CN101505762A

CN101505762A - Orally active purine-based inhibitors of heat shock protein 90

Info

Publication number: CN101505762A
Application number: CNA2006800527352A
Authority: CN
Inventors: S·R·卡西布哈特拉; L·张; M·F·贝姆; 范俊华; K·D·霍格; M·比亚蒙特; 史建栋
Original assignee: Conforma Therapeutics Corp
Current assignee: Conforma Therapeutics Corp
Priority date: 2005-12-22
Filing date: 2006-12-18
Publication date: 2009-08-12

Abstract

Novel purine compounds and tautomers and pharmaceutically acceptable salts thereof are described, as are pharmaceutical compositions comprising the same, complexes comprising the same, e.g., HSP90 complexes, and methods of using the same. Methods of using the novel purine compounds of the invention,and tautomers and pharmaceutically acceptable salts thereof, include their use in inhibiting heat shock protein 90's (HSP90) to thereby treat or prevent HSP90-dependent diseases, e.g., proliferative disorders such as breast cancer.

Description

The Orally active purine-based inhibitors of heat shock protein 90

Technical field

[0001] the present invention relates generally to purine analogue and they and is suppressing heat shock protein 90 (HSP90 ' s) thereby treatment or prevention HSP90 dependence disease, for example application in proliferative disease such as the breast carcinoma.

Cross reference

[0002] the application requires the U.S. Provisional Application 60/753 of December in 2005 submission on the 22nd, the U.S. Provisional Application 60/753 of No. 636,2005 on Decembers submission in 22,, the rights and interests that No. 60/753,698, No. 448 and the U.S. Provisional Application also submitted in 22nd at December in 2005.

[0003] the application also relates to the U.S. Provisional Application serial number 10/494 of submission on April 30th, 2004,414, it is the American National phase application of the International Application PCT US02/35069 of submission on October 30th, 2002, described international application requires the priority of No. 60/335,391, the U.S. Provisional Application submitted to October 30 calendar year 2001 again.

[0004] content whole of all above-mentioned applications is incorporated this paper into as a reference.

Background technology

[0005] following description comprises understanding the information that the present invention comes in handy.This is not to recognize that: any information provided herein is prior art or relevant with present invention required for protection, or the concrete or in secret any publication quoted of quilt is a prior art.

[0006] heat shock protein 90 ' s (Hsp90s) makes many " client (client) " albumen keep the omnipresence chaperone of correct conformation (referring to Kamal et.al.Trends Mol.Med.2004,10,283-290; Dymock et.al.Expert Opin.Ther.Patents 2004,14,837-847; Isaacs et.al.Cancer Cell, 2003,3,213; Maloney et.al.Expert Opin.Biol.Ther.2002,2,3-24 and Richter et.al.J.Cell.Physiol.2001,188,281-290), and it participates in a large amount of Protein Folding, activation and assembling, comprises the key protein matter that participates in signal transduction, cell cycle regulating and transcriptional regulatory.Research worker reports that the HSP90 chaperone is relevant with important signal transducer, as steroid hormone receptor and protein kinase, comprise for example Raf-1, EGFR, v-Src family kinase, Cdk4 and ErbB-2 (Buchner, TIBS, 1999,24,136-141; Stepanovaet.al., GenesDev.1996,10,1491-502; Dai et.al., J.Biol.Chem.1996,271,22030-4).Research further shows, but some auxilliary chaperones for example Hsp70, p60/Hop/Sti1, Hip, Bag1, HSP40/Hdj2/Hsj1 are exempted from albumen, p23 and p50, can assist HSP90 to bring into play its function (referring to for example, Caplan, Trends in Cell Biol., 1999,9,262-268).The inhibition of Hsp90 is caused that these client's albumen take unusual conformation, and these unusual folding protein are eliminated fast by cell via ubiquitination and proteasome degraded.What is interesting is that Hsp90 client's albumen is itemized and comprised a series of well-known oncogenes.In them four kinds be the cancer target of confirming clinically: HER-2/neu (

(Herceptin (trastuzumab))), Bcr-Abl (

(imatinib mesylate (imatinib mesylate))), estrogen receptor (zitazonium (tamoxifen)) and androgen receptor (

(bicalutamide (bicalutamide))), and other oncogene plays an important role in cancer takes place.Some the most responsive Hsp90 client's albumen participate in growth signals transduction (Raf-1, Akt, cdk4, Src, Bcr-Abl etc.).On the contrary, if exist, some tumor suppressor genes seemingly the client of Hsp90 (client's albumen is itemized referring to Prattet.al.Exp.Biol.Med.2003,228,111-133; Workman et.al.CancerLett.2004,206,149-157 and Zhang et.al.J.Mol.Med.2004,82,488-499.), and the result is, the inhibition of Hsp90 is had comprehensive anti-proliferative effect.In addition, some client's albumen participate in tumorigenic other basic process, and promptly apoptosis is escaped (for example, Apaf-1, RIP, Akt), immortalization (for example, hTert), blood vessel generation (for example VEGFR, Flt-3, FAK, HIF-1) and transfer (c-Met).

[0007] various client's albumen have different reactions to the Hsp90 inhibitor, depend on cell line, and some client's albumen experience degraded under lower inhibitor concentration, or have kinetics faster.Comparatively Min Gan client's albumen normally participates in those client's albumen of growth signals transduction, but the albumen of some sudden changes of in tumor cell, finding (mutant p53, Gleevec-resistance Bcr-Abl, referring to Gorre et.al.Blood, 2002,100,3041-3044) depend on Hsp90 especially and keep their conformation and function.This peculiar property makes tumor cell to the sensitization of Hsp90 inhibitor, and can be fashionable when these factors, and they give Hsp90 inhibitor remarkable vitro and vivo antitumor character.

Exhaust when [0008] significant advantage of targeting Hsp90 is multiple oncogene protein, necessary several ways takes place and reduce tumor to obtain probability the resistance of Hsp90 inhibitor thereby attack cancer.Another marked feature of Hsp90 is that it exists with activated form in cancerous cell, and has (Kamal et.al.Nature with the form of hiding in normal cell, 2003,425,407-410 and Workman et.al.Trends Mol.Med.2004,10,47-51.).This provides to use has to activated form that optionally inhibitor is selectively targeted in the chance of cancerous cell.How also fully not know in the activated form and the form of hiding of molecular level differentiation Hsp90.Yet, be clear that, the activity of Hsp90 is to regulate by the process of high complexity, described process relates at least: (1) Hsp90 dimerization, (2) have the formation of polyprotein complex of numerous auxilliary chaperones and the circulation of (3) chaperone and the necessary ATP/ADP combination of function, ATP hydrolysis.

[0009] the company function of Hsp90 can be by suppressing its atpase activity " closing (switched off) ".Nucleotide ADP and ATP can be incorporated into two sites, and a site is near the N end, and another site is near the C end.Separation is identified owing to its protozoacide, weeding and antifungal activity at first from the geldanamycin (Geldanamycin) of microorganism streptomyces hygroscopicus (Streptomyces hygroscopicus).Ansamycins antibiotic (Ansamycin antibiotics), be considered to bring into play their antitumaous effect as geldanamycin (GM), herbimycin (herbimycin) A (HA) and 17-AAG by combining closely with the N port bag (pocket) of HSP90, (and for example novobiocin is incorporated into C end structure territory, referring to Yun et.al.Biochemistry, 2004,43,8217-8229), thereby make usually and the interactional substrate of HSP90 removes to stablize (Stebbins et al.Cell, 1997,89,239-250).This pocket high conservative and with the homology of the ATP-binding site of dna gyrase poor (Stebbins, C.et al. as above; Grenert, J.P et al., 1997, J.Biol.Chem., 272:23843-50).Further, ATP and ADP all illustrated with low-affinity in conjunction with this pocket and have weak atpase activity (Proromou, et.al., Cell, 1997,90,65-75 and Panaretou, et.al., EMBOJ., 1998,17,4829-36).The interior research of external and body proves that ansamycin and other HSP90 inhibitor are folding to function and Profilin matter that occupying of this N-port bag changes HSP90.Under high concentration, ansamycin and other HSP90 inhibitor have demonstrated (Scheibel, T., H.et al., 1999, the Proc.Natl.Acad.Sci.U S A 96:1297-302 of combining of Profilin substrate and HSP90; Schulte, T.W.et al., 1995, J.Biol.Chem.270:24585-8; Whitesell, L, et al., 1994, Proc.Natl.Acad.Sci.U S A 91:8324-8328).Ansamycin has also proved ATP dependent release (Schneider, C., Let al., 1996, Proc.Natl.Acad.Sci.U S A, the 93:14536-41 of Profilin companion associated protein substrate; Sepp-Lorenzino et al., 1995, J.Biol.Chem.270:16580-16587).In either case, substrate by ubiquitin dependency process in proteasome, degrade (Schneider, C., L, as above; Sepp-Lorenzino, L, et al., 1995, J.Biol.Chem., 270:16580-16587; Whitesell, L.et al., 1994, Proc.Natl.Acad.Sci.USA, 91:8324-8328).

[0010] the HSP90 substrate that occurs in tumor and the non-transformed cell goes to stablize and shown the subgroup of signal transduction modulators effective especially, Raf (Schulte for example, T.W.et al., 1997, Biochem.Biophys.Res.Commun.239:655-9; Schulte, T.W., et al., 1995, J.Biol.Chem.270:24585-8), nuclear steroid receptor (Segnitz, B., and U.Gehring.1997, J.Biol.Chem.272:18694-18701; Smith, D.F.et al., 1995, Mol.Cell.Biol.15:6804-12), v-src (Whitesell, L, et al., 1994, Proc.Natl.Acad.Sci.U S A 91:8324-8328) and some stride film tyrosine kinase (Sepp-Lorenzino, L.et al., .1995, J.Biol.Chem.270:16580-16587) as EGF receptor (EGFR) and Her2/Neu (Hartmann, F., et al., 1997, Int.J.Cancer70:221-9; Miller, P.etal., 1994, Cancer Res.54:2724-2730; Mimnaugh, E.G., et al., 1996, J.Biol.Chem.271:22796-801; Schnur, R.et al., 1995, J.Med.Chem.38:3806-3812), CDK4 and sudden change p53.Erlichman et al., Proc.AACR (2001), 42, summary 4474.Inductive these the proteinic forfeitures of ansamycin cause some selective destruction of regulating approach and the growth retardation (Muise-Heimericks that causes in the cell cycle moment, R.C.et al., 1998, J.Biol.Chem.273:29864-72), and apoptosis, and/or the differentiation (Vasilevskaya of the cell of so handling, A.et al., 1999, Cancer Res., 59:3935-40).

[0011] except anticancer and antitumorgienesis activity, the HSP90 inhibitor also participates in other application of wide region, the medicament that comprises as antiinflammatory, anti-infectious disease medicament, is used for the treatment of autoimmune medicament, is used for the treatment of the medicament of ischemia and is used to promote neuranagenesis is (referring to for example, Rosen et al., WO 02/09696; PCT/US01/23640; Degranco et al., WO 99/51223; PCT/US99/07242; Gold, U.S.Patent6,210,974B1).Report in the document, fiber generates disease, include but not limited to scleroderma, polymyositis, systemic lupus erythematosus (sle), rheumatoid type arthritis, liver cirrhosis, cicatrization, interstitial nephritis and pulmonary fibrosis be treatable (Strehlow, WO 02/02123; PCT/US01/20578).

[0012] therefore ansamycin and other HSP90 inhibitor have very big potentiality to be used for the treatment of and/or prevent many kinds of diseases.Yet the deutero-Hsp90 inhibitor of many natural prodcuts shows the materia medica defective, and they insoluble relatively make them be difficult to preparation and use, and they are difficult to be synthesized, and necessary at present---generation by fermentation at least in part---.Further, the dose-limiting toxicity of ansamycin is at liver.For example, semi-synthetic inhibitor 17-allyl amino, 17-de-methoxy-geldanamycin (17-AAG) is in the II clinical trial phase at present, its make expensive, be difficult to preparation (the NCI clinical protocol is made of the DMSO solution of injection 17-AAG) and at present only intestinal use outward.Though 17-dimethylamino ethylamino analog (17-DMAG) is more solvable, it shows whole side effect and gastrointestinal hemorrhage (the Glaze et.al.Proc.Am.Assoc.Cancer.Res.2003 of 17-AAG in the toxicity test before clinical, 44,162-162 and Eiseman et.al.Cancer Chemother.Pharmacol.2005,55,21-32).Radicicol (RC) is another natural Hsp90 inhibitor product, its poorly water-soluble and the activity of not having in the tumor xenogeneic graft model.The 9 oxime derivate of semisynthetic radicicol provides better dissolubility and has improved materia medica character in the murine model in fact, but still be confined to intravenous administration (Ikuina et.al.J.Med.Chem.2003,46,2534-2541).And radicicol and oxime thereof comprise epoxide ring, and described epoxide ring is regarded as being easy to obtain stability and toxicity, promote synthesizing of cycloproparadicicol: Yang et.al.J.Am.Chem.Soc.2004,126,7881 and 2003,125,9602-9603.).Though the ansamycin potentialization, but still need optional HSP90 inhibitor.

[0013] seeks synthetic fully, as to have Orally active Hsp90 inhibitor, so that provide dosage regimen more flexibly to select and avoid possibly the side effect of natural inhibitor product.Thereby Chiosis et al. has described simulation geldanamycin and other ansamycin in conjunction with the ATP binding pocket of HSP90 and suppress the design of purine analogue of ability of HSP90 and synthetic.(WO 02/36075 referring to International Patent Application PCT/US01/46303; Chemistry ﹠amp; Biology 8:289-299 (2001).The specific compound that Chiosis et al. describes is included in 3,4 and 5 substituted trimethoxy benzyl entities.Use gel-combination test, these demonstrate than 17-AAG in conjunction with active low about 20 times of HSP90. Chiosis et al. does not attempt the quinone analogies of methoxy-benzyl entity, Consider to do like this and can cause hepatotoxicity.Id.，pg.290，col.1，

4。Also not instruction of Chiosis et al., Sulfide, sulfoxide and sulfone are used in suggestion or report, and be as described herein.

[0014] more recent, other novel non-natural Hsp90 inhibitor product is in the news, and (for example PU3 and CCT018159 are referring to Chiosis et.al.Bioorg.Med.Chem.Lett.2002,10,3555-3564; Vilenchik et.al.Chem.Biol.2004,11,787-797; Chiosis et.al.WO0236075,2002; Drysdale et.al.WO 03/055860 A1,2003; Wright et.al.Chem.Biol.2004,11,775-785; Dymock et.al.Bioorg.Med.Chem.Lett.2004,14,325-328; Dymock et.al.J.Med.Chem.2005,48,4212-4215.Structure of Hsp90 in complex with PU3 pdb code 1UY6, and with PU24FCl:pdb code 1UYF and Clevenger et.al.Org.Lett.2004,6,4459-4462).The compound crystal structure of the structure applications Hsp90 of these inhibitor and ATP, geldanamycin or radicicol designs.8-benzyladenine such as PU3 are designed to adopt the C shape conformation identical with geldanamycin (Chiosis et.al.Current Cancer Drug Targets, 2003,3,371-376), the adenine fourth finger is to adenine binding site (hinge region), and the H keyed jointing of the quinone ring of trimethoxy phenyl ring imitation geldanamycin is subjected to character.(phenyl ring of PU3 is not designed to have identical direction with the quinone ring of geldanamycin.On the contrary, trimethoxy-benzene partly is designed to point to identical general direction and forms hydrogen bond with Lys112, and Lys112 is the aminoacid that forms hydrogen bond with the quinone ring of geldanamycin).The compound crystal structure of HSP90 that obtains at present and PU3 confirms that purine ring occupies the position that is occupied by ADP/ATP usually, but phenyl ring points to and the rightabout of prediction direction, the π of formation and Phe138-interact to folded.However, PU3 suppresses Hsp90 (the HER-2 test of degrading, HER-2IC ₅₀=40 μ M) and the valuable starting point further optimized of being used for is provided.Structure-activity research based on PU3 produces more activated PU24FCl (HER-2IC ₅₀=1.7 μ M), its subsequently also with the Hsp90 cocrystallization.When PU24FCl prepares in DMSO/EtOH/ phosphate-buffered saline 1:1:1 and intraperitoneal when being applied in the mice that has MCF-7 xenotransplantation tumor, it induces HER-2 and Raf-1 downward modulation with 100-300mg/kg, this pharmacokinetics reaction suppresses consistent with Hsp90, when 200mg/kg, it significantly suppresses tumor growth.Need the unusual PU24FCl of high dose (500-1000mg/kg) to observe similar pharmacokinetics reaction after Orally administered, and do not report that 8-benzyladenine by oral route suppresses tumor promotion.Under our operation, can not effectively prepare and oral delivery to such an extent as to confirm that PU24FCl is very insoluble.So far, render a service and pharmaceutical properties though there is a large amount of SAR research to improve, the Hsp90 inhibitor does not also confirm to have activity in the animal model that human cancer (xenograft) arranged when oral using.

[0015] discovery of 8-benzyladenine has caused design (the Kasibhatla et.al.WO 3037860 of 8-sulfane base adenine (sulfanyladenine), 2003 and Llauger et.al.J.Med.Chem.2005,48,2892-2905), example is 8-(2-iodo-5-methoxyl group-phenyl sulfane base (phenylsulfanyl))-9-penta-4-alkynyl-9H-purine-6-base amine, it shows excellent effectiveness in several tests based on cell, but is insoluble in water and does not have competent oral bioavailability in clinical acceptable preparation.

[0016] the invention provides the available purine analogue of water miscible, oral biology, suppressing heat shock protein 90 with them ' thus the application in s treatment or the prevention Hsp90 dependence disease, as confirming by their oral effects in the tumor xenogeneic graft model.

Geldanamycin (GM) 17AAG 17DMAG radicicol (RC)

CCT018159 PU3 PU24FCI 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-

Penta-4-alkynyl-9H-purine-6-base amine

Summary of the invention

In one embodiment, the invention provides formula I chemical compound:

Formula I

Or its tautomer or pharmaceutically acceptable salt, wherein

R ^sIndependently be selected from H and F;

Each R ^a, R ^b, R ^cAnd R ^dIndependently be selected from H, halogen, low-carbon alkyl, OR ³, SR ³, C (O) N (R ⁴) ₂, NR ⁴R ⁴, C (O) R ²With-C (O) OR ⁴

R ^xIndependently be selected from the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₂-C ₆Thiazolinyl and the optional C that replaces ₂-C ₆Alkynyl;

R ^yIndependently be selected from O, NR ¹And key;

R ^zIndependently be selected from H, C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl ,-P (O) (OR ⁴) ₂And C (O) R ²

R ¹Independently be selected from H, the optional alkyl that replaces, the optional thiazolinyl that replaces, the optional alkynyl that replaces, the optional cycloalkyl that replaces, the optional assorted alkyl that replaces, the optional aryl that replaces, optional heterocyclic radical, C (O) R that replaces ²,-C (O) OR ², C (O) NR ⁴ ₂, C (S) OR ², C (S) NR ⁴ ₂, P (O) (OR ⁴) and SO ₂R ²

R ²Independently be selected from the optional alkyl that replaces, the optional cycloalkyl that replaces, the optional assorted alkyl that replaces, the optional aryl that replaces, the optional heterocyclic radical that replaces and the optional heteroaryl that replaces;

R ³Independently be selected from H, the optional alkyl that replaces, the optional cycloalkyl that replaces, the optional assorted alkyl that replaces, the optional aryl that replaces, optional heterocyclic radical, C (O) NR that replaces ⁴ ₂, C (O) R ²With-C (O) OR ²With

R ⁴Independently be selected from H, the optional alkyl that replaces, the optional cycloalkyl that replaces, the optional assorted alkyl that replaces, the optional aryl that replaces, the optional heterocyclic radical that replaces.The present invention also provides following embodiment:

-Shi I chemical compound, wherein R ^a, R ^b, R ^cAnd R ^dIndependently be selected from halogen and OR ³

-Shi I chemical compound, wherein R ^a, R ^b, R ^cAnd R ^dIn at least two independently be selected from halogen and methoxyl group;

-Shi I chemical compound, wherein R ^a, R ^b, R ^c, and R ^dIn at least three independently be selected from halogen and OR ³

-Shi I chemical compound, wherein R ^a, R ^b, R ^c, and R ^dIn at least three independently be selected from halogen and methoxyl group;

-Shi I chemical compound, wherein R ^aBe halogen and R ^dBe OR ³

-Shi I chemical compound, wherein R ^xBe the optional C that replaces ₂-C ₃Alkyl, the optional C that replaces ₂-C ₃Thiazolinyl or the optional C that replaces ₂-C ₃Alkynyl, R ^yBe NR ¹And R ^zBe C ₁-C ₆Alkyl;

-Shi I chemical compound, wherein R ^xBe the optional C that replaces ₂-C ₃Alkyl, the optional C that replaces ₂-C ₃Thiazolinyl or the optional C that replaces ₂-C ₃Alkynyl; R ^yIt is key; And R ^zBe H;

-Shi I chemical compound, wherein R ^xBe the optional C that replaces ₂-C ₃Alkyl, the optional C that replaces ₂-C ₃Thiazolinyl or the optional C that replaces ₂-C ₃Alkynyl; R ^yBe NR ¹And R ^zBe C (O) R ²

-Shi I chemical compound, wherein R ^xBe the optional C that replaces ₂-C ₃Alkyl, the optional C that replaces ₂-C ₃Thiazolinyl or the optional C that replaces ₂-C ₃Alkynyl; R ^yBe NH; And R ^zBe H.

-Shi I chemical compound, wherein R ^xBe the optional C that replaces ₂-C ₃Alkyl, the optional C that replaces ₂-C ₃Thiazolinyl or the optional C that replaces ₂-C ₃Alkynyl; R ^yBe NH; And R ^zBe C ₁-C ₆Alkyl; With

-Shi I chemical compound, wherein R ^xBe the optional C that replaces ₂-C ₃Alkyl; R ^yBe NH; And R ^zBe C ₁-C ₆Alkyl.

In another embodiment, the invention provides formula II chemical compound:

Formula II

Or its tautomer or pharmaceutically acceptable salt, wherein

R ^sIndependently be selected from H and F;

Each R ^a, R ^b, R ^cAnd R ^dIndependently be selected from H, halogen, low-carbon alkyl, OR ³, SR ³, C (O) N (R ⁴) ₂, NR ⁴R ⁴, C (O) R ², and-C (O) OR ⁴

R ^xIndependently be selected from the optional C that replaces ₂-C ₆Alkyl, the optional C that replaces ₂-C ₆Thiazolinyl and the optional C that replaces ₂-C ₆Alkynyl;

R ^yIndependently be selected from O, NR ¹Or key;

R ¹Independently be selected from H, the optional alkyl that replaces, the optional thiazolinyl that replaces, the optional alkynyl that replaces, the optional cycloalkyl that replaces, the optional assorted alkyl that replaces, the optional aryl that replaces, optional heterocyclic radical, C (O) R that replaces ²,-C (O) OR ², C (O) NR ⁴ ₂, C (S) OR ², C (S) NR ⁴ ₂, P (O) (OR ⁴) ₂And SO ₂R ²

R ³Independently be selected from H, the optional alkyl that replaces, the optional cycloalkyl that replaces, the optional assorted alkyl that replaces, the optional aryl that replaces, optional heterocyclic radical, C (O) NR that replaces ⁴ ₂, C (O) R ², and-C (O) OR ²With

R ⁴Independently be selected from H, the optional alkyl that replaces, the optional cycloalkyl that replaces, the optional assorted alkyl that replaces, the optional aryl that replaces and the optional heterocyclic radical that replaces.

The present invention also provides following embodiment:

-Shi II chemical compound, wherein R ^a, R ^b, R ^cAnd R ^dIn at least one be halogen; R ^xBe the optional C that replaces ₂-C ₃Alkyl; R ^yIt is key; And R ^zBe H;

-Shi II chemical compound, wherein R ^a, R ^b, R ^cAnd R ^dIn at least one be halogen; R ^xBe the optional C that replaces ₂-C ₃Alkyl; R ^yBe NR ¹And R ^zBe H;

-Shi II chemical compound, wherein R ^a, R ^b, R ^cAnd R ^dIn at least one be halogen; R ^xBe the optional C that replaces ₂-C ₃Alkyl; R ^yBe NR ¹And R ^zBe C ₁-C ₆Alkyl;

-Shi II chemical compound, wherein R ^a, R ^b, R ^cAnd R ^dIn at least one be halogen; R ^xBe the optional C that replaces ₂-C ₃Alkyl; R ^yIt is key; And R ^zBe-P (O) (OR ⁴) ₂With

-Shi II chemical compound, wherein R ^a, R ^b, R ^cAnd R ^dIn at least one be methoxyl group; R ^xBe the optional C that replaces ₂-C ₃Alkyl; R ^yIt is key; And R ^zBe H.

In another embodiment, the invention provides the formula III chemical compound:

Formula III

Or its tautomer or pharmaceutically acceptable salt, wherein

R ^sIndependently be selected from H and F;

R ^yIndependently be selected from O, NR ¹And key; With

The present invention also provides following embodiment:

-formula III chemical compound, wherein R ^a, R ^cAnd R ^dIn at least one be halogen; R ^xBe the optional C that replaces ₂-C ₃Alkyl; R ^yIt is key; And R ^zBe H;

-formula III chemical compound, wherein R ^a, R ^cAnd R ^dIn at least one be halogen; R ^xBe the optional C that replaces ₂-C ₃Alkyl; R ^yBe NR ¹And R ^zBe H;

-formula III chemical compound, wherein R ^a, R ^cAnd R ^dIn at least one be halogen; R ^xBe the optional C that replaces ₂-C ₃Alkyl; R ^yIt is key; And R ^zBe C ₁-C ₆Alkyl; With

-formula III chemical compound, wherein R ^a, R ^cAnd R ^dIn at least one be halogen; R ^xBe the optional C that replaces ₂-C ₃Alkyl; R ^yIt is key; And R ^zBe-P (O) (OR ⁴) ₂

In another embodiment, the invention provides formula IV chemical compound:

Formula IV

Or its tautomer or pharmaceutically acceptable salt, wherein

X independently is selected from H, halogen, CN, N ₃, N (R ¹) ₂, NR ¹S (O) ₂R ², OR ³, SR ³, low-carbon alkyl, C (O) N (R ⁴) ₂, perhaloalkyl radical (perhaloalkyl), C (O) R ²With-C (O) OR ⁴

Y independently is selected from the optional alkyl that replaces, the optional thiazolinyl that replaces, the optional alkynyl that replaces, the optional aryl that replaces, the optional alicyclic ring that replaces, the optional aralkyl that replaces, the optional aryloxy alkyl that replaces, the optional alkoxyalkyl that replaces, the optional heterocyclic radical that replaces, optional alkyl amino the alkyl ((CH that replaces ₂) _n-NHR ²), optional alkyl amino the dialkyl group ((CH that replaces ₂) _n-NR ²R ²), the optional alkyl-carbonyl-amino alkyl that replaces ,-(CH ₂) _n-C (O)-NR ⁴R ⁴), optional alkyl carbonyl oxy the alkyl ((CH that replaces ₂) _n-C (O)-O-R ⁴), hydroxyalkyl ((CH ₂) _n-OH), alkylhalide group ((CH ₂) _n-halogen), perhaloalkyl radical, aminoalkyl ((CH ₂) _n-NH ₂), C (O) R ², S (O) ₂R ², C (O) NR ⁴ ₂And C (O) OR ²

Z independently is selected from H and halogen;

R ¹Independently be selected from H, the optional alkyl that replaces, the optional cycloalkyl that replaces, the optional assorted alkyl that replaces, the optional aryl that replaces, optional heterocyclic radical, C (O) R that replaces ²,-C (O) OR ², C (O) NR ⁴ ₂, C (S) OR ², C (S) NR ⁴ ₂, P (O) (OR ⁴) ₂And SO ₂R ²

R ³Independently be selected from H, the optional alkyl that replaces, the optional cycloalkyl that replaces, the optional assorted alkyl that replaces, the optional aryl that replaces, optional heterocyclic radical, C (O) NR that replaces ⁴ ₂, C (O) R ²With-C (O) OR ²

R ⁴Independently be selected from H, the optional alkyl that replaces, the optional cycloalkyl that replaces, the optional assorted alkyl that replaces, the optional aryl that replaces and the optional heterocyclic radical that replaces; With

N is 1 to 3.

In another embodiment, the invention provides formula V chemical compound:

Formula V

Or its tautomer or pharmaceutically acceptable salt, wherein

X independently is selected from H, halogen, CN, N ₃, N (R ¹) ₂, NR ¹S (O) ₂R ², OR ³, SR ³, low-carbon alkyl, C (O) N (R ⁴) ₂, perhaloalkyl radical, C (O) R ²With-C (O) OR ⁴

Z independently is selected from H and halogen;

N is 1 to 3.

In another embodiment, the invention provides formula VI chemical compound:

Formula VI

Or its tautomer or pharmaceutically acceptable salt, wherein

Z independently is selected from H and halogen;

N is 1 to 3.

In another embodiment, the invention provides and be selected from following chemical compound:

9 - (tert-butyl - dimethyl - silyloxy methyl (silanyloxymethyl)) -8 - (2 - iodo-5 - methoxy - phenyl Sulfanyl)-9H-purin-6 - amine; 9 - (2 - chloro - ethyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - Ylamine; 9 - (3 - chloro - propyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 9 - (4 - chloro - Ding Yl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 8-( 2 - iodo-5 - methoxy - phenyl thioalkoxy Yl) -9 - [3 - (4 - methyl - piperazin-1 - yl) - propyl]-9H-purin-6 - amine; 9 - (3 - dimethylamino - propyl) -8 - (2 - iodo- -5 - Methoxy - phenylsulfanyl)-9H-purin-6 - amine; 8-( 2 - iodo-5 - methoxy - phenylsulfanyl) -9 - (3 - piperidin- -1 - Yl - propyl)-9H-purin-6 - amine; 9 - (3 - cyclopropylamino - propyl) -8 - (2 - iodo-5 - methoxy - phenyl thioalkoxy Yl)-9H-purin-6 - amine; 8-( 2 - iodo-5 - methoxy - phenylsulfanyl) -9 - (3 - morpholin-4 - yl - propyl)-9H - allopurinol Methotrexate -6 - ylamine; 8-( 2 - iodo-5 - methoxy - phenylsulfanyl) -9 - (3 - methylamino - propyl)-9H-purin-6 - amine; 9 - (3 - ethylamino - propyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 8-( 2 - Iodo-5 - A Group - phenylsulfanyl) -9 - [2 - (4 - methyl - piperazin-1 - yl) - ethyl]-9H-purin-6 - amine; 8-( 2 - Iodo-5 - methoxy- - Phenylsulfanyl) -9 - (2 - piperidin-1 - yl - ethyl)-9H-purin-6 - amine; 8-( 2 - iodo-5 - methoxy - phenyl thioalkoxy Yl) -9 - (2 - propyl-amino - ethyl)-9H-purin-6 - amine; 8-( 2,5 - dimethoxy - phenylsulfanyl) -9 - (3 - two armor Ylamino - propyl)-9H-purin-6 - amine; 8-( 2 - iodo-5 - methoxy - phenylsulfanyl) -9 - (2 - isopropylamino - B Yl)-9H-purin-6 - amine; 9 - (2 - butylamino - ethyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purine -6 - Ylamine; 9 - (2 - sec-butylamino - ethyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 9 - [2 - (1 - ethyl - propyl-amino) - ethyl]-8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - yl amine; 9 - (2 - Cyclopropylamino - ethyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 8-( 2 - iodo-5 - methoxy- Yl - phenylsulfanyl) -9 - [2 - (3 - methyl - butylamino) - ethyl]-9H-purin-6 - amine; 9 - [2 - (3,3 - dimethoxyphenyl base - Butylamino) - ethyl]-8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; {2 - [6 - amino-8 - (2 - Iodo-5 - methoxy - phenylsulfanyl) - purin-9 - yl] - ethylamino} - acetonitrile; 2 - {2 - [6 - amino-8 - (2 - iodo-5 - methoxy- Yl - phenylsulfanyl) - purin-9 - yl] - ethylamino} - ethanol; 8-( 2 - iodo-5 - methoxy - phenyl thioalkoxy Yl) -9 - [2 - (2 - methoxy - ethylamino) - ethyl]-9H-purin-6 - amine; 9 - (2 - cyclopentyl-amino - ethyl) -8 - ( 2 - Iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 9 - (2 - cyclohexyl-amino - ethyl) -8 - (2 - iodo-5 - methoxy- Yl - phenylsulfanyl)-9H-purin-6 - amine; 9 - (2 - cycloheptyl amino - ethyl) -8 - (2 - iodo-5 - methoxy - phenyl sulfide Alkyl)-9H-purin-6 - amine; 9 - (2 - amino cyclooctyl - ethyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H- Purin-6 - amine; 9 - [2 - (cyclopropylmethyl - amino) - ethyl]-8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purine -6 - Ylamine; 8-( 2 - iodo-5 - methoxy - phenylsulfanyl) -9 - [2 - (2 - methyl - allyl-amino) - ethyl]-9H-purine -6 - Ylamine; 9 - (2 - tert-butyl-amino - ethyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 9 - (3 - Amino - propyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 9 - (2 - cyclopropylamino - B Yl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 9 - (2 - allyl-amino - ethyl) -8 - (2 - Iodine -5 - Methoxy - phenylsulfanyl)-9H-purin-6 - amine; 8-( 2 - iodo-5 - methoxy - phenylsulfanyl) -9 - (2 - morpholin- -4 - yl - ethyl)-9H-purin-6 - amine; 8-( 2 - iodo-5 - methoxy - phenylsulfanyl) -9 - (3 - propylamino - C Yl)-9H-purin-6 - amine; 9 - (3 - heptyl-amino - propyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purine -6 - Ylamine; 9 - (3 - cyclopentyl-amino - propyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 9 - (3 - amino cyclooctyl - propyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 8-( 2 - iodo - 5 - Methoxy - phenylsulfanyl) -9 - (3 - isobutyl-amino - propyl)-9H-purin-6 - amine; 8-( 2 - iodo-5 - methoxy - phenyl Ylsulfanyl) -9 - [3 - (1,2,2 - trimethyl - propylamino) - propyl]-9H-purin-6 - amine; 4 - {3 - [6 - amino - 8-( 2 - Iodo-5 - methoxy - phenylsulfanyl) - purin-9 - yl] - propyl-amino} - piperidine-1 - carboxylic acid tert-butyl ester; 9 - (2 - benzylamino - Ethyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 9 - [3 - (1,1 - dimethyl - propyl group ) - Propyl]-8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 9 - (3 - cyclobutylamino - propyl) -8 - ( 2 - Iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 9 - (3 - amino - propyl) -8 - (2 - iodo-5 - methoxy - phenyl Sulfanyl)-9H-purin-6 - amine; {2 - [6 - amino-8 - (2 - iodo-5 - methoxy - phenylsulfanyl) - purin-9 - yl] - acetic Yl} - carbamic acid tert-butyl ester; 9 - (2 - amino - ethyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - Ylamine; 2 - [6 - amino-8 - (2 - iodo-5 - methoxy - phenylsulfanyl) - purin-9 - yl] - acetamide; 1 - [6 - amino-8 - ( 2 - Iodo-5 - methoxy - phenylsulfanyl) - purin-9 - yl] - propan-2 - one; N-{2 - [6 - amino-8 - (2 - iodo-5 - methoxy- - Benzene Ylsulfanyl) - purin-9 - yl] - ethyl} - acetamide; N-{2 - [6 - amino-8 - (2 - iodo-5 - methoxy - phenylsulfanyl) - Purin-9 - yl] - ethyl} - methanesulfonamide; N-{2 - [6 - amino-8 - (2 - iodo-5 - methoxy - phenylsulfanyl) - purin-9 - Yl] - ethyl}-N-isobutyl - acetamide; N-{2 - [6 - amino-8 - (2 - iodo-5 - methoxy - phenylsulfanyl) - purin-9 - Yl] - ethyl}-N-isobutyl - methanesulfonamide; 8-( 3 - bromo-2 ,5 - dimethoxy - phenylsulfanyl) -9 - (4 - methyl - amyl - 3 - Enyl)-9H-purin-6 - amine; 8-( 3 - bromo-2 ,5 - dimethoxy - phenylsulfanyl) -9 - pent-4 - ynyl-9H-purin-6 - Ylamine; 8-( 2,5 - dimethoxy - biphenyl-3 - yl sulfanyl) -9 - pent-4 - ynyl-9H-purin-6 - amine; 9 - (4 - armor Yl - pent-3 - enyl) -8 - (thiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 8-( benzothiazol-2 - yl sulfanyl) -9 - ( 4 - Methyl - pent-3 - enyl)-9H-purin-6 - amine; 8-( 1H-benzimidazol-2 - yl sulfanyl) -9 - (4 - methyl - pent-3 - ene Yl)-9H-purin-6 - amine; 2 - [6 - amino-8 - (naphth-2 - yl sulfanyl) - purin-9 - yl] - acetate; 2 - [6 - amino- -8 - (Naphthalen-1 - yl sulfanyl) - purin-9 - yl] - acetate; 2 - [6 - amino-8 - (quinolin-8 - yl sulfanyl) - purin-9 - Yl] - acetate; 2 - [6 - amino -8 - (1H-indol-2 - yl sulfanyl) - purin-9 - yl] - acetate; 2 - [6 - amino- -8 - (2,5 - dimethoxy - phenylsulfanyl) - purin-9 - yl] - acetate; 2 - [6 - amino-8 - (benzo [b] thiophene-2 - Ylsulfanyl) - purin-9 - yl] - acetate; 8-( benzothiazol-2 - yl sulfanyl) -9 - pent-4 - ynyl-9H-purin-6 - Ylamine; 9 - pent-4 - alkynyl-8 - (quinolin-2 - yl sulfanyl)-9H-purin-6 - amine; 8-( 1 - allyl-1H-benzimidazol- Oxazol-2 - yl sulfanyl) -9 - (4 - methyl - pent-3 - enyl)-9H-purin-6 - amine; 8-( 1 - methyl-1H-benzimidazol-2 - Ylsulfanyl) -9 - (4 - methyl - pent-3 - enyl)-9H-purin-6 - amine; 2 - [6 - amino-8 - (naphth-2 - ylthio group) - purine -9 - Yl] - ethanol; 2 - [6 - amino-8 - (naphthalen-1 - yl sulfanyl) - purin-9 - yl] - ethanol; 2 - [6 - amino-8 - (quinolin - 8 - Ylsulfanyl) - purin-9 - yl] - ethanol; 2 - [6 - amino-8 - (3 - chloro-1H-indol-2 - yl sulfanyl) - purin-9 - yl] - acetic Ethyl; 2 - [6 - amino-8 - (3 - bromo-1H-indol-2 - yl sulfanyl) - purin-9 - yl] - acetate; 2 - [6 - amino- -8 - (3 - iodo-1H-indol-2 - yl sulfanyl) - purin-9 - yl] - acetate; 2 - [6 - amino-8 - (1 - propyl-1H-indole indole -2 - Yl sulfanyl) - purin-9 - yl] - acetate; 2 - [6 - amino-8 - (3 - iodo-1 - propyl-1H-indol-2 - yl sulfanyl ) - Purin-9 - yl] - acetate; 2 - [6 - amino-8 - (1,4 - dimethoxy - naphthalene-2 - yl sulfanyl) - purin-9 - yl] - ethyl acetate Ester; 3 - [6 - amino-8 - (benzo [1,3] dioxole (dioxol) -5 - yl sulfanyl) - purin-9 - yl] -1 - propanol; 3 - [6 - amino-8 - (2,3 - dihydro - benzo [1,4] dioxin -6 - yl sulfanyl) - purin-9 - yl] -1 - propanol; 9 - butyl -8 - (7 - chloro - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 9 - ethyl-8 - (7 - chloro - benzothiazol-2 - yl thioalkoxy Yl)-9H-purin-6 - amine; 9 - propyl-8 - (7 - chloro - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 9 - E -8 - (7 - chloro - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 8-( 7 - bromo - benzothiazol-2 - yl thioalkoxy Yl) -9 - butyl-9H-purin-6 - amine; 9 - butyl-8 - (7 - methyl - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - Ylamine; 9 - butyl-8 - (7 - methoxy - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 9 - butyl-8 - (7 - B Oxy - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 9 - butyl-8 - (7 - fluoro - benzothiazol-2 - yl thioalkoxy Yl)-9H-purin-6 - amine; 9 - butyl-8 - (7 - (trifluoromethyl) - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - yl Amine; 8-( benzothiazol-2 - yl sulfanyl) -9 - butyl-9H-purin-6 - amine; 9 - butyl-8 - (6 - chloro - benzothiazol-2 - Ylsulfanyl)-9H-purin-6 - amine; 9 - butyl-8 - (5 - chloro - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - yl Amine; 9 - butyl-8 - (4 - chloro - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 9 - butyl-8 - (4 - chloro - benzothiazol Oxazol-2 - yl sulfanyl)-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - pent-4 - ynyl-9H- Purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - (2 - methoxy - ethyl)-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - (2 - vinyloxy (vinyloxy) - ethyl)-9H-purin-6 - amine; 9 - butyl-8 - (thiazolo [5,4-b] pyridin-2 - yl sulfanyl)-9H-purin-6 - amine; 4 - [6 - amino-8 - (7 - fluoro - phenyl and thiophene Oxazol-2 - yl sulfanyl) - purin-9 - yl] - Titanium Dioxide; 8-( 4 - bromo-6 ,7 - difluoro - benzothiazol-2 - yl sulfanyl)-9 - D Yl-9H-purin-6 - amine; 9 - butyl-8 - (6,7 - dichloro - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 9 - Butyl-8 - (6,7 - difluoro - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 8-( 6,7 - dichloro - benzothiazol-2 - Ylsulfanyl) -9 - pent-4 - ynyl-9H-purin-6 - amine; 3 - [6 - amino-8 - (6,7 - dichloro - benzothiazol-2 - yl thioalkoxy Yl) - purin-9 - yl] - propyl acetate; 9 - t -3 - en-8 - (7 - chloro - benzothiazol-thiazol-2 - yl sulfanyl)-9H-purine -6 - Ylamine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - pent-4 - ynyl-9H-purin-6 - amine; 8-( 7 - methoxy- base - Benzothiazol-2 - yl sulfanyl) -9 - pent-4 - ynyl-9H-purin-6 - amine; 8-( 7 - methyl - benzothiazol-2 - yl thioalkoxy Yl) -9 - pent-4 - ynyl-9H-purin-6 - amine; 9 - butyl-8 - (7 - methoxymethoxy-methyl - benzothiazol-2 - ylthio Alkyl)-9H-purin-6 - amine; 3 - [6 - amino-8 - (7 - methoxy - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] - Propyl acetate; 3 - [6 - amino-8 - (7 - methyl - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] - propyl acetate; 8-( 4 - Amino-7 - fluoro - benzothiazol-2 - yl sulfanyl) -9 - pent-4 - ynyl-9H-purin-6 - amine; 8-( 7 - ethoxy - benzothiazole Oxazol-2 - yl sulfanyl) -9 - pent-4 - ynyl-9H-purin-6 - amine; 2 - [6 - amino-8 - (7 - methoxy - benzothiazol-2 - Ylsulfanyl) - purin-9 - yl] - acetate; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - ethyl-9H-purin-6 - Ylamine China; - chloro-8 - (7 - chloro - benzothiazol-2 - yl sulfanyl)-9 - methyl-9H-purin-6 - amine; 8-( 7 - bromo - thiazole [5,4-b] pyridin-2 - yl sulfanyl) -9 - butyl-9H-purin-6 - amine; 8-( 7 - bromo - thiazolo [4,5-c] pyridin-2 - Base sulfane Yl) -2 - chloro-9 - methyl-9H-purin-6 - amine; 2 - [6 - amino-8 - (7 - bromo - thiazolo [4,5-c] pyridin-2 - yl thioalkoxy yl) - Purin-9 - yl] - acetate; 8-( 7 - bromo - thiazolo [5,4-b] pyridin-2 - yl sulfanyl) -9 - butyl-9H-purin-6 - Ylamine; 3 - [6 - amino-8 - (7 - bromo - thiazolo [4,5-c] pyridin-2 - yl sulfanyl) - purin-9 - yl] - propyl acetate; 8-( 7 - Bromine - thiazolo [4,5-c] pyridin-2 - yl sulfanyl) -9 - (4 - methyl - pent-3 - enyl)-9H-purin-6 - amine; 2 - [6 - amino -8 - (7 - bromo - thiazolo [4,5-c] pyridin-2 - yl sulfanyl) - purin-9 - yl] - acetate; 8-( 7 - bromo - thiazolo [5,4 -b] Pyridin-2 - yl sulfanyl) -2 - chloro-9 - methyl-9H-purin-6 - amine; 3 - [6 - amino-8 - (7 - chloro - thiazolo [4,5-c ] pyridine -2 - yl sulfanyl) - purin-9 - yl] - propyl acetate; 9 - butyl-8 - (7 - chloro - benzoxazol-2 - yl sulfanyl)-9H- Purin-6 - amine; 2 - [6 - amino-8 - (7 - chloro - benzoxazol-2 - yl sulfanyl) - purin-9 - yl] - acetate; 3 - [6 - Amino-8 - (7 - chloro - benzoxazol-2 - ylsulfanyl) - purin-9 - yl] - propyl acetate; 9 - butyl-8 - (7 - fluoro - benzoxathiol Oxazol-2 - yl sulfanyl)-9H-purin-6 - amine; 2 - [6 - amino-8 - (7 - chloro - benzothiazol-2 - yl sulfanyl) - purin-9 - Yl] - acetate; 2 - [6 - amino-8 - (7 - fluoro - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] - acetate; 4 - [6 - Amino-8 - (7 - chloro - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] - Titanium Dioxide; 3 - [6 - amino-8 - (7 - fluoro - benzo Thiazol-2 - yl sulfanyl) - purin-9 - yl] - propyl acetate; 3 - [6 - amino-8 - (7 - bromo - benzothiazol-2 - yl sulfanyl) - Purin-9 - yl] - propyl acetate; 2 - [6 - amino-8 - (7 - chloro - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] - ethanol; 2 - [6 - amino-8 - (7 - fluoro - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] - ethanol; 2 - [6 - amino-8 - (7 - chloro - benzene and Thiazol-2 - yl sulfanyl) - purin-9 - yl] -1 - propanol; 4 - [6 - amino-8 - (7 - chloro - benzothiazol-2 - yl sulfanyl) - allopurinol Methotrexate -9 - yl] -1 - butanol; 4 - [6 - amino-8 - (7 - fluoro - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] -1 - butanol; 3 - [6 - Amino-8 - (7 - fluoro - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] - propanol; 3 - [6 - amino-8 - (6,7 - dichloro - benzo thiophene Oxazol-2 - yl sulfanyl) - purin-9 - yl] -1 - propanol; 3 - [6 - amino-8 - (7 - bromo - benzothiazol-2 - yl sulfanyl) - purine -9 - Yl] - propanol; 3 - [6 - amino-8 - (7 - methoxy - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] - propanol; 2 - [ 6 - Amino-8 - (7 - methoxy - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] - ethanol; 3 - [6 - amino-8 - (7 - methyl - phenyl And thiazol-2 - yl sulfanyl) - purin-9 - yl] - propanol; 2 - [6 - amino-8 - (7 - bromo - thiazolo [4,5-c] pyridin-2 - ylthio Alkyl) - purin-9 - yl] - ethanol; 2 - [6 - amino-8 - (7 - chloro - thiazolo [5,4-b] pyridin-2 - yl sulfanyl) - purin-9 - Yl] - ethanol; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - [3 - (1 - ethyl - propyl-amino) - propyl]-9H-purin-6 - Ylamine; 9 - (3 - tert-butylamino - propyl) -8 - (7 - chloro - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 8-( 7 - Chloro - benzothiazol-2 - yl sulfanyl) -9 - (3 - isobutyl-amino - propyl)-9H-purin-6 - amine; 9 - (3 - sec-butylamino - Propyl) -8 - (7 - chloro - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 9 - [2 - (2,2 - dimethyl - propyl group ) - Ethyl]-8 - (7 - chloro - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 9 - [2 - isopropylamino - ethyl] -8 - (7 - Methoxy - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 9 - [2 - tert-butylamino - ethyl]-8 - (7 - methoxy- - Benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 9 - (2 - isobutyl-amino - ethyl) -8 - (7 - methoxy - benzo Thiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - [3 - (2,2 - dimethyl base - Propylamino) - propyl]-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - (2 - prop-2 - ynyl ammonia Yl - ethyl)-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - (2 - cyclopentyl-amino - ethyl Yl)-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - [2 - (3 - methyl - butylamino) - B Yl]-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - [2 - (1,1 - dimethyl - propylamino) - B Yl]-9H-purin-6 - amine; 9 - (2 - allyl-amino - ethyl) -8 - (7 - chloro - benzothiazol-2 - yl sulfanyl)-9H-purine Methotrexate -6 - ylamine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - (3 - isopropylamino - propyl)-9H-purin-6 - amine; 8-( 7 - chloro-1 - benzothiazol-2 - yl sulfanyl) -9 - (3 - pyrrol-1 - yl - propyl)-9H-purin-6 - amine; 8-( 7 - chloro- - benzo Thiazol-2 - yl sulfanyl) -9 - [2 - (3,3 - dimethyl - butylamino) - ethyl]-9H-purin-6 - amine; 8-( 7 - chloro - benzene and Thiazol-2 - yl sulfanyl) -9 - (3 - morpholin-4 - yl - propyl)-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl Sulfanyl) -9 - (2 - morpholin-4 - yl - ethyl)-9H-purin-6 - amine; 9 - (2 - bromo - ethyl) -8 - (7 - chloro - benzene benzothiazole -2 - Yl sulfanyl)-9H-purin-6 - amine; 8-( 7 - fluoro - benzothiazol-2 - yl sulfanyl) -9 - (2 - vinyl group - B Yl)-9H-purin-6 - amine; 8-( 7 - fluoro - benzothiazol-2 - yl sulfanyl) -9 - pent-4 - ynyl-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - (2 - chloro - ethyl)-9H-purin-6 - amine; 9 - (3 - bromo - propyl) - 8-( 7 - Chloro - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - pent-4 - Enyl-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - hex-5 - enyl-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - [2, (2,5 - dimethoxy - phenyl) - ethyl]-9H-purin-6 - yl amine ; 9 - Butan-2 - yn-8 - (7 - chloro - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - ylthio Alkyl) -9 - (3,4,4 - trifluoro - but-3 - enyl)-9H-purin-6 - amine; 6 - [6 - amino-8 - (7 - chloro - benzothiazole -2 - yl sulfide Alkyl) - purin-9 - yl] - cyclohexanecarbonitrile; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - (3 - methyl - but-3 - enyl)-9H - allopurinol Methotrexate -6 - ylamine; 4 - [6 - amino-8 - (7 - chloro - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] - butyronitrile; 8-( 7 - chloro - benzo Thiazol-2 - yl sulfanyl) -9 - hex-5 - ynyl-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl thioalkoxy Yl) -9 - [3 - (tetrahydro - furan-2 - yl) - propyl]-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl thioalkoxy Yl) -9 - (tetrahydro - furan-2 - ylmethyl)-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl thioalkoxy Yl) -9 - [2 - (2 - ethoxy - ethoxy) - ethyl]-9H-purin-6 - amine; 5 - [6 - amino-8 - (7 - chloro - benzothiazole -2 - Ylsulfanyl) - purin-9 - yl] - pentanenitrile; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - (4 - methoxy-3 ,5 - dimethyl base - Pyridin-2 - ylmethyl)-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - prop-2 - ynyl-9H- Purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - (2 - piperidin-1 - yl - ethyl)-9H-purin-6 - yl amine ; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - (2 - methylsulfanyl - ethyl)-9H-purin-6 - amine; 8-( 7 - chloro - benzene And thiazol-2 - yl sulfanyl) -9 - (2 - ethyl-sulfanyl - ethyl)-9H-purin-6 - amine; 3 - [6 - amino-8 - (7 - chloro - benzene And thiazol-2 - yl sulfanyl)-9 - yl] - propyl phosphate, diethyl ester; 2 - [6 - amino-8 - (7 - chloro - benzothiazol-2 - yl thioalkoxy Yl) - purin-9 - yl] - ethyl-II - (2 - chloro - ethyl) phosphate; {3 - [6 - amino-8 - (7 - chloro - benzothiazol-2 - yl thioalkoxy Yl) - purin-9 - yl] - propenyl} - phosphonic acid diethyl ester; 2 - [6 - amino-8 - (7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - Yl] -, diethyl ester; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl)-9 - methyl-9H-purin-6 - amine; 4 - [6 - Amino-8 - (7 - chloro - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] - butan-2 - one; 8-( 7 - chloro - benzothiazol-2 - ylthio Alkyl) -9 - (2 - ethylsulfinyl - ethyl)-9H-purin-6 - amine; 4 - [6 - amino-8 - (7 - chloro - benzothiazol-2 - yl Sulfanyl) - purin-9 - yl] - D - 2 - thione; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - (2 - ethylsulfonyl - B Yl)-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - (2 - methylsulfonyl - ethyl)-9H-purine -6 - Ylamine; (6 - amino-9 - butyl-9H-purin-8 - yl sulfanyl) - benzothiazol-7 - yl) - methanol; 9 - (2 - dimethyl- Amino - ethyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 9 - (2 - diethylamino - B Yl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 8-( 2 - iodo-5 - methoxy - phenyl thioalkoxy Yl) -9 - (2 - pyrrolidin-1 - yl - ethyl)-9H-purin-6 - amine; 8-( 2 - iodo-5 - methoxy - phenylsulfanyl) -9 - (2 - Vinyloxy - ethyl)-9H-purin-6 - amine; 8-( 2 - iodo-5 - methoxy - phenylsulfanyl) -9 - (2 - isopropoxy - Ethyl)-9H-purin-6 - amine; {3 - [6 - amino-8 - (2 - iodo-5 - methoxy - phenylsulfanyl) - purin-9 - yl] - C Yl} - methyl - amino acid - tert-butyl ester; 8-( 2 - iodo-5 - methoxy - phenylsulfanyl) -9 - (3 - pyrrol-1 - yl - C Yl)-9H-purin-6 - yl amine; (2,4 - iodo-5 - methoxy - phenylsulfanyl) -9 - pent-4 - ynyl-9H-purin-6 - yl Amine; {3 - [6 - amino-8 - (2 - iodo-5 - methoxy - phenylsulfanyl) - purin-9 - yl] - propyl} - carbamic acid - tert-butyl ester; 8-( 2 - iodo-5 - (Trifluoromethoxy) - phenylsulfanyl) -9 - pent-4 - ynyl-9H-purin-6 - yl amine and 8-( 2 - iodo-5 - Three fluorine Methyl - phenylsulfanyl) -9 - pent-4 - ynyl-9H-purin-6 - amine. ...

