined by the "Hsp90 Binding Assay" provided herein is less than 10 uM. In another embodiment, the ICso determined by the "Hsp90 Binding Assay" provided herein is less than 1 pM. In another embodiment, the ICSO determined by the "Hsp90 Binding Assay" provided herein is 50.1 pM. Another embodiment relates to the use of a Compound of Formulae (IA) or (IE) in formulating a pharmaceutical ition for the inhibition ofHsp90.

The following examples are set forth to assist in understanding the invention and should not be construed as specifically limiting the invention as described and claimed . Variations of the invention, ing the substitution of all equivalents now known or later developed, that would be within the purview ofthose in the art, and changes in formulation or s in experimental design, are to be considered to fall within the scope of the invention orated herein. 4. EXAIVEPLES Certain examples below relate to the sis of illustrative compounds of the disclosure.

Synthetic Methods: .Ml-Mz—R is -S(O)NRARB, -NRAS(O)RB, -SO;NRARB, —N'RASOZRB, -C(O)NRARB, or — NRAC(O)RB, n each RA and RE is independently selected from H, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, cycloalkyl, alkyl, heterocycloalkyi, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl.

Scheme 1. sis of S—linker Adenine Derivatives NHz NH2 x1 l@ N Q \ N 3,1) N \ + U H. u / *8 N/ N N H j] H or 6 member ring NH2 NH2 x1 x2 0 \ N d N \ N\ —*M ifiNHKDQ W N Br/N 1MzR N Q n=1—4 [ )n=1-4 (A;n=1-4 [M1 / 1 (a) Cui, neocuproine, NaOt—Bu. DMF, 110 0C; (b) NIS, acetonitriie, RT; (0) 082003; (d) X2M, Pd (cat), DMF, 50-100 °C.

Scheme 2. Synthesis ene-linker Adenine Derivatives NH2 NH2 H000 a, b " QK; NJENHZ. —* + HgN/kN/ A / V@[HEN NH2 F N E or 6 member ring NH2 NH2 X1 x2 0 N \ e N *4 AEVQ —> 1 / F N N F N N M1«R Br M2 (2)n=’|-4 (21n:1i4 /\(:i=14 ,M1 ,M1 . M2 M2 R R (a) iriphenyi phosphite, pyridine, microwave; (b) HF-pyridine, NaNOz; (0) Nis, acetonitrile, rt; (d) CSQCOE; (e)X2M, Pd (cat), DMF, 50-100 °C.

Scheme 3. Synthesis of Pyridine Derivatives (The definitions ofR and X; as an amino group in this scheme are described above.) N02 HZNPMB N02 Fe/HCI “Hz N 032, KOHN N,PMB 5:):3 NH3 ::M>:sCul, nBu4NBrtBuONa NH2 @N@%sHZN -—> H Im 052003. RBr riws N \ N NaBHaCN 27H General Methods: 1H and 13C NlV[R spectra were recorded on a Bruker 500 MHZ instrument. Chemical shifts are reported in 5 values in ppm downfield from TMS as the internal standard. 1H data are ed as follows: chemical shifi, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br 2 broad, m = multuplet), coupling constant (Hz), integration. 13C chemical shifts are reported in 5 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 ospray ionization and SQ detector. High-performance liquid chromatography analyses were performed on a Waters Autopurification system with PDA, ass ZQ, and ELSD detector, and a reversed phase column s X-Bridge C18, 4.6 X 150 mm, 5 um).

N—(3—(6-amino—8-(6-iodo-benzo[1,3]dioxolylsulfanyl)-pu1in-9—yl)—propyl)—methanesulfonamide (WSS4): To a solution of oethaneamomium bromide (2g, 9.8 mmol) in 60 mL of CH2012 was added triethylamine (3.4 mL, 24.4 mmol). The ing mixture was stirred at a temperature of about 25°C for 30 min, then cooled down at 0°C, methanesulfonic chloride ( 0.83 mL, 10.7 mmol) was added dropwise, kept stirring for 1 hr and allowed to warm up to a temperature of about 25°C and stirred for about 16 hours. The resulting mixture was sed and dried under reduced pressure to provide romoethyl)methanesulfonamide without r purification. N—(3— bromopropyl)methanesulfonamide was prepared in a r manner.

To a solution of 8-((6—iodobenzo[d][1,3]dioxol~5-yl)thio)—9H—purin—6-amine (150 mg, 0.36 mmol) in 10 mL of dry DMF was added N-(3-bromopropyl)methanesulfonamide (300 mg, 1.4 mmol) and CszCO3 (190 mg, 0.58 mmol). The resulting mixture was stirred at a temperature of about 25°C for 3 hrs, condensed under reduced pressure and d by flash chromatography to provide compound W834 as White solid (49 mg, 25% yield). 1H NMR (500 MHz, MeOH-d4/CDC13, 5): 8.21 (s, 1H), 7.41 (s, 1H), 7.10 (s, 1H), 6.08 (s, 2H), 4.34 (t, J= 7.2‘Hz, 2H), 3.16 (t, J: 6.5 Hz, 2H), 2.96 (s, 3H), 2.09 (m, 2H).

HRMS (E81) m/z [M+H]+ calc'd. for 1N60482 : 548.9876; found 548.9858.

Scheme 4. Synthesis ofW834 and W835 lily—SQI\ N NH2 I H Ilk/\ N\>—S o BrflA b O "““2‘3r Br NHSOgMe —*’ n=12 (“=12 n=12 ' HN\ (a) triethylamine, MsCI, RT; (b) C52C03, RT N—(2-(6—amino—8-(6—iodo—benzo[1,3]dioxol-S-ylsu1fanyl)-purin—9-y1)-ethyl)-methanesulfonarrude (W835): To a solution of 8-((6-iodobenzo[d][1,3]dioxol-S-y1)thio)—9H—pu1‘inamine (100 mg, 0.24 mmol) in 5 mL of dry DMF was added N—(2-bromoethyl)methanesulfonamide (150 mg, 0.7 mmol) and C52C03 (150 mg, 0.46 mmol). The resulting mixture was stirred at a temperature of about 25°C for 3 hrs, condensed under reduced pressure and purified by flash chromatography to provide compound W835 as white solid (35 mg, 27% yield). 1H NMR (500 MHz, MeOH-d4/CDC13, a): 8.19 (s, 1H), 7.41 (s, 1H), 7.18 (s, 1H), 6.07 (s, 2H), 4.23 (m, 2H), 3.65 (m, 2H), 2.97 (s, 3H).

HRMS (E81) m/z [Md-H]+ calc'd. for C15H161N50482 = 534.9719; found 534.9709.

Scheme 5. Synthesis of W836, W837, and W838 HzN t”fn“fipdHZN 3-1 3-2 8-3 NH2 NH2 inefflfiHzN 1 e \ Lfba\ N / N ’ l N N N H H NHz \\ NH2 1 N \ N \ m S \ S / AKidQ I N —* g} ) n=2 )n=1,2 MsHN MSHN n=1, wss7; n=2, wsse wsss NHZBr Br NHMs n=1,2 Br/V Reagents and ions: 0, e, 0°C to rt; (b) KNO3, H2804, 0°C to 11; (c) NaNOz, KI, AcOH, 0°C to rt; (d) Fe, NH4C1, isopropanol, reflux; (e) 8-mercaptoadenine, CuI, nBu4NBr, NaOt- Bu, mv; (f) NaNOZ, KI, ACOH, 0°C; (g) 1,3—dibromopropane or 1,2—dibromoethane, CSQCO3, DMF, rt; (h)triethy1amine, MsCl, Oo-rt; (i) Cul, PdClZ(PPh3)Z, trimethylsilanylacetylene, Et3N, DMF, 90°C.

—Amino-6—nitro-indane (8-2): A solution of S-aminoindane (8—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 a temperature of about 25°C for 2 days. The resulting mixture was condensed and dried under reduced re. The residue was dissolved in 100 mL of concentrated H2804, cooled in ice bath. KNO3 in 15 mL of concentrated H2804 was added dropwise. The resulting solution was stirred at 0°C for 2 h and then at a temperature of about 25°C 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 provide 8-2 (7.1 g, 43% yield). 1H NMR (500 MHz,CDC13,6): 7.94 (s, 1H), 6.65 (s, 1H), 6.02 (br, 2H), 2.83 (m, 4H), 2.06 (m, 2H). 13CNMR (125 MHZ, CDC13, 8): 154.4, 144.2, 134.1, 131.2, 120.8, 113.5, 33.1, 31.4, 25.7.

-Iodonitro-indane (8-3): To a solution of 8—2 (0.14 g, 0.78 mmol) in acetic acid cooled in ice bath was added NaNOZ (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 a temperature of about 25°C for 20 minutes. The resulting suspension was ed with water (15 mL) and extracted with ethyl acetate (2 x 20 mL). The organic layer was washed with saturated aqueous Na25203 solution, washed with brine and dried over MgSO4 and evaporated to dryness to provide a residue that was purified by flash chromatography (ethyl acetate/hexane, gradient 0% to 50%) to provide 8-3 (0.12 g, 65% yield) as a yellow solid. 1HNlVIR (500 MHz, CDC13, 5): 7.83 (s, 1H), 7.71 (s, 1H), 2.95 (m, 4H), 2.11 (m, 2H).

-Aminoiodo-indane (8-4): To a on of 3-3 (1.65 g, 5.7 mmol) in isopropanol (100 mL) and saturated aqueous ch1 solution (20 mL) was added iron powder (1.1 g). The resulting suspension was refluxed for 1h. The reaction e was filtered and the filtrate was condensed and purified by flash chromatography (ethyl acetate/hexane, gradient 0% to 50%) to provide 8—4 (1.36 g, 92% yield) as a pale yellow solid. 1HNMR (500 MHz, CDC13, 5): 7.44 (s, 1H), 6.59 (s, 1H), 3.88 (s, 2H), 2.74 (m, 4H), 1.98 (m, 2H). 13c NW (125 MHz, CDC13, 5): 146.2, 144.9, 136.5, 134.1, 111.0, 32.8, 31.8, 26.1.

MS (ESI): m/z = 259.99 [M+H]+. 8-((6-Amino—2,3—dihydro—lH—indcn—S-yl)thio)—9—H—purinamine (8-5): The mixture of 8-mercaptoadenine (64 mg, 0.38 mmol), 8-4 (100 mg, 0.38 mmol), Cul (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 lene chloride/methanol, gradient 0% to 10%) to provide S-5 (54 mg, 47% yield) as a while solid. 1H NMR (500 MHz, 4/CDC13, a): 8.11 (s, 1H), 7.36 (s, 1H), 6.81 (s, 1H), 2.85 (m, 4H), 2.06 (m, 2H).