The accompanying drawing summary

[0017] novel feature of the present invention elaborates in appended claims.Following the detailed description and the accompanying drawings that the better understanding of feature of the present invention and advantage---is wherein used principle of the present invention---with reference to the illustrated example embodiment and obtaining, accompanying drawing is as follows:

[0018] Fig. 1(a) be illustrated in 200mg/kg single oral administration 89H ₃PO ₄After, in Mus A549 tumor xenogeneic graft, the level of Hsp90 client Hsp70 and PI-3K p85; (b) at 17-AAG (intraperitoneal, 1 * 90mg/kg/ days) or 126H ₃PO ₄After (oral, 2 * 200 or 2 * 100mg/kg/ days) course of treatment on the three 24 hours, in Mus N87 tumor xenogeneic graft, the level of Hsp90 client and PI-3K.

[0019] Fig. 2Be illustrated in by (a) inhibitor 109H ₃PO ₄And 126H ₃PO ₄, oral delivery (1 * 200mg/kg/ days, 5 days/week) or (b) inhibitor 132H ₃PO ₄, the tumor growth in the inductive Mus N87 xenograft models of oral delivery (2 * 100mg/kg/ days, 5 days/week) suppresses level.Error bar (Errorbars)=SEM

[0020] Fig. 3264 the pharmacokinetic studies that expression is sent with the 100mg/kg oral gavage.

[0021] Fig. 4Be illustrated in the N87 xenograft models, 264 tumor growth suppresses research.

Invention is described in detail

[0022], although the preferred embodiment of the present invention illustrates in this article and describes, it will be apparent for a person skilled in the art that these embodiments only provide by the mode of demonstration. Those skilled in the art will know now numerous changes, variation and substitute, and this does not deviate from the present invention. Should be appreciated that, can be for implementing the present invention to the multiple change of embodiment described herein. Below claim intention limit scope of the present invention, and in the method and structure in these claim scopes and equivalent intention thereof cover.

Definition

[0023] " pharmaceutically acceptable salt " can prepare for any compound that has the functional group that can form salt in the present invention, for example sour functional group or alkali functional group. Pharmaceutically acceptable salt can be derived from the organic or inorganic bronsted lowry acids and bases bronsted lowry.

[0024] contain for example the compounds of this invention of amino or alkyl amino of one or more alkali functional group, can form and have pharmaceutically acceptable salt with pharmaceutically acceptable organic acid and inorganic acid. These salt can be in the final separation of the compounds of this invention and the preparation of purge process situ, or the compounds of this invention of the free alkali form by making respectively purifying prepares with the salt that separates formation like this with suitable organic acid or inorganic acid reaction. The example of suitable acid comprises hydrochloric acid, hydrobromic acid, sulfonic acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic, gluconic acid, lactic acid, salicylic acid, butanedioic acid, P-TOLUENE SULFO ACID 99, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, 1,2-ethanesulfonic acid (ethionic acid (edisylate)), galactolipin-d-gluconic acid etc. Other acid,, although as oxalic acid itself, be not pharmaceutically acceptable, can be used in the preparation of salt, for the intermediate that obtains the compounds of this invention and their pharmaceutically acceptable acid, adds salify. Referring to, for example, Berge et al. ＂ Pharmaceutical Salts ＂, J.Pharm.Sci.66:1-19 (1977).

[0025] contain the compounds of this invention of one or more sour functional groups, can form pharmaceutically acceptable salt with pharmaceutically acceptable alkali. Term " pharmaceutically acceptable salt " refers to inorganic and organic base addition salts relatively nontoxic, the compounds of this invention in this case. These salt can be equally in the final separation of compound and the preparation of purge process situ; Or the compound of the free acid form by making respectively purifying and suitable alkali such as hydroxide, carbonate or bicarbonate and the ammonia of pharmaceutically acceptable metal cation, or with pharmaceutically acceptable organic primary amine, secondary amine or reactive tertiary amine, prepare. Representational alkali salt or alkaline earth salt comprise lithium salts, sodium salt, sylvite, calcium salt, magnesium salts and aluminium salt etc. The exemplary example of more adaptable alkali comprises NaOH, potassium hydroxide, bursine, sodium carbonate etc. The representative organic amine that is used to form base addition salts comprises ethamine, diethylamine, 1,2-ethylenediamine, monoethanolamine, diethanol amine, piperazine etc. Referring to, for example, Berge et al., as above.

[0026] " pro-drug (Prodrugs) " gives by adding the derivatization compound of expecting that the larger deliquescent group of compound of sending is derivatized. In case in body, pro-drug generally passes through for example effect generation reactive compound of esterase, amidase or phosphatase of enzyme. Be used for the derivative of the compounds of this invention and include but not limited to Y group, the benzyl ring of purine, and Q group with the correct position that produces " pro-drug ". Those of ordinary skill has had this process and has not needed knowledge and the means too much tested. The example of the pro-drug that the present invention considers comprises without limitation:

The alcohols pro-drug

Medicine-OH

Medicine-OX, X=pro-drug part

R=alkyl, aryl or heteroaryl

R ', R " independently be selected from hydrogen, alkyl, aryl or heteroaryl

R=alkyl, aryl or heteroaryl

R=alkyl, aryl or heteroaryl

R=alkyl, aryl or heteroaryl

The amine precursor medicine

Medicine-NHX

R=alkyl, aryl or heteroaryl

R=hydrogen, alkyl, aryl or heteroaryl

R=alkyl, aryl or heteroaryl

X＝——CH ₂NHC (O) R R=aryl or heteroaryl

R=aryl or heteroaryl

The carboxyl pro-drug

Medicine-COOX

X=alkyl, aryl or heteroaryl.

[0027] " dynamic isomer (Tautomers) " is its structure compound that difference but balance exist aspect the atom arrangement. By the example mode, hereinafter shown in and the structure of called after T and the second tautomeric form balance of called after T '.

[0028] a kind of dynamic isomer is controlled by following factor for the advantage of another dynamic isomer, its include but not limited to solvent character, temperature, pressure, other molecule existence whether and have substituent character on the molecule of tautomeric form.

[0029] term " alkyl " is used alone or in combination, and refers to the optional straight chained alkyl that replaces, the optional branched alkyl that replaces or the optional cycloalkyl that replaces, and it has 1 to about 30 carbon, more preferably 1 to 12 carbon. The example of alkyl comprises methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, tertiary pentyl, amyl group, hexyl, heptyl, octyl group etc. Term " cycloalkyl " comprises the ring-type configuration, is included in the definition of alkyl and specifically refers to the alkyl of monocycle, dicyclo, three rings and more rings, and wherein each ring portion is divided and had 3 to about 8 carbon atoms. The example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc. " low-carbon alkyl " is shorter alkyl, for example, comprises 1 alkyl to about 6 carbon atoms.

[0030] term " thiazolinyl " is used alone or in combination, refer to the optional straight-chain alkenyl that replaces, the optional branched-chain alkenyl that replaces or the optional cycloalkenyl group that replaces, it has the two keys of one or more carbon carbon and has 2 to about 30 carbon atoms, and more preferably 2 to about 18 carbon. The example of thiazolinyl comprises vinyl, acrylic, cyclobutenyl, 1,4-butadiene base etc. This term also can comprise the cycloalkenyl group structure. " low-carbon (LC) thiazolinyl " refers to have 2 thiazolinyls to about 6 carbon.

[0031] term " alkynyl " is used alone or in combination, refer to the optional straight-chain alkynyl that replaces, an optional alkynyl group that replaces or the optional cycloalkynyl group that replaces, it has one or more carbon carbon triple bonds and has 2 to about 30 carbon atoms, and more preferably 2 to about 12 carbon atoms. This term also comprises the optional straight-chain alkyl that replaces or the optional branched hydrocarbyl that replaces, and it has one or more carbon carbon triple bonds and has 2 to about 6 carbon atoms and have 2 to about 4 carbon atoms. The example of alkynyl comprises acetenyl, propinyl, butine base etc.

[0032] the assorted alkyl of term, assorted thiazolinyl and assorted alkynyl comprise optional alkyl, thiazolinyl and the alkynyl structure that replaces, and as mentioned above, and it has one or more backbone atoms that are selected from non-carbon atom, for example, and oxygen, nitrogen, sulphur, phosphorus or its combination.

[0033] term " carbochain " can comprise any alkyl, thiazolinyl, alkynyl or assorted alkyl, assorted thiazolinyl or assorted alkynyl, and can be linear, ring-type or its any combination. If part joint and this joint comprise the part of one or more rings as the core skeleton, in order to calculate chain length, " chain " only comprises the carbon atom that forms to bottom or the top of fixed ring, rather than both carbon atoms, and when the length of the top of encircling (a plurality of) and bottom is unequal, shorter distance will be used to determine chain length. If chain comprises the part of hetero atom as skeleton, those atoms are not calculated as the part of carbochain length.

[0034] term " alkoxyl " is used alone or in combination, and refers to alkyl ether groups, alkyl-O-, and wherein the term alkyl as above defines. The example of alkoxyl comprises methoxyl group, ethyoxyl, positive propoxy, isopropoxy, positive butoxy, isobutoxy, sec-butoxy, tert-butoxy etc.

[0035] term " aryloxy group " is used alone or in combination, and refers to aryl ether group, and wherein the term aryl is as giving a definition. The example of aryloxy group comprises phenoxy group, benzyloxy etc.

[0036] term " alkyl sulfide generation (alkylthio) " is used alone or in combination, and refers to the alkyl sulfide group, alkyl-S-, and wherein the term alkyl as above defines.

[0037] term " aryl sulfo-(arylthio) " is used alone or in combination, and refers to the aryl methylthio group, aryl-S-, and wherein the term aryl is as giving a definition.

[0038] term " oxo " refers to=O.

[0039] term " aryl " is used alone or in combination, and refers to the optional aromatic ring system that replaces. The term aryl comprises and contains 6 aromatic rings of the monocycle to about 20 carbon atoms, many aromatic rings and many cyclophanes ring. The term aryl also comprises and contains 6 aromatic rings of the monocycle to about 12 carbon atoms, many aromatic rings and encircle aromatic ring system more, and contains 6 those systems to about 10 carbon atoms. Many aromatic rings and many ring aromatic ring systems can comprise 2 to 4 rings. The example of aryl comprises phenyl ring, cyclohexyl biphenyl, naphthalene nucleus and anthracene nucleus system without limitation.

[0040] term " heteroaryl " refers to the optional aromatic ring system that replaces, and it comprises about 5 to about 20 framework ring atoms and has one or more hetero atoms as for example, oxygen, nitrogen, sulphur and phosphorus. The term heteroaryl also comprises the aromatic ring system with 5 optional replacements to about 12 framework ring atoms, and has 5 those systems to about 10 framework ring atoms. The term heteroaryl can comprise 5 yuan or 6 yuan of heterocycles, encircle hetero-aromatic ring system and many hetero-aromatic rings system more, and wherein the ring body cording has 2,3 or 4 rings. The term heterocycle, encircle hetero-aromatic ring and many hetero-aromatic rings more and comprise and contain the ring body system (for example, having 6 rings of 2 nitrogen-atoms) with hetero-aromatic ring of above-mentioned heteroatomic optional replacement more than, comprise many heterocycles system of 2 to 4 rings. The term heteroaryl comprises ring body system as for example, furyl, benzofuranyl, benzopyranyl, pyridine radicals, pyrrole radicals, indyl, quinolyl, N-alkyl pyrrole radicals, pyridine radicals-N-oxide, pyrimidine radicals, pyrazinyl, imidazole radicals, piperazine azoles base, oxazolyl, benzothienyl, purine radicals, indolizine base, thienyl etc.

Term " heteroarylalkyl " refers to contain the C1-C4 alkyl of heteroaryl, and wherein each can be optionally substituted.

[0041] term " heteroaryl sulfo-(heteroarylthio) " refers to group-S-heteroaryl.

[0042] art " acidic group " refers to ester group group-OC (O)-R, and wherein R is H, alkyl, thiazolinyl, alkynyl, aryl or aralkyl, and wherein alkyl, thiazolinyl, alkynyl, aryl and aralkyl can be chosen replacement wantonly.

[0043] term " carboxylate " refers to-C (O) OR, and wherein R is alkyl, aryl or aralkyl, and wherein said alkyl, aryl and aralkyl can be optionally substituted.

[0044] term " formamido " refers to

Wherein each in R and R ' independently is selected from H, alkyl, aryl and aralkyl, and wherein alkyl, aryl and aralkyl can be optionally substituted.

[0045] term " aralkyl " is used alone or in combination, and refers to alkyl as defined above, and one of them H atom is replaced by aryl as defined above, as for example, and benzyl, 2-phenethyl etc.

[0046] term " alkaryl " is used alone or in combination, and refers to aryl as defined above, and one of them H atom is replaced by alkyl as defined above, as for example, and tolyl, xylyl etc.

[0047] term alkylhalide group, haloalkenyl, alkynyl halide and halogen alkoxyl comprise alkyl described above, thiazolinyl, alkynyl and alkoxyl structure, and it is replaced by one or more fluorine, chlorine, bromine or iodine or their combination.

[0048] term cycloalkyl, aryl, aralkyl, heteroaryl, alkyl, alkynyl, thiazolinyl, alkylhalide group and assorted alkyl comprise optional cycloalkyl, aryl, aralkyl, heteroaryl, alkyl, alkynyl, thiazolinyl, alkylhalide group and the assorted alkyl that replaces.

[0049] term " carbocyclic ring " comprises the optional saturated or unsaturated ternary that replaces to the octatomic ring structure, and wherein all skeletal atoms are all carbon.

[0050] term " heterocycle " comprises the optional saturated or unsaturated ternary that replaces to the octatomic ring structure, and wherein one or more skeletal atoms are oxygen, nitrogen, sulphur or phosphorus or its combination. Exemplary example comprises pyridine, pyrans, thiophane (thiophan), pyrroles, furans, thiophene, five yuan or hexa-atomic lactams ring etc.

[0051] term " ring (membered ring) " can comprise any ring structure, comprises carbocyclic ring as above and heterocycle. Term " unit (membered) " refers to the number that generation forms the skeletal atom of ring. Therefore, for example, pyridine, pyrans and thiophane are 6 rings, and pyrroles, furans and thiophene are 5 rings.

[0052] term " acyl group " comprise by the carbonyl functional group be connected to compound alkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl substituting group (for example ,-CO-alkyl ,-the CO-aryl ,-the CO-aralkyl or-CO-heteroarylalkyl etc.).

[0053] " optional replacement " group can be substituted or not be substituted. " the optional replacement " substituting group of group can comprise one or more substituting groups of the subset that independently is selected from following group or its appointment without limitation: alkyl, thiazolinyl, alkynyl, assorted alkyl, alkylhalide group, haloalkenyl, alkynyl halide, cycloalkyl, aryl, heteroaryl, assorted alkyl, heteroarylalkyl, alkoxyl, aryloxy group, halogen alkoxyl, amino, alkyl amino, dialkyl group are amino, alkyl sulfide generation, aryl sulfo-, heteroaryl sulfo-, oxo, carboxylate (C (O) OR^y), formamido (C (O) NR^y ₂), acyloxy, H; Halogen, CN, NO₂、N ₃、OH、C(O)R ^y, pyridine radicals, thienyl, furyl, indyl, indazolyl, phosphonate ester (P (O) (OR^y) ₂), phosphate (O-P (O) (OR^y) ₂), phosphamide (NR^x-P(O)(OR ^y) ₂), sulphonic acid ester (S (O)₂-O-), sulfuric ester (O-S (O)₂-O-R ^y), sulfonamide (NR^x-S(O) ₂-O-R ^y), carbamate (NH-C (O)-O-R^y), urea groups, ghiourea group, sulfonyl amido, sulfanyl. The optional group that replaces can not be substituted (for example-CH₂CH ₃), all replaced (for example-CF₂CF ₃), coverlet replaces (for example-CH₂CH ₂F) or with the arbitrary level between all replacing and singly replacing be substituted (for example-CH₂CF ₃)。

[0054] term " halogen " comprises F, Cl, Br and I.

[0055] term sulfide refers to that sulphur atom is covalently bound to two atoms; The regular state of oxidation of described sulphur is (II). Term " thioether " can use with term " sulfide " exchange.

[0056] term " sulfoxide " refers to that sulphur atom is covalently bound to three atoms, and wherein at least one is oxygen atom; The regular state of oxidation of described sulphur atom is (IV).

[0057] " " refer to that sulphur atom is covalently bound to four atoms, wherein at least one is oxygen atom to sulfone to term; The regular state of oxidation of described sulphur atom is (VI).

[0058] compounds more of the present invention can comprise one or more chiral centres and thereby can exist with enantiomer and diastereomer form. Scope intention of the present invention comprises all isomers itself, also comprises the mixture of cis and transisomer, the mixture of diastereomer and the racemic mixture (optical isomer) of enantiomer. Further, may apply known technology and separate various forms, and some embodiments of the present invention can be characterized purifying or the enrichment kind of given enantiomer or diastereomer.

[0059] " pharmaceutical composition " refers to one or more compounds as herein described or its pharmaceutically acceptable salt, with the mixture of other chemical constituent such as pharmaceutically acceptable carrier and/or excipient. Compound using to organism assisted in being intended that of pharmaceutical composition.

[0060] as described herein, phrase " pharmaceutically acceptable carrier " means pharmaceutically acceptable material, component or medium (vehicle), as liquid or solid filler, diluent, excipient, solvent or capsule material, it relates to and carrying or the object of transport medicament arrives another organ or body part from an an organ or body part. Compatible and be that on harmless meaning, each carrier must be " acceptable " to the patient at other composition with preparation. Some examples that can be used as the material of pharmaceutically acceptable carrier comprise: (1) sugar, as lactose, dextrose plus saccharose; (2) starch, as cornstarch and farina; (3) cellulose and derivative thereof, as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; (4) powder bassora gum; (5) Fructus Hordei Germinatus; (6) gelatin; (7) mica; (8) excipient such as cocoa butter and suppository wax; (9) oil, as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) polyalcohol such as propane diols; (11) polyalcohol such as glycerine, sorbierite, sweet mellow wine and polyethylene glycol; (12) ester, as ethyl oleate and ethyl laurate; (13) agar; (14) buffer, as magnesium hydroxide and aluminium hydroxide; (15) alginic acid; (16) apyrogeneity water; (17) isotonic saline solution; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; (21) be used for other nontoxic compatible material of pharmaceutical preparation. Physiologically acceptable carrier should not cause obvious stimulation and not cancel BA and the character of institute's administered compound body.

[0061] " excipient " refers to add pharmaceutical composition so that the inert substance of further assisting compound to use. The example of excipient includes but not limited to calcium carbonate, calcium phosphate, various sugar and starch type, cellulose derivative, gelatin, vegetable oil and polyethylene glycol.

[0062] measure the test of HSP90 combination and downstream effect

Multiple in vitro and in vivo test can be used for detecting the effect of the compounds of this invention to HSP90. HSP90 CBA and function test can be carried out as known in the art, wherein compound are replaced with compound of the present invention. Chiosis et al., Chemistry ﹠ Biology 8:289-299 (2001), described and wherein can carry out some known methods of described mensuration. For example, can apply with geldanamycin for example or 17-AAG as the competitiveness of the HSP90 CBA in conjunction with inhibitor, measure the relative HSP90 compatibility of the compounds of this invention, this following enforcement: compound interested or other competitive inhibitor are fixed on gel or solid-phase matrix, make HSP90 and other inhibitor precincubation, make the mixture of precincubation through gel or matrix, and measure subsequently the amount that adheres to or do not adhere to the HSP90 of gel or matrix.

The downstream effect also can suppress multiple steroid receptor and signal transducer are comprised that for example Raf1 and the function of Her2 and known being used for of stability estimate according to HSP90. The compounds of this invention is induced the dose dependent degraded to these molecules, and this can the application standard technology measure. HSP90 suppresses also to cause HSP90 and can be by the rise of the relevant chaperone of similar mensuration. Antiproliferative activity to multiple cancerous cell line also can be determined, because can measure the form relevant with the HSP90 inhibition and function differentiation. For example,

many dissimilar methods known in the art are used for measuring the protein level of protein concentration and mensuration or prediction fluid sample cell. technology comprises nucleic acid hybridization and amplification indirectly, applies for example PCR (PCR). these technology are known to the skilled, and at for example Sambrook, Fritsch ﹠ Maniatis, Molecular Cloning:A Laboratory Manual, Second Edition (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., Ausubel, et al., Current Protocols in Molecular Biology, John Wiley ﹠ Sons, NY, discuss in 1994, and be particularly to Her-2/neu in patient's sample quantitatively, detect and relative activity, at United States Patent (USP) 4, 699, 877, 4, 918, 162, 4, 968, 603 and 5, 846, discuss in 749. the brief discussion of adaptable two kinds of ordinary skills is as follows.

Whether cell crosses the determining of HER-2 of expressing or comprising the increase level, can apply known antibody technique such as Western blotting, radiommunoassay, Western blotting, immunoprecipitation, enzyme linked immunosorbent assay (ELISA) (ELISA) and application and measure for the deriving technology of the antibody of HER-2. As an example, the HER-2 in breast cancer cell expresses and can measure as Dako Hercep with immunohistochemistry^TMTest (Dako Corp., Carpinteria, CA) is measured. Hercep^TMTest is to be designed for the detection tumour to organize HER-2 in sample to cross the antibody staining assay method of expression. This specific assay method is expressed that HER-2 be divided into four levels: 0,1,2 and 3, and the HER-2 of level 3 expression highest levels expresses. Quantitatively can strengthen by application Automated Cellular Imaging System (ACIS) accurately, Press for example, M, et al, (2000), Modern Pathology 13:225A is described.

Polyclone or monoclonal antibody can be available from multiple suppliers, or the preparation of adaptable known method, for example, as Harlow et al., Antibodies:A Laboratory Manual, second edition; Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1988) is described.

HER-2 crosses expression and also can measure on the nucleic acid level because according to reporting, the mistake of HER-2 albumen express and its amplification of gene of encoding between have the height relevance. A method of testing it is application RT-PCR. The genome of HER-2 and cDNA sequence are known. Specific DNA primer can application standard known technology produce, and can be used for subsequently the amplification cell and have template. An example is described in Kurokawa, H et al, Cancer Res.60:5887-5894 (2000). PCR can be by standardization so that the difference of the amount of observing, as between normal cell and abnormal cell, for example, between carcinous energy and non-cancer cell. Apply for example known method of densitometry and can be used for quantitatively and/or relatively applying the nucleic acid level of pcr amplification.

Similarly, can apply FISH (FISH) test and other test, for example RNA trace and/or southern blotting technique. These tests depend on the nucleic acid hybridization between HER-2 gene or mRNA and corresponding nucleic acid probe, and described probe can be designed in the same or analogous mode of PCR primer with as above. Referring to for example, Mitchell MS, and Press MF., 1999, Semin.Oncol., Suppl.12:108-16. For FISH, this nucleic acid probe can be connected to the fluorescence molecule, for example, fluorescein and/or rhodamine, it does not preferably disturb hybridization, and its fluorescence can be determined after hybridization subsequently. Referring to for example, Kurokawa, H et al, Cancer Res.60:5887-5894 (2000) (described have sequence 5 '-specific dna probe of FAM-nucleic acid-TAMRA-p-3 ' sequence). Method based on ACIS described above can be used for making test more quantize (de la Torre-Bueno, J, et al, 2000, Modern Pathology 13:221A).

[0063] detect also can be directly for the protein outside HSP90 and Her-2 for immunity and nucleic acid, but described protein in response to the HSP90 inhibition by influenced.

[0064] the compounds of this invention is synthetic

Following synthetic schemes is applicable to multiple compounds of the present invention, composition, method and formulation.

Synthetic schemes A

[0065] formula 1[X=C] compound synthetic

Synthetic some or all that can comprise in following general step of synthetic schemes A Chinese style 1 (working as X=C) compound.

Formula

5 or 2 8-replace purine analogue can be from 4, the preparation such as 5-di-amino-pyrimidine and carboxylate or derivatives thereof such as acid amides, ester, nitrile, ortho esters, imino-ester is (referring to for example, Townsend Chemistry of Nucleosides and Nucleotides, the 1st volume; Plenum Press, New York and London, 148-158 page; Tetrahedron Lett.36,4249,1995). Replace 4, the 5-di-amino-pyrimidine can business obtains or from the 2-chloro-3-aminopyrimidine or the 2-chloro-3-nitro-pyrimidine that replace, as known in the art. Referring to for example, Tetrahedron, 40,1433 (1984); J.Am.Chem.Soc., 118,135 (1975); Synthesis 135 (1975); J.Med.Chem.39,4099 (1996).

By application alkali such as NaH, Cs₂CO ₃Or K₂CO ₃In polar solvent as in THF, DMF or DMSO, with the simple esterification of alkyl halide, alkyl tosylate, methanesulfonates (mesolates) or TFMS ester (triflate), or by known Mitsunobu alkylation method, formula 5 compounds can be converted into formula 2 compounds.

Formula 2 compounds can further be modified the intermediate that obtains formula 1 compound or preparation formula 1 compound, for example with ammonia or alkylamine, replace 6-chloropurine. The C-2Q of purine replaces, for example, and with F, Cl or Br halogenation, can introduce by 2-aminopurine, as Eaton et al., J.Org.Chem.34 (3), 747-8 (1969) is described, or by nucleophilic, replace, as J.Med.Chem.36,2938 (1993) and Heterocycles, 30,435, (1990) are described. These C-2 substituting groups also can be introduced by metallization, and as for example J.Org.Chem.62 (20), 6833 (1997) is described, adds subsequently required electrophilic reagent. General purine replaces can be as J.Med.Chem.42,2064 (1999) described completing.

Alternatively, the intermediate of formula 2 can prepare by following two steps from the chloro amido pyrimidine suc as formula 6: (1) exists alkali such as triethylamine or N, in the situation of N-diisopropylamine, in polar solvent such as n-BuOH, with corresponding amine (Y-NH2) for example butylamine process formula 6 compounds, obtain replacement two amines of formula 4; (2) use with front to formula 7 to the identical method of the described method of formula 5, processing formula 4 compounds. Previously described similar method can be used for introducing C-2 and replace (site that connects Z or G part).

Formula 1 compound, wherein A is not NH₂, be for example halogen, methoxyl group, alkyl or three fluoroalkyls, can apply in position corresponding substituting group (if it can transform) and start preparation, or for the amine of halogen or replacement, they can prepare from 6-amine.

Formula 1 compound also can be from formula 3 compound preparations, and wherein L is halogen, and the coupling of application Negishi-type (for example, as J.Org.Chem.2001,66,7522; J.Org.Chem.1991,56,1445 is described). [0066] synthetic [the X=hetero atom is S, O, the N for example] of formula 1 compound

Formula 1 compound, wherein X is hetero atom such as S, O or N, can prepare by option b. Usually, these compounds are connected to one of hetero atom X=S, O or N by their C-8, and can be from corresponding 8-halo (for example, bromine, iodine or chlorine) compound suc as formula 10, application nucleophilic reagent such as sulfide, alkyl or aryl sulfo-, amine, azide and alcohol preparation.

Synthetic schemes B

With reference to option b, the purine of the adenine of replacement or formula 8 can apply halogenating agent such as bromine or iodine is processed, and obtains formula 10 compounds in the N-9 alkylation subsequently, and wherein M is halogen such as bromine or iodine (Dang et.al.PCT, WO 98/39344). The compound of formula 16 can prepare by nitrated suc as formula 12 from three halogen pyrimidines, obtains the compound of formula 13. Use subsequently amine (YNH₂) replace halogen and nitroreduction and obtain the diamines of formula 15. Alternatively, nitroreduction can be replaced prior to halogen. The easily cyclisation of the diamines of formula 15 is the imidazole ring of formula 16 compounds, and wherein L is H, SH, OH or NH₂(Org.Syn.Collective Vol.2,65; Org.Syn.Collective Vol. 4,569). Formula 1 compound also can be synthetic from formula 16 compounds, and wherein L is SH, OH or NH₂, by in the situation that catalyst such as palladium or copper exist with aromatic halide, boric acid, TFMS ester or the reaction of its equivalent, carrying out (Buchwald, S.L.et.al.J.Am.Chem.Soc., 1998,120,213-214; Buchwald, S.L.et.al.Acc.Chem.Res.1998,31,805; Buchwald, S.L.et.al Org.Lett., 2002,4,3517-3520).

Alternatively, formula 1 and 11 compound (wherein X=S or O) can be in the situation that alkali such as t-BuOK, NaH etc. exist, and in solvent such as DMF, MeOH etc., (wherein M or L are N by coupling formula 10 or 16 compounds₂.BF ₄，N ₂.HCl，N ₂.H ₂SO ₄Deng) diazol and HXE or HXQ (wherein X=S or O) and synthesize.

The Z base of formula 1 can be introduced by 2 substituting groups such as the G that modification exists. For example, the 2-halogen purine of formula 1 can be from 2-aminopurine (G=NH₂) by the chemical method of fully describing in document, prepare. Other substituting group such as S-alkyl or aryl, O-alkyl, can make from nucleophilic substitution, metal catalytic reaction etc. (referring to for example, Aerschot et.al., J.Med.Chem.36:2938 (1993); Buchwald, S.L.et.al., Heterocycles, 30:435 (1990)).

The E composition of formula 11 compounds (aryl or heteroaryl or alkyl) can be applied known method and further be modified on demand, for example comprise, nucleophilic addition, electrophilic addition, halogenation etc., to obtain Q (referring to for example, Advanced Organic Chemistry, March.J.Wiley Interscience).

Formula 1 compound, wherein X is S (O) or S (O)₂, oxidation that can through type 1 compound and preparing, X=S wherein, application reagent such as MCPBA, H₂O ₂，、NaIO ₄, oxone (oxone) etc. is at solvent such as CHCl₃、CH ₂Cl ₂Deng in carry out. Equally, these sulfone compounds can be in polar solvent such as DMF by coupling sulfone salt such as Li, Na, K (ArS (O)₂Li) and the compound of formula 10 or 16 (wherein M or L are halogen such as Br or I) preparation (Chem.Abstr.1952,4549). By controlling the reduction of these sulfones, can make formula 1 compound, wherein X is S (O) and S (O)₂。

[0067] from synthetic 8-(sulfanyl) adenine of 8-halogen adenine

8-halogen adenine can be coupled to benzenethiol under alkaline condition. Multiple alkali can be applied, for example, and LiOH, NaOH, t-BuONa, K₂CO ₃、KOH、t-BuOK、Cs ₂CO ₃Or CsOH. Benzenethiol can carry all required substituting groups of BA or can be modified (scheme C) after coupling.

X=halide or other leaving group

The alkyl that Y=replaces

Synthetic schemes C:(sulfur alkyl aryl) adenine is from the preparation of 8-halogen adenine

According to first approach, use a kind of preparation phenylmercaptan. in many known methods.These methods are widely studied (Wardell, J.L.Preparation of Thiols.In The Chemistry of the Thio Group, Part 1.Patai S.Ed.John Wiley ﹠amp; Sons.London, 1974, pp 163-263.).Wherein the most frequently used the chances are Leuckart is synthetic, and wherein aryl diazonium salts is used sulfur nucleophilic thing---be generally EtOCS ₂K handles, and obtains xanthate, and it uses basic hydrolysis.For example, 2-iodo-5-(methoxyl group) the benzene phenylmercaptan. (benzenethiophenol) that scheme C points out prepares (Ma, C.J.Org.Chem.2001,66,4525.Flynn, B.LOrg.Lett.2001,3,651) in this way.Phenylmercaptan. is subsequently by deprotonation (K for example ₂CO ₃), and be coupled to 8-halogen adenine.Coupling can be with transition metal Ni (acac) for example ₂Catalysis.

Second approach of scheme C has described 8-halogen adenine in detail and has been coupled to phenylmercaptan. and uses the standard reagent that replaces at electrophilic aromatics subsequently, uses electrophilic reagent matter (Cl ⁺, Br ⁺, I ⁺, NO ⁺Deng) handle.

[0068] 8-(sulfane base) adenine synthesizing from 8-sulfydryl adenine

8-(sulfur alkyl aryl) adenine can be from 8-sulfydryl adenine and the preparation of electrophilic reagent matter, shown in scheme D.In polar solvent such as DMF or DMSO, under alkali existence or non-existent situation, make sulfydryl adenine and diazol reaction (Biamonte, M.A., J.Org.Chem., 2005,70,717), or cation group is used PhI (OCOCF ₃) ₂Produce and catch (Kita, Y., J.Org.Chem., 1995,60,7144) with 8-sulfydryl adenine.

The coupling of 8-sulfydryl adenine and diazol

The coupling of 8-sulfydryl adenine and cation group

Synthetic schemes D:(sulfur alkyl aryl) adenine is from the preparation of 8-sulfydryl adenine

[0069] benzothiazole purine or pyrido thiazole purine is synthetic

These chemical compounds can prepare by the intermediate 10 from option b.Formula 3 chemical compounds, wherein L is a halogen, Y be H or can adorned when needed substituent group (for example-(CH ₂) _nO (CO) CH ₃, n=2-4), G is H or halogen, A is NH ₂, can be at alkali for example t-BuOK, NaH or K ₂CO ₃Exist down, in polar solvent such as DMF, THF or DMSO, handle with benzothiazole-2-mercaptan that replaces or pyrido thiazol-2-thiol, obtain formula 17 chemical compounds, wherein T is ' O ' or ' S ', V is ' C ' or ' N ', R is substituent group such as halogen, alkyl, aryl, alkoxyl, CN etc., scheme E.

Synthetic schemes E:(heteroaryl sulfane base) preparation of purine

Benzothiazole-2-the mercaptan that replaces and benzoxazole-2-mercaptan are synthetic from concentrating O-ethoxy-dithioformic acid, potassium salt or any suitable salt and 2-halo aniline (haloaniline) or 2-amino-phenol (hydroxyaniline) respectively, scheme 5.These chemical compounds also can be from 2-aminobenzothiazole (list of references Kasibhatla et.al.US Patent6,489,476 B1) by diazotising use subsequently thiourea or O-ethoxy-dithioformic acid, potassium salt with the SH displacement (referring to list of references The Chemistry of the Thio Group, Part1, Patai S.Ed.John Wiley ﹠amp; Sons.London, 1974, the 163-263 pages or leaves; And Ma, C.J.Org.Chem.2001,66,4525.) preparation.

X=halogen T=O or S

X＝OH

Synthetic schemes F: the preparation of benzothiazole-2-mercaptan

Similarly, the condensation of 2-amino-3-haloperidid or 4-amino-3-haloperidid or 3-amino-2-haloperidid and O-ethoxy-dithioformic acid, potassium salt can obtain other pyridine thiazol-2-thiol isomer, scheme G.These also can be from 2-aminopyridine and thiazole preparation.

The X=halogen

Scheme G: the preparation of pyrido thiazol-2-thiol

[0070] the 8-benzyladenine is synthetic

The 8-benzyladenine is synthetic by one of two kinds of methods shown in the scheme H.First method is according to carrying out with the closely-related order of the described method of Drysdale et al.; and originate in coml 4; 6-two chloro-5-aminopyrimidines; it is used butylamine and handles; use suitable phenacyl chloride acidylate; and cyclisation obtains required 9-butyl-8-(2, the 5-dimethoxy-benzyl)-9H-purine-6-base amine.Second method is similar to the method for Chiosis et al. and originates in 4,5, the 6-Triaminopyrimidine, and it is produced 8-(3-methoxyl group-benzyl)-9H-purine-6-base amine by acidylate and cyclisation.Last acidylate mainly obtains required N (9)-alkyl isomer, and together with stereoisomer in a small amount, described stereoisomer is removed by chromatography that (stereo selectivity=5:1 is by to crude product ¹H NMR analyzes).Application standard reagent (SO ₂Cl ₂, Br ₂, NIS/AcOH) to the methyl phenyl ethers anisole halogenation.One in the synthetic order is improved relevant acidylate step.Disclosed method relates to 4,5, and 6-Triaminopyrimidine Hemisulphate is in the acidylate of aqueous solution (4,5, the 6-Triaminopyrimidine is only solvable in the water of pH 〉=7), and grasps according to us, needs the suitable acid chloride of some equivalent to compensate the reagent hydrolysis of following.We find, by neutralization of commercial Hemisulphate aqueous solution be cooled to 0-5 ℃, and 4,5, the free alkali of 6-Triaminopyrimidine is separated as spicule easily.Verified, this free alkali dissolves in N-N-methyl-2-2-pyrrolidone N-(NMP), and can obtain amide with the effective acidylate of single normal acid chloride in this solution.DMF is not very satisfactory as the application of solvent, because it produces 5-NH by the reaction of Vilsmeier-Haack type ₂The competitive formylated of group.Preferably avoid alkali such as Et ₃N, so that prevented acidylate, and required amide is as its hydrochlorate precipitation.Acylate ¹H-NMR spectrum symmetry shows that acidylate selectivity on 5 takes place.At last, amide uses MeONa to the cyclisation of required purine and just refluxing-carry out among the BuOH, and this and primary MeOH have small departing from, but stronger and general available condition are provided.

Method A

Method B

The preparation of synthetic schemes H:8-benzyladenine

Reagent and condition: (a) BuNH ₂, Et ₃N, just-BuOH, 90 ℃, 16h (83%);

(b) 2,5-dimethoxy benzene guanidine-acetic acid, TsCl, Et ₃N, DCE, 40 ℃, 16h (71%);

(c)NH ₃、MeOH、120℃、3d(80％)；(d)NaOH、H ₂O，0-5℃(67％)；

(e) 3-methoxyphenyl chloroacetic chloride, NMP, 40-50 ℃ (98%);

(f) MeONa, just-BuOH, backflow 2h (75%);

(g) BuI, Cs ₂CO ₃, DMF, room temperature 16h (54%);

(h) SO ₂Cl ₂, Br ₂Or NIS (31-57%).

[0071] 8-sulfur alkyl aryl adenine is synthetic

Need diverse ways to study the effect of the joint between purine and the phenyl ring.According to the example shown in the scheme I, preparation has the chemical compound of sulphur atom as joint.Alkylation obtains the 2:1 mixture of N (9) and N (3) alkylation isomer to 8-bromine adenine, from wherein passing through required N (the 9)-butyl isomer of chromatography.Replace bromine atoms with required phenylmercaptan. ester (thiophenolate), obtain required 8-sulfane base adenine.

The preparation of synthetic schemes I:8-(sulfur alkyl aryl) adenine

Reagent and condition: (a) BuI, Cs ₂CO ₃, DMF, room temperature, 16h (62%);

(b) 2,5-dimethoxy benzenethiol, 150 ℃, 4h (69%).

[0072] 8-(iodo-replaces-phenyl sulfane base)-adenine is synthetic

Use similar approach,, be created in and have the substituent 8-of iodine (benzene sulfane base)-adenine on the phenyl ring by the convergent synthesis method shown in the scheme J.Methoxyl group-nitroaniline is changed (1.NaNO in three known steps ₂, KI.2.H ₂N-NH ₂/ Fe.3.NaNO ₂, HBF ₄) be diazol, this is at the synthetic (4.EtOCS of two step Leuckart ₂K obtains the potassium salt of 2-iodo-5-methoxyl group-benzene phenylmercaptan. after 5.KOH).The purification of this chemical compound is proved to be challenging.Dissolving and obtain the required phenylmercaptan. ester of the low response rate (＜20%) in MeOH with EtOAc precipitation, and neutralization and chromatography are owing to the abnormal smells from the patient of phenylmercaptan. and be easy to be oxidized to correspondingly the disulphide complexity that becomes.In the case, the highest total recovery that transforms to benzene sulfane base adenine is by with 2 normal KOH hydrolysis intermediate xanthate, concentrated reaction mixture in MeOH, and under the situation of not removing excessive potassium salt application it realize.8-bromine adenine is used with isoprene bromine (homoprenyl bromide) alkylation and is obtained the 2:1 mixture of required N (9) to N (3)-alkylate, and required isomer separates by chromatography.Obtain required 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-(4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine with 8-bromine adenine coupling phenylmercaptan. ester.Similarly, 8-bromine adenine can obtain 8-bromo-9-penta-4-alkynyl-9H-purine-6-base amine with the alkylation of 5-chloro-1-pentyne, and is coupled to the phenylmercaptan. ester and obtains pentyne analog 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine.

By conceptive similar approach, from 2,6-diaminourea-8-bromine purine begins, and uses Balz-Schiemann and reacts (different-AmONO/HBF ₄) come to replace 2-NH with fluorine ₂Base, preparation 2-fluoro-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine.

The preparation of synthetic schemes J:8-(the phenyl sulfane base that iodo-replaces)-adenine

Reagent and condition: (a) EtOCS ₂K ,-40 ℃ to room temperature, 30min, KOH then, MeOH, 40 ℃, 2h;

(b) 5-bromo-2-methyl-penta-2-alkene, Cs ₂CO ₃, DMF, rt, 3h (38%);

(c) 21, DMF, 100 ℃, 16h (15%); (d) 5-chloro-1-pentyne, Cs ₂CO ₃, DMF, 70 ℃, 3h (25%);

(e) 21, DMF, 70 ℃, 16h (71%); (f) 5-chloro-1-pentyne, Cs ₂CO ₃, DMF, 85 ℃, 16h (66%);

(g)21，DMF，100℃，16h(43％)；(h)i-AmONO，HBF ₄，THF，-20℃-+40℃，10min(13％)。

Yet these approach have two defectives.At first, alkylation is not stereoselective, and needs tediously long chromatography.Secondly, phenylmercaptan. ester foul smelling is difficult to purification, and if use without chromatography purification then obtain the highstrung result of its purity.An improvement (scheme K, approach A) comprises that from pure adenine it only carries out alkylation at N (9).Br-(CH ₂) ₂-OAc or Cl-(CH ₂) ₃-OAc is selected as alkylating agent, and wherein masked oh group is provided for further functionalized.Different with unsubstituted adenine, alkylate easily at C (8) by bromination.Bromine atoms is replaced with phenylmercaptan. potassium subsequently, and excises the acetyl group protecting group in position and obtain 8-sulfane base adenine.Hydroxyl is replaced by methylsulfonylization and with amine, obtains having the corresponding N-alkylamine (scheme K) of general structure A.

Yet this approach still needs unfavorable phenylmercaptan. ester preparation.We thus work out with the anion that has contained the 8-thion adenine (thionoadenine) of required sulphur atom and directly handle diazol (scheme K, approach B), therefore avoided preparation phenylmercaptan. ester.4,5, after 6-Triaminopyrimidine and the thiourea condensation, handle with diazol, obtain required 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine.Yield (optimize) is low and use Br-(CH subsequently ₂) ₃-Cl carries out alkylation and still obtains N (9)-and the 2:1 mixture of N (3)-stereoisomer.Except these problems are arranged, be effective but this approach produces the amine of a spot of formula A.Yet, need improved approach to prepare the A of gram rank amount.Select the third approach (scheme K, approach C), it has been eliminated the application of phenylmercaptan. ester and has only provided stereoisomer.Alkylation bromo adenine from the approach A of scheme K is changed into 8-thion adenine with thiourea, its directly and the diazol coupling obtain required known adduct.At last, side chain is carried out the required amine that identical standard operation (deacetylation, methylsulfonylization, amination) obtains general formula A.Approach A and C obtain similar total recovery and can exchange use, but the latter can repeat to be consistent, and avoid using the phenylmercaptan. ester.

Synthetic schemes K: the preparation of the water solublity 8-sulfane base adenine of formula A

Reagent and condition: (a) AcO-(CH ₂) ₂-Br, Cs ₂CO ₃, DMF, 45 ℃, 5h (67%) or

AcO-(CH ₂) ₃-Cl, Cs ₂CO ₃, DMF, 70 ℃, 12h (88%), Br then ₂, AcOH, THF, H ₂O (34-81%);

(b) DMF, 50 ℃, 16h; K then ₂CO ₃, MeOH (37%);

(c) MsCl, Et ₃N ， diox, room temperature, 30min; Amine then, 55 ℃, 16h (45-75%);

(d) DMF ,-60 ℃ to room temperature, 2h (26%); (e) Br-(CH ₂) ₃-Cl, Cs ₂CO ₃, DMF, 50 ℃, 2h (21%);

(f) amine, 90-110 ℃, 16h, (67-73%); (g) thiourea, just-BuOH, reflux 3h (88%)

(h) DMSO, room temperature, 24h (51%); (i) K ₂CO ₃, MeOH (37%).

Synthesizing of the benzimidazole thiophanate generation of [0073] 7 '-replacement and pyrido thiazole purine

The total program preparation of three-step approach that the Hsp90 inhibitor analogue is listed in also can application scheme L.Cs in DMF ₂CO ₃Under the situation about existing, use suitable alkyl halide and carry out the isomer that the adenine alkylation mainly obtains the N-9 replacement.The purine bromination subsequently with the benzothiazole-t-BuOK of 2-mercaptan in DMF that replaces in the presence of, coupling at elevated temperatures, obtain end-product.

Synthetic schemes L

Reagent and condition: (a) R ₁X, Cs ₂CO ₃, DMF, room temperature ,～70 ℃;

(b) Br ₂, buffer; (c) t-BuOK, DMF, 80-150 ℃

By preparing representative compounds through different route of synthesis, the adenine alkylation obtains the N-9 stereoisomer and is clearly indicated (scheme M).In the synthetic back of describing (Howson et al.J.Med.Chem.1988,23,433-439), and 5-amino-4, the 6-dichloro pyrimidine is handled with aminopropanol, obtains the pyrimidine that diaminourea replaces.Obtain the 6-chloropurine derivant with the cyclisation in acetic anhydride of triethyl group orthoformate, its not purified and ammonia further reaction in MeOH obtains the adenine that 9-replaces.Obtain shielded alcohol with acetic anhydride cyclisation in the presence of DMAP and pyrimidine, its NMR spectrum is identical with the chemical compound that obtains by such scheme.This has clearly established, and the alkylation of purine in this this step mainly occurs in 9.

Synthetic schemes M

Reagent and condition: (a) EtOH, reflux 1h; (b) HC (OEt) ₃, (CH ₃CO) ₂O refluxes 3h;

(c) NH ₃.MeOH, 120 ℃; (d) pyridine, DMAP, (CH ₃CO) ₂O, DCM

Synthesizing of benzimidazole thiophanate generation (benzolothio)-2-mercaptan of [0074] 7 '-replacement

Four kinds of different synthetic methods by the scheme described among scheme N, O, P, the Q obtain benzothiazole-2-mercaptan.The key reaction of all four kinds of approach relates to the condensation of 2-halobenzene amine and ethoxy-dithioformic acid potassium salt, obtains benzothiazole-2-mercaptan.The 2-halobenzene amine that replaces prepares by three different approaches: 1) the 2-halobenzene amine that obtains replacing with Fe reductase 12-nitro bromobenzene in EtOH, 2) react by Sandmeyer and in EtOH, reduce bromination 2-nitroaniline (scheme O) and 3 subsequently with Fe) HNO used ₃At H ₂SO ₄Middle nitration 1,2-dibromobenzene (scheme P) obtains 3-and 4-NO ₂The mixture of stereoisomer reduces required 3-NO with Fe subsequently in EtOH ₂Stereoisomer obtains 2, the 3-dibromo aniline.The chemical compound that obtains by these methods carry out potassium salt with ethoxy-dithioformic acid in DMF in 160 ℃ of condensations 4 hours, obtain the benzothiazole-2-mercaptan of the good replacement of yield.6-Cl-, 5-Cl-, 4-Cl-and the isomer of 7-H-benzothiazole are available from Acros.

Synthetic schemes N

Reagent and condition: (a) Fe, EtOH, H ⁺(b) EtOCSSK, DMF, 160 ℃, 4h

Synthetic schemes O

Reagent and condition: (a) R ₂I, K ₂CO ₃, DMF;

(b)EtOCSSK，DMF，160℃，4h；(c)[X＝NH ₂→Br]NaNO ₂，H ⁺，CuBr，(d)[Y＝NO ₂→NH ₂]Fe，EtOH，H ⁺

Synthetic schemes P

Reagent and condition: (a) HNO ₃/ H ₂SO ₄(b) Fe, EtOH, HCl; (c) EtOCSSK, DMF, 160 ℃, 4h

[0075] thiazole [4,5-c] pyridine-2-mercaptan is synthetic

The halogenation of 3-nitro-pyridine-4-alcohol (Nantka-Namirski et.al.Acta Poloniae Pharmaceutica; 1961; 18,391-399) (scheme Q) introduces 5-Cl or 5-Br group.Subsequently, 4-OH base POCl ₃Processing changes 4-Cl (Molecules:EN into; 7; 1; 2002; 7-17), and nitro SnCl ₂Be reduced to amino (Chaudhun et.al.Synth.Commun.26,20; 1996; 3783-3790).At last, use potassium salt cyclisation generation target thiazole [4,5-c] pyridine-2-mercaptan of ethoxy-dithioformic acid.

Synthetic schemes Q

Reagent and condition: (a) Br ₂Or Cl ₂Gas, 50% acetic acid;

(b)POCl ₃，DMF，120℃，0.5h；(c)SnCl ₂.H ₂O，HCl，rt，4h；(d)EtOCSSK，DMF，160℃，4h

Shown in the scheme that further the is modified at R of 9-alkyl-side chain.The 9-Arrcostab is by using NH ₃Handle and hydrolysis in MeOH, form the purine that the 9-hydroxyl replaces, it is handled with the MsCl among the DMF, and thick methylsulfonyl ester that obtains and the reaction of suitable amine obtain final chemical compound.

Scheme R

Reagent and condition: (a) NH ₃.MeOH, rt spends the night; (b) MsCl, Et ₃N, DMF, 0 ℃ to room temperature; (c) amine, room temperature is spent the night

[0076] the following example only provides by way of example, is not intended to limit four corner of the present invention and spirit.

The chemical reagent of using below all is that commerce can get, for example, from Aldrich Chemical Co., Milwaukee, WI, USA, and/or the goods that they obtain easily well known by persons skilled in the art, or describe in addition in this article or quote.Except as otherwise noted, all are reflected under the blanket of nitrogen and carry out.Organic solvent is available from Fisher Scientic.Thin layer chromatography (TLC) is used Whatman K6F silica gel 60A plate and is carried out; The 1H-NMR spectrum is measured on Bruker 400MHz equipment.The HPLC method that is used for these chemical compounds: Agilent Zorbax300SB C18,4.6 * 150mm, 5 μ m; Column temperature: room temperature; Flow velocity: 1.0ml/min, gradient: 5% acetonitrile (0.05% TFA) in water (0.1% TFA) to 100% acetonitrile (0.05% TFA), 7 minutes, maintenance 100% reaches 2 minutes) (method: 5-100-7), or gradient: 5% acetonitrile (0.05% TFA) in water (0.1% TFA) to 100% acetonitrile (0.05% TFA), 15 minutes, maintenance 100% reached 2 minutes) (method: 5-100-15).

[0077] chemical compound is synthetic

Synthesizing of embodiment 1 8-(2, the 5-dimethoxy-benzyl)-N9-butyl adenine (1)

Step 1:5-amino-4,6-dichloro pyrimidine (1mmol) just-solution Et among the BuOH ₃N (1.2mmol) and n-butylamine (1.0mmol) are handled in 80C.Behind the 16h, decompression goes down to desolventize.Residue is dissolved among the EtOAc, and organic layer washes subsequent drying (MgSO with water ₄).Filter and remove solvent and obtain 6-chloro-5-amino-4-butyl pyrimidine, be brown solid.R _f=0.5, at 1:1EtOAc: in the hexane. ¹H NMR(CDCl ₃)δ8.07(s，1H)，4.88(brs，1H)，3.49(m，2H)，3.35(br s，2H)，1.6(m，2H)，1.44(m，2H)，0.95(t，3H)。

Step 2: under the room temperature, to 2,5-dimethoxy benzene guanidine-acetic acid (1mmol) and Et ₃N (1mmol) is at CH ₂Cl ₂In solution in add paratoluensulfonyl chloride (1mmol).(1mmol is at CH for the solution of the product 6-chloro-5-amino-4-butyl pyrimidine of usefulness step 1 behind the 1h ₂Cl ₂In) treatment mixture, add Et subsequently ₃N (2mmol).The mixture backflow 20h that obtains.Remove solvent and residue is dissolved among the EtOAc, organic layer washes with water and is dry.To slightly carry chemical compound and add acetone, and precipitated product be filtered out and wash, obtain N-(4-fourth amino-6-chloro-pyrimidine-5-yl)-2-(2, the 5-Dimethoxyphenyl) acetamide with small amount of acetone.R _f=0.45, at 1:1EtOAc: in the hexane. ¹H NMR(DMSO-d ₆)δ 9.37(s，1H)，8.17(s，1H)，7.11(t，1H)，6.9(d，1H)，6.88(d，1H)，6.78(dd，1H)，3.73(s，3H)，3.69(s，3H)，3.63(s，3H)，3.35(m，2H)，1.48(m，2H)，1.29(m，2H)，0.88(t，3H)。

Step 3:N-(4-fourth amino-6-chloro-pyrimidine-5-yl)-2-(2, the 5-Dimethoxyphenyl) acetamide (1mmol) and the mixture of p-TSA (0.5mmol) in toluene are by the 72h that refluxes.Remove solvent, with also water, bicarbonate washing and dry of EtOAc dilution.Purification on silicagel column (the 200-400 order, Fisher Scientific, Tustin, CA USA), obtains 6-chloro-8-(2, the 5-dimethoxy-benzyl)-N9-butyl purine.R _f=0.65, at 1:1EtOAc: in the hexane. ¹HNMR(DMSO-d ₆)δ 8.7(s，1H)，6.96(d，1H)，6.84(m，1H)，6.8(dd，1H)，4.28(s，2H)，4.23(t，2H)，3.69(s，3H)，3.67(s，3H)，1.62(m，2H)，1.25(m，2H)，0.88(t，3H)。

Step 4: (add 28%NH in the solution of 1mmol) Zai diox to 6-chloro-8-(2, the 5-dimethoxy-benzyl)-N9-butyl purine ₄OH (50mmol), 100 ℃ of heating blends 48 hours in the sealing test tube subsequently.By removing solvent with the distillation of methylbenzene azeotropic (mixing) thing.At purification on the silicagel column (on seeing), obtain pure 8-(2, the 5-dimethoxy-benzyl)-9-butyl adenine, 1.1.R _f=0.35, in the EtOAc of 5% MeOH solution. ¹H NMR(DMSO-d ₆)δ 8.08(s，1H)，7.04(br s，2H)，6.94(d，1H)，6.80(dd，1H)，6.66(d，1H)，4.14(s，2H)，4.04(t，2H)，3.72(s，3H)，3.63(s，3H)，1.52(m，2H)，1.22(m，2H)，0.82(t，3H)。

Alternatively, 8-(2, the 5-dimethoxy-benzyl)-9-butyl adenine also can be from N-(4-fourth amino-6-chloro-pyrimidine-5-yl)-2-(2, the 5-Dimethoxyphenyl) acetamide prepares according to following method: with the 7M NH among N-(4-fourth amino-6-chloro-pyrimidine-5-yl)-2-(2, the 5-Dimethoxyphenyl) acetamide solution (1mmol) adding MeOH ₃(70mmol), in steel high pressure receiver (bomb) in 120 ℃ of heating blends 72 hours.By removing solvent through the azeotropic mixture distillation with toluene.Obtain pure 8-(2, the 5-dimethoxy-benzyl)-9-butyl adenine at purification on the silicagel column (on seeing).

Synthesizing of embodiment 2 8-(2, the 5-dimethoxy-benzyl)-N9-pentynyl-2-fluoroadenine (2)

Step 1:2-(2,5-dimethoxy-phenyl)-N-(2,5,6-triamido-pyrimidine-4-yl)-acetamide, HCl

2,4,5, the 6-tetraminopyrimidine (52.8g, nmp solution 378mmol) (750ml) in 70 ℃ with 2, (90g 419mmol) handles 5-Dimethoxyphenyl chloroacetic chloride.After being cooled to room temperature,,, obtain title compound, be buff powder (127g, 95%) with the EtOAc washing by filtering the collecting precipitation thing.1H NMR(DMSO-d ₆)δ 9.12(s，1H)，7.80-7.40(m，3H)，6.22(s，2H)，6.04(s，4H)，4.41(s，3H)，4.29(s，3H)，4.25(s，2H)；MS319(M+1)。

Step 2:8-(2,5-dimethoxy-benzyl)-9H-purine-2, the 6-diamidogen

With sodium metal (2.3g, 100mmol) in 70 ℃ just be dissolved in-BuOH (50ml) in.(5.0g, 14.1mmol), heating blends is to refluxing 1.5 hours for the acetamide of step 1 above wherein adding.Be neutralized to pH8-9 with 6N HCl, with the EtOAc extraction, dry and evaporation obtains title compound, is buff powder (3.2g, 76%).R _f=0.45, in 1:3MeOH:EtOAc.1H NMR(DMSO-d ₆)δ 12.3-11.7(br.s，1H)，6.92(d，J＝10.0Hz，1H)，6.82(dd，J＝10.0 & 3.0Hz，1H)，6.73(s，1H)，6.70-6.50(br.s，2H)，5.85-5.70(br.s，2H)，3.95(s，2H)，3.74(s，3H)，3.67(s，3H)；MS 301(M+1)。

Step 3:8-(2,5-dimethoxy-benzyl)-9-penta-4-alkynyl-9H-purine-2, the 6-diamidogen

Purine 8-(2,5-dimethoxy-benzyl)-9H-purine-2, the 6-diamidogen (19.0g, 63mmol), 5-chloro-penta-1-alkene (12.3ml, 116mmol) and Cs ₂CO ₃(37.8g, 116mmol) mixture in DMF (180g) is heated to 50 ℃ of 16h.Filter and washing (2 * 200ml H ₂O), obtain required product (5.8g, 25%).Concentrated mother liquor with the EtOAc dilution, and is heated to backflow 1 hour, produces extra product (6.0g, 26%).After being cooled to room temperature, hexane to the EtOAc mother solution that adds 1 volume obtains extra product (2.6g, 11%).Final operation (CH ₂Cl ₂: MeOH 4:1-water) produce extra product (5.3g contains 1 normal penta-4-alkynes-1-alcohol, 18%).R _f=0.65, in 1:10MeOH:EtOAc.1H NMR (DMSO-d ₆) δ 6.92 (d, J=8.9Hz, 1H), 6.98 (dd, J=8.9 ﹠amp; 3.0Hz, 1H), 6.59 (s, J=2.9Hz, 1H), 6.58-6.53 (br.s, 2H), 5.72-5.68 (br.s, 2H), 4.02 (s, 2H), 3.92 (t, J=7.4Hz, 2H), 3.73 (s, 3H), 3.62 (s, 3H), 2.84 (t, J=2.5Hz, 1H), 2.13 (td, J=7.0 ﹠amp; 1.7Hz, 2H), 1.74 (quintet (quint), J=7.3Hz, 2H); MS 367 (M+1).

Step 4:8-(2,5-dimethoxy-benzyl)-2-fluoro-9-penta-4-alkynyl-9H-purine-6-base amine

Above-mentioned purine-2, (11.8g is 32.2mmol) at 48%HBF for the 6-diamidogen ₄(250ml) solution in the aqueous solution-10 ℃ with amyl nitrite (5.20ml 38.8mmol) handles, and at 2.5 hours internal heating to room temperature.With MeOH (400ml) and CH ₂Cl ₂(1500ml) diluted reaction mixture is used K ₂CO ₃The careful neutralization of aqueous solution (125g) (500ml).Attention: a large amount of gas evaporations.Water layer MeOH:CH ₂Cl ₂(500ml, 1:5) extraction again.Concentrate organic facies and twice flash chromatography purification (CH ₂Cl ₂: EtOAc: hexane: MeOH:Et ₃N 1500:750:750:50:10 → 1500:750:750:150:10) produce 8-(2,5-dimethoxy-benzyl)-2-fluoro-9-penta-4-alkynyl-9H-purine-6-base amine (4.5g, 38%), 2.1, be colourless powder.R _f=0.45, at 1:1 EtOAc: in the hexane. ¹H NMR (DMSO-d ₆) δ 6.82 (d, J=8.9Hz, 1H), 6.75 (dd, J=8.9 ﹠amp; 3.0Hz, 1H), 6.68 (d, J=2.9Hz, 1H), 6.25-6.10 (br.s, 2H), 4.20 (s, 2H), 4.13 (t, J=7.4Hz, 2H), 3.79 (s, 3H), 3.70 (s, 3H), 2.16 (td, J=7.0 ﹠amp; 2.6Hz, 2H), 1.97 (t, J=2.6Hz, 1H), 1.95 (quintet, J=7.3Hz, 2H); MS 370 (M+1).

The 2 described substantially the same method preparations of following compounds 3-5 applicating adn implementing example, except in the step 3, electrophilic reagent 1-bromo-4-methyl-penta-3-alkene, 1-chloro-penta-4-alkene and 1, the 5-bromo pentane silane is used to replace 5-chloro-penta-1-alkene:

Embodiment 3 8-(2,5-dimethoxy-benzyl)-2-fluoro-9-(4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine (3)

Be separated into solid, retention time=7.70.

Embodiment 4 8-(2,5-dimethoxy-benzyl)-2-fluoro-9-penta-4-thiazolinyl-9H-purine-6-base amine (4)

Be separated into solid, retention time=7.61.

Embodiment 5 8-(2,5-dimethoxy-benzyl)-2-fluoro-9-(5-bromo-amyl group)-9H-purine-6-base amine (5)

Be separated into solid, retention time=7.86.

Embodiment 6 8-(2,5-dimethoxy-benzyl)-2-chloro-9-penta-4-alkynyl-9H-purine-6-base amine (6)

This chemical compound and embodiment 5, the similar preparation of the described method of step 4 are wherein used HCl and CuCl and are substituted HBF ₄Rt=8.02 ¹H NMR (CDCl3) δ 6.83 (d, J=8.9Hz, 1H), 6.77 (dd, J=8.9 ﹠amp; 3.0Hz, 1H), 6.68 (d, J=3.0Hz, 1H), 6.18-6.00 (s, 2H), 4.20 (s, 2H), 4.18 (t, J=7.4Hz, 2H), 3.78 (s, 3H), 4.93 (s, 3H), 2.20 (td, J=7.0﹠amp; 2.4Hz, 2H), 2.63 (t, 2.4Hz, 1H), 1.97 (quintet, J=7.3Hz, 2H).

HPLC method: Agilent Zorbax 300 SB C18,4.6 * 150mm, 5 μ m; Column temperature: room temperature; Flow velocity: 1.0ml/min, Gradient: 10% acetonitrile (0.05%TFA) (0.1% TFA) in water 10 minutes, remained on 100%1 minutes to 100% acetonitrile (0.05%TFA)); Retention time is with a minute measurement.

By with 4,5,6, the Triaminopyrimidine sulfuric ester is initial and use suitable electrophilic reagent, and said method can be used similarly to produce chemical compound, and wherein 2 are not substituted (that is, being H).

Embodiment 7 9-(4-chloro-butyl)-8-(2,5-dimethoxy-benzyl)-9H-purine 6-base amine (7)

Be separated into solid; Retention time=6.34.

Embodiment 8 8-(2,5-dimethoxy-benzyl)-9-penta-4-alkynyl-9H-purine-6-base amine (8)

Be separated into solid, retention time=5.88min.

Embodiment 9 8-(2,5-dimethoxy-benzyl)-9-(2-[1,3] dioxolanes-2-base-ethyl)-9H-purine-6-base amine (9)

Be separated into solid, retention time=5.36.

Embodiment 10 8-(2,5-dimethoxy-benzyl)-9-(4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine (10)

Be separated into solid, retention time=6.60.

Embodiment 11 9-(5-bromo-amyl group)-8-(2,5-dimethoxy-benzyl)-9H-purine-6-base amine (11)

Be separated into solid, retention time=6.94.

Embodiment 12 9-(5-bromo-3-methyl-amyl group)-8-(2,5-dimethoxy-benzyl)-9H-purine-6-base amine (12)

Be separated into solid, retention time=7.32.

Embodiment 13 9-(5-chloro-amyl group)-8-(2,5-dimethoxy-benzyl)-9H-purine 6-base amine (13)

Be separated into solid, retention time=6.34.

Embodiment 14 8-(2,5-dimethoxy-benzyl)-9-(4-ethylamino-butyl)-9H-purine-6-base amine (14)

Be separated into solid, retention time=3.9.

Embodiment 15 6-[6-amino-8-(2,5-dimethoxy-benzyl)-purine-9-yl]-ethyl-1-alcohol (15)

Carry out alkylation with 1-bromo-4-chlorobutane, handle with ethamine subsequently, obtain 4-ethylamino butyl, be separated into solid.

Embodiment 16 8-(2,5-dimethoxy-benzyl)-9-[2-(dimethyl-bicyclo-[3.1.1] hept-2-ene"-2-yl)-ethyl]-9H-purine-6-base amine (16)

Be separated into solid.

Embodiment 17 5-[6-amino-8-(2,5-dimethoxy-benzyl)-purine-9-yl]-pentyl acetate (17)

Be separated into solid, retention time=6.06.

Embodiment 18 8-(2,5-dimethoxy-benzyl)-9-(3,3,3-three fluoro-propyl group)-9H-purine-6-base amine (19)

Be separated into solid.

Embodiment 19 8-(2,5-dimethoxy-benzyl)-9-penta-4-alkynyl-9H-purine-6-base amine (20)

Be separated into solid, retention time=5.88.

Embodiment 20 9-butyl-8-(2-iodo-5-methoxyl group-benzyl)-9H-purine 6-base amine (20)

To 9-butyl-8-(3-methoxyl group-benzyl)-9H-purine-6-base amine (1.24g, 4mmol) in the solution of AcOH (6ml), add N-iodo-succinamide (NIS) (1.8g, 8mmol).At room temperature behind the 3h, (1.8g, 8mmol), other 24h stirs the mixture to add extra NIS.Use CH ₂Cl ₂(500ml) diluted reaction mixture, and use saturated K ₂CO ₃(2 * 100ml) aqueous solutions carefully neutralize, and use 0.1N Na subsequently ₂S ₂O ₃(3 * 100ml), saline (3 * 100ml) washings, dry (Na ₂SO ₄), evaporation, and by flash chromatography purification (CH ₂Cl ₂: MeOH=100:5), obtain 9-butyl-8-(2-iodo-5-methoxyl group-benzyl)-9H-purine-6-base amine (20), be colourless powder (0.53g, 30%); Room temperature=7.7min.; ¹H NMR (CDCl ₃-d) δ 8.36 (s, 1H), 7.77 (d, J=7.9Hz, 1H), 6.68 (s, 1H), 6.61 (d, J=7.9Hz, 1H), 5.62 (s, 2H), 4.33 (s, 2H), 4.06 (t, J=7.7Hz, 2H), 3.72 (s, 3H), 1.67 (quintets, J=7.7Hz, 2H), 1.36 (sextet, J=7.5Hz, 2H), 0.92 (t, J=7.4Hz, 3H).

Use same procedure and prepare bromine and chlorine derivative, suitably replace NIS with NBS and NCS.Also suitably use NIS, NCS or the synthetic following compounds of NBS according to substantially the same method:

Embodiment 21 9-butyl-8-(5-iodo-2-methoxyl group-benzyl)-9H-purine-6-base amine (21)

From 9-butyl-8-(2-methoxyl group-benzyl)-9H-purine-6-base amine is the starting material preparation, yield 48%, ¹H NMR (CDCl ₃) δ 8.32 (s, 1H), 7.55 (dd, J=8.7,2.2Hz, 1H), 7.37 (d, J=2.2Hz, 1H), 6.68 (d, J=8.7Hz, 1H), 6.05-5.85 (br.s, 2H), 4.17 (s, 2H), 4.07 (t, J=7.6Hz, 2H), 3.82 (s, 3H), 1.62 (quintet, J=7.5Hz, 2H), 1.30 (sextets, J=7.5Hz, 2H), 0.89 (t, J=7.4Hz, 3H).

Embodiment 22 9-butyl-8-(5-ethyl-2-methoxyl group-benzyl)-9H-purine-6-base amine (22)

Rt=7.59; ¹HNMR (CDCl3-d) δ 8.35 (s, 1H), 7.34 (d, J=8.8Hz, 1H), 6.79 (dd, J=8.7,2.8Hz, 1H), 6.69 (d, J=2.7Hz, 1H), 5,64 (s, 2H), 4.36 (s, 2H), 4.07 (t, J=7.7Hz, 2H), 3.73 (s, 3H), 1.64 (quintet, J=7.7Hz, 2H), 1.32 (sextets, J=7.5Hz, 2H), 0.90 (t, J=7.4Hz, 3H).

Embodiment 23 8-(2-bromo-5-methoxyl group-benzyl)-9-butyl-9H-purine-6-base amine (23)

Rt=7.66; ¹HNMR (CDCl3-d) δ 8.36 (s, 1H), 7.52 (d, J=8.7Hz, 1H), 6.74 (dd, J=8.7,3.0Hz, 1H), 6.89 (d, J=3.0Hz, 1H), 5,64 (s, 2H), 4.36 (s, 2H), 4.07 (t, J=7.7Hz, 2H), 3.72 (s, 3H), 1.64 (quintet, J=7.6Hz, 2H), 1.34 (sextets, J=7.5Hz, 2H), 0.90 (t, J=7.4Hz, 3H).

Use 2-methoxyphenyl chloroacetic chloride or 3-methoxybenzene guanidine-acetic acid respectively, by being similar to above-mentioned method, from 4,5,6-Triaminopyrimidine sulfuric ester prepares 9-butyl-8-(2-methoxyl group-benzyl)-9H-purine-6-base amine and 9-butyl-8-(3-methoxyl group-benzyl)-9H-purine-6-base amine.Also by being similar to above-mentioned method, from 2,4,5, the 6-tetraminopyrimidine prepares 2-fluoropurine analog.Referring to embodiment 2, step 4.

For chemical compound 24-29, wherein the N9 substituent group is to the halogenation sensitivity, and the substituent interpolation of N9 is finished as final step:

Embodiment 24 8-(2-bromo-5-methoxyl group-benzyl)-9-(4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine (24)

Rt=8.22; ¹HNMR (CDCl3-d) δ 8.37 (s, 1H), 7.51 (d, J=8.7Hz, 1H), 6.73 (dd, J=8.7Hz, 3.0Hz, 1H), 6.65 (d, J=3.0Hz, 1H), 5.53 (s, 2H), 5.12 (t, J=7.1Hz, 2H), 4.35 (s, 2H), 4.07 (t, J=7.1Hz, 2H), 3.72 (s, 3H), 2.43 (quartet (quart.), J=7.1Hz, 2H), 1.65 (s, 3H), 1.40 (s, 3H).

Embodiment 25 8-(2-bromo-5-methoxyl group-benzyl)-9-penta-4-alkynyl-9H-purine-6-base amine (25)

Rt=8.17; ¹HNMR (CDCl3-d) δ 8.35 (s, 1H), 7.52 (d, J=8.8Hz, 1H), 6.74 (dd, J=8.8Hz, 2.9Hz, 1H), 6.66 (d, J=2.9Hz, 1H), 5.61 (s, 2H), 4.39 (s, 2H), 4.21 (t, J=7.4Hz, 2H), 3.73 (s, 3H), 2.24 (td, J=6.8Hz, 2.5Hz, 2H), 2.03 (t, J=2.5Hz, 1H), 1.99 (quintet, J=7.2Hz, 2H).