MS (ESI): m/z= 299.02 [M+H]+. 8—((6-Iod0-2,3-dihydro— 1H—inden-5—yl)thio)—9—H—purin—6-amine (8-6): To a solution of 8-5 (54 mg, 0.18 mmol) in acetic acid (5 mL) cooled in ice bath was added NaNOz (15 mg, 0.22 mmol) followed by K1 (90 mg, 0.54 mmol). The on e was stirred at 0°C for 15 min and quenched with water (10 mL). The resulting mixture was extracted with methylene chloride (2 x 20 mL). The organic layer was washed with saturated aqueous Na28203, washed with brine, dried over MgSO4 and evaporated to dryness. The residue was purified by flash chromatography lene chloride/methanol, gradient 0% to 10%) to provide 8-6 (42 mg, 56% yield) as a white solid. 1H NMR (500 MHz, CDC13, a): 8.12 (s, 1H), 7.84 (s, 1H), 7.39 (s, 1H), 2.91 (m, 4H), 2.11 (m, 2H).

MS (E81): m/z= 410.10 [M+H]*.

N—(3—(6-amino(6-iodo-indanylsulfanyl)—purin—9—yl)-propyl)-methanesulfonamide (W836): To a solution of 8-6 (50 mg, 0.12 mmol) in 3 mL of dry DMF was added N—(3- bromopropyl)methanesulfonamide (200 mg, 0.9 mmol) and C82C03 (100 mg, 0.31 mmol). The resulting mixture was stirred at a temperature of about 25°C for about 16 hours, condensed under reduced pressure and d by flash chromatography to provide nd W836 as a white solid (30 mg, 30% yield). 1H NMR (500 MHz, CDCl,, 5): 8.33 (s, 1H), 7.78 (s, 1H), 7.17 (s, 1H), 5.89 (br, 2H), 4.37 (t, J: 6.2 Hz, 2H), 2.99 (q, 2H), 2.90 (t, J: 7.5 Hz, 2H), 2.81 (t, J= 7.5 Hz, 2H), 2.08 (m, 2H), 1.94 (m, 2H). 13CNMR (125 MHZ, CDC13, 5): 154.7, 153.0, 151.9, 147.6, 146.6, 136.1, 132.6, 127.9, 119.9, 98.4, 40.7, 40.2, 39.1, 32.5, 32.3, 30.3, 25.5.

HRMS (E81) m/z [M+H]+ calc'd. for C13H221N60482 = 545.0290; found 545.0284.

N-(2-(6-amino(6-iodo-indanylsulfanyl)—purin—9-yl)—ethyl)—methanesulfonamide (W837): To a solution of 8-6 (50 mg, 0.12 mmol) in 3 mL of dry DMF was added N—(3— bromopropyl)methanesulfonamide (200 mg, 0.99 mmol) and Cs2C03 (100 mg, 0.31 mmol). The resulting mixture was stirred at a temperature of about 25°C for about 16 hours, condensed under reduced pressure and purified by flash chromatography to provide compound W837 as a white solid (18 mg, 28% yield).

‘H N1V£R (500 MHz, CDC13, 5): 8.29 (s, 1H), 7.74 (s, 1H), 7.01 (s, 1H), 6.91 (hr, 111), 5.96 (br, 2H), 4.41 (t, J= 5.4 Hz, 2H), 3.60 (m, 2H), 2.88 (m, 2H), 2.76 (t, J: 10.2 Hz, 2H), 2.05 (m, 2H).

”CNMR (125 MHz, CDC13, 5): 154.6,153.5,151.8, 146.8,146.0,135.9,133.2, 127.1, 119.8, 97.3, 44.7, 42.5, 40.7, 32.5, 32.2, 25.4.

HRMS (E81) m/z [M+H]+ calc'd. for 1N50282 2 531.0134; found 531.0121.

N-(3—(6—amino—8—(6-ethyny1—indan-5—ylsulfanyl)~purinyl)propyl)-methanesulfonamide (W838): To a solution ofWS36 (10 mg, 0.02 mmol) in 2 mL ofDMF was added Cul (0.7 mg, 0.004 mmol), PhC12(Ph3)2 (2.6 mg, 0.004 mmol), ethynyltrimethylsilane (8.6 “L, 0.06 mmol) and triethylamine (25 uL). The resulting mixture was stirred at 60°C for 15 min, condensed and purified by chromatography. The intermediate was treated with KOH (5 mg) in ol (1 mL) for 30 min at a temperature of about 25°C. The reaction mixture was condensed and purified by flash chromatography to provide compound W338 as white solid (1.8 mg, 22% yield). 1H NMR (500 MHz,CDC13,5): 8.25 (s, 1H), 7.36 (s, 1H), 7.11 (s, 1H), 6.33(br, 1H), 5.54 (br, 2H), 4.30 (t, J = 6.1 Hz, 2H), 3.25 (s, 1H), 2.89 (q, 2H), 2.80 (m, 4H), 2.00 (m, 2H), 1, 2H).

HRMS (ESI) m/z [M+H]+ calc'd. for C20H23N60252 = 443.1324; found 443.1328.

Scheme 6. Synthesis of Dihydrobenzofuran Intermediate m —+a 9b \ N c I \>*8 ~—> H2N 0 I o N/ N H o 82-1 32.2 52-3 NH2 , I1 / N>—S\ N E 1 Reagents and ions: (a) NaNOZ, KI, AcOH/TFA, 0°C; (b) 8—mercaptoadenine, CsZCO3, PdC12(dppt), DMF, 80°C, 48h; (0) N18, TFA, CH3CN, rt, 2h 6-Iodo-2,3-dihydrobenzofuran (82-2): A solution of 2,3—dihydrobenzofi1ran—6—amine (82—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. NaNOz (0.454g, 6.6 mmol) was added in 3 portions followed by K1 (2.73 g, 16.4 mmol). The resulting e was stirred at 0°C for 15 minutes and quenched with H20 (20 mL). The mixture was extracted with EtOAc (3 x 150 mL) and the organic layer was washed with g, washed with brine, dried over MgSO4 and filtered. The e was condensed under reduced pressure and the residue was purified by flash chromatography (hexanezEtOAc, 90: 10 to 40:60) to provide 82-2 (0.82 g, 61% yield) as a pale- yellow solid. 1H NMR (500 MHz, CDC13, 6): 7.14 (d, J: 7.6 Hz, 1H), 7.11 (s, 1H), 6.89 (d, J: 7.6 Hz, 1H), 4.54 (t, J: 8.7 Hz, 2H), 3.14 (t, J: 8.7 Hz, 2H). 13CN1\/[R (125 MHz, CDClg, 5): 161.1,129.4,127.1,126.4,118.7, 91.7, 71.6, 29.4. 8—(2,3-Dihydrobenzofi1ranylthio)~9H-purin—6—amine (82-3): To a on of 82-2 (50 mg, 0.2 mmol) in DMF (2 mL) was added S—mercaptoadenine (34 mg, 0.2 mmol), CszC03 (99.4 mg, 0.3 mmol) and PdC12(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 (CH2ClzzMeOH, 100:0 to 90:10) to provide 82-3 (25 mg, 44% yield) as a yellow solid. 1H NMR (500 MHz, CD3OD, 5): 8.14 (s, 1H), 7.24 (d, J= 7.6 Hz, 1H), 7.07 (d, J= 7.3 Hz, 1H), 6.97 (s, 1H), 4.62 (t, J= 8.7 Hz, 2H), 3.25 (t, J: 8.7 Hz, 2H).

MS (1381): m/z= 285.8 .

HRMS (EST) m/z [M+H]+ calc‘d. for SOS = 286.0763; found 286.0768. odo-2,3—dihydrobenzofi1ran—6-ylthio)—9H—purin-6—amine (82-4): To a solution of 82-3 (40 mg, 0.14 mmol) in 6 mL of acetonitrile was added TFA (40 11L) and NTS (63 mg, 0.28 mmol). The resulting mixture was stirred at a temperature of about 25°C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash tography (CH2C12:MeOH, 100:0 to 90:10) to provide S2-4 (48 mg, 53% yield) as a yellow gum. 1H NMR (500 MHz, CDC13, a): 8.26 (s, 1H), 7.79 (s, 1H), 7.12 (s, 1H), 4.65 (t, J: 8.8 Hz, 2H), 3.28 (t, J= 8.7 Hz, 2H).

Ms (Esr): m/z = 412.0 [M+H]*.

Scheme 7. sis of Compounds from W839 through W844 l): \>_3 I N N b J Br\/\ a Brv\ Xb NHgBr ——-—> ”“50 ”—‘ L HN Xa=Xb=o. wsas c ‘50 Xa=Xb=CH2,WS40 , Xb=0, W841 23 ZIM TU)0M é Xb HN Xa=Xb=0, ws42 o2 Xa=Xb=CH2, ws43 Xa=CH2, xn=o, wsq4 (a): triethylamine, tbutylsulfinie chloride; (b) adenine intermediates. 032003; (c) MCPBA yl-pr0pane—2—sulfinic acid (2-bromo-ethyl)~amide: To a solution of 2-bromoethaneamomium bromide (410 mg, 2 mmol) in 20 mL of CH2C12 was added triethylamine (3697 pL, 5 mmol). The resulting mixture was stirred at a temperature of about 25°C for 30 min, then cooled down at 0°C. 2-methylpropanesulfinic chloride ( 0.73 mL, 2.2 mmol) was added dropwise, kept stirring for 1 hr and allowed to warm up to a temperature of about 25°C and stirred for about 16 hours. The resulting mixture was condensed and d by flash chromatography to provide 2-methyl-propane—2—sulfinic acid (2—bromo—ethyl)-amide as a white solid (0.42g, 86% yield). 1HNMR (500 MHz, CDC13, 5): 3.80 (br, 1H), 3.45—3.56 (In, 4H), 1.20 (s, 9H).

”CNMR (125 MHz, CDC13, 5): 56.1, 47.3, 33.4, 22.6. 2—Methyl-propanesulf0nic acid (2—bromo—ethyl)-amide: To a solution of Z-methyl—propane—2-sulfinic acid (2—brom0—ethyl)—amide (0.8g, 3.5 mmol) was added mCPBA (77%, 0.95g, 4.2 mmol) and stirred at a temperature of about 25°C for 2 hrs.

The reaction mixture was condensed and purified to e 2-methyl-propane—2-sulf0nic acid (2- bromo—ethyl)—amide as a white solid (0.4g, 46% yield).