Embodiment 26 8-(2-iodo-5-methoxyl group-benzyl)-9-penta-4-alkynyl-9H-purine-6-base amine (26)

Rt=7.35; ¹HNMR (CDCl3-d) δ 8.36 (s, 1H), 7.77 (d, J=8.5Hz, 1H), 6.64-6.60 (m, 2H), 5.56 (s, 2H), 4.35 (s, 2H), 4.20 (t, J=7.4Hz, 2H), 3.73 (s, 3H), 2.26 (td, J=6.9Hz, 2.7Hz, 2H), 2.03 (t, J=2.7Hz, 1H), 2.02 (quintet, J=7.0Hz, 2H).

Embodiment 27 8-(2-iodo-5-methoxyl group-benzyl)-9-(4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine (27)

Rt=8.17; ¹HNMR (CDCl3-d) δ 8.58 (s, 1H), 8.33 (d, J=8.6Hz, 1H), 6.60 (d, J=2.9Hz, 1H), 6.57 (dd, J=8.6,2.9Hz, 1H), 6.15 (s, 2H), 5.12 (t, J=7.4Hz, 2H), 4.29 (s, 2H), 4.04 (t, J=7.3Hz, 2H), 3.67 (s, 3H), 2.42 (quartet, J=7.2Hz, 2H), 1.65 (s, 3H), 1.39 (s, 3H).

Embodiment 28 2-fluoro-8-(2-iodo-5-methoxyl group-benzyl)-9-(4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine (28)

Rt=10.04; 1HNMR (CDCl3-d) δ 7.76 (d, J=8.6Hz, 1H), 6.65 (d, J=2.5Hz, 1H), 6.60 (dd, J=8.6,2.5Hz, 1H), 6.14 (s, 2H), 5.13 (t, J=6.9Hz, 1H), 4.26 (s, 2H), 4.01 (t, J=7.0Hz, 2H), 3.72 (s, 3H), 2.43 (quintet, J=7.0Hz, 2H), 1.68 (s, 3H), 1.42 (s, 3H).

Embodiment 29 2-fluoro-8-(2-iodo-5-methoxyl group-benzyl)-9-penta-4-alkynyl-9H-purine-6-base amine (29)

Rt=8.75; ¹HNMR (CDCl3-d) δ 7.77 (d, J=8.7Hz, 1H), 6.67 (d, J=2.7Hz, 1H), 6.62 (dd, J=8.7,2.7Hz, 1H), 5.99 (s, 2H), 4.32 (s, 2H), 4.16 (t, J=7.2Hz, 2H), 3.74 (s, 3H), 2.26 (td, J=6.7,2.6Hz, 2H), 2.02 (t, J=2.4Hz, 1H), 1.99 (quintet, J=6.9Hz, 2H); MP:172-177 ℃.

Palladium mediated link coupled general process

9-butyl-8-(5-iodo-2-methoxyl group-benzyl)-9H-purine-6-base amine (50mg, 0.1mmol) and Pd (PPh ₃) ₄(12mg, mixture 0.01mmol) under room temperature at N ₂It is middle that (0.5ml 0.5mmol) handles with 1M organic metal coupling gamete (partner) solution.Reaction was generally carried out 10 minutes with organo-magnesium compound under the room temperature in THF, carried out 16 hours with organic zinc compound under the room temperature in THF, or carried out 3 hours with organic stannane in 80 ℃ in DMF.Operation (work-up refers to separate the sequence of operations with purified product) afterwards, (1000uM, SiO on the preparation template ₂) by the chromatography purification product, use CH ₂Cl ₂: EtOAc: hexane: MeOH:Et ₃The N1500:750:750:50:10 eluting.

Chemical compound 30,31,32 is used corresponding commerce can get the organic zinc compound preparation, and the technical staff will know that organic stannane of equal value and organic boron and organic-magnesium coupling gamete can be used to replace organic zinc compound.General summary to appropriate method is found in " Palladium Reagents in Organic Synthesis " Richard F.Heck, Academic Press, 1990.

Embodiment 30 9-butyl-8-(5-ethyl-2-methoxyl group-benzyl)-9H-purine-6-base amine (30)

Rt＝8.23； ¹HNMR(CDCl3)δ 8.30(s，1H)，7.07(dd，J＝8.4 & 2.0Hz，1H)，6.91(d，J＝2.0Hz，1H)，6.83(d，J＝8.4Hz，1H)，5.65-5.55(s，2H)，4.23(s，2H)，4.04(t，J＝7.6Hz，2H)，3.83(s，3H)，2.51(q，J＝7.6Hz，2H)1.65-1.55(m，2H)，1.30-1.25(m，2H)，1.41(t，J＝7.6Hz，3H)，0.86(t，J＝7.3Hz，3H)。

Embodiment 31 9-butyl-8-(5-butyl-2-methoxyl group-benzyl)-9H-purine-6-base amine (31)

Rt=9.24; ¹H NMR (CDCl3) δ 8.33 (s, 1H), 7.05 (dd, J=8.4 ﹠amp; 1.9Hz, 1H), 6.88 (d, J=1.8Hz, 1H), 6.82 (d, J=8.3Hz, 1H), 5.58-5.48 (s, 2H), 4.23 (s, 2H), 4.04 (t, J=7.6Hz, 2H), 3.83 (s, 3H), 2.47 (q, J=7.6Hz, 2H), 1.57 (quintet, J=7.5Hz, 2H), 1.48 (quintets, J=7.6Hz, 2H), 1.32-1.22 (m, 4H), 0.87 (t, J=7.3Hz, 3H), 0.86 (t, J=7.3Hz, 3H).

Embodiment 32 9-butyl-8-(2-methoxyl group-5-vinyl-benzyl)-9H-purine-6-base amine (32)

Rt=7.91; ¹H NMR (CDCl3) δ 8.31 (s, 1H), 7.31 (dd, J=8.5 ﹠amp; 2.3Hz, 1H), 7.16 (d, J=2.2Hz, 1H), 6.87 (d, J=8.5Hz, 1H), 6.59 (dd, J=17.6 ﹠amp; 10.9Hz, 1H), and 5.82-5.72 (s, 2H), 5.53 (dd, J=17.6 ﹠amp; 0.7Hz, 1H), 5.09 (dd, J=10.9 ﹠amp; 0.7Hz, 1H), 4.22 (s, 2H), 4.06 (t, J=7.6Hz, 2H), 3.85 (s, 3H), 1.62 (quintet, J=7.7Hz, 2H), 1.30 (sextet, J=7.4Hz, 2H), 0.87 (t, J=7.4Hz, 3H).

The general process of the nitrated and derivatization of phenyl ring

In 0 ℃ with 1 normal HNO ₃Processing is at H ₂SO ₄Or at H ₂SO ₄: the purine analogue solution among the AcOH 1:4.With EtOAc diluted mixture thing, use NaHCO ₃Neutralization is also passed through at SiO ₂Preparation plate (1000uM) is gone up chromatography purification, uses CH ₂Cl ₂: EtOAc: hexane: MeOH:Et ₃N 1500:750:750:50:10.

Nitro-derivative (20mg) can use 10%Pd/C (Aldrich) (20mg) at H ₂Under room temperature, reduce 6h under the atmosphere, in THF.The aniline that obtains can be by further monoalkylation (chloroacetic chloride, CH ₂Cl ₂) or reductive alkylation (RCHO, NaBH (OAc) ₃, 1,2-dichloroethanes, room temperature)

Chemical compound 33-38 prepares by the method:

Embodiment 33 8-(2,5-dimethoxy-4 '-nitro-benzyl)-2-fluoro-9-penta-4-alkynyl-9H-purine-6-base amine (33)

Rt=8.05; ¹H NMR (CDCl3) δ 7.94 (s, 1H), 6.85 (s, 1H), 6.37-6.27 (s, 2H), 4.06 (s, 2H), 4.01 (t, J=7.3Hz, 2H), 3.69 (s, 3H), 3.66 (s, 3H), 2.13 (td, J=7.0 ﹠amp; 2.6Hz, 2H), 1.87 (t, J=2.6Hz, 1H), 1.82 (quintet, J=7.3Hz, 2H).

Embodiment 34 9-butyl-8-(3,5-dimethoxy-2-nitro-benzyl)-9H-purine-6-base amine; Sulfate (34)

Rt=7.33; ¹H NMR (DMSO-d6) δ 8.27 (s, 1H), 8.15-7.90 (br.s, 2H), 6.78 (d, J=2.4Hz, 1H), 6.55 (d, J=2.4Hz, 1H), 4.32 (s, 2H), 4.12 (t, J=7.3Hz, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 1.58 (quintets, J=7.5Hz, 2H), 1.21 (sextet, J=7.5Hz, 2H), 0.84 (t, J=7.4Hz, 3H).

Embodiment 35 8-(4-amino-3,5-dimethoxy-benzyl)-9-butyl-9H-purine-6-base amine (35)

Rt=805; ¹H NMR (CDCl3) δ 8.31 (s, 1H), 7.31 (dd, J=8.5 ﹠amp; 2.3Hz, 1H), 7.16 (d, J=2.2Hz, 1H), 6.87 (d, J=8.5Hz, 1H), 6.59 (dd, J=17.6 ﹠amp; 10.9Hz, 1H), and 5.82-5.72 (s, 2H), 5.53 (dd, J=17.6 ﹠amp; 0.7Hz, 1H), 5.09 (dd, J=10.9 ﹠amp; 0.7Hz, 1H), 4.22 (s, 2H), 4.06 (t, J=7.6Hz, 2H), 3.85 (s, 3H), 1.62 (quintet, J=7.7Hz, 2H), 1.30 (sextet, J=7.4Hz, 2H), 0.87 (t, J=7.4Hz, 3H).

Embodiment 36 8-(4-amino-2,5-dimethoxy-benzyl)-9-butyl-9H-purine-6-base amine (36)

Rt=6.95; 1H NMR (CDCl3) δ 8.33 (s, 1H), 6.57 (s, 1H), 6.33 (s, 1H), 6.37-6.27 (s, 2H), 4.20 (s, 2H), 4.01 (t, J=7.3Hz, 2H), 3.74 (s, 3H), 3.68 (s, 3H), 1.59 (quintets, J=7.5Hz, 2H), 1.32 (sextet, J=7.5Hz, 2H), 0.86 (t, J=7.4Hz, 3H).

Embodiment 37 8-(2-amino-3,5-dimethoxy-benzyl)-9-butyl-9H-purine-6-base amine (37)

¹H NMR (CDCl3) δ 8.28 (s, 1H), 6.40 (d, J=2.5Hz, 1H), 6.30 (d, J=2.5Hz, 1H), 5.85-5.75 (s, 2H), 4.14 (s, 2H), 4.13 (t, J=7.6Hz, 2H), 3.80 (s, 3H), 3.73 (s, 3H), 1.62 (quintets, J=7.5Hz, 2H), 1.48 (sextet, J=7.5Hz, 2H), 0.91 (t, J=7.4Hz, 3H).

Embodiment 38 2-(6-amino-9-butyl-9H-purine-8-ylmethyl)-4-methoxyl group-benzaldehyde-neighbour-methyl-oxime (38)

Rt=7.69; ¹H NMR (CDCl3) δ 8.88 (s, 1H), 8.31 (s, 1H), 7.72 (d, J=7.9Hz, 1H)), 6.80 (d, J=8.0Hz, 1H), 6.74 (s, 1H), 5.80-5.76 (s, 2H), 4.24 (s, 2H), 4.00 (t, J=7.7Hz, 2H), 3.94 (s, 3H), 3.76 (s, 3H), 1.58 (quintet, J=7.7Hz, 2H), 1.28 (sextets, J=7.5Hz, 2H), 0.86 (t, J=7.3Hz, 3H).

The formation of phenyl ring and deriving

9-butyl-8-(3-methoxyl group-benzyl)-9H-purine-6-base amine (100mg, 0.32mmol), 1, the 1-dichlorodimethyl ether (40mg, 0.35mmol) and TiCl ₄(133mg is 0.70mmol) at CH ₂Cl ₂Solution (10ml) stirs under 0 ℃ of preparation and room temperature and spends the night.Use CH ₂Cl ₂Dilution, washing (Na ₂SO ₄, NH ₄Cl), drying obtains title aldehyde through preparation type thin layer chromatography, is yellow glass (47mg, 43%).

Standard method can obtain corresponding alcohol (NaBH ₄, MeOH, room temperature), tosylhydrazone (TsNHNH ₂, EtOH refluxes), oxime (RONH ₂HCl, DMF, 60 ℃), amine (R ₁R ₂NH, NaBH (OAc) ₃, Cl-(CH ₂) ₂-Cl room temperature), homoallylic alcohol (AllSiMe ₃, TiCl ₄), CH ₂Cl ₂,-78 ℃) or alkene.

Embodiment 39 2-(6-amino-9-butyl-9H-purine-8-ylmethyl)-4-methoxyl group-benzaldehyde (39)

Rt=6.52; ¹HNMR (CDCl3-d) δ 10.39 (s, 1H), 8.32 (s, 1H), 7.76 (d, J=7.8Hz, 1H), 6.87 (m, 2H), 6.22 (s, 2H), 4.28 (s, 2H), 4.03 (t, J=7.6Hz, 2H), 3.85 (s, 3H), 1.61 (quintets, J=7.3Hz, 2H), 1.29 (sextet, J=7.4Hz, 2H), 0.86 (t, J=7.2Hz, 3H).

The Negishi coupling

Stir 3 under the room temperature in flame-dried Schlenk test tube, (0.47g is 1.96mmol) with Rieke Zinc (3.0ml for 4-dichloro benzyl bromine, 5g/100ml THF, mixture overnight 2.35mmol), and drain, provide 3 of 0.65M, 4-dichloro benzyl zinc bromide stock solution.In 66 ℃ in flame-dried Schlenk test tube, stir 8-bromo-9-butyl-9H-purine-6-base amine (42.7mg, 0.158mol), Pd (dppf) Cl ₂(16.8mg, 0.020mmol) with 3, the solution of 4-dichloro benzyl zinc bromide (0.61ml, 0.65M is in THF) spends the night, and uses saturated NH ₄Cl aqueous solution and the cancellation of saturated EDTA aqueous solution, EtOAc is advanced in extraction, and is dry and concentrated.Preparation type TLC purification (EtOAc/CH ₂Cl ₂/ MeOH 14:14:2) provides title compound, be colorless oil (about 15mg, 20%).

Embodiment 40 9-butyl-8-(3,4-two chloro-benzyls)-9H-purine-6-base amine (40)

Compound separation is a solid, retention time=7.98.

Embodiment 41 3-(6-amino-9-butyl-9H-purine-8-base sulfane base)-phenol (41)

Step 1: with adenine (47g 0.35mole) is suspended among the 200ml CHCl3, add subsequently a bromine (180ml, 3.5mole).Under the room temperature in closed system stirred suspension 72 hours, described system is by the ventilation of 20G pin.Before slowly being neutralized to pH8-9 with ammonia, by being joined in the suspension, shaved ice reacts, precipitate required product with acetic acid subsequently.Drying under reduced pressure crude product 2 days obtains 8-bromine adenine, is light brown powder (45g, yield 60%). ¹H NMR(DMSO-d ₆)δ 8.12(s，1H)，7.22(s，2H).Rf(75％EtOAc/Hex)＝0.4。

Step 2: with 8-bromine purine (2.2g 10mmole) is dissolved among the 50ml DMF, subsequently with 1-bromo-butane (2.2ml, 20mmol) and cesium carbonate (6.7g 20mmol) adds in the solution.Make under the reactant mixture room temperature and to stir 16 hours, water cancellation subsequently also extracts with EtOAc.Wash organic layer with water, and use the MgSO4 drying, decompression subsequently goes down to desolventize.The white powder (0.9g, 33%) that separates 8-bromo-9-butyl-9H-purine-6-base amine with silica gel column chromatography (50% EtOAc/ hexane). ¹H NMR(CDCl ₃)δ 8.32，(s，1H)，5.81(s，2H)，4.20(t，2H)，1.82(m，2H)，1.40(m，2H)，0.96(t，3H).Rf(75％EtOAc/Hex)＝0.6。

Step 3: to sodium hydride (96mg, 4mmol) mixture in DMF (4ml) add 3-methoxyl group-benzenethiol (1.12g, 8mmol).Behind the 30min, add 8-bromo-9-butyl-9H-purine-6-base amine (0.54g, 2mmol) solution in DMF (6ml) and stir 12h in 70 ℃.By adding MeOH (4ml) cancellation reactant mixture,, use Na with EtOAc (400ml) dilution ₂CO ₃(3 * 100ml), saline (3 * 100ml) washings, dry (Na ₂SO ₄), evaporation, flash chromatography (CH ₂Cl ₂: MeOH=100:5) purification, obtain 3-(6-amino-9-butyl-9H-purine-8-base sulfane base)-phenol, be colourless powder (0.59g, 89%).Retention time=6.75min ¹HNMR (DMSO-d ₆): δ 9.69 (s, 1H), 8.17 (s, 1H), 7.45 (s, 2H), 7.17 (t, J=7.9Hz, 1H), 6.76 (d, J=7.4Hz, 1H), 6.68 (d, J=8.2Hz, 1H), 6.62 (s, 1H), 4.11 (t, J=7.0Hz, 2H), 1.57 (quintet, J=7.3Hz, 2H), 1.19 (sextet, J=6.8Hz, 2H), 0.81 (t, J=7.4Hz, 3H).

The HPLC method that is used for these chemical compounds: Agilent Zorbax 300 SB C18,4.6 * 150mm, 5 μ m; Column temperature: room temperature; Flow velocity: 1.0ml/min, gradient: 5% acetonitrile (0.05% TFA) (0.1% TFA) in water 15 minutes, kept 2 minutes in 100% to 100% acetonitrile (0.05%TFA)).

As embodiment 41 preparation following compounds, use the 3-methoxybenzene mercaptan of using in the corresponding mercaptan replacement step 3:

Embodiment 42 9-butyl-8-(3-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (42)

Retention time=8.6min; ¹H NMR (DMSO-d ₆) δ 0.80 (t, J=7.4Hz, 3H, CH ₃), 1.20 (m, 2H, CH ₂), 1.61 (m, 2H, CH ₂), 3.60 (s, 3H, OCH ₃), 3.76 (s, 3H, OCH ₃), 4.13 (t, J=7.4Hz, 2H, CH ₂), 6.46 (s, 1H, Ar-H), 6.85 (d, J=8.9Hz, 1H, Ar-H), 7.02 (d, J=8.9Hz, 1H, Ar-H), 7.41 (bs, 2H, NH ₂), 8.15 (s, 1H, purine-H).

Embodiment 43 9-butyl-8-(2,5-dimethoxy-phenyl sulfane base)-9H-purine-6-base amine) (43)

Rt=7.62min; ¹HNMR (CDCl ₃-d ₆): δ 8.30 (s, 1H), 7.18 (t, J=8.2Hz, 1H), 6.90 (m, 2H), 6.77 (m, 3H), 4.17 (t, J=7.6Hz, 2H), 3.70 (s, 3H), 1.67 (quintet, J=7.5Hz, 2H), 1.28 (sextet, J=7.5Hz, 2H), 0.86 (t, J=7.4Hz, 3H).

Embodiment 44 9-butyl-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (44) and

Embodiment 45 9-butyl-8-(4-iodo-3-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (45)

For embodiment 42, be subsequently:

Step 4: to 9-butyl-8-(3-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (0.26g, 0.73mmol) in the solution in AcOH (4ml) by part add a NIS (0.53g, 2.19mmol).24h stirs the mixture under the room temperature.With EtOAc (200ml) diluted reaction mixture, and use K ₂CO ₃(2 * 50ml) solution carefully neutralize, and use Na subsequently ₂S ₂O ₃(3 * 50ml), saline (3 * 50ml) washings, dry (Na ₂SO ₄), evaporation is by preparation type TLC chromatography (CH ₂Cl ₂: MeOH=100:5) purification, obtain 2-iodine isomer (60mg), and

Rt=8.45min; ¹HNMR (CDCl ₃-d): δ 8.38 (s, 1H), 7.73 (d, J=8.7Hz, 1H), 6.71 (d, J=2.7Hz, 1H), 6.58 (dd, J=8.7,2.7Hz, 1H), 5.91 (s, 2H), 4.22 (t, J=7.4Hz, 2H), 3.68 (s, 3H), 1.75 (quintets, J=7.7Hz, 2H), 1.34 (sextet, J=7.5Hz, 2H), 0.93 (t, J=7.4Hz, 3H).4-iodine isomer (65mg).

Rt=8.63min; ¹HNMR (CDCl ₃-d): δ 8.38 (s, 1H), 7.72 (d, J=8.1Hz, 1H), 6.92 (d, J=1.8Hz, 1H), 6.58 (dd, J=8.1,1.8Hz, 1H), 5.82 (s, 2H), 4.22 (t, J=7.4Hz, 2H), 3.85 (s, 3H), 1.75 (quintets, J=7.7Hz, 2H), 1.37 (sextet, J=7.5Hz, 2H), 0.93 (t, J=7.4Hz, 3H).

For wherein the N9 substituent group is to the chemical compound of halogenation condition responsive, it can use the iodide preparation that has been present in the benzenethiol part:

(96mg 4mmol) adds 2-iodo-5-methoxyl group-benzenethiol (1.06g, 4mmol in the solution in DMF (3ml) to sodium hydride; J Org.Chem, 2001,66 (13), 4525-4542).Behind the 30min, adding 8-bromo-9-(4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine (296mg, the 1mmol) solution in DMF (3ml), and in 70 ℃ of 12h that stir the mixture.By adding MeOH (2ml) cancellation reactant,, use Na with EtOAc (200ml) dilution ₂CO ₃(3 * 50ml), saline (3 * 50ml) washings, dry (Na ₂SO ₄), evaporation, and by flash chromatography (CH ₂Cl ₂: MeOH=100:5) purification, obtain 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-(4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine, be colourless powder (280mg, 58%).

Use electrophilic reagent 1-bromo-4-methyl-penta-3-alkene and 1-chloro-penta-4-alkynes respectively, prepare following compounds by this method:

Embodiment 46 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-(4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine (46)

Rt=9.14min; ¹HNMR (CDCl ₃-d): δ 8.39 (s, 1H), 7.72 (d, J=8.7Hz, 1H), 6.72 (d, J=2.7Hz, 1H), 6.58 (dd, J=8.7,2.7Hz, 1H), 5.18 (s, 2H), 5.15 (t, J=7.3Hz, 1H), 4.25 (t, J=7.4Hz, 2H), 3.69 (s, 3H), 2.50 (quintet, J=7.3Hz, 2H), 1.66 (s, 3H), 1.44 (s, 3H); MP:167-167.5 ℃.

Embodiment 47 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine (47)

Rt=7.93min; ¹HNMR (CDCl ₃-d): δ 8.38 (s, 1H), 7.75 (d, J=8.7Hz, 1H), 6.74 (d, J=2.7Hz, 1H), 6.60 (dd, J=8.7,2.7Hz, 1H), 5.72 (s, 2H), 4.32 (t, J=7.3Hz, 2H), 3.70 (s, 3H), 2.28 (td, J=6.8,2.6Hz, 2H), 2.06 (quintet, J=7.3Hz, 2H), 2.00 (t, J=2.4Hz, 1H); MP:168-169 ℃.

Use corresponding mercaptan and replace the NaH that uses in 3-methoxybenzene mercaptan and the alkali t-BuOK replacement step 3, the preparation following compounds:

Embodiment 48 8-(benzothiazole-2-base sulfane base)-9-butyl-9H-purine-6-base amine (48)

Rt＝6.53min； ¹H NMR(CDCl ₃)δ 8.41(s，1H)，7.94(d，1H)，7.74(d，1H)，7.47(t，1H)，7.38(t，1H)，6.01(s，2H)，4.32(t，2H)，1.79(m，2H)，1.35(m，2H)，0.89(t，3H)。

Embodiment 49 9-butyl-8-(5-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (49)

Mass(M+1)＝391.8et(M+3)＝393.8； ¹H NMR(CDCl ₃)δ 8.43(s，1H)，7.92(s，1H)，7.65(d，1H)，7.35(d，1H)，6.01(s，2H)，4.32(t，2H)，1.79(m，2H)，1.35(m，2H)，0.89(t，3H)。

Embodiment 50 9-butyl-8-(5-methoxyl group-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (50)

¹H NMR(CDCl ₃)δ 8.42(s，1H)，7.60(d，1H)，7.43(s，1H)，7.02(d，1H)，5.82(s，2H)，4.33(t，2H)，3.99(s，3H)，1.80(m，2H)，1.35(m，2H)，0.89(t，3H)。

Embodiment 51 9-butyl-8-(2,5-two chloro-phenyl sulfane bases)-9H-purine-6-base amine (51)

¹H NMR(CDCl ₃)δ 8.37(s，1H)，7.35(d，1H)，7.20(dd，1H)，7.14(d，1H)，5.72(s，2H)，4.24(t，2H)，1.79(m，2H)，1.35(m，2H)，0.89(t，3H)。

Embodiment 52 9 butyl-8-(2,4,5-three chloro-phenyl sulfane bases)-9H-purine-6-base amine (52)

Rt＝7.8min； ¹H NMR(CDCl ₃)δ 8.37(s，1H)，7.62(s，1H)，7.35(s，1H)，5.98(s，2H)，4.27(t，2H)，1.80(m，2H)，1.36(m，2H)，0.92(t，3H)。

General process

By being similar to the method for said method, from 2, the 6-diaminopurine prepares 8-(2,5-dimethoxy-phenyl sulfane base)-2-fluoro-9 (4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine and 8-(2,5-dimethoxy-phenyl sulfane base)-2-amino-9 (4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine.Amino final transformation to chlorine is to be undertaken by being similar to embodiment 2 steps 4 reported method.

Embodiment 53 8-(2,5-dimethoxy-phenyl sulfane base)-2-amino-9 (4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine (53)

¹H NMR(DMSO-d6)δ 1.28(s，3H，CH ₃)，1.58(s，3H，CH ₃)，2.35(m，2H，CH ₂)，3.60(s，3H，OCH ₃)，3.76(s，3H，OCH ₃)，4.12(t，J＝7.0Hz，2H，CH ₂)，5.05(t，J＝7Hz，1H，CH＝)，6.50(s，1H，Ar-H)，6.91(d，J＝8.9Hz，1H，Ar-H)，7.05(d，J＝8.9Hz，1H，Ar-H)。

Embodiment 54 8-(2,5-dimethoxy-phenyl sulfane base)-2-fluoro-9 (4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine (54)

¹H NMR(DMSO-d6)δ 1.30(s，3H，CH ₃)，1.55(s，3H，CH ₃)，2.35(m，2H，CH ₂)，3.60(s，3H，OCH ₃)，3.76(s，3H，OCH ₃)，4.10(t，J＝7.0Hz，2H，CH ₂)，5.05(t，J＝7Hz，1H，CH＝)，6.47(s，1H，Ar-H)，6.86(d，J＝8.9Hz，1H，Ar-H)，7.02(d，J＝8.9Hz，1H，Ar-H)；MS(m/z)426(M+Na)。

Be similar to the foregoing description 41 described methods, use multiple electrophilic reagent and prepare following 12 kinds of chemical compounds, produce N9 substituted compound storehouse.Using 2, after 5-dimethoxy phenylmercaptan. carried out the bromine displacement to 8-bromine purine, the N9 alkylation was carried out as final step.

Embodiment 55 8-(2,5-dimethoxy-phenyl sulfane base)-9H-purine-6-base amine (55)

¹H NMR (DMSO-d ₆) δ 3.62 (s, 3H, OCH ₃), 3.76 (s, 3H, OCH ₃), 6.61 (s, 1H, Ar-H), 6.85 (d, J=8.9Hz, 1H, Ar-H), 7.02 (d, J=8.9Hz, 1H, Ar-H), 7.24 (bs, 2H, NH ₂), 8.13 (s, 1H, purine-H) 13.33 (s, 1H, purine-NH); Electrophilic reagent: on N9, do not replace.

Embodiment 56 8-(2,5-dimethoxy-phenyl sulfane base)-9-amyl group-9H-purine-6-base amine (56)

¹H NMR (DMSO-d ₆) δ 0.80 (t, J=7.4Hz, 3H, CH ₃), 1.20 (m, 4H, 2CH ₂), 1.61 (m, 2H, CH ₂), 3.60 (s, 3H, OCH ₃), 3.76 (s, 3H, OCH ₃), 4.13 (t, J=7.4Hz, 2H, CH ₂), 6.46 (s, 1H, Ar-H), 6.85 (d, J=8.9Hz, 1H, Ar-H), 7.02 (d, J=8.9Hz, 1H, Ar-H), 7.41 (bs, 2H, NH ₂), 8.15 (s, 1H, purine-H); Electrophilic reagent: 1-bromine amyl group.

Embodiment 57 8-(2,5-dimethoxy-phenyl sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine (57)

¹H NMR (DMSO-d ₆) δ 1.89 (m, 2H, CH ₂), 2.20 (t, J=8.0Hz, 2H, CH ₂), 2.78 (s, 1H, CH ≡), 3.62 (s, 3H, OCH ₃), 3.76 (s, 3H, OCH ₃), 4.23 (t, J=7.4Hz, 2H, CH ₂), 6.46 (s, 1H, Ar-H), 6.85 (d, J=8.9Hz, 1H, Ar-H), 7.02 (d, J=8.9Hz, 1H, Ar-H), 7.41 (bs, 2H, NH ₂), 8.15 (s, 1H, purine-H); Electrophilic reagent: 1-chloro-penta-4-alkene.

Embodiment 58 8-(2,5-dimethoxy-phenyl sulfane base)-9 (3,3,3-trifluoromethyl propyl group)-9H-purine-6-base amine (58)

¹H NMR (DMSO-d ₆) δ 2.54 (t, J=8.0Hz, 2H, CH ₂), 3.62 (s, 3H, OCH ₃), 3.74 (s, 3H, OCH ₃), 4.46 (t, J=8.0Hz, 2H, CH ₂), 6.46 (s, 1H, Ar-H), 6.85 (d, J=8.9Hz, 1H, Ar-H), 7.02 (d, J=8.9Hz, 1H, Ar-H), 7.41 (bs, 2H, NH ₂), 8.30 (s, 1H, purine-H); Electrophilic reagent: 1-bromo-3,3,3-three fluoro-propane.

Embodiment 59 8-(2,5-dimethoxy-phenyl sulfane base)-9 (4-chlorobutyl)-9H-purine-6-base amine (59)

¹H NMR (DMSO-d ₆) δ 1.82 (m, 2H, CH ₂), 1.98 (m, 2H, CH ₂), 3.56 (t, J=6.4Hz, 2H, CH ₂), 3.75 (s, 3H, OCH ₃), 3.78 (s, 3H, OCH ₃), 4.23 (t, J=7.4Hz, 2H, CH ₂), 6.46 (s, 1H, Ar-H), 6.85 (d, J=8.9Hz, 1H, Ar-H), 7.02 (d, J=8.9Hz, 1H, Ar-H), 7.41 (bs, 2H, NH ₂), 8.15 (s, 1H, purine-H); Electrophilic reagent: 1-bromo-4-chlorobutane.

Embodiment 60 8-(2,5-dimethoxy-phenyl sulfane base)-9 (4-acetoxyl group butyl)-9H-purine-6-base amine (60)

¹H NMR (DMSO-d ₆) δ 1.70 (m, 2H, CH ₂), 1.90 (m, 2H, CH ₂), 2.02 (s, 3H, CH ₃), 3.75 (s, 3H, OCH ₃), 3.78 (s, 3H, OCH ₃), 4.10 (t, J=6.4Hz, 2H, CH ₂), 4.30 (t, J=7.4Hz, 2H, CH ₂), 6.46 (s, 1H, Ar-H), 6.85 (d, J=8.9Hz, 1H, Ar-H), 7.02 (d, J=8.9Hz, 1H, Ar-H), 7.41 (bs, 2H, NH ₂), 8.15 (s, 1H, purine-H); Electrophilic reagent: 1-bromo-4-acetoxyl group butane.

Embodiment 61 8-(2,5-dimethoxy-phenyl sulfane base)-9 (5-bromine amyl group)-9H-purine-6-base amine (61)

¹H NMR (DMSO-d ₆) δ 1.46 (m, 2H, CH ₂), 1.85 (m, 4H, 2CH ₂), 3.36 (t, J=6.7Hz, 2H, CH ₂), 3.72 (s, 3H, OCH ₃), 3.80 (s, 3H, OCH ₃), 4.30 (t, J=7.4Hz, 2H, CH ₂), 6.46 (s, 1H, Ar-H), 6.85 (d, J=8.9Hz, 1H, Ar-H), 7.02 (d, J=8.9Hz, 1H, Ar-H), 7.41 (bs, 2H, NH ₂), 8.15 (s, 1H, purine-H); Electrophilic reagent: pentamethylene bromide.

Embodiment 62 8-(2,5-dimethoxy-phenyl sulfane base)-9 (2-[1,3] dioxolanes-2-base-ethyl)-9H-purine-6-base amine (62)

¹H NMR (DMSO-d ₆) δ 2.26 (m, 2H, CH ₂), 3.75 (s, 3H, OCH ₃), 3.77 (s, 3H, OCH ₃), 3.85 (t, J=7.0Hz, 2H, CH ₂), 3.98 (t, J=7.0Hz, 2H, CH ₂), 4.46 (t, J=7.4Hz, 2H, CH ₂), 4.96 (t, J=4.1Hz, 1H, CH), 6.46 (s, 1H, Ar-H), 6.85 (d, J=8.9Hz, 1H, Ar-H), 7.02 (d, J=8.9Hz, 1H, Ar-H), 7.41 (bs, 2H, NH ₂), 8.15 (s, 1H, purine-H); Electrophilic reagent: 2-(2-chloro-ethyl)-[1,3] dioxolanes.

Embodiment 63 8-(2,5-dimethoxy-phenyl sulfane base)-9-(4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine (63)

¹H NMR (DMSO-d ₆) δ 1.28 (s, 3H, CH ₃), 1.54 (s, 3H, CH ₃), 2.35 (m, 2H, CH ₂), 3.60 (s, 3H, OCH ₃), 3.76 (s, 3H, OCH ₃), 4.15 (t, J=7.0Hz, 2H, CH ₂), 5.05 (t, J=7Hz, 1H, CH=), 6.46 (s, 1H, Ar-H), 6.86 (d, J=8.9Hz, 1H, Ar-H), 7.02 (d, J=8.9Hz, 1H, Ar-H), 7.42 (bs, 2H, NH ₂), 8.17 (s, 1H, purine-H); Electrophilic reagent: 1-bromo-4-methyl-penta-3-alkene; MP:148-150 ℃.

Embodiment 64 8-(2,5-dimethoxy-phenyl sulfane base)-9-(penta-4-thiazolinyl)-9H-purine-6-base amine (64)

¹H NMR (DMSO-d ₆) δ 1.89 (m, 2H, CH ₂), 2.19 (t, J=8.0Hz, 2H, CH ₂), 3.62 (s, 3H, OCH ₃), 3.76 (s, 3H, OCH ₃), 4.23 (t, J=7.4Hz, 2H, CH ₂), 5.05 (m, 2H, CH ₂=), 5.82 (m, 1H, CH=), 6.46 (s, 1H, Ar-H), 6.85 (d, J=8.9Hz, 1H, Ar-H), 7.02 (d, J=8.9Hz, 1H, Ar-H), 7.41 (bs, 2H, NH ₂), 8.15 (s, 1H, purine-H); Electrophilic reagent: 1-chloro-penta-4-alkene.

Embodiment 65 8-(2,5-dimethoxy-phenyl sulfane base)-9-(3-hydroxypropyl)-9H-purine-6-base amine (65)

¹H NMR (DMSO-d ₆) δ 1.82 (m, 2H, CH ₂), 3.60 (s, 3H, OCH ₃), 3.76 (s, 3H, OCH ₃), 4.12 (m, 2H, CH ₂), 4.21 (t, J=7.0Hz, 2H, CH ₂), 6.47 (s, 1H, Ar-H), 6.86 (d, J=8.9Hz, 1H, Ar-H), 7.02 (d, J=8.9Hz, 1H, Ar-H); 8.15 (s, 1H, purine-H); Electrophilic reagent: 1-bromo-3-hydroxypropyl alkane.

Embodiment 66 4-[6-amino-8 (2,5-dimethoxy sulfane base)-purine-9-yl]-butyronitrile (66)

¹H NMR (DMSO-d ₆) δ 1.89 (m, 2H, CH ₂), 2.20 (t, J=8.0Hz, 2H, CH ₂), 3.62 (s, 3H, OCH ₃), 3.76 (s, 3H, OCH ₃), 4.23 (t, J=7.4Hz, 2H, CH ₂), 6.46 (s, 1H, Ar-H), 6.85 (d, J=8.9Hz, 1H, Ar-H), 7.02 (d, J=8.9Hz, 1H, Ar-H), 7.41 (bs, 2H, NH ₂), 8.15 (s, 1H, purine-H); Electrophilic reagent: 1-bromine butyronitrile.

Embodiment 67 9-butyl-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (67)

This chemical compound is used diazol and mercaptan prepares as the coupling gamete.

Step 1:8-bromo-9-butyl-9H-purine-6-base amine (0.50g, 1.85mmol) and thiourea (1.49g, 19.6mmol) suspension in n-butyl alcohol (10ml) is heated to backflow 14h.Use CH ₂Cl ₂(70ml) dilution washes with water and concentrates, and produces 6-amino-9-butyl-7, and 9-dihydro-purine-8-thioketone is white powder (0.42g, 1.87mmol, 100%). ¹H NMR (DMSO-d ₆) δ 12.35-12.25 (br.s, 1H), 8.13 (s, 1H), 6.92-6.72 (br.s., 2H), 4.09 (t, J=7.6Hz, 2H), 1.71 (quintet, J=7.5Hz, 2H), 1.29 (sextet, J=7.5Hz, 2H), 0.87 (t, J=7.4Hz, 3H).

Step 2: above-mentioned thioketone (30.8mg, 0.138mmol) and t-BuOK (15.5mg, 0.138mmol) solution in MeOH (0.55ml) is used rough 2-iodo-5-methoxyl group-benzene diazonium tetrafluoroborate (48mg is 0.138mmol) by part handling.Violent N ₂Evaporation stops behind 2min.Operation and preparation type TLC (MeOH:CH ₂Cl ₂5:95) produce title sulfide.

Embodiment 68 2-fluoro-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine (68)

Step 1 8-bromo-9-penta-4-alkynyl-9H-purine-2, the 6-diamidogen

8-bromo-9H-purine-2,6-diamidogen (600mg; Beaman et al, J.Org.Chem., 1962,27,986), Cs ₂CO ₃(1.94g), the mixture of 5-chloro-penta-1-alkene (0.56mL) and DMF (5mL) is heated to 85 ℃ and spends the night.Operation and evaporation obtain title compound, for slightly carrying solid. ¹H NMR (CDCl ₃) δ 6.80 (s, 2H), 5.95 (s, 2H), 3.98 (t, 2H), 2.81 (t, 1H), 2.22 (t, 2H), 1.96 (quintet, 2H).

Step 2 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-penta-4-alkynyl-9H-purine-2, the 6-diamidogen

8-bromo-9-penta-4-alkynyl-9H-purine-2, the mixture of 6-diamidogen (500mg), 2-iodo-5-methoxyl group-benzenethiol (1.34g), t-BuOK (475mg) and DMF (7mL) is heated to 100 ℃ and spends the night.Extraction and chromatography obtain title compound.Rt=7.85min. ¹H NMR (CDCl ₃) δ 7.72 (d, 1H), 6.98 (s, 2H), 6.63 (d, 1H), 6.22 (dd, 1H), 6.01 (s, 2H), 4.01 (t, 2H), 3.60 (s, 3H), 2.67 (t, 1H), 2.12 (dt, 2H), 1.78 (quintet, 2H), 1.97 (t, 1H).

Step 3 2-fluoro-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine

8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-penta-4-alkynyl-9H-purine-2,6-diamidogen (79mg) and 48% aqueous HBF ₄(0.5mL) mixture in THF (0.5mL) is handled with amyl nitrite (22uL) down by-20 ℃.Make reactant mixture reach room temperature and further be heated to 40 ℃ 10 minutes.Operation (DCM/aq.K ₂CO ₃) and chromatography (EtOAc/ hexane 1:4) obtain title compound, be solid.Rt=9.43min. ¹H NMR (CDCl ₃) δ 7.72 (d, 1H), 6.70 (d, 1H), 6.59 (dd, 1H), 4.25 (t, 2H), 3.69 (s, 3H), 2.25 (dt, 2H), 2.02 (quintet, 2H), 1.97 (t, 1H).