‘H NMR (500 MHz, 4/CDC13, a): 337-397 (m, 2H), 3.36-3.47 (m, 2H), 1.32 (s, 9H). 13CNMR (125 MHz, CD013, a): 42.8, 29.6, 25.6, 23.2. 2-Methy1—propane—2-su1fmic acid (2-(6—amino—8-(6-iodo-benzo[ l ,3]dioxol~5-ylsulfanyl)-purin—9— yl)—ethyl)-amide (W839): To a solution of 8-((6—iodobenzo[d][1,3]dioxol—S—yl)thio)-9H-purin-6—amine (100 mg, 0.24 mmol) in 3 mL of dry DMF was added 2—methyl—propanesulfinic acid (2-bromo-ethyl)-amide (90 mg, 0.37 mmol) and Cs2C03 (159 mg, 0.49 mmol). The resulting mixture was stirred at a temperature of about 25°C for 3 hrs, condensed under reduced pressure and purified by flash chromatography to provide nd W839 as pale yellow solid (70 mg, 51% yield). 1H NMR (500 MHZ, 4/CDC13, 5): 8.21 (s, 1H), 7.39 (s, 1H), 7.04 (s, 1H), 6.06 (s, ’ 2H), 4.81 (m, 1H), 4.35—4.44 (m, 2H), 3.63 (m, 1H), 3.46 (m, 1H), 1.11 (s, 9H). 13CNMR (125 MHZ, MeOH—d4/CDC13, 5): 154.8, 153.2, 151.9, 149.4, 149.1, 146.1, 128.0, 120.1, 119.2, 112.0, 102.4, 90.6, 56.0, 45.1, 44.4, 22.6.

MS (E81): m/z = 561.0 [M+H]+.

HRMS (E81) m/z [M+H]+ . for C18H221N60382 = 561.0239; found 561.0233. yl—propane-2—sulfmic acid {2—[6—amino—8—(6—iodo—indan—5—ylsulfanyl)-purin-9—yl]-ethy1}- amide (W840): To a solution of 8-6 (50 mg, 0.12 mmol) in 3 mL of dry DMF was added 2-methy1« propane-Z-sulfinic acid (2—bromo—ethyl)-amide (40 mg, 0.18 mmol) and C32C03 (80 mg, 0.25 mmol). The resulting mixture was stirred at a temperature of about 25°C for 3 hrs, condensed under reduced re and purified by flash chromatography to e compound W840 as pale yellow solid (35 mg, 51% yield). 1H NMR (500 MHz, MeOH-d4/CDC13, a): 8.22 (s, 1H), 7.82 (s, 1H), 7.34 (s, 1H), 4.36- 4.44 (m, 2H), 3.60 (m, 1H), 3.44 (m, 1H), 2.92 (t, J = 7.4 Hz, 2H), 2.86 (t, J = 7.5 Hz, 2H), 2.10 (m, 2H), 1.10 (s, 9H).

MS (ESI); m/z = 557.0 [M+H]+.

HRMS (ESI) m/z [M+H]+ calc'd. for IN6082 = 557.0654; found 557.0676.

N—(2-(6—amino((5-iodo—2,3-dihydrobenzofuran~6~y1)thio)—9H—purin—9 -yl)ethyl)—2— methylpropane—Z-sulfinamide (W841): To a solution of 82-4 (10 mg, 0.02 mmol) in 1 mL of dry DMF was added 2—methyl— propane—Z—sulfinic acid (2—bromo-ethyl)—amide (27 mg, 0.12 mmol) and CszC03 (16 mg, 0.05 mmol). The resulting mixture was stirred at a temperature of about 25°C for 3 hrs, condensed under reduced pressure and purified by flash chromatography to provide compound W841 as pale yellow solid (2.7 mg, 20% yield).

MS (ESI): m/z = 559.0 [M+H]+.

HRMS (ESI) m/z [M+H]+ calc‘d. for C19H21IN50282 = 559.0447; found 559.0439.

N-(2-(6-amino—8-((6-iodobenzo[d][l ,3]dioxol—5-y1)thio)—9H-purin—9-yl)ethyl)methylpropane sulfonamide (W842): To a on of 8-((6-iodobenzo[d][1,3]dioxol-S-yl)thio)-9H-purinamine (30.4 mg, 0.07 mmol) in 3 mL of dry DMF was added 2-methyl-propane-2~su1fonic acid (2—bromo—ethyl)—amide (90 mg, 0.37 mmol) and CSZCO3 (80 mg, 0.25 mmol). The resulting mixture was stirred at a temperature of about 25°C for 3 hrs, condensed under reduced pressure and purified by flash Chromatography to provide compound W842 as pale yellow solid (17 mg, 41% yield). 1H NMR (500 MHz, CDC13, a); 8.16 (s, 1H), 7.19 n(s, 2H), 6.83 (br, 1H), 5.90 (hr, 211), .88 (s, 2H), 4.32 (t, J : 5.6 Hz, 2H), 3.68 (m, 2H), 1.23 (s, 9H).

MS (E81): m/z: 577.1 [M+H]+.

HRMS (E81) m/z [M+H]+ calc‘d. for 1N60482 = 577.0189; found 577.0172.

N-(2-(6-amino((6-iodo-2,3-dihydro—1H-inden—S-yl)thio)—9H-purin—9—y1)ethyl)—2—methylpropane- 2-sulfonamide (W843): To a solution of 82-4 (25 mg, 0.06 mmol) in 2 mL of dry DMF was added 2-methyl- propane—Z—sulfonic acid (2-bromo—ethyl)-amide (90 mg, 0.37 mmol) and CSZCO3 (60 mg, 0.18 mmol). The resulting e was stirred at a temperature of about 25°C for 3 hrs, condensed under reduced pressure and purified by flash chromatography to provide compound W843 as a white powder (3.6 mg, 10% yield). 1H NMR (500 MHz, CD013, a): 8.25 (s, 1H), 7.56 (s, 1H), 6.42 (s, 1H), 5.88 (brs, 1H), .58 (brs, 2H), 4.49 (m, 2H), 4.31 (m, 2H), 3.51 (m, 2H), 3.11 (m, 2H), 1.12 (s, 9H).

MS (ESI): m/z = 575.0 [M+H]+.

HRMS (ESI) m/z [M+H]+ calc'd. for IN60382 = 575.0396; found 575.0399.

N—(2-(6-amino((5-iodo—2,3—dihydrobenzofuran—6~y1)thio)-9H—purin—9 ~yl)ethyl) methylpropanesulfonarnide (W844): To a solution of S-6(20 mg, 0.05 mmol) in 2 mL of dry DMF was added 2-methyl- propane-Z-sulfonic acid m0—ethyl)—amide (90 mg, 0.37 mmol) and CS2C03 (60 mg, 0.18 mmol). The ing mixture was stirred at a temperature of about 25°C for 3 hrs, sed under reduced pressure and purified by flash chromatography to provide compound W844 as a white powder (1 1 mg, 31% yield). 1H NMR (500 MHZ, CDC13, a): 8.34 (s, 1H), 7.74 (s, 1H), 6.89 (s, 1H), 6.58 (brs, 1H), .78 (hrs, 2H), 4.42 (m, 2H), 3.71 (m, 2H), 2.89 (m, 2H), 2.75 (m, 2H), 2.06 (m, 2H), 1.32 (s, 9H).

MS (ESI): m/z = 573.1 [M+H]*.

HRMS (ESI) m/z [M+H]Jr calc'd. for ConszfiOZSZ = 573.0603; found 573.0597.

Scheme 8. sis of S-linked dimethylamino derivatives. o a AcHNU8o b AcHN o> c HZN o d I 0 l o) A B C D NH2 —N/ N \ N>_ O K / S ) N §N O R = cyclopropane carbonyl MRP-I-ZB R = t-butylcarbonyl MRP-l-29 R = cyciopropane sulfonyl MRP-l-31 Reagents and conditions: (21) A020, AcOH, rt; (b) IC1, CH2C12, AcOH, rt; (c) NaOH, EtOH, H20, reflux; (d) parafonnaldehyde, NaBH3CN, MeOH, 50°C; (e) 8-mercaptoadenine, roine, CuI, NaOtBu, DMF, 115°C; (1") 2-(3-bromopropy1)isoindoline—1,3-dione, CsZCO3, DMF, rt; (g) hydrazine hydrate, CHZCIZ/MeOH, rt; (h) TEA, corresponding acid chlorides or sulfonarnide, DMF; 2-(3—(6—Amino-8—(6-(dimethylamin0)benzo [d] [1,3] dioxol—S-ylthio)-9H—purin—9— pyl)isoindoline—1,3-dione. F (0.720 g, 2.18 mmol), Cs2C03 (0.851 g, 2.62 mmol), 2- (3—bromopropy1)isoind01ine-1,3-dione (2.05 g, 7.64 mmol) in DMF (15 mL) was stirred for 2 h at rt. The mixture was dried under reduced pressure and the residue purified by column chromatography (CHZClzzMeOH:AcOH, 5) to give 0.72 g (63%) of the titled compound. 1H NMR (500 MHz, CDC13/MeOH-d4): 5 8.16 (s, 1H), 7.85-7.87 (m, 2H), 7.74-7.75 (m, 2H), 6.87 (s, 1H), 6.71 (s, 1H), 5.88 (s, 2H), 4.37 (t, J= 6.4 Hz, 2H), 373 (t, J= 6.1 Hz, 2H), 2.69 (s, 6H), 2.37—2.42 (m, 2H); HRMS (ESI) m/z [M+H]+ calcd. for C25H24N7O4S, 518.1610; found 518.1601. 9-(3-Aminopr0pyl)(6—(dimethylamino)benzo [d] [1,3] dioxol-S-ylthio)-9H—purin-6— amine. 2—(3-(6—Amino-8—(6-(dimethylamino)benzo[d][1,3]dioxol-5—ylthio)-9H-purin—9— pyl)isoindoline—1,3-dione (0.72 g, 1.38 mmol), hydrazine hydrate (2.86 g, 2.78 mL, .75 mmol), in 2Me0H (4 mL:28 mL) was stirred for 2 h at rt. The mixture was dried under reduced pressure and the residue purified by column chromatography (CH2C12:MeOH—NH3(7N), 20: 1) to give 430 mg (80%) ofthe titled nd. 1H NMR (500 MHz, CDC13): 8 8.33 (s, 1H), 6.77 (s, 1H), 6.49 (s, 1H), 5.91 (s, 2H), 5.85 (br s, 2H), 4.30 (t, J= 6.9 Hz, 2H), 2.69 (s, 6H), 2.65 (t, J: 6.5 Hz, 2H), 1.89-1.95 (m, 2H); 13C NMR (125 MHz, CDC13)25154.5,153.1,151.7, 148.1,147.2,146.4, 144.8, 1202,1201, 109.3, 109.2, 101.7, 45.3, 45.2, 40.9, 38.6, 33.3; HRMS (ESI) m/z [M+H]+ calcd. for C17H22N7OZS, 388.1556; found 388.1544. 6—Amino(6-(dimethylamino)benzo [d] [1,3] dioxol—S-ylthio)-9H-purin—9- yl)propyl)cyclopropanecarboxamide (MRP—I—28). 9-(3-Aminopropyl)—8-(6— (dimethylamino)benzo[d][1,3]dioxol—5—ylthio)-9H-purin—6-amine (60 mg, 0.155 mmol), triethylamine (17 mg, 24 uL, 0.170 mmol), cyclopropane carbonyl chloride (16 mg, 14 uL 0.155 mmol) in CH2C12 (3 mL) was stirred for 2 h at rt. The mixture was dried under reduced pressure and the residue purified by preparatory TLC (CH2C122MeOH-NH3(7N) :1) to give MRP-I—ZS (66 mg, 93%). 1H NMR (600 MHZ, CDC13): 6 8.33 (s, 1H), 7.40 (t, J: 6.1 Hz, 1H), 6.77 (s, 1H), 6.52 (s, 1H), 6.40 (br s, 2H), 5.90 (s, 2H), 4.29 (t, J: 6.2 Hz, 2H), 3.11 (q, J: 6.0 Hz, 2H), 2.68 (s, 6H), 1.87-1.91 (m, 2H), 1.45-1.49 (m, 1H), 0.98— 0.96 (m, 2H), 0.77-0.74 (m, 2H); 13C NMR (150 MHz, CDC13)I 5 173.7, 154.9, 153.0,151.8, 148.3,147.5,146.6, 144.7, 119.9,119.5, 109.6,102.5,101.7, 45.3, 40.6, 35.3, 29.1, 14.9, 7.1 HRMS (ESI) m/z [M+H]Jr calcd. for C21H26N703S, 456.1818; found 12.

N-(3—(6—Amino(6—(dimethylamino)benzo[d] [1,3] dioxol—S—ylthio)-9H—pmin yl)propyl)pivalamide (MRP—I—29). 9-(3—Amjnopropyl)—8-(6— (dimethylamino)benzo[d][1,3]dioxol—5-y1thio)-9H-purin—6-amine (60 mg, 0.155 mmol), triethy1amine (17 mg, 24 ML, 0.170 rnrnol),pivaloy1 chloride (19 mg, 19 uL 0.155 mmol) in CH2C12 (3 mL) was stirred for 2 h at rt. The mixture was dried under reduced pressure and the residue purified by preparatory TLC (CH2C12:MeOH-NH3(7N) 20: 1) to give 29 (65 mg, 89%). 1H NMR (600 MHz, CDC13)Z 5 8.30 (s, 1H), 7.65 (t, J= 6.2 Hz, 1H), 6.77 (s, 1H), 6.50 (s, 1H), 6.39 (br s, 2H), 5.90 (s, 2H), 4.26 (t, J= 6.0 Hz, 2H), 3.04 (q, J: 6.0 Hz, 2H), 2.68 (s, 6H), 1.83-1.87 (m, 2H), 1.27 (s, 9H); 13C NMR (150 MHz, CDC13):5178.8, 154.9, 152.9, 151.9,148.3,147.5,146.6,144.7,119.8, 119.7,1095, 102.5, 101.7, 45.3, 40.3, 38.8, 34.8, 28.9, 277; (E81) m/z [M4—H]Jr calcd. for C22H30N703S, 472.2131; found 472.2128.

N-(3-(6~Amin0(6-(dimethylamino)benzo [(1] [1,3] diox0lylthi0)—9H-purin-9— y1)propyl)cyclopropanesulfonamide (MRP-I—3 l). 9—(3—Aminopropy1)—8-(6- (dimethy1amino)benzo[d][1,3]dioxolylthio)—9H—purin—6-amine (61 mg, 0.158 mmol), triethylamine (18 mg, 24 pL, 0.174 mmol), cyclopropane yl chloride (22 mg, 17 11L , 0.158 mmol) in CH2C12 (3 mL) was stirred for 2 h at rt. The mixture was dried under reduced pressure and the residue purified by atory TLC (CH2C12:MeOH-NH3(7N) :1) to give MRP—I-31 (55 mg, 71%). 1H NMR (600 MHz, CDC13): 5 8.30 (s, 1H), 6.78 (s, 1H), 6.66 (t, J= 6.8 Hz, 1H), 6.51 (s, 1H), 6.29 (br s, 2H), 5.91 (s, 2H), 4.31 (t, J: 6.0 Hz, 2H), 3.02 (q, J= 6.1 Hz, 2H), 2.70 (s, 6H), 2.34-2.38 (m, 1H), 1.95-1.99 (In, 2H), 1.15« 1.17 (m, 2H),0.93-0.96(m,2H);13C NMR (150 MHz,CDC13):5154.9, 153.1, 151.7, 148.4, 147.6, 146.3, 1448,1198, 119.4, 109.6, 102.4, 101.8, 45.4, 40.0, 39.0, 30.4, 30.2, 5.26; HRMS (ESI) m/z [Mi-H]+ calcd. for C20H25N7O482, 492.1488 ; found 492.1468.

Scheme 9. sis of ed amide, sulfonarnide or sulfinamide derivatives NH2 , IL / ysQXE’ NH N f)“ l 2 I Xb N + K / \>_S Xa a H b N J Br\/\/NH2Br—_> N‘R —> i Xb Xa=Xb=O, R = t—butylcarbonyl W845 Xa=CH2, Xb=O, R= cyclopropanecarbonyl W861 Xa=Xb=Ov R=|~PFOPVlcarb0nyl W545_ X=CH2,Xb=O, R=t-buty|sulfinyl wssz Xa=Xb=O, R= i—propylsulfonyl W848 CH2, R= t—butylsulfinyl WS63 Xa=H, Xb=O, R= t-butylcarbonyl W864 Xa=Xb=O, R = t—butylsulfinyl W849 Xa=Xb=O, R = isobuiylsulfonyl W850 Xa=Xb=O, R = cyclopropanecarbonyl W851 Xa=Xb=O, R = t—butylsulfonyl W852 Xa=Xb=O, R = lactyl W855 Xa=Xb=O, R = cyclopropanesulfonyl W856 Xa=Xb=O, R =2-hydroxy-2—meihylpropanyl W358 Reagents and conditions: (a) triethylamine, acid chloride or sulfonyl chloride or sulfinyl chloride; (b) 032003. DMF.

N—(3~Bromopropyl)pivalamide. To a suspension of 3-bromopropylamine romide (290 mg, 1.3 mmol) in CH2C12 (10 mL) cooled in ice bath was added triethylamine (470 uL). The ing mixture was stirred for 5 min and trimethylacetyl chloride (163 uL, 1.3 minol) was added dropwise. The reaction mixture was stirred at 0 °C for 2 hrs, condensed under vacuum, purified by flash tography to yield N—(3—bromopropyl)pivalamide as colorless oil (160 mg, 55%). 1H NMR (500 MHZ, CDC13): 8 (5.97 (br s, 1H), 3.40 (m, 4H), 2.07 (m, 2H), 1.17 (s, 9H); 13C NMR (125 MHz, CDC13):5178.7, 37.2, 32.1, 31.1, 27.6.

The preparation of other amides, sulfonamides and sulfinamides followed the same procedure as bed above using 3—bromopropylamine hydrobromide and ponding acid chloride, sulfonyl chloride or sulfinyl chloride.

N-(3-(6-amino((6-iodobenzo [J] [1,3] dioxol—S-yl)thio)—9H-purin yl)propyl)pivalamide (WS45). To a solution of 8-((6-iodobenzo[d][l,3]dioxolyl)thio— 9H—purin—6»amine (74 mg, 0.18 mmol) in DMF ( 2 mL) was added N—(3— bromopropyl)pivalamide (80 mg, 0.36 mmol) and CszC03 (117 mg, 0.36 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed under vacuum and the residue was purified by Prep TLC (CH2ClerH3-MeOH (7N), 20:1) to yield WS45 as a white solid (18 mg, 18%). 1H NMR (500 MHz, CDC13): 5 8.23 (s,1H), 7.45 (br s, 1H), 7.19 (s, 1H), 6.88 (s, 1H), 5.93 (s, 2H), 5.69 (br s, 2H), 4.20 (t, J= 6.1 Hz, 2H), 3.00 (m, 2H), 1.80 (m, 2H), 1.21 (s, 9H); HRMS (ESI) m/z [M+H]+ calcd. for C20H241N603S, 555.0675; found 555.0681.

N—(3—(6—Amino-8—((6—iodobenzo[d] [1,3] dioxol—S-yl)thio)—9H—purin—9- yl)propyl)isobutyramide (W846). To a solution of 8—((6—iodobenzo[d][1,3]dioxol—5- yl)thio-9H—purin—6—amine (50 mg, 0.12 mmol) in DMF ( 2 mL) was added N—(3— bromopropyl)isobutyramide (50 mg, 0.24 mmol) and CszC03 (78 mg, 0.24 mmol). The resulting mixture was d at room temperature overnight. The reaction mixture was sed under vacuum and the residue was purified by Prep TLC (CH2C122NH3-MeOH (7N), 20: 1) to yield WS46 as a white solid (22 mg, 34%). 1H NMR (500 MHz, CDClg/MeOH-d4): 5 8.22 (s,1H), 7.61 (br s, 1H), 7.41 (s, 1H), 7.08 (s, 1H), 6.07 (s, 2H), 4.27 (m, 2H), 3.21 (m, 2H), 2.45 (s, 1H), 2.02 (m, 2H), 1.19 (d, J: 6.9 Hz, 6H); HRMS (ESI) m/z [M+H]+ calcd. for C19H221N603S, 19; found 541.0508.

N- ( 3-(6-Amino-8—((6-iodobenzo[d] [1,3]dioxol-S-yl)thio)-9H~pmin-9— yl)propyl)propane—Z—sulfonamide (WS48). To a solution of 8-((6- iodobenzo[d][1,3]dioxol-S—yl)thio—9H—purin—6—arnine (118 mg, 0.28 mmol) in DMF ( 2 mL) was added N—(3—bromopropyl)propanesulfonamide (350 mg, 1.4 mmol) and CszC03 (188 mg, 0.56 mmol). The resulting e was stirred at room temperature overnight.

The reaction mixture was condensed under vacuum and the residue was purified by Prep TLC 2:NH3—MeOH (7N), 20:1) to yield WS48 as a white solid (33 mg, 20%). 1H NMR (500 MHz, MeOH-d4): 5 8.20 (s, 1H), 7.41 (s, 1H), 7.09 (s, 1H), 6.08 (s, 2H), 4.35 (t, J: 7.0 Hz, 2H), 3.10-3.22 (m, 3H), 2.07 (m, 2H), 1.37 (d, J: 6.9 Hz, 6H); 13C NMR (125 MHz, CDClg/MeOH-d4):8 158.4, 156.1, 155.1, 153.9, 1518, 129.2, 123.5, 123.3, 117.9, 106.6, 98.3, 57.0, 44.8, 43.9, 34.3, 20.2; HRMS (ESI) m/z [M-l—H]+ calcd. for C18H221N504S2, 577.0189; found 577.0193.