The embodiment 69 9-(tert-butyl group-dimethyl-silanyloxy ylmethyl-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (69)

9-(tert-butyl group-dimethyl-silanyloxy ylmethyl)-8-iodo-9H-purine-6-base amine (817mg; Lang, J.Org.Chem.2000,65,7825) and potassium 2-iodo-5-methoxyl group-benzenethiol ester (920mg; Flynn, Org.Lett.2001,3,651) solution in DMF (10mL) is heated to 60 ℃ of 1h and is heated to 100 ℃ of another hours.Operation and flash chromatography (CH ₂Cl ₂: EtOAc 67:33 → 0:100) obtain title compound is white solid.Rt＝10.47min. ¹H NMR(CDCl ₃)δ 8.37(s，1H)，7.70，(d，1H)，6.83(d，1H)，6.56(dd，1H)，5.83(s，2H)，5.75(s，2H)，3.67(s，3H)，0.83(s，9H)，0.09(s，6H)。

Embodiment 70 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (70)

Step 1 6-amino-7,9-dihydro-purine-8-thioketone

3,4,5-Triaminopyrimidine (50g) and thiourea (60g, 2 equivalents) are ground in mortar jointly, and heating is until melting (T _Int=150 ℃), the endothermic reaction wherein takes place.Stirred reaction mixture under this temperature until solidifying generation (2h), is cooled to room temperature, fine gtinding, and in water, stir and spend the night so that remove excessive thiourea.Desired substance obtains (yield 88-94%, purity 100%) by filtration.Rt＝1.99min. ¹H-NMR(DMSO-d ₆)δ 13.04(s，1H)，12.05(s，1H)，8.07(s，1H)，6.75(s，2H). ¹³C-NMR(DMSO-d ₆)

167.0，153.1，150.33，147.8，108.5。

Step 2 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9h-purine-6-base amine

The 6-amino-7 of fine gtinding, the 9-dihydro-purine-suspension of 8-thioketone (46g) in DMF (700ml) is cooled to-60 ℃, and handles (100g, 1.1 equivalents with 2-iodo-5-methoxybenzene diazonium tetrafluoroborate; (a) Ma, J.Org.Chem.2001,66,4525 (b) Flynn, Org.Lett, 2001,3,651).Mixture is heated gradually.When it reaches-10 ℃, observe gas evaporation, and owing to less but highly colored by-product forms peony.Make reactant mixture reach room temperature, use NaHCO subsequently ₃(38g, 1.7 equivalents) neutralization concentrates, and is suspended in the chloroform, filters until there not being more orchil to be washed off, and further washes with water and produce thick title thing (64g, " 61% ").This material can be used without being further purified.Alternatively, and operation (NaOH1M is advanced in extraction, and the HCl acidify is used in the EtOAc washing, the EtOAc washing, and neutralization, EtOAc is advanced in extraction) be feasible.Rt＝6.08min(5-100-12). ¹HNMR(DMSO)δ(br.s，1H)，8.13(s，1H)，7.79(d，1H)，7.38(br.，s，2H)，6.71(d，1H)，6.62(s，2H)，3.65(s，3H)。

Step 3 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine

8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (7.3g) is used 1-bromo-2-ethyl chloride (3.7ml, 2.5 equivalents) and K ₂CO ₃The DMF solution of (7.6g, 3 equivalents) is handled 16h at 40 ℃.Concentrated reaction mixture is dissolved among the MeOH:CH2Cl2 10:90 and washes with water.Chromatography (EtOAcCH ₃CN:MeOH 800:200:2) obtains the desired substance of 1.7g (21%).Merge impurity part and crystallization (70ml EtOH) and obtain other 0.9g (11%).Rt＝7.61min(5-100-12). ¹HNMR(CDCl ₃)δ(s，1H)，7.73(d，J＝8.4Hz，1H)，6.77(s，1H)，6.60(d，1H)，5.93(br.，s，2H)，4.61(t，J＝4.4Hz，2H)，3.90(t，J＝4.4Hz，2H)，3.70(s，3H)。

Embodiment 71 9-(3-chloro-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (71)

As embodiment 15 steps 1, title compound obtains by making 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and the reaction of 1-bromo-3-chloro-propane.Rt=7.93min (5-100-12). ¹H NMR (CDCl ₃) δ .8.36 (s, 1H), 7.73 (d, 1H), 6.72 (d, 1H), 6.59 (dd, 1H), 6.07 (br.s, 2H), 4.38 (t, 2H), 3.68 (s, 3H), 3.55 (t, 2H), 2.27 (quintet 2H).

Embodiment 72 9-(4-chloro-butyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (72)

As embodiment 15 steps 1, title compound obtains by making 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and the reaction of 1-bromo-4-chloro-butane.Step 1.Rt=8.27min (5-100-12). ¹H NMR (CDCl ₃)

8.36 (s, 1H), 7.72 (d, 1H), 6.73 (s, 1H), 6.58 (d, 1H), 6.30 (br.s, 2H), 4.40 (m, 2H), 3.68 (s, 3H), 3.53 (m, 2H), 1.93 (m, 2H), 1.79 (m, 2H).

General process A

In the sealing test tube, the mixture heated of alkyl chloride and suitable amine (5-30 equivalent, in DMF or pure) is spent the night to 40-120 ℃.Evaporation, operation (CH ₂Cl ₂/ saturated NaHCO ₃Aqueous solution) and preparation type TLC obtain required amine.

Chemical compound 73-82,84-120 prepare in the same manner.

Embodiment 73 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-[3-(4-methyl-piperazine-1-yl)-propyl group]-9H-purine-6-base amine (73)

According to conventional method A, title compound obtains by making 9-(3-chloro-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and N methyl piperazine reaction.Rt=5.24min. ¹H NMR (CDCl ₃) δ 8.37 (s, 1H), 7.70, (d, 1H), 6.62 (d, 1H), 6.52 (dd, 1H), 5.78 (s, 2H), 4.30 (t, 2H), 3.62 (t, 3H), 2.30 (m, 10H), 2.22 (s, 3H), 1.95 (quintet, 2H).

Embodiment 74 9-(3-dimethylamino-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (74)

According to general process A, title compound obtains by making 9-(3-chloro-propyl group)-8-(2-iodine 5-methoxyl group-phenyl sulfane base)-9H-purine 6-base amine and dimethylamine (producing the t-BuOK in Dimethylammonium chloride and DMF) reaction.Rt=5.37min. ¹H NMR (CDCl ₃) δ 8.34 (s, 1H), 7.71, (d, 1H), 6.71 (d, 1H), 6.56 (dd, 1H), 5.83 (s, 2H), 4.31 (t, 2H), 3.68 (s, 3H), 2.29 (t, 3H), 2.37 (s, 6H), 2.11 (quintet, 2H).

Embodiment 75 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-(3-piperidines-1-base-propyl group)-9h-purine-6-base amine (75)

According to general process A, title compound prepares by making 9-(3-chloro-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and piperidines reaction.Rt=5.78min. ¹H NMR (CDCl ₃/ CD ₃OD 10:1) δ 8.17 (s, 1H), 7.71 (d, 1H), 6.80 (d, 1H), 6.57 (dd, 1H), 4.20 (t, 2H), 3.66 (s, 3H), 2.30 (m, 4H), 1.94 (quintet, 2H), 1.46 (quintet, 4H), 1.21 (m, 2H).

Embodiment 76 9-(3-cyclopropyl amino-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (76)

According to general process A, title compound obtains by making 9-(3-chloro-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and cyclopropylamine reaction.Rt=5.58min. ¹H NMR (CDCl ₃) δ 8.34 (s, 1H), 7.72 (d, 1H), 6.79 (d, 1H), 6.57 (dd, 1H), 5.80 (s, 2H), 4.28 (t, 2H), 3.66 (s, 3H), 2.67 (t, 2H), 2.05 (m, 1H), 1.99 (quintet, 2H), 0.42 (m, 4H).

Embodiment 77 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-(3-morpholine-4-base-propyl group)-9H-purine-6-base amine (77)

According to general process A, title compound prepares by making 9-(3-chloro-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and morpholine reaction.Rt=5.34min. ¹H NMR (CDCl ₃/ CD ₃OD 10:1) δ 8.21 (s, 1H), 7.72 (d, 1H), 6.79 (d, 1H), 6.57 (dd, 1H), 4.26 (t, 2H), 3.67 (s, 3H), 3.61 (t, 4H), 2.36 (m, 6H), 1.96 (quintet, 2H).

Embodiment 78 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-(3-methylamino-propyl group)-9H-purine-6-base amine (78)

According to general process A, title compound prepares by making the 40% aqueous methylamine reaction among 9-(3-chloro-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and the DMF.Rt=5.34min. ¹H NMR (CDCl ₃) δ 8.35 (s, 1H), 7.71 (d, 1H), 6.68 (d, 1H), 6.56 (dd, 1H), 5.82 (s, 2H), 4.29 (t, 2H), 3.66 (s, 3H), 2.53 (t, 2H), 2.87 (s, 3H), 2.73 (quintet, 2H).

Embodiment 79 9-(3-ethylamino-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (79)

According to general process A, title compound obtains by making the 70% aqueous ethamine reaction among 9-(3-chloro-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and the DMF.Rt=5.53min. ¹H NMR (CDCl ₃) δ 8.35 (s, 1H), 7.72 (d, 1H), 6.69 (d, 1H), 6.57 (dd, 1H), 5.78 (s, 2H), 4.31 (t, 2H), 3.67 (s, 3H), 2.56 (m, 4H), 1.96 (quintet, 2H), 1.08 (t, 3H).

Embodiment 80 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-[2-(4-methyl-piperazine-1-yl)-ethyl]-9H-purine-6-base amine (80)

According to general process A, title compound obtains by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and N methyl piperazine reaction.Rt＝5.56min.1H NMR(CDCl ₃)δ8.34(s，1H)，7.69(d，1H)，6.67(d，1H)，6.54(dd，1H)，5.73(s，2H)，4.34(t，2H)，3.66(s，3H)，2.69(t，2H)，2.50(m，4H)，2.30(m，4H)，2.24(s，3H)。

Embodiment 81 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-(2-piperazine-Ji-ethyl)-9H-purine-6-base amine (81)

According to general process A, title compound obtains by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and piperazine reaction.Rt＝5.80min. ¹H NMR(CDCl ₃)δ 8.34(s，1H)，7.69(d，1H)，6.69(d，1H)，6.52(dd，1H)，5.68(s，2H)，4.33(t，2H)，3.66(s，3H)，2.63(t，2H)，2.41(m，4H)，1.51(m，4H)，1.30(m，2H)。

Embodiment 82 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-(2-third amino-ethyl)-9H-purine-6-base amine (82)

According to general process A, title compound prepares by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and propylamine reaction.Rt=5.69min. ¹H NMR (CDCl ₃) δ 8.34 (s, 1H), 7.69 (d, 1H), 6.69 (d, 1H), 6.60 (dd, 1H), 5.85 (s, 2H), 4.33 (t, 2H), 3.65 (s, 3H), 2.97 (t, 2H), 2.53 (t, 2H), 1.39 (sextet, 2H), 0.85 (t, 3H).

Embodiment 83 8-(2,5-dimethoxy-phenyl sulfane base)-9-(3-dimethylamino-propyl group)-9H-purine-6-base amine (83)

8-(2,5-dimethoxy-phenyl sulfane base)-9H-purine-6-base amine (127mg), Me ₂N-(CH ₂) ₃-Cl.HCl (236mg), Cs ₂CO ₃(680mg) suspension in DMF (2mL) is heated to 90 ℃ of 2h.Operation and preparation type TLC (MeOH:DCM 1:10) obtain title compound.Rt=4.83min. ¹H NMR (CDCl ₃) δ 8.33 (s, 1H), 6.85 (d, 1H), 6.81 (d, 1H), 6.75 (d, 1H), 5.68 (s, 2H), 4.42 (t, 2H), 3.79 (s, 3H), 3.70 (s, 3H), 2.35 (t, 2H), 2.22 (s, 6H), 1.99 (quintet, 2H).

Embodiment 84 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-(2-isopropylamino-ethyl)-9H-purine-6-base amine (84)

According to general process A, title compound obtains by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and 2-aminopropane. reaction.Rt=5.61min. ¹H NMR (CDCl ₃) δ 8.34 (s, 1H), 7.69 (d, 1H), 6.69 (d, 1H), 6.52 (dd, 1H), 5.68 (s, 2H), 4.33 (t, 2H), 3.66 (s, 3H), 3.02 (t, 2H), 3.85 (septet (sept.), 1H), 0.95 (d, 6H).

Embodiment 85 9-(2-fourth amino-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (85)

According to general process A, title compound obtains by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and butylamine reaction.Rt=6.10min. ¹H NMR (CDCl ₃) δ 8.34 (s, 1H), 7.70 (d, 1H), 6.72 (d, 1H), 6.55 (dd, 1H), 5.78 (s, 2H), 4.32 (t, 2H), 3.67 (s, 3H), 3.00 (t, 2H), 2.60 (t, 2H), 1.40 (sextet, 2H), 1.28 (quintet, 2H), 0.87 (t, 3H).

Embodiment 86 9-(2-Zhong Ding amino-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (86)

According to general process A, title compound is by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and obtaining with the sec-butylamine reaction.Rt=5.91min. ¹H NMR (CDCl ₃) δ 8.35 (s, 1H), 7.70 (d, 1H), 6.72 (d, 1H), 6.55 (dd, 1H), 5.67 (s, 2H), 4.35 (t, 2H), 3.68 (s, 3H), 3.03 (m, 1H), 2.95 (m, 1H), 2.54 (sextet, 1H), 1.38 (sextet, 1H), 1.24 (m, 1H), 0.96 (d, 3H), 0.82 (t, 3H).

Embodiment 87 9-[2-(1-ethyl-third amino)-ethyl]-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (87)

According to general process A, title compound obtains by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and 1-ethyl-propylamine reaction.Rt=6.34min. ¹H NMR (CDCl ₃) δ 8.33 (s, 1H), 7.69 (d, 1H), 6.71 (d, 1H), 6.54 (dd, 1H), 6.07 (s, 2H), 4.33 (t, 2H), 3.65 (s, 3H), 2.96 (t, 2H), 2.34 (quintet, 1H), 1.31 (m, 4H), 0.77 (t, 6H).

Embodiment 88 9-(2-cyclopropylamino-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (88)

According to general process A, title compound obtains by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and cyclopropylamine reaction.Rt=5.51min. ¹H NMR (CDCl ₃) δ 8.36 (s, 1H), 7.69 (d, 1H), 6.71 (d, 1H), 6.54 (dd, 1H), 5.71 (s, 2H), 4.33 (t, 2H), 3.66 (s, 3H), 3.07 (t, 2H), 2.11 (septet, 1H), 0.34 (m, 2H), 0.23 (m, 2H).

Embodiment 89 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-(2-isobutyl amino-ethyl)-9H-purine-6-base amine (89)

According to general process A, title compound obtains by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and isobutyl amine reaction.Rt＝6.10min(5-100-12). ¹H NMR(DMSO-d ₆)δ 8.16(s，1H)，7.74(d，1H)，6.45(br.s，1H)，6.67(dd，1H)，6.46(d，1H)，4.19(t，2H)，3.60(s，3H)，2.77(t，2H)，2.22(d，2H)，1.41(m，1H)，0.75(d，6H)。

Embodiment 90 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-[2-(3-methyl-Ding amino)-ethyl]-9H-purine-6-base amine (90)

According to general process A, title compound obtains by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and isobutylcarbylamine reaction.Rt＝6.53min(5-100-12). ¹H NMR(CDCl ₃)δ 8.34(s，1H)，7.98(d，1H)，6.71(d，1H)，6.65(dd，1H)，5.70(br.s，2H)，4.33(t，2H)，3.68(s，3H)，3.25(q，2H)，2.97(t，2H)，2.70(t，2H)，1.95(m，1H)，0.91(d，6H)。

Embodiment 91 9-[2-(3,3-dimethyl-butyl amino)-ethyl]-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (91)

According to general process A, title compound is by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and 3, and 3-dimethyl-butylamine reacts and obtains.Rt＝6.87min(5-100-12)。

Embodiment 92 2-[6-amino-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-purine-9-yl]-ethylamino }-acetonitrile (92)

According to general process A, title compound obtains by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and aminoacetonitriles reaction.Rt＝6.31min(5-100-12).1H NMR(CDCl3)δ 8.37(s，1H)，7.74(d，1H)，6.73(d，1H)，6.60(dd，1H)，5.63(br.s，2H)，4.38(t，2H)，3.67(s，3H)，2.58(m，2H)，3.10(m，2H)。

Embodiment 93 2-{2-[6-amino-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-purine-9-yl]-ethylamino }-ethanol (93)

Obtain by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and ethanolamine reaction according to general process A title compound.Rt＝5.14min(5-100-12).1H NMR(CDCl3)δ 8.37(s，1H)，7.70(d，1H)，6.76(d，1H)，6.56(dd，1H)，5.71(br.s，2H)，4.33(t，2H)，3.68(s，3H)，3.56(t，2H)，3.01(t，2H)，2.97(3，2H)。

Embodiment 94 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-[2-(2-methoxyl group-ethylamino)-ethyl]-9H-purine-6-base amine (94)

According to general process A, title compound is by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and MeO-(CH ₂) ₂-NH ₂The reaction and obtain.Rt＝5.52min(5-100-12).1HNMR(CDCl ₃)δ 8.32(s，1H)，7.68(d，1H)，6.72(d，1H)，6.56(dd，1H)，5.68(br.s，2H)，4.32(t，2H)，3.68(s，3H)，3.42(t，2H)，3.32(s，3H)，3.03(t，2H)，2.81(3，2H)。

Embodiment 95 9-(3-tert-butyl group amino-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (95)

Step 1 methanesulfonic acid 3-[6-amino-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-purine-9-yl]-propyl ester and uncle-butylamine react according to general process A.Crude reaction product is extracted in the HCl aqueous solution, and this aqueous solution CHCl ₃Wash ten times.Neutralization (NaHCO ₃) and be stripped into CHCl ₃In obtain title compound, be thick grease.Free alkali (4.34g) is dissolved among the MeOH (100mL), is evaporated to drying with concentrated hydrochloric acid (2.7mL) processing and this solution.This hydrochlorate is dissolved among the backflow MeOH once more, and makes its precipitation with acetone.Filtration obtains pure hydrochloric acid salt.This salt is dissolved in the water, uses saturated NaHCO ₃The aqueous solution neutralization, and use CHCl ₃Extraction.Dry and the concentrated pure title compound that obtains its free alkali form.Rt=5.87min (5-100-12). ¹HNMR (CDCl ₃) δ 8.33 (s, 1H), 7.70 (d, 1H), 6.69 (d, 1H), 6.55 (dd, 1H), 5.90 (br.s, 2H), 4.30 (t, 2H), 3.66 (s, 3H), 2.50 (t, 2H), 1.96 (quintet, 2H), 1.05 (s, 9H).

Step 2 9-(3-tert-butyl group amino-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine, phosphate

9-(3-tert-butyl group amino-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (7.29g) is dissolved among the backflow EtOH, and uses H ₃PO ₄(0.84M in EtOH, 17.0mL) handles solution, so occur precipitation at once.This precipitation is collected by filtering, washing (EtOH), and dry to obtain this phosphate.Rt=4.77min (5-100-7). δ 8.04 (br.s, 1H), 7.72 (br.d, 1H), 6.89 (br.s, 1H), 6.65 (br.d, 1H), 4.21 (br.t, 2H), 3.61 (br.s, 3H), 2.86 (br.t, 2H), 2.04 (the br. quintet, 2H), 1.15 (s, 9H).

Embodiment 96 9-(2-cyclopenta amino-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (96)

According to general process A, title compound obtains by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and Aminocyclopentane reaction.Rt=6.05min (5-100-12) .1H NMR (CDCl ₃) δ 8.34 (s, 1H), 7.70 (d, 1H), 6.71 (d, 1H), 6.58 (dd, 1H), 5.85 (br.s, 2H), 4.38 (t, 2H), 3.65 (s, 3H), 3.03 (quintet, 2H), 2.98 (t, 2H), 1.80 (m, 4H), 1.60 (m, 4H).

Embodiment 97 9-(2-cyclohexyl amino-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (97)

According to general process A, title compound obtains by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and cyclohexylamine reaction.Rt＝6.40min(5-100-12).1H NMR(CDCl ₃)δ 8.34(s，1H)，7.70(d，1H)，6.75(d，1H)，6.62(dd，1H)，5.80(br.s，2H)，4.25(t，2H)，3.65(s，3H)，3.03(m，1H)，2.98(t，2H)，1.301.10(m，10H)。

Embodiment 98 9-(2-suberyl amino-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (98)

According to general process A, title compound obtains by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and cycloheptylamine reaction.Rt＝6.80min(5-100-12). ¹H NMR(CDCl ₃)δ 8.34(s，1H)，7.68(d，1H)，6.75(d，1H)，6.32(dd，1H)，5.80(br.s，2H)，4.30(t，2H)，3.65(s，3H)，2.98(t，2H)，2.80(m，1H)，1.73(m，4H)，1.55(m，4H)，1.42(m，4H)。

Embodiment 99 9-(2-ring octyl group amino-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (99)

According to general process A, title compound obtains by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and cyclooctylamine reaction.Rt＝7.10min(5-100-12). ¹HNMR(CDCl ₃)δ 8.34(s，1H)，7.68(d，1H)，6.82(d，1H)，6.66(dd，1H)，5.72(br.s，2H)，4.40(t，2H)，3.65(s，3H)，3.00(t，2H)，2.72(m，1H)，1.60-1.10(m，14H)。

Embodiment 100 9-(2-cyclopropyl methyl-amino-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (100)

According to general process A, title compound obtains by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and cyclopropyl-methyl-amine reaction.Rt＝5.82min(5-100-12). ¹HNMR(CDCl ₃/CD ₃OD 3:1)δ8.13(s，1H)，7.67(d，1H)，6.82(d，1H)，6.59(dd，1H)，4.24(t，2H)，3.63(s，3H)，2.91(t，2H)，2.37(d，2H)，0.78(m，1H)，036(m，2H)，0.00(m，2H)。

Embodiment 101 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-[2-(2-methyl-allyl amino)-ethyl]-9H-purine-6-base amine (101)

According to general process A, title compound obtains by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and 2-methyl-allylamine reaction. ¹H NMR(CDCl ₃/CD ₃OD 10:1)δ8.16(s，1H)，7.69(d，1H)，6.84(d，1H)，6.58(dd，1H)，4.76(s，2H)，4.32(t，2H)，3.66(s，3H)，3.12(br.s，2H)，2.94(t，2H)，1.61(s，3H)。

Embodiment 102 9-(2-tert-butyl group amino-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (102)

According to general process A, title compound is by making toluene-4-sulfonic acid 2-[6-amino-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-purine-9-yl] reaction of ethyl ester and tert-butylamine obtains.Solid, Rt=4.73min (5-100-7).

Embodiment 103 9-(3-amino-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (103)

According to general process A, title compound is by making 9-(3-chloro-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and NH ₃(7M is in MeOH) reacts and obtains.Rt=5.45min (5-100-12). ¹HNMR (CD ₃OD) 8.21 (s, 1H), 7.86 (d, 1H), 7.00 (s, 1H), 6.79 (d, 1H), 4.31 (t, 2H), 3.76 (s, 3H), 2.74 (t, 2H), 1.88 (quintet, 2H), 1.57 (quintet, 2H).

Embodiment 104 9-(2-cyclopropyl amino-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (104)

According to general process A, title compound obtains by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and cyclopropylamine reaction.Rt＝5.48min. ¹H NMR(CD ₃OD)δ 8.21(s，1H)，7.83(d，1H)，6.94(d，1H)，6.57(dd，1H)，4.40(t，2H)，3.72(s，3H)，3.06(t，2H)，2.05(m，1H)，0.69(m，2H)，0.44(m，2H。

Embodiment 105 9-(2-allyl amino-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (105)

According to general process A, title compound obtains by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and allylamine reaction.Rt＝5.62min. ¹H NMR(CD ₃OD)δ 8.21(s，1H)，7.85(d，1H)，6.96(d，1H)，6.48(dd，1H)，5.90(m，1H)，5.20(m，2H)，4.41(m，2H)，3.74(s，3H)，3.24(m，2H)，3.06(t，2H)，2.05(m，1H)，0.69(m，2H)，0.44(m，2H)。

Embodiment 106 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-(2-morpholinyl-4-base-ethyl)-9H-purine-6-base amine (106)

According to general process A, title compound obtains by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and morpholine reaction.Rt＝5.33min. ¹H NMR(CDCl ₃)δ 8.36(s，1H)，7.69(d，1H)，6.70(d，1H)，6.53(dd，1H)，5.76(s，2H)，4.36(t，2H)，3.68(s，3H)，2.70(t，2H)，2.49(m，4H)，1.82(m，4H)。

Embodiment 107 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-(3-propyl group amino-propyl group)-9H-purine-6-base amine (107)

According to general process A, title compound obtains by making 9-(3-chloro-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and n-propylamine reaction.Rt=5.78min (5-100-12M). ¹H NMR (MeOH) δ 8.21 (s, 1H), 7.85 (d, 1H), 6.97 (d, 1H), 6.77 (dd, 1H), 4.34 (t, 2H), 3.75 (s, 3H), 2.57 (t, 2H), 2.47 (t, 2H), 2.03 (quintet, 2H), 1.51 (q, 2H), 0.94 (t, 3H).

Embodiment 108 9-[3-(1-ethyl-propyl group amino)-propyl group]-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (108)

According to general process A, title compound obtains by making 9-(3-chloro-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and 1-ethyl-propylamine reaction.Rt=6.28min (5-100-12). ¹H NMR (MeOH) δ 8.20 (s, 1H), 7.82 (d, 1H), 6.96 (d, 1H), 6.75 (dd, 1H), 4.35 (t, 2H), 3.73 (s, 3H), 2.74 (t, 2H), 2.55 (quintet, 1H), 2.08 (s, quintet, 2H), 1.52 (m, 4H), 0.91 (t, 6H).

Embodiment 109 9-(3-sec-butyl amino-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (racemate) (109)

According to general process A, title compound obtains by making 9-(3-chloro-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and sec-butylamine reaction.Same process also can be used for enantiotopic pure (S-or R)-sec-butylamine to obtain corresponding enantiomer.Rt=5.93min (5-100-12). ¹H NMR (MeOH) δ 8.21 (s, 1H), 7.85 (d, 1H), 6.96 (d, 1H), 6.76 (dd, 1H), 4.35 (t, 2H), 3.73 (s, 3H), 2.70-2.64 (m, 3H), 2.07 (quintet, 2H), 1.58 (m, 1H), 1.34 (m, 1H), 1.08 (d, 3H), 0.92 (s, 3H).

Embodiment 110 9-(3-heptyl amino-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (110)

According to general process A, title compound obtains by making 9-(3-chloro-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and positive heptyl amice reaction.Rt=7.50min (5-100-12). ¹H NMR (MeOH) δ 8.21 (s, 1H), 7.85 (d, 1H), 6.99 (d, 1H), 6.79 (dd, 1H), 4.39 (t, 2H), 3.75 (s, 3H), 2.99 (t, 2H), 2.89 (t, 2H), 2.19 (quintet, 2H), 1.65 (m, 2H), 1.34 (m, 8H), 0.90 (t, 3H).

Embodiment 111 9-(3-cyclopenta amino-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (111)

According to general process A, title compound obtains by making 9-(3-chloro-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and Aminocyclopentane reaction.Rt=6.12min (5-100-12). ¹H NMR (CDCl ₃) δ 8.30 (s, 1H), 7.69 (d, 1H), 6.68 (d, 1H), 6.55 (dd, 1H), 6.06 (br.s., 2H), 4.29 (t, 2H), 3.65 (s, 3H), 2.98 (quintet, 1H), 2.56 (t, 2H), 1.99 (quintet, 2H), 1.64-1.40 (m, 8H).

Embodiment 112 9-(3-ring octyl group amino-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (112)

According to general process A, title compound obtains by making 9-(3-chloro-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and cyclooctylamine reaction.Rt=7.07min (5-100-12). ¹H NMR (CDCl ₃) δ 8.31 (s, 1H), 7.70 (d, 1H), 6.68 (d, 1H), 6.55 (dd, 1H), 6.00 (br.s., 2H), 4.30 (t, 2H), 3.65 (s, 3H), 2.70 (quintet, 1H), 2.59 (t, 2H), 1.53-1.40 (m, 14H).

Embodiment 113 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-(3-isobutylamino-propyl group)-9H-purine-6-base amine (113)

According to general process A, title compound obtains by making 9-(3-chloro-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and isobutyl amine reaction.Rt=6.00min (5-100-12). ¹H NMR (CDCl ₃) δ 8.32 (s, 1H), 7.70 (d, 1H), 6.67 (d, 1H), 6.56 (dd, 1H), 5.97 (br.s., 2H), 4.30 (t, 2H), 3.65 (s, 3H), 2.56 (t, 2H), 2.33 (d, 2H), 1.79 (quintet, 2H), 1.72 (m, 1H), 0.90 (d, 14H).

Embodiment 114 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-[3-(1,2,2-trimethyl-propyl group amino)-propyl group]-9H-purine-6-base amine (114)

According to general process A, title compound is by making 9-(3-chloro-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and 1,2, and 2-trimethyl-propylamine reacts and obtains.Rt＝6.56min(5-100-12). ¹HNMR(CDCl ₃)δ 8.35(s，1H)，7.72(d，1H)，6.70(d，1H)，6.59(dd，1H)，5.95(br.s.，2H)，4.33(t，2H)，3.67(s，3H)，2.79(m，1H)，2.50(m，1H)，2.21(m，1H)，1.99(m，2H)，0.90(s，9H)。

Embodiment 115 4-{3-[6-amino-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-purine-9-yl]-propyl group amino }-piperidines-1-carboxylic acid tert-butyl ester (115)

According to general process A, title compound obtains by making 9-(3-chloro-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and 4-amino-piperadine-1-carboxylic acid tert-butyl ester reaction.Rt=6.14min (5-100-12). ¹H NMR (CDCl ₃) δ 8.29 (s, 1H), 7.69 (d, 1H), 6.66 (d, 1H), 6.55 (dd, 1H), 6.29 (br.s., 2H), 4.29 (t, 2H), 3.64 (s, 3H), 3.15 (quintet, 1H), 2.79 (t, 2H), 2.57 (m, 4H), 1.96 (m, 2H), 1.80 (m, 2H), 1.23 (s, 9H).

Embodiment 116 9-(2-benzyl amino-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (116)

According to general process A, title compound obtains by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and benzylamine reaction.Rt＝6.31min. ¹H NMR(CDCl ₃)δ 8.35(s，1H)，7.71(d，1H)，7.36-7.22(m，5H)，6.75(d，1H)，6.57(dd，1H)，5.84(br.s，2H)，4.39(t，2H)，3.79(s，2H)，3.67(s，3H)，3.04(t，2H)。

Embodiment 117 (R)-9-(3-sec-butyl amino-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (117)

According to general process A, title compound obtains by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and R-(-)-2-butylamine reaction.Rt=5.915min. ¹H NMR (CDCl ₃) δ 8.27 (s, 1H), 7.63 (d, 1H), 6.74 (br.s., 2H), 6.61 (d, 1H), 6.48 (dd, 1H), 4.26 (t, 2H), 3.58 (s, 3H), 2.57-2.14 (m, 3H), 1.92 (quintet, 2H), 1.43 (7,1H), 1.28 (7,1H), 1.02 (t, 2H), 0.94 (d, 3H), 0.81 (t, 3H).

Embodiment 118 (s)-9-(3-sec-butyl amino-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (118)

According to general process A, title compound obtains by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and S-(-)-2-butylamine reaction.Rt=5.941min. ¹H NMR (CDCl ₃) δ 8.32 (s, 1H), 7.68 (d, 1H), 6.65 (d, 1H), 6.54 (dd, 1H), 6.39 (br.s., 2H), 4.29 (t, 2H), 3.63 (s, 3H), 2.59-2.44 (m, 3H), 1.95 (quintet, 2H), 1.45 (7,1H), 1.28 (7,1H), 1.05 (t, 2H), 0.97 (d, 3H), 0.84 (t, 3H).

Embodiment 119 9-[3-(1,1-dimethyl-propyl group amino)-propyl group]-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (119)

According to general process A, title compound is by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and 1, and 1-dimethyl-propylamine reacts and obtains.Rt=6.218min. ¹HNMR (CDCl ₃) δ 8.35 (s, 1H), 7.71 (d, 1H), 6.68 (d, 1H), 6.56 (dd, 1H), 6.12 (br.s., 2H), 4.31 (t, 2H), 3.66 (s, 3H), 2.50 (t, 3H), 1.95 (quintet, 2H), 1.07 (q, 2H), 0.99 (s, 6H), 0.80 (t, 3H).

Embodiment 120 9-(3-cyclobutyl amino-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (120)

According to general process A, title compound obtains by making 9-(2-chloro-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and the reaction of ring butylamine.Rt=5.785min. ¹H NMR (CDCl ₃) δ 8.37 (s, 1H), 7.72 (d, 1H), 6.67 (d, 1H), 6.56 (dd, 1H), 6.02 (br.s., 2H), 4.30 (t, 2H), 3.67 (s, 3H), 3.17 (quintet, 1H), 2.50 (t, 3H), 2.16 (d, 2H), 1.94 (quintet, 2H), 1.64 (m, 4H).

Embodiment 121 9-(3-amino-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (121)

Step 1 3-[6-amino-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-purine-9-yl]-propyl group }-t-butyl carbamate

Among the DMF (3mL), 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (260mg), BocNH-(CH ₂) ₃-Cl and Cs ₂CO ₃Mixture (1.29g) be heated to 50 ℃ 16 hours.Operation and flash chromatography (1%MeOH among the DCM, EtOAc, 5%MeOH among the EtOAc then then) obtain expecting product.Rt=8.23min.1H NMR (CDCl ₃) δ 8.34 (s, 1H), 7.70 (d, 1H), 6.70 (d, 1H), 6.55 (dd, 1H), 6.15 (s, 2H), 5.59 (t, 1H), 4.28 (t, 2H), 3.65 (t, 3H), 3.01 (q, 2H), 1.90 (quintet, 2H), 1.44 (s, 9H).

Step 2 9-(3-amino-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine

DCM (3mL) solution of { 3-[6-amino-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-purine-9-yl]-propyl group }-t-butyl carbamate was handled 30 minutes with TFA (0.5mL) and with its evaporation.Anti-phase MPLC (C ₁₈, gradient H ₂O/CH ₃CN 1%TFA) obtains the title compound of tfa salt form, and it is diluted in DCM, uses NaHCO ₃Washing, and be concentrated to obtain the title compound of free alkali form.Rt=5.21min. ¹HNMR (CDCl ₃/ CD ₃OD) δ 8.18 (s, 1H), 7.77 (d, 1H), 7.12 (d, 1H), 6.68 (dd, 1H), 4.30 (t, 2H), 3.74 (s, 3H), 2.89 (t, 2H), 2.16 (quintet, 2H).

Embodiment 122 2-[6-amino-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-purine-9-yl]-ethyl }-t-butyl carbamate (122)

Step 1 (2-chloro-ethyl)-t-butyl carbamate

Cl-(CH ₂) ₂-NH ₂.HCl DCM (10mL) suspension at 0 ℃ down with Et3N (1.39mL) and (tBoc) ₂O (2.18g) handles.This reaction is at room temperature stirred then and is spent the night, and concentrates and carries out separation and purification operation (EtOAc/1/2 saturated brine) to obtain title compound.

Step 2 2-[6-amino-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-purine-9-yl]-ethyl }-t-butyl carbamate

8-(2-iodo-5-methoxyl group-phenyl sulfane base) among the DMF (1mL)-9H-purine-6-base amine (0.15g), (2-chloro-ethyl)-t-butyl carbamate (0.10g) and Cs ₂CO ₃Mixture (0.45g) be heated to 80 ℃ 2 hours, and be heated to 100 ℃ 1.5 hours again.(EtOAc/ hexane 1:1 → 1:0) obtains title compound to flash chromatography.Rt＝7.85min. ¹H NMR(CDCl ₃)δ 8.30(s，1H)，7.80(d，1H)，6.80(d，1H)，6.65(dd，1H)，6.02(s，2H)，4.40(t，2H)，3.66(s，3H)，3.53(q，2H)，1.23(s，9H)。

Embodiment 123 9-(2-amino-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (123)

{ 2-[6-amino-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-purine-9-yl]-ethyl }-t-butyl carbamate (6.4mg) was at room temperature handled 1 hour with TFA/DCM 1:10, used NaHCO ₃Solution washing and with its evaporation.Rt＝5.16min. ¹H NMR(CDCl ₃)δ 8.24(s，1H)，7.82(d，1H)，7.20(d，1H)，6.72(dd，1H)，4.61(t，2H)，3.77(s，3H)，3.42(t，2H)。

Embodiment 124 2-[6-amino-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-purine-9-yl]-acetamide (124)

8-(2-iodo-5-methoxyl group-phenyl sulfane base) among the DMF (1mL)-9H-purine-6-base amine (80mg), 2-acetbromamide (55mg) and Cs ₂CO ₃Mixture (316mg) at room temperature stirs and spends the night.Preparation type TLC obtains title compound.Rt＝5.70min. ¹H NMR(DMSO-d ₆)δ 8.26(s，1H)，8.08(s，1H)，7.67(d，1H)，7.50(s，1H)，6.96(d，1H)，6.51(dd，1H)，4.93(s，2H)，3.59(s，2H)，3.31(s，3H)。

Embodiment 125 1-[6-amino-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-purine-9-yl]-propane-2-ketone (125)

8-in DMF (1mL) (2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (80mg), chlroacetone (32uL) and Cs ₂CO ₃(350mg) stirring is spent the night under 75 ℃.Operation and preparation type TLC (5% MeOH is in DCM) obtain this chemical compound.Rt＝6.74min. ¹H NMR(CDCl ₃)δ 8.32(s，1H)，7.68(d，1H)，6.74(d，1H)，6.55(dd，1H)，5.67(s，2H)，5.05(s，2H)，3.67(s，3H)，2.23(s，3H)。

Embodiment 126 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-(3-isopropyl amino-propyl group)-9H-purine-6-base amine H ₃PO ₄Salt (126)

Step 1 3-[6-amino-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-purine-9-yl]-propane-1-alcohol

3-[6-amino-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-purine-9-yl]-propyl acetate (831mg; Biamonte, J.Org.Chem., 2005,70,717) MeOH (10mL) solution at room temperature use K ₂CO ₃(88mg) handle 2h and concentrated.This solid is at room temperature at water (4mL) and Et ₂Stir 1h in the mixture of O (15mL).Filtration obtains expecting product.Rt=5.04min (5-100-7). ¹H NMR (DMSO-d ₆) δ 8.18 (s, 1H), 7.78 (d, 1H), 7.48 (s, 2H), 6.71 (dd, 1H), 6.47 (d, 1H), 4.66 (t, 1H), 4.21 (t, 2H), 3.61 (s, 3H), 3.40 (q, 2H), 1.82 (quintet, 2H).

Step 2 3-[6-amino-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-purine-9-yl]-the methanesulfonic acid propyl ester.

3-[6-amino-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-purine-9-yl]-propane-1-alcohol is dissolved in 1 under 80 ℃, in the 4-diox.Add triethylamine (3 equivalent), and add MsCl (1.5 equivalent) before this mixture be cooled to 40 ℃.Evaporating solvent and triethylamine in a vacuum after 15 minutes, to obtain the title compound of raw oil form, it is used to next step at once, and does not have other purification.

Step 3 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-(3-isopropyl amino-propyl group)-9H-purine-6-base amine

According to general process A, methanesulfonic acid 3-[6-amino-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-purine-9-yl]-propyl ester and 2-aminopropane. reaction.This rough product HCl aqueous solution extraction, and this aqueous solution CHCl ₃Extract ten times.Neutralization (NaHCO ₃) and be stripped into CHCl ₃In obtain the title compound of raw oil form.This free alkali is dissolved in the isopropyl alcohol.Add 48% HBr and cause crystallization, and this crystal washing with acetone.With this dissolution of crystals at CH ₂Cl ₂With saturated NaHCO ₃In the mixture of aqueous solution.This organic layer (Na that is dried ₂SO ₄) and concentrate, obtain the pure title compound of free alkali form.Rt=5.61min (5-100-12). ¹H NMR (CD ₃OD) δ 8.24 (s, 1H), 7.86 (d, 1H), 6.87 (d, 1H), 6.64 (dd, 1H), 4.42 (t, 2H), 3.77 (s, 3H), 3.37-3.33 (m, 3H), 3.08 (t, 2H), 2.24 (quintet, 2H), 1.34 (d, 6H).

Step 4 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-(3-isopropyl amino-propyl group)-9H-purine-6-base amine, H ₃PO ₄Salt

Backflow EtOH (30mL) the solution 0.84M H of 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-(3-isopropyl amino-propyl group)-9H-purine-6-base amine (1.03g) ₃PO ₄EtOH (2.1mL) solution-treated.This phosphate precipitates at once and collects by filtering, and washs with EtOH.Rt=4.46min (5_100_7). ¹H NMR (D ₂O) δ 8.04 (br.s, 1H), 7.71 (br.d, 1H), 6.87 (br.s, 1H), 6.64 (br.d, 1H), 4.18 (br.t, 2H), 3.62 (br.s, 3H), 3.13 (septet, 1H), 2.88 (br.t., 2H), 2.03 (the br. quintet, 2H), 1.13 (d, 6H).

Embodiment 127 N-{2-[6-amino-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-purine-9-yl]-ethyl }-acetamide (127)

9-(2-amino-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (123; 12mg) 1,2-dichloroethanes (200uL) solution is at room temperature used Ac ₂O (40uL) handles and spends the night.Concentrated and preparation type TLC (EtOAC/DCM/MeOH 7:7:1) obtains title compound.Rt＝5.97min(5-100-12). ¹H NMR(CDCl ₃/CD ₃OD 5:1)δ 8.32(s，1H)，7.68(d，1H)，7.30(t，1H)，6.88(d，1H)，6.60(dd，1H)，4.28(t，2H)，3.65(s，3H)，3.48(q，2H)，1.80(s，3H)。

Embodiment 128 N-{2-[6-amino-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-purine-9-yl]-ethyl }-Methanesulfomide (128)

1 of 9-(2-amino-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (123) and triethylamine (3 equivalent), the 2-dichloroethane solution spends the night with handling under MsCl (1.5 equivalent) room temperature.Concentrated and preparation type TLC (EtOAC/DCM/MeOH 7:7:1) obtains title compound.Rt＝6.20min(5-100-12). ¹H NMR(CDCl ₃/CD ₃OD 5:1)δ 8.33(s，1H)，7.70(d，1H)，6.90(t，1H)，6.50(d，1H)，4.27(dd，1H)，3.65(s，3H)，3.38(y，2H)，2.74(s，3H)。

Embodiment 129 N-{2-[6-amino-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-purine-9-yl]-ethyl }-N-isobutyl group-acetamide (129)

1 of 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-(2-isobutylamino-ethyl)-9H-purine-6-base amine (15mg), 2-dichloroethanes (500uL) solution is at room temperature used Ac ₂O (60uL) handled 45 minutes.Concentrated and preparation type TLC (EtOAC/DCM/MeOH 70:70:4) obtains title compound.Rt=7.70min (5-100-12). ¹HNMR (CDCl ₃) the 3:1 mixture of the trans and s-cis rotamer of s-.Main rotamer: δ 8.32 (s, 1H), 7.72 (d, 1H), 6.80 (d, 1H), 6.58 (dd, 1H), 5.78 (br.s, 2H), 4.42 (t, 2H), 3.68 (t, 2H), 3.65 (s, 3H), 2.75 (d, 2H), 1.72 (m, 1H), 0.80 (d, 6H).