N—3-(6-Arnin0((6-i0dobenzo [d] [1 ,3] dioxol—S—yl)thio)—9H—purin—9—yl)propyl)—2— methylpropane-Z—sulfinamide (W849). To a solution of 8-((6—iodobenzo[d][1,3]dioxol-5— yl)thio-9H—purin—6-amine (118 mg, 0.07 mmol) in DMF (2 mL) was added N—(3— bromopropyl)—2-meth1propane—2-sulfinamide (50 mg, 0.21 mmol) and CszC03 (23 mg, 0.14 mmol). The resulting mixture was stirred at room temperature overnight. The reaction e was condensed under vacuum and the residue was purified by Prep TLC (CH2C121NH3—MeOH (7N), 20:1) to yield W849 as a white solid (14 mg, 35%). 1H NMR (600 MHz, CDC13): 5 8.31 (s, 1H), 7.33 (s, 1H), 6.94 (s, 1H), 6.02 (s, 2H), 5.87 (br s, 2H), 4.91 (t, J: 6.7 Hz, 1H), 4.40-4.45 (m, 1H), 4.31-4.36 (m, 1H),3.10—3.17(m, 1H), 2.97- 3.04 (m, 1H),2.11-2.17(m, 1H), 1.96-2.08 (m, 1H), 1.26 (s, 9H); 13C NMR (150 MHZ, CDC13)35154.5,152.9,151.9,149.3,149.2, 146.5, 127.3, 119.9, 119.3, 112.6, 102.4, 91.8, 55.9, 42.1, 40.5, 31.1, 22.8; HRMS (ESI) m/z [M+H]+ calcd. for C19H241N603S2, 575.0396; found 575.0379.

N(6—Amin0((6-i0dobenzo [d] [1,3] di0x01—5-yl)thio)—9H-purinyl)propyl)—2— methylpropane-l—sulfonamide (WS50). To a solution of 8-((6-iodobenzo[d][1,3]dioxol~ —yl)thio-9H—purin—6—am1’ne (24 mg, 0.06 mmol) in DMF ( 1.5 mL) was added N—(3~ bromopropyl)-2—methlpropane-l-sulfonamide (60 mg, 0.24 mmol) and CszC03 (38 mg, 0.12 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed under vacuum and the residue was purified by Prep TLC zzNHg-MeOH (7N), 20:1) to yield W550 as a white solid (16 mg, 46%). 1H NMR (500 MHz, CDClg/MeOH—d4): 8 8.07 (s, 1H), 7.25 (s, 1H), 6.94 (s, 1H), 5.93 (s, 2H), 4.20 (t, J= 6.2 Hz, 2H), 2.97 (t, J= 5.6 Hz, 2H), 2.78 (d, J: 6.5 Hz, 2H), 2.05—2.16 (m, 1H), 1.87-1.97 (m, 2H), 0.98 (d, J: 6.7 Hz, 6H); 13C NMR (125 MHz, MeOH-d4): 5 158.3, 156.2, 155.1, 153.9, 153.4, 151.6, 129.3, 123.5, 123.2, 117.9, 106.6, 98.3, 64.2, 44.7, 43.4, 34.0, 28.8, 26.3; HRMS (ESI) m/z [M+H]+ calcd. for C19H24IN604SZ, 591.0345 ; found 591.0333.

N-3—(6-amino((6—iodobenzo [d] [1,3] dioxol—S—yl)thi0)—9H~pmin yl)propyl)cyclopr0pane amide (W851). To a solution of 8—((6— iodobenzo[d][l,3]dioxol-5—yl)thio-9H—purinamine (30 mg, 0.07 mmol) in DMF ( 1.5 mL) was added N—(3-bromopropyl) cyclopropanecarboxamide (60 mg, 0.28 mmol) and CS2C03 (48 mg, 0.14 mmol). The resulting mixture was d at room temperature overnight. The reaction mixture was condensed under vacuum and the residue was purified by Prep TLC (CH2C12:NH3-MeOH (7N), 20:1) to yield WSSl as a white solid (14 mg, %). 1H NMR (500 MHz, CDC13/ MeOH—d4): 6 8.16 (s,1H), 7.31 (s, 1H), 6.99 (s, 1H), .98 (s, 2H), 4.21 (t, J: 7.0 Hz, 2H), 3.16 (t, J= 6.6 Hz, 2H), 1.88-1.98 (m, 2H), .44 (m, 1H), 0.83—0.91 (m, 2H), .74 (m, 2H); 130 NMR (125 MHZ, CDClg/MeOH—d4): 5 179.1,174.7, 154.3, 152.2, 151.2, 149.9,149.4,147.7,125.4,119.5, 113.9, 102.6, 94.3, 41.1, 35.9, 28.9, 14.5, 7.0; HRMS (EST) m/z [M+H]+ calcd. for C19H201N603S, 539.0362; found 539.0362.

N—3—(6—Amino—8-((6—iodobenzo [(1] [1,3] dioxol—S—yl)thio)—9H—purin—9-yl)propyl)—2— propane-Z—sulfonamide WVSSZ). To a solution of 8-((6-iodobenzo[d][1,3]dioxol- -y1)thio-9H—purin—6—amine (37 mg, 0.09 mmol) in DMF ( 1.5 mL) was added N—(3- bromopropyl)methylpropane—2—sulfonamide (70 mg, 0.27 mmol) and CszC03 (59 mg, 0.18 mmol). The ing mixture was d at room temperature overnight. The reaction mixture was condensed under vacuum and the residue was purified by Prep TLC (CH2C12:NH3-MeOH (7N), 20: 1) to yield W852 as a white solid (9 mg, 16%). 1H NMR (600 MHz, CDC13): 5 8.20 (s, 1H), 7.25 (s, 1H), 6.89 (s, 1H), 6.35 (t, J: 6.7 Hz, 1H), 5.94 (s, 2H), 5.69 (br s, 2H), 4.32 (t, J: 6.0 Hz, 2H), 2.93-2.99 (m, 2H), 1.87—1.99 (m, 2H), 1.28 (s, 9H); 13C NMR (150 MHz, CDC13): 8 154.5, 152.8, 152.0, 149.34, 149.32, 146.9, 126.9, 119.8, 119.4, 112.9, 102.4, 92.3, 59.7, 40.3, 40.1, 31.3, 24.4; HRMS (EST) m/z [M+H]+ calcd. for C19HZ4IN60482, 591.0345; found 591.0353. 3-(6—Amino-8~((6-iod0benzo [41'] [1,3] dioxol—S—yl)thio)—9H—purin-9—yl)propyl) hydroxypropanamide (W855). To a solution of 8-((6-iodobenzo[d][1,3]dioxoly1)thio- 9H—purin—6—amine (71 mg, 0.17 mmol) in DMF (2 mL) was added (S)—l—(3— bromopropyl)amino)-1—oxopr0payl acetate (130 mg, 0.51 mmol) and CS2C03 (112 mg, 0.34 mmol). The resulting mixture was stirred at room temperature over night. The on mixture was condensed under vacuum and the residue was purified by Prep TLC (CH2C12:NH3—MeOH (7N), 20:1) to yield WSSS as a white solid (13 mg, 14%). 1H NMR (600 MHZ, CDCI3): 5 8.23 (s,lH), 7.64 (t, J= 6.0 Hz, 1H), 7.26 (s, 1H), 6.90 (s, 1H), 5.94 (s, 2H), 5.73 (br s, 2H), 4.10-4.23 (m, 3H), 3.05-3.25 (m, 2H), 1.85—1.95 (m, 2H), 1.39 (dd, J= 15.1, 6.8 Hz, 3H); HRMS (EST) m/z [M+H]+ caled. for 1N504S, 543.0312; found 543.0310.

N—3-(6—Ami110((6—iodobenz0 [(1] [1,3] dioxol—S-yl)thio)-9H-purin~9- yl)propyl)cyclopropanesulfonamide (WS56). To a solution of 8—((6— iodobenzo[d][1,3]dioxoly1)thio—9H—purin—6-arnine (45 mg, 0.11 mmol) in DMF ( 2 mL) was added N-(3-bromopropyl)cyclopropanesulfonamide (120 mg, 0.44 mmol) and CszC03 (71 mg, 0.22 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed under vacuum and the residue was purified by Prep TLC (CH2C122NH3-MeOH (7N), 20:1) to yield wsss as a white solid (12 mg, 19%). 1H NMR (600 MHz, CDC13/MeOH-d4): 5 8.13 (s, 1H), 7.32 (s, 1H), 7.00 (s, 1H), 5.99 (s, 2H), 4.26 (t, J= 7.0 Hz, 2H), 3.08 (t, J: 6.3 Hz, 2H), 2.32—2.38 (m, 1H), 1.95—2.02 (m, 2H), 1.03- 1.09 (m, 2H), 0.89—0.95 (in, 2H); HRMS (ESI) m/z [M+H]+ calcd. for clgH20m6o4sz, 575.0032; found 575.0042. 1~((3—(6-Amino—8-((6-iodobenzo [d] [1,3]dioxol—S—yl)thio)—9H—purinyl)propyl)amin0)- 2-methyl—1-oxopropan-Z-yl acetate (WSS7). To a solution of 8-((6— nzo[d][1,3]dioxoly1)thio—9H—purin—6—amine (59 mg, 0.14 mmol) in DMF ( 1.5 mL) was added 1-((3 propy1)amino)—2—rnethy1—l—oxopropan-Z-yl acetate (120 mg, 0.48 mmol) and C52C03 (93 mg, 0.28 mmol). The resulting mixture was stirred at room temperature overnight. The on mixture was condensed under vacuum and the residue was purified by Prep TLC (CHzClzzNHg-MeOH (7N), 20: 1) to yield WS57 as a white solid (19 mg, 22%). 1H NMR (600 MHz, CDCl3): 6 8.23 (s,1H), 7.90 (t, J= 6.0 Hz, 1H), 7.26 (s, 1H), 6.85 (s, 1H), 5.95 (s, 2H), 5.54 (br s, 2H), 4.21 (t, J= 5.9 Hz, 2H), .99 (m, 2H), 2.08 (s, 3H), 1.83-1.90 (m, 2H), 1.59 (s, 6H); HRMS (ESI) m/z [M+H]+ calcd. for C21H24IN605S, 599.0574; found 599.0579.