Embodiment 130 N-{2-[6-amino-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-purine-9-yl]-ethyl }-N-isobutyl group-Methanesulfomide (130)

9-(2-amino-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (123; 34mg) and triethylamine (35uL) 1,2-dichloroethanes (0.5mL) solution at room temperature uses MsCl (10uL) to handle 10 minutes.Concentrated and preparation type TLC (EtOAC/DCM/MeOH 70:70:4) obtains title compound.Rt＝8.03min(5-100-12). ¹H NMR(CDCl ₃/CD ₃OD 5:1)

8.20(s，1H)，7.70(d，1H)，6.83(d，1H)，6.59(dd，1H)，4.39(t，2H)，3.66(s，3H)，3.49(t，2H)，2.95(d，2H)，1.78(m，1H)，0.84(d，6H)。

Embodiment 131 2-chloro-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine (131)

8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-penta-4-alkynyl-9H-purine-2,6-diamidogen (55mg; Referring to embodiment 15) DCM (2mL) suspension at room temperature use TMSCl (205uL) and Et ₃N (30uL) handled 10 minutes.Add BnEt ₃N ⁺NO ₂ ^-(83mg; Francom, J.Org.Chem.2003,68,666) DCM (1.5mL) solution, and this reactant mixture at room temperature stirred 30 minutes.(EtOAc/ hexane 1:1 → 1:0) obtains title compound for operation and flash chromatography.Rt=9.73min (5-100-12). ¹H NMR (CDCl ₃) δ .7.74 (d, 1H), 6.75 (d, 1H), 6.60 (dd, 1H), 4.27 (t, 2H), 3.70 (s, 3H), 2.26 (dt, 2H), 2.04 (quintet, 2H), 1.96 (t, 1H).

Embodiment 132 9-[2-(2,2-dimethyl-propyl group amino)-ethyl]-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (132)

Step 1 2-(6-amino-purine-9-yl)-ethyl acetate

Adenine (60.0g), Cs ₂CO ₃(223g), AcO-CH ₂-CH ₂The mixture of-Br (75.8ml) and DMF (187g) stirred 5 hours at 45 ℃.DMF is evaporated and residue is joined in the mixture of AcOH (50ml, 2 equivalents), water (100ml) and ice (100g).This solid is filtered, and with 100ml ice-cold water washing, and dry under the fine vacuum in rotary evaporator, obtains the title compound (62.4g, 67%) of white powder form.Rt＝3.05min(5-100-12). ¹H NMR(DMSO) 8.13(s，1H)，8.12(s，1H)，4.37(s，4H)，191(s，3H)。

Step 2 2-(6-amino-8-bromo-purine-9-yl)-ethyl acetate

At room temperature 2-(6-amino-purine-9-yl)-ethyl acetate (16.6g) is dissolved in the mixture of AcOH buffer (100ml, labelling 1), MeOH (30ml) and THF (30ml) with magnetic agitation.Bromine (7.0ml) was added in 1 minute, and stop to stir, so the product of expectation crystallizes out from solution gradually.This crystal is collected by filtering after 1 hour, washing (H ₂O) also air-dry, to obtain the title compound of the prismatic form of purple.Rt＝4.01min(5-100-12). ¹H NMR(DMSO)δ 8.188.32(s，1H)，5.69(s，2H)，4.47(m，4H)，2.00(s，3H)。

Step 3 2-[6-amino-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-purine-9-yl]-ethanol

2-(6-amino-8-bromo-purine-9-yl)-ethyl acetate (16.5g) and 2-iodo-5-methoxyl group-benzenethiol potassium (33g; (a) Ma, J.Org.Chem.2001,66,4525 (b) Flynn, Org.Lett, 2001,3,651) DMF (600ml) solution be heated to 50 ℃ and spend the night.This reactant mixture is concentrated, is dissolved among the MeOH, and at 50 ℃ of K that use catalytic amount down ₂CO ₃Handled 3 hours, with original position cutting Acetyl Groups.This mixture is concentrated once more, and at water and Et ₂Stir in the mixture of O and spend the night.The expectation alcohol---it is insoluble to Et ₂O is also water insoluble, passes through filtered and recycled.With ether washing and dry, obtain the title compound (9g, 37%) of orange-brown ceramic powder form.Rt＝6.13min(5-100-12). ¹H NMR(DMSO)δ 8.18(s，1H)，7.76(d，1H)，7.35(s，2H)，6.68(dd，1H)，6.55(d，1H)，5.03(s，1H)，4.26(t，2H)，3.70(t，2H)，3.69(s，3H)。

Step 4 9-[2-(2,2-dimethyl-propyl group amino)-ethyl]-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine

2-[6-amino-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-purine-9-yl]-(6.0g) De diox (400ml) suspension is heated to 80 ℃ until whole dissolvings to ethanol.This solution is cooled to 40 ℃, uses Et ₃N (3 equivalent) and MsCl (1.5 equivalent) handle.This reaction is cooled to room temperature, filters to remove Et ₃N.HCl and being evaporated obtains rough methylsulfonyl ester, its placed at once diox (75mL) and neopentyl amine (25ml) and pressurizing vessel be heated to 70 ℃ 4 hours.Concentrate the rough amine obtain expecting, its dilute with water, with the HCl acidified aqueous solution to pH1, and with the CHCl of 1% MeOH ₃Solution washing 10 times.This water layer solid NaHCO ₃Neutralization, and this amine is at the CHCl of 1% MeOH ₃Extract in the solution, (output is approximately: 50%) to obtain the title compound of light yellow oil form.Recrystallization obtains exquisite white needles title compound from MeOH.Rt＝5.13min(5-100-12). ¹H NMR(CDCl ₃/CD ₃OD 3:1)

8.03(s，1H)，7.65(d，1H)，6.80(d，1H)，6.59(dd，1H)，4.48(br.t，2H)，3.62(s，3H)，3.20(br.t，2H)，2.76(s，2H)，0.88(s，9H)。

Step 5 9-[2-(2,2-dimethyl-propyl group amino)-ethyl]-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine, H ₃PO ₄Salt

The amine (1.0g) of this purification is dissolved among the backflow EtOH (30ml), and under very violent stirring with H ₃PO ₄Solution (0.84M, in EtOH, 2.3mL, 1 equivalent) add quickly.Crystallization appears at once.After the cooling, filter the phosphate that obtains expecting, be the meticulous spicule of canescence (1.0g, 83%).Rt＝5.08min(5-100-12). ¹H NMR(D ₂O)δ 8.09(s，1H)，7.75(d，1H)，6.89(d，1H)，6.68(dd，1H)，4.51(br.t，2H)，3.63(s，3H)，3.36(br.t，2H)，2.83(s，2H)，0.95(s，9H)。

General process C

8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (1 equivalent), alkyl halide (RCl, RB or RI; 1.1-3 equivalent) and Cs ₂CO ₃, the DMF suspension of (3-5 equivalent) is heated to 40-80 ℃ of 2-16h, obtains N (9)-and the 2:1 mixture of N (3)-alkylation isomer usually.This reactant mixture dilutes with EtOAc, and water and salt water washing.Dry (Na ₂SO ₄), evaporation and preparation type TLC or flash chromatography be (as AcOEt/ ethane/Et ₃N 80:20:3) obtains expecting chemical compound.

Embodiment 133 9-(2-dimethylamino-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (133)

According to general process C, title compound obtains by making 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and (2-chloro-ethyl)-dimethyl-amine reaction.Rt＝5.18min. ¹H NMR(CDCl ₃)δ 8.33(s，1H)，7.67(d，1H)，6.69(d，1H)，6.52(dd，1H)，6.11(s，2H)，4.31(t，2H)，3.67(s，3H)，2.67(t，2H)，2.63(s，6H)。

Embodiment 134 9-(2-diethylamino-ethyl)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (134)

According to general process C, title compound obtains by making 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and (2-chloro-ethyl)-diethyl-amine reaction.Rt＝5.60min. ¹H NMR(CDCl ₃)δ 8.38(s，1H)，7.68(d，1H)，6.72(d，1H)，6.54(dd，1H)，5.86(s，2H)，4.30(t，2H)，3.67(s，3H)，2.74(t，2H)，2.53(q，4H)，1.07(t，6H)。

Embodiment 135 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-(2-pyrrolidine-1-base-ethyl)-9H-purine-6-base amine (135)

According to general process C, title compound obtains by the hydrochlorate reaction that makes 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and 1-(2-chloro-ethyl)-pyrrolidine.Rt＝5.55min. ¹H NMR(CDCl ₃)δ8.35(s，1H)，7.68(d，1H)，6.68(d，1H)，6.53(dd，1H)，6.14(s，2H)，4.38(t，2H)，3.65(s，3H)，2.83(t，2H)，2.55(m，4H)，1.74(m，4H)。

Embodiment 136 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-(2-ethyoxyl-ethyl)-9H-purine-6-base amine (136)

According to general process C, title compound obtains with (2-chloro-ethyoxyl)-ethylene reaction by making 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine.Rt＝9.91min. ¹H NMR(CDCl ₃)δ 7.97(s，1H)，7.69(d，1H)，7.20(s，1H)，6.54-6.35(m，4H)，4.78(t，2H)，4.05(t，2H)，3.74(s，3H)。

Embodiment 137 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-(2-isopropoxy-ethyl)-9H-purine-6-base amine (137)

According to general process C, title compound obtains by making 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and 2-(2-chloro-ethyoxyl)-propane reaction.Rt＝8.20min. ¹H NMR(CDCl ₃)δ 8.37(s，1H)，8.08(d，1H)，7.12(d，J＝2.6Hz1H)，6.84(dd，1H)，5.80(s，2H)，4.48(m，2H)，3.85-3.80(m，3H)，3.74(s，3H)，1.18(d，6H)。

Embodiment 138 3-[6-amino-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-purine-9-yl]-propyl group }-methyl-t-butyl carbamate (138)

According to general process C, (referring to the embodiment of front, react and obtain with (3-chloro-propyl group)-t-butyl carbamate by step 1) by making 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine for title compound.Rt=8.18min (5-100-12). ¹H NMR (CDCl ₃) δ 8.28 (s, 1H), 7.73 (d, 1H), 6.74 (d, 1H), 6.59 (dd, 1H), 6.01 (br.s., 2H), 4.29 (t, 2H), 3.68 (s, 3H), 2.96 (t, 2H), 1.99 (quintet, 2H), 1.45 (s, 9H).

Embodiment 139 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-(3-pyrroles-1-base-propyl group)-9H-purine-6-base amine (139)

According to general process C, title compound obtains by making 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and 1-(3-bromo-propyl group)-1H-pyrroles's reaction.Rt=8.27min (5-100-12). ¹H NMR (CDCl ₃)

8.38 (s, 1H), 7.74 (d, 1H), 6.70 (d, 1H), 6.65 (s, 2H), 6.59 (dd, 1H), 6.15 (s, 2H), 6.00 (br.s., 2H), 4.25 (t, 3H), 3.95 (t, 3H), 3.69 (s, 3H), 2.26 (quintet, 2H).

Embodiment 140 3-[6-amino-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-purine-9-yl]-propyl group }-t-butyl carbamate (140)

Step 1 (3-chloro-propyl group)-t-butyl carbamate

21.8g (0.1mol) diamino acid di tert butyl carbonate is joined triethylamine among the THF, and (12.6g, 0.12mol) (14.0g is in mixture 0.11mol) with hydrochloric acid 3-chlorine propylamine.This mixture stirred 20 minutes down at 0 ℃, was warming up to room temperature then 18 hours, used NaHCO ₃Aqueous solution dilutes, and (2 * 80mL) extract with ether.The salt water washing of this extract, drying, and evaporation obtains title compound. ¹H NMR (DMSO) δ 6.84 (br.s., 1H), 3.59 (t, 2H), 3.02 (t, 3H), 1.81 (quintet, 2H), 1.36 (s, (H).

Step 2 (3-chloro-propyl group)-methyl-t-butyl carbamate

At N ₂Down with NaH (0.24g, 10mmol) join (3-chloro-propyl group)-t-butyl carbamate (1.03g, 5mmol) and CH ₃(1.07g is in THF 7.5mmol) (5mL) solution for I.This reactant mixture at room temperature stirs and spends the night, and water (3mL) cancellation.Extraction (3 * 100mL EtOAc), evaporation and chromatography obtain title compound. ¹HNMR (DMSO) δ 3.60 (t, 2H), 3.28 (t, 3H), 2.78 (s, 2H), 1.91 (quintet, 2H), 1.39 (s, (H).

Step 3 3-[6-amino-8-(3-methoxyl group-1-methyl-Ding-butadienyl sulfane base)-purine-9-yl]-propyl group }-methyl-t-butyl carbamate

According to general process C, title compound obtains by making 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine and (3-chloro-propyl group)-methyl-t-butyl carbamate reaction.Rt=8.51min (5-100-12). ¹HNMR (CDCl ₃) δ 8.24 (s, 1H), 7.58 (d, 1H), 6.96 (br.s., 2H), 6.45 (d, 1H), 6.36 (dd, 1H), 4.14 (s, 2H), 3.53 (t, 3H), 2.72 (s, 3H), 2.51 (t, 2H), 2.22 (s, 6H), 1.99 (quintet, 2H), 1.32 (s, 9H).

Embodiment 141 8-(2-iodo-5-trifluoromethoxy-phenyl sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine (141)

Step 1 1-iodo-2-nitro-4-trifluoromethoxy-benzene

The vigorous stirring solution of 2-nitro-4-trifluoromethoxy-aniline (4.4g) in dense HCl (19mL) and water (19mL) cools off with ice (33g), and sodium nitrite (1.5g) is added with portion.This mixture is introduced in the cold soln of KI (4.9g), and obtains a solid, and it is collected by filtering.This solid obtains crude product with 6N HCl and water washing, and its crystallization from hexane obtains pure title compound.Rt＝7.26(5-100-7). ¹H NMR(CDCl ₃)δ 8.11(d，1H)，7.77(d，1H)，7.20(dd，1H)。

Step 2 2-iodo-5-trifluoromethoxy-aniline

In methanol (100mL) solution of 1-iodo-2-nitro-4-trifluoromethoxy-benzene (5.58g), add FeCl ₃.6H ₂O (70mg) and active carbon (35mg).This mixture is heated backflow, slowly adds a hydrazine hydrate (1.6g) and this reaction process and monitors with TLC.Remove this catalyst by filtering, and vaporising under vacuum methanol.Residue is dissolved among the DCM and water and salt water washing, and organic layer is concentrated to obtain title compound (4.5g).Rt＝7.10min(5-100-7). ¹H NMR(CDCl ₃)δ 7.61(d，1H)，6.59(s，1H)，6.37(d，1H)，4.32(br.s.，2H)。

Step 3 2-iodo-5-trifluoromethoxy-Tetrafluoroboric acid diazobenzene

2-iodo-5-trifluoromethoxy-aniline (4.5g) is at water (2mL) and 48%HBF ₄(10.3mL) serosity in the aqueous solution is cooled to-10 ℃ and be added dropwise to NaNO ₂Water (1.1g) (1mL) solution is handled.The solid diazol is collected by filtering, and with diethyl ether washing and air-dry to obtain title compound 2.9g, is used under its situation about not being further purified.

Step 4 8-(2-iodo-5-trifluoromethoxy-phenyl sulfane base)-9H-purine-6-base amine

6-amino-7, DMF (10mL) suspension of 9-dihydro-purine-8-thioketone (0.99g) are cooled to-35 ℃ and handle with 2-iodo-5-trifluoromethoxy-Tetrafluoroboric acid diazobenzene (2.86g).Allow this mixture reach room temperature, and use solid NaHCO ₃(465mg) neutralization.This mixture is evaporated, at CHCl ₃In grind, filter and solid is used CHCl successively ₃, H ₂O, Et ₂O and DCM washing are to obtain title compound (0.72g).

Step 5 8-(2-iodo-5-trifluoromethoxy-phenyl sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine

8-in DMF (2mL) (2-iodo-5-trifluoromethoxy-phenyl sulfane base)-9H-purine-6-base amine (0.45g), CS ₂CO ₃(0.65g), the mixture of 4-chloro-fourth-1-alkynes (0.12g) stirs down at 80 ℃.This reaction process is monitored by TLC.Evaporate DMF and residue by chromatography purification to obtain title compound. ¹H NMR (CDCl ₃) δ 8.40 (s, 1H), 7.89 (d, 1H), 7.03 (d, 1H), 6.90 (dd, 1H), 5.80 (br.s., 2H), 4.37 (t, 2H), 2.28 (td, 2H), 2.06 (quintet, 2H), 2.00 (t, 1H).

Embodiment 142 8-(2-iodo-5-trifluoromethoxy-phenyl sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine (142)

Step 1 1-iodo-2-nitro-4-trifluoromethoxy-benzene

The vigorous stirring solution of the 2-nitro in dense HCl (19mL) and water (19mL)-4-trifluoromethoxy-aniline (4.7g) cools off by adding ice (33g), and adds a sodium nitrite (1.7g).This reactant mixture is introduced in KI (5.6g) cold soln, and obtains a solid, and it is collected by filtration.This solid washs obtaining crude product with 6N HCl and water, its from hexane crystallization to obtain pure iodide (4.9g).Rt＝7.10(5-100-7). ¹H NMR(CDCl ₃)δ 8.24(d，1H)，8.13(d，1H)，7.54(dd，1H)。

Step 2 2-iodo-5-trifluoromethoxy-aniline

In methanol (100mL) solution of 1-iodo-2-nitro-4-trifluoromethoxy-benzene (4.9g), add FeCl ₃6H ₂O (65mg) and active carbon (33mg).This mixture is heated backflow, slowly adds a hydrazine hydrate (1.5g) and this reaction process and monitors with TLC.Remove this catalyst by filtering, and vaporising under vacuum methanol.Solid residue is dissolved among the DCM and water and salt water washing, and organic layer is concentrated to obtain title compound (3.8g).Rt＝6.95min(5-100-7). ¹H NMR(CDCl ₃)δ 7.74(d，1H)，6.95(s，1H)，6.70(d，1H)，4.35(br.s.，2H)。

Step 3 2-iodo-5-trifluoromethoxy-Tetrafluoroboric acid diazobenzene

2-iodo-5-trifluoromethoxy-aniline (3.8g) is at water (2mL) and 48%HBF ₄(9.2mL) serosity in the aqueous solution is cooled to-10 ℃, and is added dropwise to NaNO ₂Water (1.0g) (1mL) solution is handled.This solid diazol is collected by filtering, and with diethyl ether washing and air-dry to obtain title compound (2.8g), it is used and is not further purified.

Step 4 8-(2-iodo-5-trifluoromethoxy-phenyl sulfane base)-9H-purine-6-base amine

6-amino-7, DMF (10mL) suspension of 9-dihydro-purine-8-thioketone (1.02g) are cooled to-35 ℃ and handle with 2-iodo-5-trifluoromethoxy-Tetrafluoroboric acid diazobenzene (2.8g).Allow this mixture reach room temperature, and use solid NaHCO ₃(460mg) neutralization.This mixture is evaporated, at CHCl ₃In grind, filter and solid is used CHCl successively ₃, H ₂O, Et ₂O and DCM washing are to obtain title compound (1.02g).

With 8-(2-iodo-5-trifluoromethoxy-phenyl sulfane base)-9H-purine-6-base amine (0.44g), CS ₂CO ₃(0.65g), the mixture of 4-chloro-fourth-1-alkynes (0.12g) and DMF (2mL) stirs down at 80 ℃.This reaction process is monitored by TLC.Evaporate DMF and residue by chromatography purification to obtain expecting product. ¹H NMR (CDCl ₃) δ 8.39 (s, 1H), 8.04 (d, 1H), 7.52 (d, 1H), 7.25 (dd, 1H), 5.76 (br.s., 2H), 4.38 (t, 2H), 2.29 (dt, 2H), 2.08 (quintet, 2H), 1.99 (t, 1H).

Embodiment 143 8-(2,4-two iodo-5-methoxyl groups-phenyl sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine (143)

Step 1 2-iodo-5-methoxyl group-aniline and 2,4-two iodo-5-methoxyl group-aniline

In methanol (100mL) solution of 1-iodo-4-methoxyl group-2-nitro-benzene (100g), add FeCl ₃6H ₂O (1.5g) and active carbon (0.76g).This mixture is heated backflow, slowly adds a hydrazine hydrate (35mL) and this reaction process and monitors with TLC.Remove this catalyst by filtering, and vaporising under vacuum methanol.Residue is dissolved among the DCM, water and salt water washing, and organic layer is concentrated to obtain crude product (83g), and it carries out purification to obtain 2-iodo-5-methoxyl group-aniline (80g) and 2,4-two iodo-5-methoxyl group-aniline (1g) by flash chromatography.

Step 22,4-two iodo-5-methoxyl group-Tetrafluoroboric acid diazobenzenes

2,4-two iodo-5-methoxyl group-aniline (0.84g) are at water (3mL) and 48%HBF ₄(1.5mL) serosity in the aqueous solution is cooled to-10 ℃, and is added dropwise to NaNO ₂Water (0.17g) (1mL) solution is handled.This solid diazol is collected by filtering, and with diethyl ether washing and air-dry to obtain title compound (0.77g), it is used and is not further purified.

Step 3 8-(2,4-two iodo-5-methoxyl groups-phenyl sulfane base)-9H-purine-6-base amine

6-amino-7, DMF (5mL) suspension of 9-dihydro-purine-8-thioketone (0.27g) are cooled to-35 ℃ and with 2, and 4-two iodo-5-methoxyl groups-Tetrafluoroboric acid diazobenzene (0.77g) is handled.Allow this mixture reach room temperature, and use solid NaHCO ₃(465mg) neutralization.This mixture is evaporated, at CHCl ₃In grind, filter and this solid is used CHCl successively ₃, H ₂O, Et ₂O and DCM washing are to obtain title compound (0.14g).

Step 4 8-(2,4-two iodo-5-methoxyl groups-phenyl sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine

With 8-(2,4-two iodo-5-methoxyl groups-phenyl sulfane base)-9H-purine-6-base amine (0.14g), CS ₂CO ₃(0.173g), the mixture of 4-chloro-fourth-1-alkynes (0.3mL) and DMF (3mL) stirred 3 hours down at 80 ℃.Evaporate DMF and residue by the product of chromatography purification to obtain expecting.Rt=8.84min. ¹H NMR (DMSO) δ 8.21 (s, 1H), 8.18 (s, 1H), 7.44 (s, 3H), 4.25 (t, 2H), 3.62 (s, 3H), 2.79 (d, 1H), 2.22 (td, 2H), 1.90 (quintet, 2H).

Embodiment 144 8-(2,5-dimethoxy-biphenyl-3-base sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine (144)

Step 12,5-dimethoxy-3-nitro-biphenyl

1-bromo-2,5-dimethoxy-3-nitro-benzene (1.35g), PhB (OH) ₂(1.00g), K ₃PO ₄(2.3g), Pd (PPh ₃) ₄(0.33g) and the mixture of toluene (20mL) be heated to 108 ℃ 24 hours.Organic layer also washs with NaOH1M and water with dilution with toluene, and is concentrated to obtain this title product. ¹H NMR(CDCl ₃)δ7.67(dd，1H)，7.55(dd，2H)，7.44(dd，2H)，7.24(d，1H)，7.10(d，1H)，3.85(s，3H)，3.46(s，3H)。

Step 22,5-dimethoxy-biphenyl-3-base amine

At H ₂(4.8atm) among the EtOAc (40mL) 2, the mixture of 5-dimethoxy-3-nitro-biphenyl (1.88g), 10%Pd/C (0.55g) shook 2 hours in Pa Er hydrogenator (Parr hydrogenator).Filtration and chromatography obtain title compound. ¹H NMR(CDCl ₃)

7.59(d，2H)，7.57(t，2H)，7.40(d，1H)，6.32(d，1H)，6.27(d，1H)，3.76(s，3H)，3.34(s，3H)。

Step 32,5-dimethoxy-3-phenyl-Tetrafluoroboric acid diazobenzene

3,5-dimethoxy-biphenyl-3-base amine (970mg) is at water (2mL) and 48%HBF ₄(2mL) serosity in the aqueous solution is cooled to-10 ℃, and is added dropwise to NaNO ₂Water (380mg) (1mL) solution is handled.The solid diazol is collected by filtering, with diethyl ether washing and air-dry to obtain title compound. ¹H NMR(DMSO-d ₆)δ7.98(d，1H)，7.76(d，1H)，7.56(m，5H)，3.96(s，3H)，3.70(s，3H)。

Step 4 8-(2,5-dimethoxy-biphenyl-3-base sulfane base)-9H-purine-6-base amine

6-amino-7,9-dihydro-purine-8-thioketone (346mg; Biamonte, J.Org.Chem.2005,70,717) DMF (2mL) suspension be cooled to-40 ℃, and with 2,4-dimethoxy-3-phenyl-Tetrafluoroboric acid diazobenzene (1.0g) is handled.Allow this mixture reach room temperature, and use solid NaHCO ₃(529mg) neutralization.This mixture is evaporated, at CHCl ₃In grind, filter and this solid is used CHCl successively ₃, H ₂O, Et ₂O and DCM washing.This solid is dissolved among the DMF again, and with the EtOAc dilution, with NaOH 1M washing and concentrated to obtain expecting product, it does not have unreacted initial substance. ¹H NMR(CDCl ₃)

8.01(s，1H)，7.42(d，2H)，7.26(m，5H)，6.59(s，2H)，3.55(s，3H)，3.29(s，3H)。

Step 5 8-(2,5-dimethoxy-biphenyl-3-base sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine

With 8-(2,5-dimethoxy-biphenyl-3-base sulfane base)-9H-purine-6-base amine (39mg, 5-chloro-penta-1-alkynes (130uL) and K ₂CO ₃DMF (167mg) (3mL) suspension is heated to 70 ℃ and spends the night.Separation and purification process and reversed phase chromatography (C18; Gradient water/CH ₃CN) obtain title compound.Rt=8.80min (5-100-12). ¹H NMR (CDCl ₃/ CD ₃OD 10:1) δ 8.23 (s, 1H), 7.52 (d, 2H), 7.53 (m, 3H), 6.94 (d, 2H), 6.92 (d, 1H), 4.36 (t, 2H), 3.79 (s, 3H), 3.34 (s, 3H), 2.32 (dt, 2H), 2.11 (quintet, 2H), 1.96 (t, 1H).

Embodiment 145 8-(3-bromo-2,5-dimethoxy-phenyl sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine (145)

Rough 8-(3-bromo-2,5-dimethoxy-phenyl sulfane base)-9H-purine-6-base amine (640mg), 5-chloro-penta-1-alkynes (420uL) and K ₂CO ₃DMF (550mg) (2mL) suspension is heated to 75 ℃ and spends the night.Operation and reversed phase chromatography (C18; Gradient water/CH ₃CN) obtain title compound.Rt=7.84min (5-100-12). ¹H NMR (CDCl ₃/ CD ₃OD 10:1)

8.25 (s, 1H), 7.06 (d, 1H), 6.74 (d, 1H), 4.36 (t, 2H), 3.85 (s, 3H), 3.71 (s, 3H), 2.28 (dt, 2H), 2.05 (quintet, 2H), 1.97 (t, 1H).

General process B

At room temperature the DMF solution of Ar-SH (1-4 equivalent) was handled 10 minutes with 1 equivalent alkali (NaH or t-BuOK, 1-4 equivalent).Adding 8-bromo adenine (1 equivalent) and this mixture stirred 2-16 hour down at 50-140 ℃.This reactant mixture dilutes with EtOAc, with NaOH 1M, water and salt water washing.Dry Na ₂SO ₄, evaporation and preparation type TLC or flash chromatography are (as AcOEt/ hexane/Et ₃N 80:20:3) obtains expecting chemical compound.Following compounds prepares by this way.

Embodiment 146 8-(benzothiazole-2-base sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine (146)

According to general process B, title compound obtains by making 8-bromo-9-(4-methyl-penta-3-alkene)-9H-purine-6-base amine and benzothiazole-2-thiol reactant.Rt=7.098min (5-100-7). ¹H NMR (CDCl ₃)

8.41 (s, 1H), 7.92 (d, 1H), 7.73 (d, 1H), 7.46 (t, 1H0,7.35 (t, 1H), 6.42 (br.s.2H), 4.45 (t, 2H), 2.25 (d, 2H), 2.13 (quintet, 2H), 1.94 (s, 1H).

Embodiment 147 9-penta-4-alkynyl-8-(quinoline-2-base sulfane base)-9H-purine-6-base amine (147)

According to general process B, title compound obtains by making 8-bromo-9-(4-methyl-penta-3-alkene)-9H-purine-6-base amine and quinoline-2-thiol reactant.Rt=7.064min (5-100-7). ¹H NMR (CDCl ₃)

8.40 (s, 1H), 8.00 (d, 1H), 7.82 (d, 1H), 7.73 (d, 1H), 7.64 (t, 1H), 7.48 (t, 1H), 7.21 (d, 1H), 6.50 (br.s.2H), 4.39 (t, 2H), 2.20 (d, 2H), 2.10 (quintet, 2H), 1.84 (s, 1H).

Embodiment 148 8-(3-bromo-2,5-dimethoxy-phenyl sulfane base)-9-(4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine (148)

Step 1 1-bromo-2,5-dimethoxy-3-nitro-benzene

2-bromo-4-methoxyl group-6-nitro-phenol (17.3g; Guay, J.Heterocycl.Chem.1987,24,1649) acetone (173mL) solution under refluxing, use Cs ₂CO ₃(55g) and Me ₂SO ₄(16mL) handled 1 hour.This mixture filters by silicagel pad (pad), concentrates and chromatography (toluene/hexane 1:1), obtains the title compound of faint yellow solid form. ¹H NMR(CDCl ₃)δ7.55(s，2H)，4.01(s，3H)，3.90(s，3H)。

Step 2 3-bromo-2,5-dimethoxy-aniline

1-bromo-2 in the water (8mL), 5-dimethoxy-3-nitro-benzene (1.82g), AcOH (250uL) and iron powder (325 orders; 2.7g) suspension be heated and refluxed 2 hours.Organic substance extracts with DCM, washing (NaHCO ₃) and evaporate to obtain title compound. ¹H NMR(CDCl ₃)

6.46(d，1H)，6.24(d，1H)，3.919s，2H)，3.78(s，3H)，3.71(s，3H)。

Step 3 3-bromo-2,5-dimethoxy-Tetrafluoroboric acid diazobenzene

3-bromo-2,5-dimethoxy-aniline (1.2g) is at water (2mL) and 48%HBF ₄(2mL) serosity in the aqueous solution is cooled to-10 ℃, and is added dropwise to NaNO ₂Water (411mg) (1mL) solution is handled.The solid diazol is by filter collecting, and with diethyl ether washing and air-dry obtaining title compound, and is not further purified and is used.

Step 4 8-(3-bromo-2,5-dimethoxy-phenyl sulfane base)-9H-purine-6-base amine

6-amino-7,9-dihydro-purine-8-thioketone (458mg; Biamonte, J.Org.Chem.2005,70,717) DMF (3mL) suspension be cooled to-35 ℃, and with 3-bromo-2,5-dimethoxy-Tetrafluoroboric acid diazobenzene (1.0g) is handled.Allow this mixture reach room temperature, and use solid NaHCO ₃(465mg) neutralization.This mixture is evaporated, at CHCl ₃In grind, filter, and this solid is used CHCl successively ₃, H ₂O, Et ₂O and DCM washing obtain unreacted starting material matter and the mixture of expecting product 1:1.

Step 5 8-(3-bromo-2,5-dimethoxy-phenyl sulfane base)-9-(4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine

Thick 8-(3-bromo-2,5-dimethoxy-phenyl sulfane base)-9H-purine-6-base amine (183mg), 5-bromo-2-methyl-penta-2-alkene (172uL) and Cs ₂CO ₃DMF (422mg) (2mL) suspension be heated to 50 ℃ 1 hour.Operation and chromatography (EtOAc/MeOH/Et ₃N 100:3:3) obtains title compound.Rt＝9.01min(5-100-12). ¹HNMR(CDCl ₃/CD ₃OD 10:1)δ 8.38(s，1H)，7.00(d，1H)，6.51(d，1H)，5.10(t，1H)，4.25(t，2H)，3.88(s，3H)，3.67(s，3H)，2.48(q，2H)，1.39(s，3H)，1.25(s，3H)。

Embodiment 149 9-(4-methyl-penta-3-thiazolinyl)-8-(thiazol-2-yl sulfane base)-9H-purine-6-base amine (149)

According to general process B, title compound obtains by making 8-bromo-9-(4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine and the reaction of 2-mercaptothiazole.Rt＝6.80min(5-100-12). ¹H NMR(CDCl ₃)δ 8.35(s，1H)，7.73(d，1H)，7.34(d，1H)，6.24(s，2H)，5.10(t，1H)，4.30(t，2H)，2.48(q，2H)，1.63(s，3H)，1.34(s，3H)。

Embodiment 150 8-(benzothiazole-2-base sulfane base)-9-(4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine (150)

According to general process B, title compound obtains by making 8-bromo-9-(4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine and 2-mercaptobenzothiazole reaction.Rt＝8.25min(5-100-12). ¹H NMR(CDCl ₃)δ.8.39(s，1H)，7.91(d，1H)，7.70(d，1H)，7.42(t，2H)，7.33(t，2H)，6.19(s，2H)，5.09(t，1H)，4.32(t，2H)，2.51(q，2H)，1.58(s，3H)，1.28(s，3H)。

Embodiment 151 8-(1H-benzimidazolyl-2 radicals-Ji sulfane base)-9-(4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine (151)

According to general process B, title compound obtains by making 8-bromo-9-(4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine and 2-mercaptobenzimidazole reaction.Rt＝5.18min(5-100-7). ¹H NMR(CDCl ₃)

12.80(s，1H)，8.12(s，1H)，7.70(br.s，1H)，7.40(br.s，1H)，7.12m(2H)，(d，1H)，6.72(s，2H)，5.10(t，1H)，4.12(t，2H)，2.39(q，2H)，1.52(s，3H)，1.25(s，3H)。

Embodiment 152 8-(1-pi-allyl-1H-benzimidazolyl-2 radicals-Ji sulfane base)-9-(4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine (152)

At 65 ℃ of following 8-(1H-benzimidazolyl-2 radicals-Ji sulfane base)-9-(4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine (151; 72mg) in DMF (4mL), use allyl bromide, bromoallylene (35uL) and Cs ₂CO ₃(237mg) handled 15 minutes.Operation and flash chromatography (0-8%MeOH is in DCM) obtain title compound.Rt＝5.90min(5-100-7). ¹H NMR(CDCl ₃)

8.28(s，1H)，7.70(d，1H)，7.26(m，3H)，6.20(s，2H)，5.88(m，1H)，5.15(m，2H)，4.96(m，3H)，4.33(t，2H)，2.51(q，2H)，1.62(s，3H)，1.36(s，3H)。

Embodiment 153 8-(1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji sulfane base)-9-(4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine (153)

At 65 ℃ of following 8-(1H-benzimidazolyl-2 radicals-Ji sulfane base)-9-(4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine (151; 62mg) in DMF (4mL), use Me ₂SO ₄(35uL) and Cs ₂CO ₃(238mg) handled 15 minutes.Analyze purification process and flash chromatography (0-8%MeOH is in DCM) and obtain title compound.Rt＝5.43min(5-100-7). ¹H NMR(CDCl ₃)

8.29(s，1H)，7.71(d，1H)，7.31(m，3H)，5.84(s，2H)，5.11(t，1H)，4.35(t，2H)，3.88(s，3H)，2.54(q，2H)，1.64(s，3H)，1.39(s，3H)。

Embodiment 154 2-[6-amino-8-(naphthalene-2-base sulfane base)-purine-9-yl]-ethanol (154)

2-[6-amino-8-in backflow EtOH (1mL) (naphthalene-2-base sulfane base)-purine-9-yl]-ethyl acetate (157; 20mg) solution is handled with a NaOH 1M and is allowed it be cooled to room temperature, so the desired compounds crystallization.Filter and wash (EtOH) and obtain title compound.Rt＝4.94min(5-100-7). ¹H NMR(CDCl ₃/CD ₃OD10:1)

8.15(s，1H)，7.97(s，1H)，7.80(m，3H)，7.49(m，2H)，7.42(m，3H)，4.32(t，2H)，3.84(t，2H)。

Embodiment 155 2-[6-amino-8-(naphthalene-1-base sulfane base)-purine-9-yl]-ethanol (155)

2-[6-amino-8-in backflow EtOH (1mL) (naphthalene-1-base sulfane base)-purine-9-yl]-ethyl acetate (158; 20mg) solution is handled with a NaOH1M and is allowed it be cooled to room temperature, so the desired compounds crystallization.Filter and wash (EtOH) and obtain title compound.Rt＝4.81min(5-100-7). ¹H NMR(CDCl ₃/CD ₃OD10:1)

8.25(s，1H)，8.13(s，1H)，7.95(d，1H)，7.89(m，1H)，7.78(dd，1H0，7.53(m，2H)，7.47(dd，1H)，4.31(t，2H)，3.90(t，2H)。

Embodiment 156 2-[6-amino-8-(quinoline-8-base sulfane base)-purine-9-yl]-ethanol (156)

2-[6-amino-8-in backflow EtOH (4.5mL) (quinoline-8-base sulfane base)-purine-9-yl]-ethyl acetate (159; 32mg) solution is handled with a NaOH 1M and is allowed it be cooled to room temperature, so the desired compounds crystallization.Filter and wash (EtOH) and obtain title compound. ¹H NMR(CDCl ₃/CD ₃OD 10:1)δ 8.85(dd，1H)，8.20(d，1H)，8.18(s，1H)，7.78(d，1H)，7.43(m，3H)，2.14(t，2H0，3.87(t，2H)。

Embodiment 157 2-[6-amino-8-(naphthalene-2-base sulfane base)-purine-9-yl]-ethyl acetate (157)

According to general process B, title compound obtains by making the reaction of 2-(6-amino-8-bromo-purine-9-yl)-ethyl acetate and 2-naphthyl mercaptan.Rt＝5.65min(5-100-7). ¹H NMR(DMSO-d ₆)

8.17(s，1H)，8.02(s，1H)，7.91(m，3H)，7.55(m，2H)，7.42(m，3H)，4.46(t，2H)，4.35(t，2H)，1.83(s，3H)。

Embodiment 158 2-[6-amino-8-(naphthalene-1-base sulfane base)-purine-9-yl]-ethyl acetate (158)

According to general process B, title compound obtains by making the reaction of 2-(6-amino-8-bromo-purine-9-yl)-ethyl acetate and 1-naphthyl mercaptan.Rt＝5.51min(5-100-7). ¹H NMR(CDCl ₃)

8.28(s，1H)，8.15(s，1H)，8.02(m，2H)，7.66(dt，1H)，7.63(dt，1H)，7.60(dd，1H)，7.51(t，1H)，7.31(s，2H)，4.47(t，2H)，4.33(t，2H)，1.87(s，3H)。

Embodiment 159 2-[6-amino-8-(quinoline-8-base sulfane base)-purine-9-yl]-ethyl acetate (159)

According to general process B, title compound obtains by making 2-(6-amino-8-bromo-purine-9-yl)-ethyl acetate and hydrochloric acid 8-quinoline thiol reactant.Rt＝4.60min(5-100-7). ¹H NMR(DMSO-d ₆)δ 8.98(dd，1H)，8.45(dd，1H)，7.83(dd，1H)，7.67(dd，1H)，7.52(s，2H)，7.48(t，1H)，7.08(dd，1H)，4.47(t，2H)，4.35(t，2H)，1.77(s，3H)。

Embodiment 160 2-[6-amino-8-(1H-indole-2-base sulfane base)-purine-9-yl]-ethyl acetate (160)

According to general process B, title compound is by making 2-(6-amino-8-bromo-purine-9-yl)-ethyl acetate and 1, and 3-dihydro-indole-2-thioketone (Takada, Chem.Phar.Bull.1984,32,877) reacts and obtains.Rt＝5.30min(5-100-7). ¹H NMR(DMSO-d ₆)δ 8.13(s，1H)，7.53(d，1H)，7，34(dd，1H)，7，28(s，2H)，7.15(ddd，1H)，6.81(dd，1H)，4.48(t，2H)，4.35(t，2H)，1.92(s，3H)。

Embodiment 161 2-[6-amino-8-(2,5-dimethoxy-phenyl sulfane base)-purine-9-yl]-ethyl acetate (161)

According to general process B, title compound is by making 2-(6-amino-8-bromo-purine-9-yl)-ethyl acetate and 2,5-dimethoxy benzene thiol reactant and obtaining.Rt＝5.94min(5-100-7). ¹H NMR(CDCl ₃)δ 8.32(s，1H)，8.21(d，1H)，8.04(d，1H)，7.58(m，1H)，7.51(m，1H)，5.82(s，2H)，4.55(t，2H)，4.43(t，2H)，3.98(s，3H)，3.85(s，3H)，1.97(s，3H)。

Embodiment 162 2-[6-amino-8-(benzo [b] thiophene-2-base sulfane base)-purine-9-yl]-ethyl acetate (162)

According to general process B, title compound obtains by making 2-(6-amino-8-bromo-purine-9-yl)-ethyl acetate and benzo [b] thiophene-2-mercaptan (Mitra, J.Sci.Indust.Res., 1957,16B, 348) reaction.Rt＝5.58min(5-100-7). ¹H NMR(CDCl ₃)δ 8.21(s，1H)，7.71(m，2H)，7.58(s，1H)，7.32(m，2H)，6.04(s，2H)，4.55(t，2H)，4.44(t，2H)，2.00(s，3H)。

Embodiment 163 2-[6-amino-8-(3-chloro-1H-indole-2-base sulfane base)-purine-9-yl]-ethyl acetate (163)

2-[6-amino-8-(1H-indole-2-base sulfane base)-purine-9-yl]-ethyl acetate (160; THF 49mg) (2mL) solution was handled 1 hour with NCS (21mg) down at 60 ℃.Separation and purification operation (EtOAc/NaHCO ₃) and preparation type TLC (EtOAc/Et ₃N 100/3) obtain title compound.Rt＝5.68min(5-100-7).1H NMR(CDCl ₃)δ 8.23(s，1H)，7.53(d，1H)，7，23(d，1H)，7.15(t，1H)，7.10(t，1H)，6.16(s，2H)，4.45(t，2H)，4.38(t，2H)，1.98(s，3H)。

Embodiment 164 2-[6-amino-8-(3-bromo-1H-indole-2-base sulfane base)-purine-9-yl]-ethyl acetate (164)

2-[6-amino-8-in DCM (2mL) and MeOH (0.5mL) (1H-indole-2-base sulfane base)-purine-9-yl]-ethyl acetate (160; 49mg) solution at room temperature uses NBS (40mg) to handle 15 minutes.Separation and purification operation (EtOAc/NaHCO ₃) and preparation type TLC (EtOAc/Et ₃N 100/3) obtain title compound.Rt＝5.77min(5-100-7). ¹H NMR(CDCl ₃)δ 9.90(s，1H)，8.39(s，1H)，7.64(m，1H)，7.28(m，3H)，6.30(s，2H)，4.53(t，2H)，4.48(s，3H)，1.97(s，3H)。

Embodiment 165 2-[6-amino-8-(3-iodo-1H-indole-2-base sulfane base)-purine-9-yl]-ethyl acetate (165)

2-[6-amino-8-(1H-indole-2-base sulfane base)-purine-9-yl]-ethyl acetate (160; THF 46mg) (2mL) solution was handled 1 hour with NIS (36mg) down at 60 ℃.Separation and purification operation (EtOAc/NaHCO ₃) and preparation type TLC (EtOAc/Et ₃N 100/3) obtain title compound.Rt＝5.81min(5-100-7). ¹H NMR(CDCl ₃)δ 8.30(s，1H)，7.38(d，1H)，7.26(m，2H)，7.18(t，1H)，5.73(s，2H)，4.45(t，2H)，4.57(t，2H)，4.45(s，3H)，2.00(s，3H)。

Embodiment 166 2-[6-amino-8-(1-propyl group-1H-indole-2-base sulfane base)-purine-9-yl]-ethyl acetate (166)

2-[6-amino-8-(1H-indole-2-base sulfane base)-purine-9-yl]-ethyl acetate (160; DMF 49mg) (2mL) solution at room temperature uses 95% NaH (36mg) and propyl iodide (370uL) to handle 1 hour.Separation and purification operation (EtOAc/NaHCO ₃) and preparation type TLC (EtOAc) obtain title compound.Rt＝6.04min(5-100-7). ¹H NMR(CDCl ₃)δ 8.26(s，1H)，7.60(d，1H)，7.34(d，1H)，7.26(t，1H)，7.11(t，1H)，6.95(s，1H)，5.80(s，2H)，4.55(t，2H)，4.44(t，2H)，4.25(t，2H)，2.03(s，3H)，1.71(sext.，2H)，0.89(t，3H)。

Embodiment 167 2-[6-amino-8-(3-iodo-1-propyl group-1H-indole-2-base sulfane base)-purine-9-yl]-ethyl acetate (167)

2-[6-amino-8-(1-propyl group-1H-indole-2-base sulfane base)-purine-9-yl]-ethyl acetate (166; THF 163mg) (2mL) solution at room temperature uses NIS (131mg) to handle 1 hour.Preparation type TLC (EtOAc) obtains title compound.Rt＝6.48min(5-100-7). ¹H NMR(CDCl ₃)δ 8.24(s，1H)，7.44(m，2H)，7.15(m，1H)，2.04(s，2H)，4.63(t，2H)，4.44(t，2H)，4.36(t，2H)，2.03(s，3H)，1.75(sext.，2H)，0.89(t，3H)。

Embodiment 168 2-[6-amino-8-(1,4-dimethoxy-naphthalene-2-base sulfane base)-purine-9-yl]-ethyl acetate (168)

2-(6-amino-8-sulfo--7,8-dihydro-purine-9-yl)-ethyl acetate (40mg) and 1,1,1,1,3,3 of 4-dimethoxy-naphthalene (30mg), 3-hexafluoro-2-propanol (400uL) solution is through N ₂Bubbling is by to solution and degasification.At room temperature adding two (trifluoroacetic acid base) iodine] (PIFA 70mg), so this reaction becomes bottle green (radical cation) from purple, becomes brown benzene then.After 1 hour, this reactant mixture is evaporated, with the EtOAc dilution, and the washing (K of dilution ₂CO ₃, Na ₂S ₂O ₃, saline).Preparation type TLC (EtOAc) provides title compound.Rt＝5.08min(5-100-7). ¹H NMR(CDCl ₃)δ 8.34(s，1H)，6.81(m，3H)，5.53(s，2H)，4.55(t，2H)，4.41(t，2H)，3.78(s，3H)，3.71(s，3H)，1.98(s，3H)。

Embodiment 169 3-[6-amino-8-(benzo [1,3] dioxole (dioxol)-5-base sulfane base)-purine-9-yl]-third-1-alcohol (169)

Step 1 3-[6-amino-8-(benzo [1,3] dioxole-5-base sulfane base)-purine-9-yl]-propyl acetate

3-(6-amino-8-sulfo--7,8-dihydro-purine-9-yl)-propyl acetate (174mg) and 1,1 of 3-benzo dioxole (75uL), 1,1,3,3,3-hexafluoro-2-propanol (0.8mL) solution is at room temperature used two (trifluoroacetic acid base) iodine] (PIFA 280mg) handled 30 minutes benzene.Separation and purification operation and preparation type TLC (EtOAc/DCM/MeOH50:50:3) obtain title compound. ¹H NMR (CDCl ₃) δ 8.27 (s, 1H), 7.00 (dd, 1H), 6.95 (d, 1H), 6.75 (d, 1H), 6.18 (s2H), 5.94 (s, 2H), 4.29 (t, 2H), 4.07 (t, 2H), 2.10 (quintet, 2H), 2.02 (s, 3H).

Step 2 3-[6-amino-8-(benzo [1,3] dioxole-5-base sulfane base)-purine-9-yl]-third-1-alcohol

3-[6-amino-8-in THF (0.5mL) and MeOH (3mL) (benzo [1,3] dioxole-5-base sulfane base)-purine-9-yl]-propyl acetate (33mg) solution at room temperature uses K ₂CO ₃(100mg) handle 30 minutes after the separation and purification operation, to obtain title compound.Rt=4.47min (5-100-7). ¹H NMR (CDCl ₃/ CD ₃OD 5:1) δ 8.12 (s, 1H), 7.05 (dd, 1H), 6.95 (d, 1H), 6.80 (d, 1H), 5.98 (s2H), 4.25 (t, 2H), 3.45 (t, 2H), 1.85 (quintet, 2H).

Embodiment 170 3-[6-amino-8-(2,3-dihydro-benzo [1,4] dioxin-6-base sulfane base)-purine-9-yl]-third-1-alcohol (170)

Step 1 3-[6-amino-8-(2,3-dihydro-benzo [1,4] dioxin-6-base sulfane base)-purine-9-yl]-propyl acetate

3-(6-amino-8-sulfo--7,8-dihydro-purine-9-yl)-propyl acetate (337mg) and 1,1,1,1,3,3 of 4-benzodioxan (225uL), 3-hexafluoro-2-propanol (2mL) solution is by N in solution ₂Bubbling and degasification.At room temperature add two (trifluoroacetic acid base) iodine] and benzene (PIFA, 814mg), so this reaction becomes navy blue (radical cation).This reactant mixture is evaporated after 30 minutes, with the EtOAc dilution, and the washing (K of dilution ₂CO ₃, Na ₂S ₂O ₃, saline).Flash chromatography (0-15%MeOH is in EtOAc) obtains title compound.Rt=5.22min (5-100-7). ¹H NMR (CDCl ₃) δ 8.24 (s, 1H), 6.99 (dd, 1H), 6.92 (d, 1H), 6.80 (d, 1H), 6.28 (s2H), 4.30 (t, 2H), 4.20 (s, 4H), 4.05 (t, 2H), 2.12 (quintet, 2H), 2.01 (s, 3H).

Step 2 3-[6-amino-8-(2,3-dihydro-benzo [1,4] dioxin-6-base sulfane base)-purine-9-yl]-third-1-alcohol

3-[6-amino-8-(2,3-dihydro-benzo [1,4] dioxin-6-base sulfane base)-purine-9-yl]-MeOH (5mL) solution of propyl acetate (54mg) at room temperature uses K ₂CO ₃(113mg) handled 30 minutes.Separation and purification operation and reversed phase chromatography (C18; Gradient water/CH ₃CN) obtain title compound.Rt=4.56min (5-100-7). ¹H NMR (CDCl ₃) δ 8.27 (s, 1H), 7.04 (d, 1H), 6.97 (dd, 1H), 6.86 (d, 1H), 5.87 (s, 2H), 4.38 (t, 2H), 4.25 (m, 4H), 3.40 (t, 2H), 1.82 (quintet, 2H).

Embodiment 171 8-(7-bromo-benzothiazole-2-base sulfane base)-9-butyl-9H-purine-6-base amine (171)

Step 1 7-bromo-benzothiazole-2-mercaptan

To the HNO that is cooled to 0 ℃ ₃(90ml) and H ₂SO ₄Add 1 in the mixture (45ml), and 2-two bromo-benzene (148.3mmol, 35g).This mixture stirred 30 minutes down at 0 ℃, poured into then in the 1.4L frozen water.Solid precipitation also filters.This solid washes with water and by the vacuum pump drying, obtains 2,3-two bromo nitrobenzenes and 3, the mixture (95% productive rate) of 4-two bromo nitrobenzene 1:4 ratios.(142mmol is 40g) by 50%EtOH/H for the mixture of two kinds of regional isomers (regioisomers) ₂(427mmol 23.9g) handles with Fe in the solution that O (270ml) and HCl (15ml) form.This mixture be heated to 85 ℃ 2 hours.This mixture is cooled to room temperature and evaporating solvent then.Thick material extracts with EtOAC.The extract water and the salt water washing that merge through the MgSO4 drying, and concentrate to obtain 2 of 1:4 ratio, 3-dibromo aniline and 3, the mixture of 4-dibromo aniline (95% productive rate).This mixture (34.86mmol, 8.75g) be added into O-ethoxy-dithioformic acid potassium salt (52.3mmol, in DMF 33.47g) (150ml) solution and be heated to 160 ℃ 4 hours.Separation and purification operation with in 7-chloro-benzothiazole-2-mercaptan, describe the same.With the 7-bromo-benzothiazole-2-mercaptan of white solid form and unreacted 3, the 4-dibromo aniline separates, and productive rate is 94%. ¹H NMR(CD ₃OD)δ 7.21(t，J＝6.34Hz，1H)，7.29(d，J＝6.30Hz，1H)，7.34(d，J＝7.34Hz，1H)。

Step 2 8-(7-bromo-benzothiazole-2-base sulfane base)-9-butyl-9H-purine-6-base amine

Except using 7-bromo-benzothiazole-2-mercaptan to replace 7-chloro-benzothiazole-2-mercaptan, the same method of describing among 8-(the basic sulfane base of 7-bromo-benzothiazole-2-)-9-butyl-9H-purine-6-base amine employing and the embodiment 232 prepares. ¹HNMR (CDCl ₃) δ 0.92 (t, J=7.45Hz, 3H), 1.38 (m, 2H), 1.83 (m, 2H), 4.34 (t, J=7.45Hz, 2H), 5.83 (s, 2H, NH ₂), 7.36 (d, 8.12Hz, 1H), 7.50 (t, J=8.12Hz, 1H), 7.87 (d, J=8.12Hz, 1H), 8.44 (s, 1H) .HPLC:RT=6.51min (methods: 5-100-7).

Embodiment 172 9-butyl-8-(7-methyl-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (172)

Step 1 7-methyl-benzothiazole-2-mercaptan

At room temperature (2.5g, (1.94g is 34.7mmol) with dense HCl (1ml) to add Fe in EtOH 11.57mmol) (18ml) solution to 2-bromo-3-Methylnitrobenzene.This reactant mixture is heated and refluxed 1.5 hours, is cooled to room temperature then.Remove solvent.This residue NH ₄Cl (saturated) dilutes and extracts with EtOAC.The extract water and the salt water washing that merge through the MgSO4 drying, concentrate to obtain thick material 2-bromo-3-monomethylaniline., and productive rate is 90%.Chemical compound 2-bromo-3-monomethylaniline. and O-ehtyl potassium xanthate reactant salt are to form 7-methyl-benzothiazole-2-mercaptan, and productive rate is 89%. ¹H NMR(CD ₃OD)δ 7.10(m，2H)，7.29(t，J＝8.08Hz，1H)。

Step 2 9-butyl-8-(7-methyl-benzothiazole-2-base sulfane base)-9H-purine-6-base amine

Except replacing with 7-methyl-benzothiazole-2-mercaptan 7-chloro-benzothiazole-2-mercaptan, 9-butyl-8-(7-methyl-benzothiazole-2-base sulfane base)-9H-purine-6-base amine by with embodiment 49.1 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.88 (t, J=7.45Hz, 3H), 1.34 (m, 2H), 1.80 (m, 2H), 2.47 (s, 3H), 4.33 (t, J=7.45Hz, 2H), 6.10 (s, 2H, NH ₂), 7.16 (d, 7.34Hz, 1H), 7.39 (t, J=7.34Hz, 1H), 7.78 (d, J=7.34Hz, 1H), 8.42 (s, 1H) .HPLC:RT=6.27min (methods: 5-100-7).

Embodiment 173 9-butyl-8-(7-methoxyl group-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (173)

Step 1 7-methoxyl group-benzothiazole-2-mercaptan

(10g adds K in DMF solution 64.9mmol) to the 2-amino-3-nitro phenol under the room temperature ₂CO ₃(9.86g, 71.4mmol) and iodomethane (10.13g, 71.4mmol).This reactant mixture is stirred and spends the night, and under reduced pressure removes solvent.Residue NH ₄Cl (saturated) dilutes and extracts with EtOAC.The extract water and the salt water washing that merge, through the MgSO4 drying, concentrate and from EtOAC and hexane recrystallization to obtain thick material 2-amino-3-Nitroanisole.Adopt common NaNO ₂, H ₂SO ₄Aqueous solution, CuBr, HBr aqueous process are transformed into 2-bromo-3-Nitroanisole with 2-amino-3-Nitroanisole.The reduction of 2-bromo-3-Nitroanisole is by finishing to obtain 2-bromo-3-aminoanisole with the ferrum processing in EtOH/HCl, and itself and O-ehtyl potassium xanthate reactant salt obtain 7-methoxyl group-benzothiazole-2-mercaptan, and productive rate is 89%. ¹H NMR(CD ₃OD)δ 3.95(s，3H)，6.74(d，J＝8.20Hz，1H)，6.95(d，J＝8.08Hz，1H)，7.34(t，J＝8.15Hz，1H)。

Step 2 9-butyl-8-(7-methoxyl group-benzothiazole-2-base sulfane base)-9H-purine-6-base amine

Except using 7-methoxyl group-benzothiazole-2-mercaptan to replace 7-chloro-benzothiazole-2-mercaptan, 9-butyl-8-(7-methoxyl group-benzothiazole-2-base sulfane base)-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.91 (t, J=7.45Hz, 3H), 1.35 (m, 2H), 1.82 (m, 2H), 3.96 (s, 3H), 4.33 (t, J=7.45Hz, 2H), 5.68 (s, 2H, NH ₂), 6.83 (d, J=8.00Hz, 1H), 7.43 (t, J=8.00Hz, 1H), 7.58 (d, J=8.00Hz, 1H), 8.44 (s, 1H) .HPLC:RT=6.14min (methods: 5-100-7).

Embodiment 174 9-butyl-8-(7-ethyoxyl-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (174)

Step 1 7-ethyoxyl-benzothiazole-2-mercaptan

Except using iodoethane to replace the iodomethane, 7-ethyoxyl-benzothiazole-2-mercaptan is that (embodiment 173, the method preparation that step 1) adopted by 7-methoxyl group-benzothiazole-2-mercaptan.Obtain 7-ethyoxyl-benzothiazole-2-mercaptan, be white powder. ¹H NMR(CD ₃OD)δ 1.44(t，J＝7Hz，3H)，4.21(m，2H)，6.84(d，J＝8.09Hz，1H)，6.91(d，J＝8.08Hz，1H)，7.34(t，J＝8.15Hz，1H)。

Step 2 9-butyl-8-(7-ethyoxyl-benzothiazole-2-base sulfane base)-9H-purine-6-base amine

Except using 7-ethyoxyl-benzothiazole-2-mercaptan to replace 7-chloro-benzothiazole-2-mercaptan, 9-butyl-8-(7-ethyoxyl-benzothiazole-2-base sulfane base)-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.90 (t, J=7.45Hz, 3H), 1.35 (m, 2H), 1.45 (t, J=7.45Hz, 3H), 1.82 (m, 2H), 4.21 (t, J=7.45Hz, 2H), 4.33 (t, J=7.45Hz, 2H), 5.76 (s, 2H, NH ₂), 6.80 (d, J=8.00Hz, 1H), 7.41 (t, J=8.00Hz, 1H), 7.56 (d, J=8.00Hz, 1H), 8.44 (s, 1H) .HPLC:RT=6.10min (method 5-100-7).

Embodiment 175 9-butyl-8-(7-fluoro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (175)

Step 1 7-fluoro-benzothiazole-2-mercaptan

Except using 2,3-two fluoro-aniline replace 2, and outside the 3-two chloro-aniline, 7-fluoro-benzothiazole-2-mercaptan is by (embodiment 232, the identical method preparation described in the step 3) with 7-chloro-benzothiazole-2-mercaptan.Obtain 7-fluoro-benzothiazole-2-mercaptan, be white powder (productive rate 92%). ¹H NMR(CDCl ₃)δ 7.0(t，J＝8.3Hz，1H)，7.10(d，J＝8.13Hz，1H)，7.38(m，1H)。

Step 2 9-butyl-8-(7-fluoro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine

Except using 7-fluoro-benzothiazole-2-mercaptan to replace 7-chloro-benzothiazole-2-mercaptan, 9-butyl-8-(7-fluoro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.90 (t, J=7.45Hz, 3H), 1.35 (m, 2H), 1.82 (m, 2H), 4.33 (t, J=7.45Hz, 2H), 5.71 (s, 2H, NH ₂), 7.1 (t, J=8.30Hz, 1H), 7.44 (m, 1H), 7.75 (d, J=8.30Hz, 1H), 8.44 (s, 1H) .HPLC:RT=6.14min. (methods: 5-100-7).

Embodiment 176 9-butyl-8-(7-trifluoromethoxy-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (176)

Step 1 7-trifluoromethoxy-benzothiazole-2-mercaptan

Except using 2-fluoro-3-trifluoromethyl-aniline to replace 2, outside the 3-two chloro-aniline, 7-trifluoromethyl-benzothiazole-2-mercaptan is by (embodiment 232, the identical method preparation described in the step 3) with 7-chloro-benzothiazole-2-mercaptan.7-trifluoromethyl-the benzothiazole that obtains-2-mercaptan is white powder (productive rate 85%). ¹H NMR(CDCl ₃)δ 7.50(m，2H)，7.57(d，J＝6.6Hz，1H)。

Step 2 9-butyl-8-(7-trifluoromethyl-benzothiazole-2-base sulfane base)-9H-purine-6-base amine

Except using 7-trifluoromethyl-benzothiazole-2-mercaptan to replace 7-chloro-benzothiazole-2-mercaptan, 9-butyl-8-(7-trifluoromethyl-benzothiazole-2-base sulfane base)-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.90 (t, J=7.45Hz, 3H), 1.30 (m, 2H), 1.84 (m, 2H), 4.36 (t, J=7.45Hz, 2H), 5.78 (s, 2H, NH ₂), 7.60 (t, J=8.12Hz, 1H), 7.68 (d, J=8.10Hz, 1H), 8.11 (d, J=8.10Hz, 1H), 8.45 (s, 1H) .HPLC:RT=6.57min (methods: 5-100-7).

Embodiment 177 9-butyl-8-(7-chloro-thiazole [4,5-c] pyridine-2-base sulfane base)-9H-purine-6-base amine (177)

Except using 7-chloro-thiazole [4,5-c] pyridine-2-mercaptan is (referring to 206, step 1) replaces outside 7-chloro-benzothiazole-2-mercaptan, 9-butyl-8-(7-chloro-thiazole [4,5-c] pyridine-2-base sulfane base)-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR(CDCl ₃)δ 0.94(t，J＝7.45Hz，3H)，1.38(m，2H)，1.86(m，2H)，4.35(t，J＝7.45Hz，2H)，5.74(s，2H，NH ₂)，8.46(s1H)，8.49(s，1H)，9.10(s，1H).HPLC：RT＝5.74min(5-100-7)。

Embodiment 178 8-(benzothiazole-2-base sulfane base)-9-butyl-9H-purine-6-base amine (178)

Except using benzothiazole-2-mercaptan (purchase) to replace 7-chloro-benzothiazole-2-mercaptan from Acros, 8-(benzothiazole-2-base sulfane base)-9-butyl-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.87 (t, 3H), 1.32 (m, 2H), 1.79 (m, 2H), 4.33 (t, 2H), 6.62 (s, 2H, NH ₂), 7.33 (m, 1H), 7.44 (m, 1H), 7.70 (d, 1H), 7.90 (d, 1H), 8.40 (s, 1H) .HPLC:RT=8.63min (methods: 5-100-15min).

Embodiment 179 9-butyl-8-(6-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (179)

Except using 6-chloro-benzothiazole-2-mercaptan (purchase) to replace 7-chloro-benzothiazole-2-mercaptan from Acros, 9-butyl-8-(6-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.92 (t, 3H), 1.27 (m, 2H), 1.84 (m, 2H), 4.33 (t, 2H), 5.82 (s, 2H, NH ₂), 7.42 (d, 1H), 7.74 (s, 1H), 7.85 (d, 1H), 8.43 (s, 1H) .MS:391 (M+1), HPLC:RT=9.743min (methods: 5-100-15min).

Embodiment 180 9-butyl-8-(5-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (180)

Except using 5-chloro-benzothiazole-2-mercaptan (purchase) to replace 7-chloro-benzothiazole-2-mercaptan from Acros, 9-butyl-8-(5-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR(CDCl ₃)δ 0.91(t，3H)，1.33(m，2H)，1.83(m，2H)，4.33(t，2H)，6.01(s，2H，NH ₂)，7.34(dd，1H)，7.65(d，1H)，7.92(d，1H)，8.43(s，1H).MS：391.8(M+1)，383.83(M+3)。

Embodiment 181 9-butyl-8-(4-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (181)

Step 1 4-chloro-benzothiazole-2-mercaptan

Except using 2,6-two chloro-aniline replace 2, and outside the 3-two chloro-aniline, 4-chloro-benzothiazole-2-mercaptan is that (embodiment 232, the described method preparation of step 3) by 7-chloro-benzothiazole-2-mercaptan.The 6-chloro-benzothiazole-2-mercaptan that obtains is white powder (productive rate 94%). ¹H NMR(CDCl ₃)δ 7.21(t，J＝8.0Hz，1H)，7.36(m，2H).HPLC。

Step 2 9-butyl-8-(4-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine

Except using 4-chloro-benzothiazole-2-mercaptan to replace 7-chloro-benzothiazole-2-mercaptan, 9-butyl-8-(4-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.90 (t, 3H), 1.35 (m, 2H), 1.83 (m, 2H), 4.35 (t, 2H), 5.98 (s, 2H, NH ₂), 7.29 (t, 1H), 7.51 (d, 1H), 7.65 (d, 1H), 8.43 (s, 1H) .HPLC:RT=9.43min (methods: 5-100-15).

Embodiment 182 9-butyl-8-(4-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (182)

9-butyl-8-(4-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 1.33 (s, 3H), 1.73 (s, 3H), 2.54 (m, 2H), 4.35 (t, 2H), 5.13 (m, 1H), 5.86 (s, 2H, NH ₂), 7.34 (d, 1H), 7.42 (m, 1H), 7.84 (d, 1H), 8.45 (s, 1H) .HPLC:RT=6.71min (methods: 5-100-7).

Embodiment 183 9-butyl-8-(thiazole is [5,4-b] pyridine-2-base sulfane base also)-9H-purine-6-base amine (183)

9-butyl-8-(thiazole is [5,4-b] pyridine-2-base sulfane base also)-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.92 (t, 3H), 1.34 (m, 2H), 1.85 (m, 2H), 4.36 (t, 2H), 5.74 (s, 2H), 7.44 (dd, 1H), 8.15 (d, 1H), 8.45 (s, 1H), 8.54 (d, 1H) .HPLC:RT=:5.33min (methods: 5-100-7).

Embodiment 184 8-(4-bromo-6,7-two fluoro-benzothiazole-2-base sulfane base)-9-butyl-9H-purine-6-base amine (184)

8-(4-bromo-6,7-two fluoro-benzothiazole-2-base sulfane base)-9-butyl-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.94 (t, 3H), 1.38 (m, 2H), 1.83 (m, 2H), 4.35 (t, 2H), 5.90 (s, 2H), 7.56 (dd, 1H), 8.70 (s, 1H) .HPLC:RT=6.83min (methods: 5-100-7).

Embodiment 185 9-butyl-8-(6,7-two chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (185)

9-butyl-8-(6,7-two chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.89 (t, 3H), 1.35 (m, 2H), 1.83 (m, 2H), 4.35 (t, 2H), 6.14 (s, 2H), 7.58 (d, 1H), 7.75 (d, 1H), 8.40 (s, 1H) .HPLC:RT=6.92min (methods: 5-100-7).

Embodiment 186 9-butyl-8-(6,7-two fluoro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (186)

9-butyl-8-(6,7-two fluoro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.92 (t, 3H), 1.35 (m, 2H), 1.83 (m, 2H), 4.35 (t, 2H), 6.26 (s, 2H), 7.34 (dd, 1H), 7.67 (dd, 1H), 8.43 (s, 1H) .HPLC:RT=6.32min (methods: 5-100-7).

Embodiment 187 9-butyl-8-(7-methoxymethoxy methyl-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (187)

9-butyl-8-(7-methoxymethoxy methyl-benzothiazole-2-base sulfane base)-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR(CDCl ₃)δ 0.89(t，3H)，1.35(m，2H)，1.83(m，2H)，3.40(s，3H)，4.35(t，2H)，4.68(s，2H)，4.77(s，2H)，5.65(s，2H)，7.31(d，1H)，7.55(t，1H)，7.90(d，1H)，8.45(s，1H).HPLC：RT＝6.06min。

Embodiment 188 4-[6-amino-8-(7-fluoro-benzothiazole-2-base sulfane base)-purine-9-yl]-butyl acetate (188)

4-[6-amino-8-(7-fluoro-benzothiazole-2-base sulfane base)-purine-9-yl]-butyl acetate be by with embodiment 232 in the identical method preparation described. ¹H NMR(CDCl ₃)δ 1.69(m，2H)，1.95(m，2H)，1.98(s，3H)，4.06(t，2H)，4.39(t，2H)，5.69(s，2H)，7.29(t，1H)，7.44(dd，1H)，7.74(d，1H)，8.44(s，1H)；HPLC：RT＝5.66min(5-100-7)。

Embodiment 189 3-[6-amino-8-(6,7-two chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-propyl acetate (189)

3-[6-amino-8-(6,7-two chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-propyl acetate be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 1.99 (s, 3H), 2.22 (m, 2H), 4.07 (t, 2H), 4.46 (t, 2H), 5.70 (s, 2H), 7.54 (d, 1H), 7.73 (d, 1H), 7.82 (d, 1H), 8.41 (s, 1H) .HPLC:RT=6.19min. (methods: 5-100-7).

Embodiment 190 8-(6,7-two chloro-benzothiazole-2-base sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine (190)

8-(6,7-two chloro-benzothiazole-2-base sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 1.90 (s, 1H), 2.14 (m, 2H), 2.28 (m, 2H), 4.43 (t, 2H), 5.74 (s, 2H), 7.53 (d, 1H), 7.73 (d, 1H), 8.43 (s, 1H) .HPLC:RT=6.48min (methods: 5-100-7).

Embodiment 191 8-(7-methoxyl group-benzothiazole-2-base sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine (191)

8-(7-methoxyl group-benzothiazole-2-base sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 1.95 (s, 1H), 2.15 (m, 2H), 2.28 (m, 2H), 4.47 (t, 2H), 5.66 (s, 2H), 6.82 (d, 1H), 7.40 (t, 1H), 7.58 (d, 1H), 8.43 (s, 1H) .HPLC:RT=6.78min (methods: 5-100-7).

Embodiment 192 8-(7-methyl-benzothiazole-2-base sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine (192)

Except replacing with 7-methyl-benzothiazole-2-mercaptan 7-chloro-benzothiazole-2-mercaptan, 8-(7-methyl-benzothiazole-2-base sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 1.94 (s, 1H), 2.13 (m, 2H), 2.28 (m, 2H), 2.48 (s, 3H), 4.47 (t, 2H), 5.98 (s, 2H), 7.16 (d, 1H), 7.40 (t, 1H), 7.78 (d, 1H), 8.43 (s, 1H) .HPLC:RT=5.90min (methods: 5-100-7).

Embodiment 193 8-(4-amino-7-fluorine (fluorol)-benzothiazole-2-base sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine (193)

8-(4-amino-7-fluoro-benzothiazole-2-base sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 2.04 (t, 1H), 2.16 (m, 2H), 2.36 (m, 2H), 4.43 (t, 2H), 5.58 (s, 2H), 7.03 (m, 2H), 8.41 (s, 1H) .HPLC:RT=5.19min (methods: 5-100-7).

Embodiment 194 8-(7-ethyoxyl-benzothiazole-2-base sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine (194)

Except replacing with 7-ethyoxyl-benzothiazole-2-mercaptan 7-chloro-benzothiazole-2-mercaptan, 8-(7-ethyoxyl-benzothiazole-2-base sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 1.43 (t, 3H), 1.95 (s, 1H), 2.15 (m, 2H), 2.28 (m, 2H), 4.19 (m, 2H), 4.47 (t, 2H), 6.14 (s, 2H), 6.78 (d, 1H), 7.40 (t, 1H), 7.55 (d, 1H), 8.42 (s, 1H) .HPLC:RT=6.08min (methods: 5-100-7).

Embodiment 195 2-[6-amino-8-(7-methoxyl group-benzothiazole-2-base sulfane base)-purine-9-yl]-ethyl acetate (195)

2-[6-amino-8-(7-methoxyl group-benzothiazole-2-base sulfane base)-purine-9-yl]-ethyl acetate be by with embodiment 232 in the identical method preparation described. ¹H NMR(CDCl ₃)δ 1.93(s，3H)，3.94(s，3H)，4.45(t，2H)，4.62(t，2H)，5.72(bs，2H)，6.81(d，1H)，7.41(t，1H)，7.55(d，1H)，8.41(s，1H).HPLC：RT＝5.36min(5-100-7)。

Embodiment 196 3-[6-amino-8-(7-methoxyl group-benzothiazole-2-base sulfane base)-purine-9-yl]-propyl acetate (196)

3-[6-amino-8-(7-methoxyl group-benzothiazole-2-base sulfane base)-purine-9-yl]-propyl acetate be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 2.06 (s, 3H), 2.25 (m, 2H), 3.95 (s, 3H), 4.13 (t, 2H), 4.47 (t, 2H), 5.90 (s, 2H), 6.81 (d, 1H), 7.42 (t, 1H), 7.58 (d, 1H), 8.50 (s, 1H) .HPLC:RT=5.47min (methods: 5-100-7).

Embodiment 197 3-[6-amino-8-(7-methyl-benzothiazole-2-base sulfane base)-purine-9-yl]-propyl acetate (197)

3-[6-amino-8-(7-methyl-benzothiazole-2-base sulfane base)-purine-9-yl]-propyl acetate be by with embodiment 232 in the identical method preparation described. ¹HNMR (CDCl ₃) δ 1.99 (s, 3H), 2.22 (m, 2H), 2.48 (s, 3H), 4.00 (t, 2H), 4.48 (t, 2H), 6.07 (s, 2H), 7.16 (d, 1H), 7.42 (t, 1H), 7.78 (d, 1H), 8.42 (s, 1H) .HPLC:RT=5.59min (methods: 5-100-7).

Embodiment 198 8-(7-bromo-thiazole [4,5-c] pyridine-2-base sulfane base)-2-chloro-9-methyl-9H-purine-6-base amine (198)

8-(7-bromo-thiazole [4,5-c] pyridine-2-base sulfane base)-2-chloro-9-methyl-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹HNMR(MeOD)δ 3.96(s，3H)，8.31(s，2H)，8.56(s1H)，9.15(s，1H).HPLC：RT＝5.86min(5-100-7)。

Embodiment 199 2-[6-amino-8-(7-bromo-thiazole [4,5-c] pyridine-2-base sulfane base)-purine-9-yl]-ethyl acetate (199)

2-[6-amino-8-(7-bromo-thiazole [4,5-c] pyridine-2-base sulfane base)-purine-9-yl]-ethyl acetate be by with embodiment 232 in the identical method preparation described. ¹HNMR (CDCl ₃) δ 1.98 (s, 3H), 4.53 (t, 2H), 4.64 (t, 2H), 5.73 (s, 2H), 8.43 (s, 1H), 8.72 (s, 1H), 9.2 (s, 1H) .HPLC:RT=4.98min (methods: 5-100-7).

Embodiment 200 3-[6-amino-8-(7-bromo-thiazole [4,5-c] pyridine-2-base sulfane base)-purine-9-yl]-propyl acetate (200)

3-[6-amino-8-(7-bromo-thiazole [4,5-c] pyridine-2-base sulfane base)-purine-9-yl]-propyl acetate be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 1.98 (s, 3H), 2.22 (m, 2H), 4.53 (t, 2H), 4.64 (t, 2H), 6.14 (s, 2H), 8.40 (s, 1H), 8.57 (s, 1H), 9.1 (s, 1H) .HPLC:RT=5.10min (methods: 5-100-7).

Embodiment 201 8-(7-bromo-thiazole [4,5-c] pyridine-2-base sulfane base)-9-(4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine (201)

8-(7-bromo-thiazole [4,5-c] pyridine-2-base sulfane base)-9-(4-methyl-penta-3-thiazolinyl)-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR(CDCl ₃)δ 9.12(s，1H)，8.58(s，1H)，8.47(s，1H)，5.80(bs，2H，NH ₂)，5.14(t，J＝1.37Hz，1H，CH)，4.37(t，J＝6.87Hz，2H，CH ₂)，2.56(m，2H，CH ₂)，1.38(s，6H，2CH ₃).HPLC：RT＝6.116(5-100-7)。

Embodiment 202 2-[6-amino-8-(7-bromo-thiazole [4,5-c] pyridine-2-base sulfane base)-purine-9-yl] ethyl }-diethyl phosphonate (202)

{ 2-[6-amino-8-(7-bromo-thiazole [4,5-c] pyridine-2-base sulfane base)-purine-9-yl] ethyl }-diethyl phosphonate be by with embodiment 232 in the identical method preparation described. ¹H NMR(CDCl ₃)δ 9.25(s，1H)，8.58(s，1H)，8.46(s，1H)，5.71(bs，2H，NH ₂)，4.65(m，2H，CH ₂)，4.07(m，4H，2CH ₂)，2.52(m，2H，CH ₂)，1.28(t，J＝7.1Hz，6H，2CH ₃).HPLC：RT＝5.013(5-100-7)。

Embodiment 203 3-[6-amino-8-(7-bromo-thiazole [4,5-c] pyridine-2-base sulfane base)-purine-9-yl] propyl group }-diethyl phosphonate (203)

{ 3-[6-amino-8-(7-bromo-thiazole [4,5-c] pyridine-2-base sulfane base)-purine-9-yl] propyl group }-diethyl phosphonate be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 9.12 (s, 1H), 8.58 (s, 1H), 8.44 (s, 1H), 5.83 (bs, 2H, NH ₂), 4.45 (t, J=7.23Hz, 2H, CH ₂), 4.04 (m, 4H, 2CH ₂), 2.21 (m, 2H, CH ₂), 1.35 (m, 2H, CH ₂), 1.26 (t, J=7.06Hz, 6H, 2CH ₃) .HPLC:RT=4.925 (method: 5-100-7).

Embodiment 204 2-[6-amino-8-(7-bromo-thiazole [4,5-c] pyridine-2-base sulfane base)-purine-9-yl]-ethyl acetate (204)

2-[6-amino-8-(7-bromo-thiazole [4,5-c] pyridine-2-base sulfane base)-purine-9-yl]-ethyl acetate be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 2.02 (s, 3H), 4.47 (t, 2H), 4.64 (t, 2H), 5.71 (s, 2H), 8.45 (s, 1H), 8.50 (s, 1H), 9.1 (s, 1H) .HPLC:RT=4.90min (methods: 5-100-7).

Embodiment 205 3-[6-amino-8-(7-chloro-thiazole is [4,5-c] pyridine-2-base sulfane base also)-purine-9-yl]-propyl acetate (205)

3-[6-amino-8-(7-chloro-thiazole is [4,5-c] pyridine-2-base sulfane base also)-purine-9-yl]-propyl acetate be by with embodiment 232 in the identical method preparation described.NMR(CDCl ₃)δ 2.02(s，3H)，2.26(m，2H)，4.09(t，J＝5.9Hz，2H)，4.47(t，J＝7.0Hz，2H)，5.75(s，2H，NH ₂)，8.45(s，1H)，8.50(s，1H)，9.09(s，1H).HPLC：RT＝5.06min(5-100-7)。

Embodiment 206 2-[6-amino-8-(7-chloro-thiazole is [4,5-c] pyridine-2-base sulfane base also)-purine-9-yl]-ethyl }-diethyl phosphonate (206)

Step 1 7-chloro-thiazole [4,5-c] pyridine-2-mercaptan

At room temperature (15g 107mmol) uses Cl to the 3-nitro-pyridine in 50% acetic acid (200ml)-4-alcohol in the solution ₂Gas bell 20 minutes.Precipitate is filtered and washes with water.Recrystallization obtains pure 3-nitro-4-chloro-pyridine from EtOH, and productive rate is 95%.At room temperature, (14g adds POCl in DMF 79.8mmol) (30ml) solution to 3-nitro-4-chloro-pyridine ₃(7.42ml, 79.8mmol).With mixture heated to 120 ℃ 30 minutes, be cooled to room temperature then.Reactant mixture NaHCO ₃(saturated) neutralization extracts with EtOAC then.The extract water and the salt water washing that merge through the MgSO4 drying, concentrate and obtain 3-nitro-4,5-two chloro-pyridines, and productive rate is 94%.3-nitro-4 in HCl under room temperature (160ml) and the ether (80ml), (14g 72.16mmol) adds SnCl to 5-two chloro-pyridines in the solution ₂(162.8g 721.6mmol), obtains 3-amino-4,5-two chloro-pyridines, productive rate is 85%, its further with O-ehtyl potassium xanthate reactant salt to form chloro-thiazole [4,5-c] pyridine-2-mercaptan, productive rate is 89%, (referring to scheme Q). ¹H NMR(DMSO)δ 8.09(s，1H)，8.35(s，1H)。

Step 2 2-[6-amino-8-(7-chloro-thiazole is [4,5-c] pyridine-2-base sulfane base also)-purine-9-yl]-ethyl }-diethyl phosphonate

Except using chloro-thiazole [4,5-c] pyridine-2-mercaptan replaces outside 7-chloro-benzothiazole-2-mercaptan, { 2-[6-amino-8-(7-chloro-thiazole is [4,5-c] pyridine-2-base sulfane base also)-purine-9-yl]-ethyl }-diethyl phosphonate be by with embodiment 232 in the identical method preparation described. ¹H NMR(CDCl ₃)δ 9.08(s，1H)，8.25(s，1H)，8.46(s，1H)，5.76(bs，2H，NH ₂)，4.65(m，2H，CH ₂)，4.07(m，2H，CH ₂)，2.52(m，2H，CH ₂)，1.28(t，J＝7.1Hz，3H，CH ₃).HPLC：RT＝4.969min(5-100-7)。

Embodiment 207 8-(7-bromo-thiazole is [5,4-b] pyridine-2-base sulfane base also)-9-butyl-9H-purine-6-base amine (207)

8-(7-bromo-thiazole is [5,4-b] pyridine-2-base sulfane base also)-9-butyl-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.92 (t, 3H), 1.34 (m, 2H), 1.85 (m, 2H), 4.36 (t, 2H), 5.74 (s, 2H), 8.50 (s, 1H), 8.70 (s, 1H), 9.20 (s, 1H) .HPLC:RT=5.79min (methods: 5-100-7).

Embodiment 208 8-(7-bromo-thiazole is [5,4-b] pyridine-2-base sulfane base also)-9-butyl-9H-purine-6-base amine (208)

Embodiment 209 8-(7-bromo-thiazole is [5,4-b] pyridine-2-base sulfane base also)-2-chloro-9-methyl-9H-purine-6-base amine (209)

8-(7-bromo-thiazole is [5,4-b] pyridine-2-base sulfane base also)-2-chloro-9-methyl-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (MeOD) δ 3.97 (s, 3H), 8.31 (s, 2H), 8.59 (s, 1H), 9.15 (s, 1H) .HPLC:RT=:5.86min (methods: 5-100-7).

Embodiment 210 9-butyl-8-(7-chloro-benzoxazole-2-base sulfane base)-9H-purine-6-base amine (210)

Except replacing with 7-chloro-benzoxazole-2-mercaptan 7-chloro-benzothiazole-2-mercaptan, 9-butyl-8-(7-chloro-benzoxazole-2-base sulfane base)-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.92 (t, 3H), 1.37 (m, 2H), 1.88 (m, 2H), 4.37 (t, 2H), 5.78 (s, 2H), 7.42 (d, 1H), 7.27 (t, 1H), 7.32 (d, 1H), 7.53 (d, 1H), 8.45 (s, 1H) .HPLC:RT=6.155min (methods: 5-100-15min).