N-(3-(6-Amino—8—((6-iodobenzo [d] [1,3] dioxol—S-yl)thio)—9H~purin—9-yl)propyl) hydroxy—Z-methylpropanamide (WSSS). To a solution ofWS57 in MeOH/THF/HzO (0.3 mL/0.3 mL/0.3 mL) was added LiOH (5 mg). The reaction mixture was stirred at room temperature for 2 hrs. The resulting mixture was condensed, d by Prep TLC (CH2C1zzNH3—MeOH (7N), 20:1) to yield W858 as a white solid (10 mg, 83%). 1H NMR (600 MHz, CDClg): 8 8.24 (s, 1H), 7.79 (br s, 1H), 7.25 (s, 1H), 6.88 (s, 1H), 5.94 (s, 2H), 5.67 (br s, 2H), 4.20 (t, J= 6.4 Hz, 2H), 3.02—3.20 (m, 2H), 1.83—1.96 (m, 2H), 1.43 (s, 6H); 13C NMR (150 MHz,CDC13):8176.9,154.5,152.9,151.9,149.32,149.31,146.9, 127.0, 120.0, 119.4, 112.9, 102.4, 92.3, 72.9, 40.6, 35.4, 29.2, 28.0; HRMS (BS1) m/z [M+H]+ caled. for C19H221N504S, 557.0468 ; found 557.0447.

N-(3-(6-Amin0((5-iodo—2,3-dihydrobenz0furan—6—yl)thio)—9H—purin—9- yl)propyl)cyclopropanecarboxamide (WS61). To a solution of 8—((5—iodo—2,3- dihydrobenzofuran—6—yl)thio)—9H—purin—6-amine (26 mg, 0.06 mmol) in DMF ( 1.5 mL) was added N-(3-bromopropy1) cyclopropanecarboxamide (39 mg, 0.18 mmol) and CSzCO3 (41 mg, 0.12 mmol). The resulting mixture was d at room temperature overnight. The reaction mixture was condensed under vacuum and the residue was purified by Prep TLC (CH2C12:NH3—MeOH (7N), 20:1) to yield W861 as a white solid (12 mg, 35%). 1H NMR (600 MHz, CDC13)15 8.30 (s, 1H), 7.57 (s, 1H), 7.16 (m, 1H), 6.55 (s, 1H), 5.67 (br s, 2H), 4.50 (t, J: 8.8 Hz, 2H), 4.22 (t, J: 6.3 Hz, 2H), 3.13 (t, J: 8.6 Hz, 2H), 3.01—3.07 (m, 2H), 1.80—1.86 (m, 2H), 1.38-1.44 (m, 1H), .93 (m, 2H), 0.67-0.72 (m, 2H); HRMS (E81) m/z [M+H]Jr calcd. for C20H22[N6028, 537.0570; found 67.

N—(3-(6-Am1'no-8—((5-iod0-2,3-dihydrobenzofuran—6-y1)thio)—9H—purin—9-yl)pr0py1) methylpropane-Z-sulfinamide (W862). To a on of iodo—2,3- dfliydrobenzofurany1)thio)—9H—purin—6—amine (26 mg, 0.06 mmol) in DMF ( 1.5 mL) was added N—(3—br0mopropy1)—2—methlpropane—2—sulfinamide (49 mg, 0.18 mmol) and C82CO3 (41 mg, 0.12 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed under vacuum and the residue was purified by Prep TLC (CH2C122NH3—MeOH (7N), 20: 1) to yield W862 as a white solid (11 mg, %). lHNMR (600 MHz, CDC13)3 6 8.33 (s, 1H), 7.66 (s, 1H), 6.61 (s, 1H), 5.85 (br s, 2H), 4.84 (t, J: 6.7 Hz, 1H), 4.59 (t, J: 8.7 Hz, 2H), 4.37-4.44 (m, 1H), 4.29—4.35 (m, 1H), 3.22 (t, J= 8.5 Hz, 2H), 3.09—3.16(m, 1H), 2.95-3.02 (In, 1H), 2.06-2.15 (m, 1H), .05 (m, 1H), 1.29 (s, 9H); HRMS (E81) m/z [M+H]+ calcd. for C20H251N50282, 573.0603; found 573.0620.

N-(3—(6—Amin0—8-((6—i0do—2,3-dihydro-lH—inden-S—yl)thio)-9H—purin—9-yl)propyl)—2~ methylpropane-Z-sulfinamide (WS63). To a solution of 8-((6—iodo—2,3—dihydIo—1H— inden—S~y1)thio)—9H—purin—6—amine (13 mg, 0.03 mmol) in DMF ( 1.5 mL) was added N- (3—bromopr0pyl)—2-methlpropane—2—sulfinamide (23 mg, 0.1 mmol) and CszC03 (21 mg, 0.06 mmol). The resulting mixture was stirred at room temperature overnight. The on mixture was condensed under vacuum and the residue was purified by Prep TLC (CHzClzzNH3—MeOH (7N), 20:1) to yield W863 as a white solid (5 mg, 27%). 1H NMR (600 MHz, CDC13)I 8 8.22 (s, 1H), 7.68 (s, 1H), 7.05 (s, 1H), 5.70 (br s, 2H), 4.83 (t, J= 6.7 Hz, 1H), 4.28—4.36 (m, 1H), 4.17-4.27 (m, 1H), 2.99-3.07 (m, 1H), 2.85-2.93 (m, 1H), 2.81 (t, J: 7.4 Hz, 2H), 2.72 (t, J= 7.5 Hz, 2H), 1.83—2.08 (m, 4H), 1.20 (In, 9H); HRMS (E81) m/z [M+H]+ calcd. for C21H231N6082, 571.0811; found 571.0809.

N—(3—(6—Amino—8—((2—i0d0—5—methoxyphenyl)thio)-9H—purinyl)pr0pyl)pivalamide (W864). To a solution of 8—((2—iodo-5—1nethoxypheny1)thio)-9H—purin—6-amine (200 mg, 0.5 mmol) in DMF (3 mL) was added N—(3-bromopropy1)pivalamide (445 mg, 2 mmol) and CszC03 (326 mg, 1 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed under vacuum and the residue was purified by Prep TLC (CH2C12:NH3—MeOH (7N), 20:1) to yield WS64 as a white solid (53 mg, %). 1H NMR (500 MHz, : 5 8.26 (s,1H), 7.66 (d, J: 8.7 Hz, 1H), 7.43 (br s, 1H), 6.66 (s, 1H), 6.50 (d, J= 8.7 Hz, 1H), 5.86 (br s, 2H), 4.20 (t, J= 6.1 Hz, 2H), 3.61 (s, 3H), 2.78 (m, 2H), 1.82 (m, 2H), 1.21 (s, 9H); 13C NMR (125 MHz, CDC13): 5 178.8, 160.5, 1550,1532, 152.0, 145.0, 140.6, 137.7, 120.1, 117.2, 115.4, 88.4, 55.5, 40.7, 38.8, 34.8, 29.1, 27.7; HRMS (ESI) m/z [M+H]+ calcd. for 1N602S, 541.0883; found 541.0898.

Scheme 10. Synthesis of S-linked reversed sulfonamide derivatives a 02 b C'Wvso Cl2 , C'WVS‘WR __. é)“ “—0’1 so2 n=o,1 HN' R R = t—butyl, n= 0 W847 R = t-butyl, n= 1 W353 R = pyl, n= 1 W854 2-(6-Amino—8-((6—iodobenzo [(1] [1,3] dioxolyl)thi0)-9H-purinyl)—N—(tert— buty1)ethanesulfonamide (WS47). To a solution of 8-((6—iodobenzo[d][1,3]dioxol—5- yl)thi0-9H—purin—6—amine (56 mg, 0.13 mmol) in DMF ( 2 mL) was added N—t-butyl—2— chloroethanesulfonamide (50 mg, 0.25 mmol) and C82C03 (88 mg, 0.27 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed under vacuum and the residue was d by Prep TLC (CHzclziNHy-MEOH (7N), 20:1) to yield WS47 as a White solid (10 mg, 13%). 1H Nh/IR (500 MHz, CDC13/MeOH-d4): 5 8.22 (s,1H), 7.39 (s, 1H), 7.08 (s, 1H), 6.06 (s, 2H), 4.69 (t, J: 7.0 Hz, 2H), 3.57 (t, J: 7.1 Hz, 2H), 1.35 (s, 9H); 13C NMR (125 MHz,CDC13/MeOH—d4): 8 158.3, 551,1539,1534,151.5,129.2,1235,123.3,117.8,106.6,98.1, 58.5, 57.3, 42.7, 33.8; HRMS (ESI) m/z [M+H]+ calcd. for C13H221N604SZ, 577.0189; found 577.0217. 3-(6—Amino-8—((6—iodobenzo [d] [1,3]dioxol—S-yl)thio)—9H-purin—9—yl)—N—(tert— butyl)propane—1-sulfonamide (W853). To a solution of 8—((6—iodobenzo[d][l,3]dioxol—5— yl)thio-9H—purinamine (56 mg, 0.13 mmol) in DMF ( 2 mL) was added N—t—butyl—3- chloro-N—propane—l—sulfonamide (144 mg, 0.65 mmol) and C32C03 (88 mg, 0.27 mmol).

The resulting mixture was stirred at room temperature overnight. The reaction mixture was sed under vacuum and the residue was purified by Prep TLC (CH2C12:NH3-MeOH (7N), 20:1) to yield WS53 as a white solid (18 mg, 22%). 1H NMR (600 MHz, CDC13/MeOH-d4): 8 8.21 (s, 1H), 7.40 (s, 1H), 7.06 (s, 1H), 6.06 (s, 2H), 4.38 (t, J: 7.3 Hz, 2H), 3.12 (t, J= 7.4 Hz, 2H), 2.13-2.44 (m, 2H), 1.33 (s, 9H); 13C NMR (150 MHz, CDCl3/MeOH—d4): 6 155.8,153.8,152.4,151.5,151.0,149.0, 1267,1210, 1208,1153, 104.1, 95.7, 55.7, 51.1, 43.6, 31.5, 25.9; HRMS (ESI) m/z [M+H]+ calcd. for 1N60482, 591.0345; found 591.0361. 3-(6—Amino-8—((6-i0dobenzo [11'] [1,3] diox0lyl)thio)—9H-purin—9¥yl)~N- isopropylpropane—l-sulfonamide (WS54). To a solution of 8-((6- iodobenzo[d][l,3]dioxol-5—y1)thio—9H—purin—6—amine (39 mg, 0.09 mmol) in DMF (2 mL) was added 3—chloro-N‘isopropylpropane—l—sulfonamide (100 mg, 0.45 mmol) and C82CO3 (62 mg, 0.19 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed under vacuum and the e was purified by Prep TLC (CHZClgzNHg—MeOH (7N), 20:1) to yield W854 as a White solid (14 mg, 26%). 1H NMR (500 MHz, CDClg/MeOH-ch): 5 8.00 , 7.19 (s, 1H), 6.86 (s, 1H), 5.86 (s, 2H), 4.17 (t, J: 7.3 Hz, 2H), 3.34 (septet, J= 6.6 Hz, 1H), 2.89 (t, J: 7.6 Hz, 2H), 2.05—2.13(m, 2H), 0.99 (d, J= 6.6 Hz, 6H); HRMS (ESI) m/z [M+H]+ calcd. for m50482, 577.0189; found 577.0194.

Scheme 11. Synthesis of methylene-linked amide, sulfonamide and sulfinamide derivatives R = t—bulylsulfinyl W860 R = H W855 R = t—butylcarbonyl W866 R = cyclopropanecarbonyl W871 R = cyclopropanesulfonyl W572 Reagents and conditions: (a) triethylamine, (Boc)20; (b) TFA; (c) acid chloride. or sulfonyl chloride or sufinyl chloride. t-Butyl (3-bromopropyl)carbamate. To a suspension of 3—bromopropylamine hydrcbromide (10 g, 45.7 mmol) in CHZClz (100 mL) cooled in an ice bath was added triethylamine (15.9 mL, 113 mmol). Di-t—butyl-dicarbonate (10 g, 45.7 mmol) was added slowly in portions and the ing mixture was stirred at 0 °C for 2 hrs and allowed to warm up to room temperature and stirred over—night. The reaction mixture was filtered, condensed and purified by flash chromatography to yield t-butyl (3- bromopropy1)carbamate (98 g, 90%). 1H NMR (500 MHz, CDClg/MeOH—d4): 5 475 (br s, 1H), 3.44 (t, J: 6.6 Hz, 2H), 3.27 (m, 2H), 2.05 (m, 2H), 1.45 (s, 9H). min0pr0pyl)—2-fluoro-8—((6—iodobenzo [(1] [1,3] dioxol-S—yl)methyl)-9H—purin—6— amine . To a solution of o—8—((6-iodobenzo[d] [1,3]dioxol-S-yl)methyl)—9H— purin—6-amine (3.3 g, 8 mmol) in DMF ( 50 mL) was added t-butyl (3— bromopropyl)carbamate (9.6 g, 40 mmol) and CSZCO3 (5.26 g, 16 mmol). The resulting mixture was stirred at room temperature for 1 day‘ The reaction mixture was condensed and purified by flash chromatography to yield t—butyl (3—(6-aminofluoro—8—((6— iodobenzo[d][1,3]dioxoly1)methyl)-9H-purin~9~y1)propyl)carbamate as white solid (3.1 g, 66%). The solution of t—butyl (3—(6-amino—2-fluoro((6—iodobenzo[d][l,3]dioxol hyl)—9H-purin—9—yl)propyl)carbamate (1.9 g, 3.3 mmol) in the e of TFA/CH2C12 (10 mL/2 mL) was stirred at room temperature for 2 hrs‘ The reaction mixture was condensed, purified by flash chromatography to yield 9-(3~aminopropyl)—2-fluoro—8- dobenzo[d][1,3]dioxol—5-y1)methyl)—9H—purinamine as yellow solid (1.4 g, 89%). 1H NMR (600 MHz, CDC13/MeOH—d4): 8 7.28 (s, 1H), 6.70 (s, 1H), 5.98 (s, 2H), 4.21 (s, 2H), 4.13 (t, J: 7.1 Hz, 2H), 2.67 (t, J= 6.8 Hz, 2H), 1.89 (m, 2H); 13C NMR (150 MHz, CDC13/MeOH—d4):8160.8,159.4,157.8,153.7,152.1, 1504,1494, 132.4, 120.1,117.2, 111.3, 103.4, 89.8, 41.7, 40.4, 39.3, 33.6; HRMS (ESI) m/z [M+H]+ calcd. for C16H17IFN602, 471.0436; found 42.

N—(3-(6-Amino-2—flu0ro~8-((6—iodobenzo [d] [1,3] dioxol-S—yl)methyl)—9H—purin pyI)methylpropanesulfinamide (WS60). To a solution of 9—(3—aminopropyl)- 2-fluoro-8—((6—iodobenzo[d][1,3]dioxol—5—yl)methyl)—9H—purinamine (80 mg, 0.17 mmol) iniDCM ( 3mL) was added t—butylsulfinyl chloride (28 uL, 0.25 mmol) and triethylamine (30 uL, 0.25 mmol). The resulting e was stirred at room temperature overnight. The reaction mixture was condensed and d by flash chromatography to yield WS60 as a white solid (45 mg, 46%). 1H NMR (500 MHz, CDC13): 5 7.28 (s, 1H), 6.62 (s, 1H), 6.04 (brs, 2H), 5.97 (s, 2H), 4.60 (t, J= 6.5 Hz, 1H), 4.24 (s, 2H), 4.20 (m, 1H), 4.09 (m, 1H), 3.13 (m, 1H), 2.97 (m, 1H), 2.00 (in, 1H), 1.85 (m, 1H), 1.27 (s, 9H). HRMS (ESI) m/z [M+H]+ calcd. for C20H25F1N603S, 575.0725; found 575.0738.

N-(3-(6-Ami11ofluoro-8—((6-iod0benz0[d] [1,3] dioxol—S—yl)methyl)—9H—purin—9— yl)propyl)pivalamide (WS66). To a on of WS65 (100 mg, 0.21 mmol) in DMF ( 3mL) was added trimethylacetyl chloride (40 uL, 0.32 mmol) and triethyiamine (90 uL, 0.96 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed and purified by flash chromatography to yield W866 as white solid (80 mg, 68%). 1H NMR (500 MHZ, CDC13): 5 7.22 (s, 1H), 6.58 (s, 1H), 6.37 (br s, 2H), .90 (s, 2H), 4.17 (s, 2H), 4.00 (t, J: 6.1 Hz, 2H), 3.10 (m, 2H), 1.66—1.73 (In, 2H), 1.16 (s, 9H); HRMS (EST) m/z [M+H]+ calcd. for C21H251FN603, 555.1017; found 555.1015.

N—(3~(6-Amin0fluoro((6-iodobenzo [(1] [1,3] dioxol—S—yl)methyl)—9H—purin pyl)cyclopr0panecarboxamide (WS71). To a solution of 9-(3-aminopropyl)—2- fluoro—S-((6—iodobenzo[d][l,3]dioxol-5—yl)methy1)-9H—purin—6—amine (100 mg, 0.21 mmol) in DMF ( 3 mL) was added cyclopropanecarbonyl chloride (29 uL, 0.32 mmol) and triethylamine (90 uL, 0.96 mmol). The resulting e was stirred at room temperature overnight. The reaction mixture was condensed and purified by flash chromatography to yield ws71 as a white solid (75 mg, 65%). 1H NMR (600 MHZ, CDC13/MeOH-d4): 6 7.32 (s, 1H), 6.77 (s, 1H), 6.02 (s, 2H), 4.24 (s, 2H), 4.16 (t, J: 7.3 Hz, 2H), 3.26 (t, J: 6.2 Hz, 2H), 1.91—2.01 (m, 2H), 1.50-1.57 (m, 1H), 0.90—0.95 (m, 2H), 0.76—0.82 (m, 2H); HRMS (ESI) m/z [M+H]+ calcd. for C20H21F1N603, 539.0704; found 539.0705.

N—(3—(6—Amino—2-fluoro((6-iodobenzo [(1] [1,3] dioxol-S-yl)methyl)—9H—purin—9— yl)propyl)cyclopropanesulfonamide (WS72). To a solution of 9-(3—amin0propy1)—2- fluoro—S—((6—iodobenzo[d][1,3]dioxol—5—y1)methy1)—9H—purin—6-amine (100 mg, 0.21 mmol) in DMF ( 3mL) was added cyclopropanesulfonyl chloride (89 mg, 0.32 mmol) and triethylamine (9O uL, 0.96 mmol). The resulting mixture was d at room temperature overnight. The reaction mixture was condensed and purified by flash chromatography to yield WS72 as a White solid (82 mg, 67%). 1H NMR (600 MHZ, CDC13/MeOH—d4): 8 7.32 (s, 1H), 6.79 (s, 1H), 6.02 (s, 2H), 4.27 (s, 2H), 4.22 (t, J: 7.3 Hz, 2H), 3.18 (t, J= 6.4 Hz, 2H), 2.45-2.50 (m, 1H), 2.00-2.06 (m, 2H), 1.12-1.17 (m, 2H), .04 (m, 2H); 13C NMR (150 MHz, CDClg/MeOH—d4): 5 159.0 (d, J: 209.8 Hz), 156.9 (d, J= 19.7 Hz), 152.4 (d, J=18.5 Hz), 1512 (d, J= 2.3 Hz),149.3,148.4,131.4,119.0,116.3(d, J: 3.6 Hz), 110.4, 102.4, 88.7, 40.7, 40.1, 39.3, 30.2, 29.9, 5.3; HRMS (ESI) m/z r calcd. for C19H21FIN604S, 575.0374; found 575.0390.

Scheme 12. Synthesis of S—linked acetylene derivatives.

R = cyclopropanecarbonyl W568 R = t—butylcarbonyl W869 R = cyclopropanesulfonyl W870 Reagents and conditions: (a) GUI, PPh3)2. trimeihylsiIanylacetylene, Eth, DMF, 60°C; (b) KOH.

N—(3-(6-Amino—8-((6-ethynylbenzo [at] [1,3] yl)thio)—9H-purin—9— yl)propyl)cyc10pr0panecarboxamide (W868). To a solution ofWSSl (150 mg, 0.28 mmol) in DMF ( 3 mL) was added trimethylsilanylacetylene (116 uL, 0.84 mmol), PdC12(PPh3)2 (20 mg, 0.03 mmol), CuI (5 mg, 0.03 mmol) and triethylamine (389 uL, 2.8 mmol). The resulting mixture was d at 60 0C for 30 min, condensed and filtered through silica gel. The filtrate was condensed under reduced pressure and the resulting residue was dissolved in CHzClg/MeOH (1 mL/ 1 mL). To the resulting mixture was added KOH (20 mg) and d for 3 hrs. The reaction mixture was condensed and purified by flash chromatography to yield W868 as a white solid (42 mg, 35%). 1H NMR (600 MHz, CDCl3/MeOH-d4): 8 8.11 (s,lH), 6.96 (s, 1H), 6.89 (s, 1H), 5.98 (s, 2H), 4.21 (t, J: 7.3 Hz, 2H), 3.45 (s, 1H), 3.18 (m, 2H), 1.88-1.96 (m, 2H), .49 (m, 1H), 0.78-0.84 (m, 2H), 0.65-0.71 (m, 2H); HRMS (ESI) m/z [M+H]+ calcd. for C21H21N603S, 437.1396; found 437.1 393.

N—(3-(6-Amino—8—((6-ethynylbenzo[d] [1,3]dioxol—S-y1)thi0)—9H—purin—9- yl)pmpyl)pivalamide . To a solution ofW845 (150 mg, 0.27 mmol) in DMF (3 mL) was added hylsilanylacetylene (113 uL, 0.81 mmol), PdC12(PPh3)2 ( 19 mg, 0.03 mmol), CuI (5 mg, 0.03 mmol) and triethylamine (377 uL, 2.7 mmol). The resulting mixture was stirred at 60 0C for 30 min, condensed and filtered h silica gel. The filtrate was condensed under reduced pressure and the resulting residue was dissolved in CH2C12/MeOH (1 mL/ 1 mL). To the resulting mixture was added KOH (20 mg) and stirred for 3 hrs. The reaction mixture was condensed and purified by flash tography to yield WS69 as a white solid (53 mg, 43%). 1H NMR (600 MHz, CDClg): 5 8.31 (s, 1H), 7.56 (t, J: 6.1 Hz, 1H), 7.00 (s, 1H), 6.88 (s, 1H), 6.01 (s, 2H), 5.77 (br s, 2H), 4.29 (t, J: .9 Hz, 2H), 3.30 (s, 1H), 3.02-3.09 (m, 2H), 1.86-1.94 (m, 2H), 1.28 (s, 9H); HRMS (ESI) m/z [M+H]+ calcd. for C22H25N503S, 453.1709; found 453.1721.

N-(3—(6—Amino—8—((6—ethynylbenzo [d] [1,3]dioxol—S-yl)thio)—9H-purin-9— yl)pr0pyl)cyclopropanesulfonamide (WS70). To a on ofW856 (100 mg, 0.17 mrnol) in DMF (3 mL) was added trimethylsilanylacetylene (72 “L, 0.61 mmol), PdClz(PPh3)2 ( 12 mg, 0.02 mmol), Cul (3 mg, 0.02 mmol) and ylamine (243 uL, 1.7 mmol). The resulting mixture was stirred at 60 °C for 30 min, condensed and filtered through silica gel. The filtrate was concentrated under reduced pressure and the resulting residue was dissolved in CH2C12/MeOH (1 mL/ 1 mL). To the resulting mixture was added KOH (20 mg) and stirred for 3 hrs. The reaction mixture was condensed and purified by flash chromatography to yield WS70 as a White solid (43 mg, 52%). 1H NMR (600 MHz, CDCl3/MeOH-d4): 5 8.20 (s, 1H), 7.06 (s, 1H), 7.00 (s, 1H), 6.08 (s, 2H), 4.37 (t, J= 7.1 Hz, 2H), 3.54 (s, 1H), 3.18 (t, J= 6.6 Hz, 2H), 2.43-2.51 (m, 1H), 2.04—2.12 (m, 2H), 1.10~ 1.14 (m, 2H), 0.99—1.04 (m, 2H); HRMS (ESI) m/z [M+H]+ calcd. for C20H21N604Sz, 473.1066; found 473.1053.

NHZ | NH2 I Nit/[MUDkN/ N O) 'KN/ N o) NHz DMF 813-1 813-2 0 DZ5N9 Scheme 13. Synthesis of —N9. 6—(6—Amino-8—(6—iodobenz0 [d] [1,3]dioxol—S-ylthi0)-9H-purin—9-yl)hexanamide [DZS- 49—N9]. 50 mg (0.121 mmol) of 8-(6-iodobenzo[d][l,3]di0xol—5—y1thio)—9H—purin—6—amine ) was dissolved in DMF (2 mL). 47 mg (0.145 mmol) of C32C03 and 117.4 mg (0.605 mmol) of ohexanamide (513-2) were added and the mixture was stirred at rt for 2 h. Solvent was removed under reduced pressure and the resulting residue was d by preparatory TLC (CH2C12:MeOH—NH3 (7N), 10:1) to give 12.7 mg (20%) ofDZ5 N9. 1H NMR (500 MHZ, CDClg/MeOH—d4): 8 8.13 (s, 1H), 7.31 (s, 1H), 6.97 (s, 1H), 5.98 (s, 2H), 4.13 (t, J: 7.6 Hz, 2H), 2.14 (t, J: 7.6 Hz, 2H), 1.71—1.80 (m, 2H), 1.55-1.65 (In, 2H), 1.28-1.39 (m, 2H); HRMS (ESI) m/z [M+H]+ calcd. for C18H201N603S, 527.0362; found 527.0364.

Hsp90 Binding Assay: For the binding studies, fluorescence polarization (FP) assays were performed similarly as was previously reported [Du et al. (2007) throughput screening fluorescence polarization assay for tumor—specific Hsp90" J. Biomol. Screen 924]. Briefly, FP measurements were performed on an Analyst GT ment (Molecular Devices, Sunnyvale, CA). Measurements were taken in black 96-well microtiter plates (Corning # 3650) Where both the excitation and the emission occurred from the top of the well. A stock of 10 11M cy3B—GM was prepared in DMSO and diluted with HFB buffer (20 mM Hepes (K), pH 7.3, 50 mM KCl, 2 mM DTT, 5 mM MgC12, mM Na2M004, and 0.01% NP4O with 0.1 mg/mL BGG). The test compounds were dissolved in DMSO and added at several trations to the HFB assay buffer containing both 6 nM cy3B- GM and transgenic mouse brain lysate (6 pg JNPL3 lysate) or human cancer cell lysate (3 SKBr3 lysate) in a final volume of 100 nL. Drugs were added to triplicate wells. Free M (6 nM M), bound cy3B—GM (6 nM cy3B-GM + lysate, as indicated above) and buffer only containing wells (background) were included as controls in each plate. Plates were incubated on a shaker at 4°C, and polarization values measured at 24 h. Percentage inhibition was calculated as follows: (% Control) = 100 - ((mPC — mPfl/(me — mPf)) x 100, where mPc is the recorded mP from compound wells, 11in is the e recorded mP from cy3B—GM—only wells, and nin is the average recorded m]? from wells containing both cy3B—GM and lysate, and plotted against values of itor concentrations. The inhibitor concentration at which 50% of bound cy3B—GM was ced was ed by fitting the data using a nonlinear regression analysis as implemented in Prism 4.0 (GraphPad Software). hERG scence Polarization Assay: Following the manufacturer’s protocol, the hERG assay was med using Predictor hERG Fluorescence Polarization Assay kit (catalog no. ) from Invitrogen. Briefly, FP measurements were performed on an Analyst GT instrument (Molecular Devices, Sunnyvale, CA).

Measurements were taken in black 384-well plates (Corning # 3677), Where both the excitation and the emission occurred from the top of the well. The test compounds were dissolved in DMSO and added at l concentrations to the Predictor hERG FP assay buffer containing 4 nM Predictor hERG tracer red and 10 uL ofPredictor hERG membrane in a final volume of 20 uL. Drugs were added to triplicate wells. E—403l as positive control was included in each plate. Plates were then kept on a shaker at room temperature and polarization values were measured after 4 hrs. The inhibition concentration at which 50% of tracer red gets displaced was obtained by fitting the data using a nonlinear regression is as implemented in Prism 5.0 (GraphPad Software).

Table 12 shows results of testing for various representative compounds for their activity in Hsp90 binding assays and hERG fluorescence polarization assay. In interpreting these test results, it will be appreciated that binding to Hsp90 is desirable for activity in the treatment of cancer or neurodegenerative disorders. In contrast, it is generally undersirable to have binding to hERG since binding to hERG can result in undesirable cardiac side effects. ore, having a low value for binding to Hsp90 and a high value for binding to hERG is desirable, bearing in mind that the units for the two measurement are different.

For comparison, it is noted that values for PU—H7 1, a compound with the structure tfigisélg‘:N has a Hsp90 binding value of 20 nM and an hERG assay result of l pM . Many of the compounds ofthe ion tested, have hERG values more than 100 times greater than PU—H71 and are therefore expected to have lower toxicity/side effect issues.

Table 12 Compound Synthetic Hsp90 Binding hERG assay Designation No. Designation Assay (13M) (pM) lA-l 0 W835 6.3 NA lA-11 WS42 71.5 NA lA-12 W839 3 3 NA 1A—15 W854 20.5 >100 lA—l 9 W853 44 NA ‘ A-22 W848 47 >100 ‘A-24 W834 11.5 NA ‘ A—25 W852 24 NA A-26 : W849 12 >100 A-27 W850 64 NA L A-28 W856 19.7 NA A-43 W845 1 1 >100 ‘A-44 W846 68 NA ‘A—45 W851 9.8 >100 Compound tic Hsp90 Binding hERG assay Designation N0. Designation Assay (nM) 1A—46 W855 24.2 1A—47 W857 16.5 1A—48 W85 8 22.1 1A-49 W864 28.3 .._|_. 1A—5 W847 78 1A—50 DZS-49—N9 76.5 1B-28 W870 53 >100 1B—43 W869 28 >100 1B~45 W868 37 >100 16—28 MRP-I-31 22 NA 1G—43 MRP-I—29 11 >100 16-45 MRP-I—28 15 76 2A-1 1 W843 51 NA 2A-12 W841 68 NA _________L_.____ 2A—26 W862 17 NA 2A-45 W861 11.8 NA 3A-10 W836 3 .5 NA 1___ 3A—1 1 W844 68 NA 3A- 12 W840 29. 6 NA .1.— 3A-24 W837 8.1 NA —____._,____ 3A—26 W863 20.1 NA 3A—43 W838 37.4 NA 4A—26 W860 26.2 >100 Compound tic Hsp90 Binding hERG assay Designation No. Designation Assay (nM) (pM) 4A-28 W872 24 >100 4A-43 W866 33.1 i >100 4A—45 W871 20 >100 The invention is not to be limited in scope by the specific embodiments disclosed in the examples that are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. , Various modifications of the invention in addition to those shown and described herein will become apparent to those in the art and are intended to fall within the scope of the appended claims. A number of nces have been cited, the entire disclosures ofwhich are incorporated herein by reference for all purposes.

Claims (1)

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. A Compound of Formula (IA) or (IB): NH2 NH 2 X2 X2 Z3 Z1 Z3 Y Xa Y Xa X4 Z2 N X4 Z2 N Xc R Xb R Xb Xd (IA) (IB) or a pharmaceutically acceptable salt f, wherein: (a) each of Z1, Z2 and Z3 is N; (b) Y is S; (c) Xa, Xb, Xc and Xd are O, O, CH2, and CH2, respectively; (d) X4 is hydrogen or halogen; and (e) X2 and R are a combination selected from the following: (i) in formula (IA): (a) X2 is NR1R2, wherein R1 and R2 are each independently H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, or alkylheteroarylalkyl, and R is ht-chain- or branched- substituted or unsubstituted alkyl, straight-chain- or ed- substituted or unsubstituted alkenyl, straight-chain- or branched- substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl wherein the R group is interrupted by one or more -S(O)N(RA)-, O)-, - SO2N(RA)-, -NRASO2-, -C(O)N(RA)-, or -NRAC(O)- groups, and/or terminated by an -S(O)NRARB, -NRAS(O)RB, -SO2NRARB, - NRASO2RB, -C(O)NRARB, or -NRAC(O)RB group, wherein each RA and RB is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, lkyl, heteroalkyl, heterocycloalkyl, aryl, H:\ACG\Interwoven\NRPortbl\DCC\ACG\9199988_1.docx-23/