Embodiment 211 2-[6-amino-8-(7-chloro-benzoxazole-2-base sulfane base)-purine-9-yl]-ethyl acetate (211)

Except replace 7-chloro-benzothiazole-2-mercaptan 2-[6-amino-8-(7-chloro-benzoxazole-2-base sulfane base)-purine-9-yl with 7-chloro-benzoxazole-2-mercaptan]-ethyl acetate be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 2.00 (s, 3H), 4.52 (t, 2H), 4.67 (t, 2H), 5.78 (s, 2H), 7.29 (t, 1H), 7.35 (d, 1H), 7.52 (d, 1H), 8.44 (s, 1H) .HPLC:RT=5.376min (methods: 5-100-7).

Embodiment 212 3-[6-amino-8-(7-chloro-benzoxazole-2-base sulfane base)-purine-9-yl]-propyl acetate (212)

Except replace 7-chloro-benzothiazole-2-mercaptan 3-[6-amino-8-(7-chloro-benzoxazole-2-base sulfane base)-purine-9-yl with 7-chloro-benzoxazole-2-mercaptan]-propyl acetate be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ=1.97 (s, 3H), 2.31 (m, 2H), 4.11 (t, 2H), 4.49 (t, 2H), 5.78 (s, 2H), 7.29 (t, 1H), 7.32 (d, 1H), 7.52 (d, 1H), 8.44 (s, 1H) .HPLC:RT=5.478min (methods: 5-100-7).

Embodiment 213 3-[6-amino-8-(7-bromo-benzothiazole-2-base sulfane base)-purine-9-yl]-propyl acetate (213)

3-[6-amino-8-(7-bromo-benzothiazole-2-base sulfane base)-purine-9-yl]-propyl acetate be by with 241 in the identical method preparation described. ¹H NMR (CDCl ₃) δ=2.00 (s, 3H), 2.22 (m, 2H), 4.07 (t, 2H), 4.46 (t, 2H), 5.70 (s, 2H), 7.54 (t, 1H), 7.73 (d, 1H), 7.92 (d, 1H), 8.41 (s, 1H) .HPLC:RT=5.81min (methods: 5-100-7).

Embodiment 214 3-[6-amino-8-(6,7-two chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-third-1-alcohol (214)

3-[6-amino-8-(6,7-two chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-third-1-alcohol be by with embodiment 244 in the identical method preparation described. ¹H NMR (CDCl ₃) δ=2.06 (m, 2H), 3.48 (m, 2H), 4.53 (t, 2H), 4.47 (t, 2H), 5.80 (s, 2H), 7.55 (d, 1H), 7.76 (d, 1H), 8.43 (s, 1H) .HPLC:RT=5.56min (methods: 5-100-7).

Embodiment 215 3-[6-amino-8-(7-bromo-benzothiazole-2-base sulfane base)-purine-9-yl]-third-alcohol (215)

3-[6-amino-8-(7-bromo-benzothiazole-2-base sulfane base)-purine-9-yl]-third-alcohol be by with embodiment 244 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 1.95 (m, 2H), 3.47 (t, 2H), 4.54 (t, 2H), 5.92 (bs, 2H), 7.13 (t, 1H), 7.44 (dd, 1H), 7.74 (d, 1H), 8.44 (s, 1H); HPLC:RT=5.19min (method: 5-100-7).

Embodiment 216 3-[6-amino-8-(7-methoxyl group-benzothiazole-2-base sulfane base)-purine-9-yl]-third-alcohol (216)

3-[6-amino-8-(7-methoxyl group-benzothiazole-2-base sulfane base)-purine-9-yl]-third-alcohol be by with embodiment 244 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 1.91 (m, 2H), 3.45 (t, 2H), 3.90 (s, 3H), 4.54 (t, 2H), 5.88 (bs, 2H), 6.82 (d, 1H), 7.45 (t, 1H), 7.57 (d, 1H), 8.41 (s, 1H); HPLC:RT=4.86min (method: 5-100-7).

Embodiment 217 2-[6-amino-8-(7-methoxyl group-benzothiazole-2-base sulfane base)-purine-9-yl]-ethanol (217)

2-[6-amino-8-(7-methoxyl group-benzothiazole-2-base sulfane base)-purine-9-yl]-ethanol be by with embodiment 244 in the identical method preparation described. ¹H NMR (CDCl3) δ 8.35 (s, 1H), 7.52 (d, J=1.08Hz, 1H), 7.41 (t, J=8.4Hz, 1H), 6.81 (d, J=1.08Hz, 1H), 4.48 (t, J=5.09,2H, CH2), 3.94 (m, 5H, CH2+CH3), 3.40 (s, 1H, OH) .HPLC:RT=4.803 (method: 5-100-7).

Embodiment 218 2-[6-amino-8-(7-bromo-thiazole is [4,5-c] pyridine-2-base sulfane base also)-purine-9-yl]-ethanol (218)

2-[6-amino-8-(7-bromo-thiazole is [4,5-c] pyridine-2-base sulfane base also)-purine-9-yl]-ethanol be by with embodiment 244 in the identical method preparation described. ¹H NMR(DMSO)δ 3.79(m，2H)，4.29(t，2H)，7.63(s2H)，8.25(s，1H)，8.66(s，1H)，9.17(s，1H)，8.24(s，1H).HPLC：RT＝4.42min(5-100-7)。

Embodiment 219 2-[6-amino-8-(7-chloro-thiazole is [5,4-b] pyridine-2-base sulfane base also)-purine-9-yl]-ethanol (219)

2-[6-amino-8-(7-chloro-thiazole is [5,4-b] pyridine-2-base sulfane base also)-purine-9-yl]-ethanol be by with embodiment 244 in the identical method preparation described. ¹H NMR (MeOD) δ 3.91 (t, 2H), 4.52 (t, 2H), 8.14 (s, 1H), 8.49 (s, 1H), 9.04 (s, 1H) .HPLC:RT=4.36min (methods: 5-100-7).

Embodiment 220 8-(7-fluoro-benzothiazole-2-base sulfane base)-9-(2-ethyleneoxy-ethyl)-9H-purine-6-base amine (220)

8-(7-fluoro-benzothiazole-2-base sulfane base)-9-(2-ethyleneoxy-ethyl)-9H-purine-6-base amine be by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 3.98 (dd, 1H), 4.09 (t, 2H), 4.13 (dd, 1H), 4.68 (t, 2H), 5.79 (s, 2H), 6.23 (dd, 1H), 7.10 (t, 1H), 7.44 (dd, 1H), 7.76 (d, 1H), 8.44 (s, 1H) .HPLC:RT=5.748min (method: 5-100-7).

Embodiment 221 8-(7-fluoro-benzothiazole-2-base sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine (221)

8-(7-fluoro-benzothiazole-2-base sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine be by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 1.96 (s, 1H), 2.18 (m, 2H), 2.26 (m, 2H), 4.47 (t, 2H), 5.79 (s, 2H), 6.23 (dd, 1H), 7.10 (t, 1H), 7.44 (dd, 1H), 7.76 (d, 1H), 8.45 (s, 1H) .HPLC:RT=5.779min (methods: 5-100-7).

Embodiment 222 2-[6-amino-8-(7-fluoro-benzothiazole-2-base sulfane base)-purine-9-yl]-ethanol (222)

2-[6-amino-8-(7-fluoro-benzothiazole-2-base sulfane base)-purine-9-yl]-ethanol be by with embodiment 244 in the identical method preparation described. ¹H NMR(DMSO)δ 3.67(m，2H)，4.32(t，2H)，5.07(t，1H)，7.31(m，1H)，7.55(m，1H)，7.73(bs，2H)，7.78(m，1H)，8.24(s，1H).HPLC：RT＝4.75min(5-100-7)。

Embodiment 223 4-[6-amino-8-(7-fluoro-benzothiazole-2-base sulfane base)-purine-9-yl]-Ding-1-alcohol (223)

4-[6-amino-8-(7-fluoro-benzothiazole-2-base sulfane base)-purine-9-yl]-Ding-1-alcohol be by with embodiment 244 in the identical method preparation described. ¹H NMR(CDCl ₃)δ 1.69(m，2H)，1.95(m，2H)，3.79(t，2H)，4.39(t，2H)，5.32(bs，2H)，7.29(t，1H)，7.44(dd，1H)，7.74(d，1H)，8.43(s，1H)；HPLC：RT＝4.969min(5-100-7)。

Embodiment 224 3-[6-amino-8-(7-fluoro-benzothiazole-2-base sulfane base)-purine-9-yl]-third-alcohol

3-[6-amino-8-(7-fluoro-benzothiazole-2-base sulfane base)-purine-9-yl]-third-alcohol be by with embodiment 244 in the identical method preparation described. ¹H NMR(CDCl ₃)δ 1.95(m，2H)，3.47(t，2H)，4.54(t，2H)，5.92(bs，2H)，7.13(t，1H)，7.44(dd，1H)，7.74(d，1H)，8.44(s，1H)；HPLC：RT＝4.863min(5-100-7)。

Embodiment 225 9-butyl-8-(7-fluoro-benzoxazole-2-base sulfane base)-9H-purine-6-base amine (225)

Except replacing with 7-fluoro-benzoxazole-2-mercaptan 7-chloro-benzothiazole-2-mercaptan, 9-butyl-8-(7-fluoro-benzoxazole-2-base sulfane base)-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.92 (t, 3H), 1.37 (m, 2H), 1.88 (m, 2H), 4.37 (t, 2H), 5.80 (s, 2H), 7.12 (t, 1H), 7.29 (d, 1H), 7.43 (d, 1H), 8.45 (s, 1H) .HPLC:RT=5.900min (methods: 5-100-15min).

Embodiment 226 2-[6-amino-8-(7-fluoro-benzothiazole-2-base sulfane base)-purine-9-yl]-ethyl acetate (226)

2-[6-amino-8-(7-fluoro-benzothiazole-2-base sulfane base)-purine-9-yl]-ethyl acetate be by with embodiment 241 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 4.13 (t, 2H), 4.64 (t, 2H), 5.73 (s, 2H), 7.09 (t, 1H), 7.42 (m, 1H), 7.74 (d, 1H), 8.43 (s, 1H) .HPLC:RT=5.31min (methods: 5-100-7).

Embodiment 227 3-[6-amino-8-(7-fluoro-benzothiazole-2-base sulfane base)-purine-9-yl]-propyl acetate (227)

3-[6-amino-8-(7-fluoro-benzothiazole-2-base sulfane base)-purine-9-yl]-propyl acetate be by with embodiment 241 in the identical method preparation described.(CDCl ₃)δ 2.00(s，3H)，2.25(m，2H)，4.09(t，2H)，4.47(t，2H)，5.92(s，2H)，7.13(t，1H)，7.44(dd，1H)，7.74(d，1H)，8.43(s，1H)；HPLC：RT＝5.448min(5-100-7)。

Embodiment 228 2-chloro-8-(7-chloro-benzothiazole-2-base sulfane base)-9-methyl-9H-purine-6-base amine (228)

2-chloro-8-(7-chloro-benzothiazole-2-base sulfane base)-9-methyl-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 3.81 (s, 3H), 5.83 (s, 2H, NH2), 7.37 (d, 1H), 7.44 (t, 1H), 7.83 (d, 1H) .HPLC:RT=6.99min (methods: 5-100-7).

Embodiment 229 9-ethyl-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (229)

9-ethyl-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR(CDCl ₃)δ 1.46(t，3H)，4.43(q，2H)，5.88(bs，2H)，7.38(d，1H)，7.43(t，1H)，7.83(d，1H)，8.43(s，1H).HPLC：RT＝5.84min(5-100-7)。

Embodiment 230 8-(7-chloro-benzothiazole-2-base sulfane base)-9-ethyl-9H-purine-6-base amine (230)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-ethyl-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.95 (t, J=7.45Hz, 3H), 4.32 (t, J=7.45Hz, 2H), 5.83 (s, 2H, NH ₂), 7.35 (d, 8.06Hz, 1H), 7.43 (t, J=8.06Hz, 1H), 7.83 (d, J=7.84Hz, 1H), 8.44 (s, 1H) .HPLC:RT=5.844min (methods: 5-100-7).

Embodiment 231 9-propyl group-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (231)

9-propyl group-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (CF1905) be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.95 (t, J=7.45Hz, 3H), 1.91 (m, 2H), 4.32 (t, J=7.45Hz, 2H), 5.83 (s, 2H, NH ₂), 7.35 (d, 8.06Hz, 1H), 7.43 (t, J=8.06Hz, 1H), 7.83 (d, J=7.84Hz, 1H), 8.44 (s, 1H) .HPLC:RT=6.09min (methods: 5-100-7).

Embodiment 232 9-butyl-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (232)

Step 1 9-butyl-9H-purine-6-base amine

At room temperature in DMF (100ml) adenine (10g, 74mmol) and cesium carbonate (28.93g, add in mixture 88.8mmol) the 1-iodobutane (10.15ml, 88.8mmol).Reactant mixture was at room temperature stirred 16 hours, water (200ml) cancellation then.Precipitate is filtered, and dry obtaining title compound under vacuum pump, productive rate be 95% (13.5g, 70mmol). ¹H NMR(DMSO)δ 0.89(t，J＝7.36Hz，3H)，1.20(m，2H)，1.77(m，2H)，4.13(t，J＝7.34Hz，2H)，7.17(s，1H)，8.14(s，1H)。

Step 2 8-bromo-9-butyl-9H-purine-6-base amine

With 9-butyl-9H-purine-(10g 52.35mmol) is suspended among HOAC/NaOAC buffer (6ml), THF (6ml) and the MeOH (6ml) 6-base amine, at room temperature slowly adds Br then ₂(16.75g, 104.7mmol).Add Br ₂After, the clarification that becomes of this reactant mixture, and continue at room temperature to stir 0.5 hour.This reactant mixture is concentrated into 1/3 of original volume then, then with the EtOAc extraction, and water, salt water washing, dry and concentrated through MgSO4 to obtain thick material.Pure material is by obtaining from the MeOH recrystallization, and productive rate is 77.6%. ¹H NMR(MeOH)δ 0.98(t，J＝7.36Hz，3H)，1.40(m，2H)，1.80(m，2H)，4.24(t，J＝7.34Hz，2H)，8.28(s，1H)。

Step 3 7-chloro-benzothiazole-2-mercaptan

Under the room temperature to 2,3-two chloro-aniline (2g, add in DMF 12.34mmol) (10ml) solution O-ethoxy-dithioformic acid potassium salt (1.98g, 12.34mmol).Reactant mixture be heated to then 150 ℃ 4 hours.This reactant mixture is cooled to room temperature and removes solvent in a vacuum.This crude material NH ₄Cl (saturated) dilution, and be settled out solid.This solid is filtered, water (50ml * 2) washing and dry obtaining 7-chloro-benzothiazole-2-mercaptan under vacuum, productive rate be 89% (2.2g, 10.94mmol). ¹H NMR(CDCl ₃)δ 7.16(d，J＝7.8Hz，1H)，7.38(m，2H)，10.0(s，1H)。

Step 4 9-butyl-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine

At room temperature to 7-chloro-benzothiazole-2-mercaptan (222mg, add in DMF 1.1mmol) (5ml) solution potassium tert-butoxide (124mg, 1.1mmol).After 15 minutes, adding 8-bromo-9-butyl-9H-purine-6-base amine (100mg, DMF 0.37mmol) (1ml) solution, and under 130 ℃, stirred 6 hours.This reactant mixture is cooled to room temperature, dilute with water.With EtOAC (200ml) extraction,,, concentrate and from flash chromatography (silica gel) (5% MeOH/CH through the MgSO4 drying with saline (50ml) washing ₂Cl ₂) (110mg, 0.28mmol), productive rate is 75.7% to purification with the end product that obtains the white powder form. ¹H NMR (CDCl ₃)

0.91 (t, J=7.36Hz, 3H), 1.37 (m, 2H), 1.83 (m, 2H), 4.33 (t, J=7.34Hz, 2H), 6.03 (s, 2H, NH ₂), 7.36 (dd, J=1.0Hz, 7.84Hz, 1H), 7.42 (t, J=7.89Hz, 1H), 7.83 (dd, J=1.0Hz, 7.84Hz, 1H), 8.43 (s, 1H) .HPLC:RT=9.73min (methods: 5-100-15).

Embodiment 233 9-amyl group-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (233)

9-amyl group-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.81 (t, J=7.45Hz, 3H), 0.94 (m, 2H), 1.31 (m, 2H), 1.86 (m, 2H), 4.35 (t, J=7.45Hz, 2H), 5.97 (s, 2H, NH ₂), 7.35 (d, 8.06Hz, 1H), 7.43 (t, J=8.06Hz, 1H), 7.83 (d, J=7.84Hz, 1H), 8.44 (s, 1H) .HPLC:RT=6.80min, (methods: 5-100-7).

Embodiment 234 8-(7-chloro-benzothiazole-2-base sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine (234)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 1.96 (t, 1H), 2.14 (m, 2H), 2.31 (m, 2H), 4.47 (t, 2H), 5.75 (s, 2H), 7.36 (d, 1H), 7.43 (t, 1H), 7.82 (d, 1H), 8.44 (s, 1H) .HPLC:RT=6.01min (methods: 5-100-7).

Embodiment 235 8-(7-chloro-benzothiazole-2-base sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine (235)

Except replacing with 7-bromo-benzothiazole-2-mercaptan 7-chloro-benzothiazole-2-mercaptan, 8-(7-chloro-benzothiazole-2-base sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 1.96 (s, 1H), 2.29 (m, 2H), 2.58 (m, 2H), 4.49 (t, 2H), 5.88 (s, 2H), 7.35 (t, 1H), 7.60 (d, 1H), 7.90 (d, 1H), 8.45 (s, 1H) .HPLC:RT=6.10min (methods: 5-100-7).

Embodiment 236 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-methoxyl group-ethyl)-9H-purine-6-base amine (236)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-methoxyl group-ethyl)-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 3.23 (s, 3H), 3.75 (t, 2H), 4.56 (t, 2H), 5.88 (s, 2H), 7.35 (d, 1H), 7.43 (t, 1H), 7.84 (d, 1H), 8.43 (s, 1H) .HPLC:RT=5.61min (methods: 5-100-7).

Embodiment 237 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-ethyleneoxy-ethyl)-9H-purine-6-base amine (237)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-ethyleneoxy-ethyl)-9H-purine-6-base amine be by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 3.96 (m, 1H), 4.09 (m, 3H), 4.69 (t, 2H), 5.77 (s, 2H), 6.25 (m, 1H), 7.35 (d, 1H), 7.43 (t, 1H), 7.84 (d, 1H), 8.44 (s, 1H) .HPLC:RT=6.01min (methods: 5-100-7).

Embodiment 238 2-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-ethyl }-diethyl phosphonate (238)

{ 2-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-ethyl }-diethyl phosphonate be by with embodiment 232 in the identical method preparation described. ¹H NMR(CDCl ₃)δ 1.28(t，6H)，2.52(m2H)，4.07(m，4H)，4.65(m，2H)，5.67(bs，2H)，7.38(d，1H)，7.43(t，1H)，7.83(d，1H)，8.53(s，1H).HPLC：RT＝5.66min(5-100-7)。

Embodiment 239 2-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-ethyl }-diethyl phosphonate (239)

{ 2-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-ethyl }-diethyl phosphonate be by with embodiment 232 in the identical method preparation described. ¹H NMR(CDCl ₃)δ 8.53(s，1H)，7.83(d，J＝7.0Hz，1H)，7.43(t，J＝7.9Hz，1H)，7.38(d，J＝7.0Hz，1H)，5.67(bs，2H，NH ₂)，4.65(m，2H，CH ₂)，4.07(m，4H，2CH ₂)，2.52(m，2H，CH ₂)，1.28(t，J＝7.1Hz，6H，2CH ₃).HPLC：RT＝5.667min(5-100-7)。

Embodiment 240 2-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-ethyl }-phosphoramidic acid diethylester (240)

{ 2-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-ethyl }-phosphoramidic acid diethylester be by with embodiment 271 in the identical method preparation described. ¹H NMR(CDCl ₃)δ 1.19(t，6H)，3.50(m2H)，3.80(m，1H)，3.90(m4H)，4.47(t，2H)，6.00(bs，2H)，7.36(d，1H)，7.41(t，1H)，7.83(d，1H)，8.38(s，1H).HPLC：RT＝5.49min(5-100-7)。

Embodiment 241 2-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-ethyl acetate (241)

Step 1 2-(6-amino-purine-9-yl)-ethyl acetate

Except replacing the 1-iodobutane with 2-bromo-alcohol, acetic acid ester (2-bromo-etanol acetate), 2-(6-amino-purine-9-yl)-ethyl acetate be by with embodiment 232, the identical method preparation of describing in the step 1.What obtain is 2-(6-amino-purine-9-the yl)-ethyl acetate of white powder form, and productive rate is 95%. ¹H NMR(CDCl ₃)δ2.06(s，3H)，4.47(m，4H)，5.62(s，2H，NH ₂)，7.85(s1H)，8.39(s，1H)。

Step 2 3-(6-amino-8-bromo-purine-9-yl)-ethyl acetate

3-(6-amino-8-bromo-purine-9-yl)-ethyl acetate be by with embodiment 49, the identical method preparation of describing in the step 2, and productive rate is 90%. ¹H NMR(CDCl ₃)δ 2.06(s，3H)，4.51(m，4H)，582(s，2H，NH ₂)，8.34(s，1H)。

Step 3 2-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-ethyl acetate

2-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-ethyl acetate be by with embodiment 232, the identical method of describing in the step 3 is with 3-(6-amino-8-bromo-purine-9-yl)-ethyl acetate preparation.What obtain is the title compound (productive rate 85%) of white powder form.H NMR (CDCl ₃) δ 1.96 (s, 3H), 4.48 (t, J=5.0Hz, 2H), 4.64 (t, J=5.0Hz, 2H), 5.87 (s, 2H, NH ₂), 7.37 (d, J=7.79Hz, 1H), 7.44 (t, J=7.80Hz, 1H), 7.83 (d, J=7.80Hz, 1H), 8.43 (s, 1H) .HPLC:RT=5.57min (methods: 5-100-7).

Embodiment 242 2-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-propyl acetate (242)

2-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-propyl acetate be by with embodiment 241 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 2.00 (s, 3H), 2.26 (m, 2H), 4.08 (t, J=5.9Hz, 2H), 4.47 (t, J=7.0Hz, 2H), 6.06 (s, 2H, NH ₂), 7.36 (d, J=7.79Hz, 1H), 7.42 (t, J=7.80Hz, 1H), 7.82 (d, J=7.80Hz, 1H), 8.42 (s, 1H) .HPLC:RT=5.76min (methods: 5-100-7).

Embodiment 243 4-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-butyl acetate (243)

4-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-butyl acetate be by with embodiment 241 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 1.66 (m, 2H), 1.95 (m, 2H), 1.96 (s, 3H), 4.11 (t, 2H), 4.39 (t, 2H), 6.31 (s, 2H), 7.33 (d, 1H), 7.42 (t, 1H), 7.82 (d, 1H), 8.40 (s, 1H) .HPLC:RT=5.89min (methods: 5-100-7).

Embodiment 244 2-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-ethanol (244)

In the methanol, 10ml 7N NH ₃In 2-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-ethyl acetate (241; 200mg, solution 0.476mmol) at room temperature stirred 4 hours.Evaporating solvent, residue flash chromatography (5% MeOH/CH ₂Cl ₂) carry out purification, obtain 2-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-ethanol, for white powder (172mg, 0.455mmol), productive rate 94%. ¹H NMR (DMSO) δ 3.58 (m, 2H), 4.33 (t, J=5.9Hz, 2H), 5.04 (t, J=5.0Hz, 1H, OH), 7.55 (m, 2H), 7.64 (s, 2H, NH ₂), 7.93d, J=5.0Hz, 1H), 8.26 (s, 1H) .HPLC:RT=5.01min (methods: 5-100-7).

Embodiment 245 2-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-third-1-alcohol (245)

2-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-third-1-alcohol by with embodiment 244 in the identical method preparation described, and obtain white powder (productive rate 94%). ¹H NMR(CDCl ₃)δ 1.93(m，2H)，3.47(m，2H)，4.52(t，J＝7.0Hz，2H)，5.78(s，2H，NH ₂)，7.39(d，J＝7.79Hz，1H)，7.42(t，J＝7.80Hz，1H)，7.82(d，J＝7.80Hz，1H)，8.43(s，1H).HPLC：RT＝5.134mm(5-100-7)。

Embodiment 246 4-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-Ding-1-alcohol (246)

4-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-Ding-1-alcohol by with embodiment 244 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 1.59 (m, 2H), 2.02 (m, 2H), 3.72 (t, 2H), 4.47 (t, 2H), 5.83 (s, 2H), 7.36 (d, 1H), 7.43 (t, 1H), 7.84 (d, 1H), 8.43 (s, 1H) .HPLC:RT=5.21min (methods: 5-100-7).

Embodiment 247 8-(7-chloro-benzothiazole-2-base sulfane base)-9-[2-(2,2-dimethyl-propyl group amino)-ethyl]-9H-purine-6-base amine (247)

Step 1 2-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-ethyl methane sulfonate

At the 2-[6-amino-8-in 5ml DMF under 0 ℃ (7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-ethanol (244; 100mg, 0.29mmol) slowly add in the solution mesyl chloride (33.7ul, 0.45mmol) and triethylamine (48.6ul, 0.35mmol).Reactant mixture stirred 10 minutes down at 0 ℃.Remove most of solvent then.Obtain product behind the water cancellation crude product, filter then, obtain the title compound (productive rate 94%) of white powder form. ¹H NMR(CDCl ₃)δ 2.9(s，3H)，4.68(t，J＝4.87Hz，2H)，4.75(t，J＝4.90Hz，2H)，5.88(s，2H，NH ₂)，7.37(d，J＝7.79Hz，1H)，7.45(t，J＝7.80Hz，1H)，7.82(d，J＝7.80Hz，1H)，8.44(s，1H)。

Step 2 8-(7-chloro-benzothiazole-2-base sulfane base)-9-[2-(2,2-dimethyl-propyl group amino)-ethyl]-9H-purine-6-base amine

To 2-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-(100mg 0.22mmol) adds 1ml 2,2-dimethyl-propylamine to ethyl methane sulfonate.Reactant mixture at room temperature stirs and spends the night.Remove excessive amine.Residue is by flash chromatography (silica gel) (5%MeOH/CH ₂Cl ₂) carry out purification, obtain 8-(7-chloro-benzothiazole-2-base sulfane base)-9-[2-(2,2-dimethyl-propyl group the amino)-ethyl of white powder form]-the 9H-purine-(30mg, 0.067mmol), productive rate is 30.5% to 6-base amine. ¹H NMR (CDCl ₃) δ 0.82 (s, 3H), 2.31 (s, 2H), 3.05 (t, J=4.87Hz, 2H), 4.47 (t, J=4.90Hz, 2H), 5.74 (s, 2H, NH ₂), 7.35 (d, J=7.79Hz, 1H), 7.43 (t, J=7.80Hz, 1H), 7.84 (d, J=7.80Hz, 1H), 8.44 (s, 1H) .HPLC:RT=5.38min (methods: 5-100-7).

Embodiment 248 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-isopropyl amino)-ethyl)-9H-purine-6-base amine (248)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-isopropyl amino)-ethyl)-9H-purine-6-base amine be by with embodiment 247 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.92 (d, 6H), 2.85 (m, 1H), 3.05 (t, 2H), 4.47 (t, 2H), 5.76 (s, 2H), 7.35 (d, 1H), 7.41 (t, 1H), 7.81 (d, 1H), 8.43 (s, 1H) .HPLC:RT=4.81min (methods: 5-100-7).

Embodiment 249 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-isobutylamino)-ethyl)-9H-purine-6-base amine (249)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-isobutylamino)-ethyl)-9H-purine-6-base amine be by with embodiment 247 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.82 (d, 6H), 1.65 (m, 1H), 2.39 (d, 2H), 3.05 (t, 2H), 4.46 (t, 2H), 5.72 (s, 2H), 7.33 (d, 1H), 7.41 (t, 1H), 7.81 (d, 1H), 8.43 (s, 1H) .HPLC:RT=5.10min (methods: 5-100-7).

Embodiment 250 8-(7-chloro-benzothiazole-2-base sulfane base)-9-[2-(1-ethyl-propyl group amino)-ethyl)-9H-purine-6-base amido

8-(7-chloro-benzothiazole-2-base sulfane base)-9-[2-(1-ethyl-propyl group amino)-ethyl]-9H-purine-6-base amine by with embodiment 247 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.73 (d, 6H), 1.24 (m, 4H), 2.27 (t, 1H), 3.01 (t, 2H), 4.44 (t, 2H), 5.75 (s, 2H), 7.34 (d, 1H), 7.44 (t, 1H), 7.82 (d, 1H), 8.43 (s, 1H) .HPLC:RT=5.19min (methods: 5-100-7).

Embodiment 251 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-propyl group amino)-ethyl)-9H-purine-6-base amine (251)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-propyl group amino)-ethyl)-9H-purine-6-base amine by with embodiment 247 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.83 (t, 3H), 1.40 (m, 2H), 2.57 (t, 2H), 3.05 (t, 2H), 4.48 (t, 2H), 5.78 (s, 2H), 7.33 (d, 1H), 7.42 (t, 1H), 7.82 (d, 1H), 8.43 (s, 1H) .HPLC:RT=4.88min (methods: 5-100-7).

Embodiment 252 8-(7-chloro-benzothiazole-2-base sulfane base)-9-[3-(1-ethyl-propyl group amino)-propyl group]-9H-purine-6-base amine (252)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-[3-(1-ethyl-propyl group amino)-propyl group]-9H-purine-6-base amine by with embodiment 247 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.95 (t, 6H), 1.58 (m, 4H), 2.20 (m, 2H), 2.79 (m, 1H), 2.95 (t, 2H), 4.50 (t, 2H), 5.67 (s, 2H), 7.47 (d, 1H), 7.54 (t, 1H), 7.86 (d, 1H), 8.32 (s, 1H) .HPLC:RT=5.158min (methods: 5-100-7).

Embodiment 253 9-(3-tert-butyl amino-propyl group)-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (253)

9-(3-tert-butyl amino-propyl group)-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine by with embodiment 247 in the identical method preparation described. ¹HNMR (CDCl ₃) δ 1.32 (s, 9H), 2.22 (m, 2H), 3.02 (t, 2H), 4.53 (t, 2H), 5.67 (s, 2H), 7.47 (d, 1H), 7.54 (t, 1H), 7.86 (d, 1H), 8.34 (s, 1H) .HPLC:RT=5.005min (methods: 5-100-7).

Embodiment 254 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(3-isobutylamino-propyl group-9H-purine-6-base amine (254)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-(3-isobutylamino-propyl group)-9H-purine-6-base amine by with embodiment 247 in the identical method preparation described. ¹H NMR(DMSO)δ 8.28(s，1H)，7.93(t，J＝8.4Hz，1H)，7.76(bs，2H，NH2)，7.57(d，J＝1.08Hz，2H)，4.36(t，J＝7.35Hz，2H)，2.90(t，J＝7.35Hz，2H)，2.38(d，J＝6.89，2H，CH ₂)，2.25(m，2H，CH ₂)，1.64(m，1H，CH)，0.83(s，6H，2CH ₃).HPLC：RT＝5.035(5-100-7)。

Embodiment 255 9-(3-the second month in a season-butyl amino-propyl group)-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (255)

9-(3-the second month in a season-butyl amino-propyl group)-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine by with embodiment 247 in the identical method preparation described. ¹H NMR(DMSO)δ 8.28(s，1H)，7.93(t，J＝8.4Hz，1H)，7.76(bs，2H，NH2)，7.57(d，J＝1.08Hz，2H)，4.36(t，J＝7.35Hz，2H)，3.17(m，1H，CH)，2.90(t，J＝7.35Hz，2H)，2.70(m，1H，CH)，2.25(m，2H，CH2)，1.51(m，2H，CH2)，1.10(m，6H，2CH3).HPLC：RT＝5.034(5-100-7)。

Embodiment 256 9-[2-(2,2-dimethyl-propyl group amino)-ethyl]-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (256)

9-[2-(2,2-dimethyl-propyl group amino)-ethyl]-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine by with embodiment 247 in the identical method preparation described. ¹H NMR (CD ₃OD) δ 8.29 (s, 1H), 7.50 (d, J=1.08Hz, 1H), 7.48 (t, J=8.4Hz, 1H), 6.99 (d, J=1.08Hz, 1H), 4.48 (t, J=5.09,2H, CH2), 3.97 (s, 3H, CH3), 2.97 (t, J=5.09,2H, CH2), 2.25 (s, 2H, CH2), 0.80 (s, 9H, 3CH3) .HPLC:RT=5.110 (method: 5-100-7).

Embodiment 257 8-(7-chloro-benzothiazole-2-base sulfane base)-9-[3-(2,2-dimethyl-propyl group amino)-propyl group]-9H-purine-6-base amine (257)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-[3-(2,2-dimethyl-propyl group amino)-propyl group]-9H-purine-6-base amine by with embodiment 247 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.88 (s, 9H), 2.02 (m, 2H), 2.24 (s, 2H), 2.62 (t, 2H), 4.47 (t, 2H), 5.73 (s, 2H), 7.35 (d, 1H), 7.43 (t, 1H), 7.84 (d, 1H), 8.43 (s, 1H) .HPLC:RT=5.21min (methods: 5-100-7).

Embodiment 258 8-(7-chloro-benzothiazole-2-base sulfane base)-9-[2-(cyclopropyl methyl-amino)-ethyl]-9H-purine-6-base amine (258)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-[2-(cyclopropyl methyl-amino)-ethyl]-9H-purine-6-base amine by with embodiment 247 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.09 (m, 2H), 0.41 (m2H), 0.85 (m, 1H), 2.46 (d, 2H), 3.07 (t, 2H), 4.47 (t, 2H), 5.82 (s, 2H), 7.35 (d, 1H), 7.43 (t, 1H), 7.84 (d, 1H), 8.43 (s, 1H) .HPLC:RT=4.97min (methods: 5-100-7).

Embodiment 259 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-Propargyl amino-ethyl)-9H-purine-6-base amine (259)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-Propargyl amino-ethyl)-9H-purine-6-base amine by with embodiment 247 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 2.10 (t, 1H), 3.16 (m, 2H), 3.51 (s, 2H), 4.49 (t, 2H), 5.83 (s, 2H), 7.35 (d, 1H), 7.43 (t, 1H), 7.84 (d, 1H), 8.43 (s, 1H) .HPLC:RT=4.74min (methods: 5-100-7).

Embodiment 260 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-cyclopenta amino-ethyl)-9H-purine-6-base amine (260)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-cyclopenta amino-ethyl)-9H-purine-6-base amine by with embodiment 247 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 8.42 (s, 1H), 7.83 (d, J=7.0Hz, 1H), 7.43 (t, J=7.9Hz, 1H), 7.38 (d, J=7.0Hz, 1H), 5.70 (bs, 2H, NH ₂), 4.48 (t, J=5.95Hz, 2H, CH ₂), 3.08 (t, J=5.95Hz, 2H, CH ₂), 1.75 (m, 1H, CH), 1.61 (m, 4H, 2CH2), 1.48 (m, 4H, 2CH ₂) .HPLC:RT=5.090 (method: 5-100-7).

Embodiment 261 8-(7-chloro-benzothiazole-2-base sulfane base)-9-[2-(3-methyl-butyl amino)-ethyl]-9H-purine-6-base amine (261)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-[2-(3-methyl-butyl amino)-ethyl]-9H-purine-6-base amine by with embodiment 247 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 8.44 (s, 1H), 7.83 (d, J=7.0Hz, 1H), 7.43 (t, J=7.9Hz, 1H), 7.38 (d, J=7.0Hz, 1H), 5.79 (bs, 2H, NH ₂), 4.49 (t, J=5.95Hz, 2H, CH ₂), 3.06 (t, J=5.95Hz, 2H, CH ₂), 2.61 (t, J=8.19Hz, 2H, CH ₂), 1.55 (m, 3H, CH+CH ₂), 0.85 (d, J=6.62,6H, 2CH ₃) .HPLC:RT=5.323 (method: 5-100-7).

Embodiment 262 8-(7-chloro-benzothiazole-2-base sulfane base)-9-[2-(1,1-dimethyl-propyl group amino)-ethyl]-9H-purine-6-base amine (262)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-[2-(1,1-dimethyl-propyl group amino)-ethyl]-9H-purine-6-base amine by with embodiment 247 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 8.44 (s, 1H), 7.81 (d, J=7.0Hz, 1H), 7.43 (t, J=7.9Hz, 1H), 7.35 (d, J=7.0Hz, 1H), 5.74 (bs, 2H, NH2), 4.43 (t, J=5.95Hz, 2H, CH ₂), 2.95 (t, J=5.95Hz, 2H, CH ₂), 1.30 (m, 2H, CH ₂), 0.92 (s, 6H, 2CH3), 0.74 (t, J=6.12Hz, 3H, CH ₃) .HPLC:RT=5.145 (method: 5-100-7).

Embodiment 263 9-(2-allyl amino-ethyl)-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (263)

9-(2-allyl amino-ethyl)-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine by with embodiment 247 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 3.03 (t, 2H), 3.223 (d2H), 4.47 (t, 2H), 5.00 (m, 2H), 5.71 (m, 1H), 5.80 (s, 2H), 7.35 (d, 1H), 7.43 (t, 1H), 7.84 (d, 1H), 8.43 (s, 1H) .HPLC:RT=:4.82min (methods: 5-100-7).

Embodiment 264 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-cyclopropyl amino)-ethyl)-9H-purine-6-base amine (264)

Except replacing 2, outside 2-dimethyl-propylamine, 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-cyclopropyl amino)-ethyl) with cyclopropylamine-9H-purine-6-base amine by with embodiment 247 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.16 (m, 2H), 0.36 (m, 2H), 2.15 (m, 1H), 3.15 (t, J=4.87Hz, 2H), 4.46 (t, J=4.90Hz, 2H), 5.70 (s, 2H, NH ₂), 7.35 (d, J=7.79Hz, 1H), 7.43 (t, J=7.80Hz, 1H), 7.84 (d, J=7.80Hz, 1H), 8.44 (s, 1H) .HPLC:RT=4.95min (methods: 5-100-7).

Embodiment 265 9-(2-tert-butyl group amino-ethyl)-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (265)

Except replacing 2 with tert-butylamine, outside 2-dimethyl-propylamine, 9-(2-tert-butyl group amino-ethyl)-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine by with embodiment 247 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 0.96 (s, 9H), 3.00 (t, J=4.87Hz, 2H), 4.46 (t, J=4.90Hz, 2H), 5.77 (s, 2H, NH ₂), 7.35 (d, J=7.79Hz, 1H), 7.43 (t, J=7.80Hz, 1H), 7.84 (d, J=7.80Hz, 1H), 8.43 (s, 1H) .HPLC:RT=5.04min (methods: 5-100-7).

Embodiment 266 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(3-isopropyl amino-propyl group)-9H-purine-6-base amine (266)

Except replacing 2 with 2-aminopropane., outside 2-dimethyl-propylamine, 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(3-isopropyl amino-propyl group)-9H-purine-6-base amine by with embodiment 247 in the identical method preparation described. ¹H NMR (DMSO) δ 1.09 (s, 3H), 1.10 (s, 3H), 2.10 (m, 2H), 2.90 (m, 2H), 3.17 (m, 1H), 4.36 (t, 2H), 7.57 (d, 2H), 7.76 (bs, 2H), 7.93 (t, 1H), 8.28 (s, 1H) .HPLC:RT=4.811min (methods: 5-100-7).

Embodiment 267 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(3-pyrroles-1-base-propyl group)-9H-purine-6-base amine (267)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-(3-pyrroles-1-base-propyl group)-9H-purine-6-base amine by with embodiment 247 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 2.40 (m, 2H), 3.97 (t, 2H), 4.35 (t, 2H), 5.82 (bs, 2H), 6.11 (d, 2H), 6.66 (d, 2H), 7.37 (d, 1H), 7.44 (t, 1H), 7.83 (d, 1H), 8.45 (s, 1H) .HPLC:RT=6.372min (methods: 5-100-7).

Embodiment 268 8-(7-chloro-benzothiazole-2-base sulfane base)-9-[2-(3,3-dimethyl-butyl amino)-ethyl]-9H-purine-6-base amine (268)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-[2-(3,3-dimethyl-butyl amino)-ethyl]-9H-purine-6-base amine by with embodiment 247 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 8.44 (s, 1H), 7.83 (d, J=7.0Hz, 1H), 7.43 (t, J=7.9Hz, 1H), 7.38 (d, J=7.0Hz, 1H), 5.70 (bs, 2H, NH ₂), 4.47 (t, J=5.95Hz, 2H, CH ₂), 3.06 (t, J=5.95Hz, 2H, CH ₂), 2.55 (t, J=8.19Hz, 2H, CH ₂), 1.22 (t, J=8.19Hz, 2H, CH ₂), 0.83 (s, 9H, 3CH ₃) .HPLC:RT=5.558 (method: 5-100-7).

Embodiment 269 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(3-morpholine-4-base-propyl group)-9H-purine-6-base amine (269)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-(3-morpholine-4-base-propyl group)-9H-purine-6-base amine by with embodiment 247 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 1.30 (m, 2H), 2.22 (m, 4H), 2.40 (m, 2H), 3.62 (m, 4H), 4.48 (t, 2H), 5.70 (s, 2H), 7.37 (d, 1H), 7.44 (t, 1H), 7.83 (d, 1H), 8.44 (s, 1H) .HPLC:RT=4.77min (methods: 5-100-7).

Embodiment 270 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-morpholine-4-base-ethyl)-9H-purine-6-base amine (270)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-morpholine-4-base-ethyl)-9H-purine-6-base amine by with embodiment 247 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 2.50 (t, 4H), 2.76 (t, 2H), 3.64 (t, 4H), 4.46 (t, 2H), 5.85 (s, 2H), 7.35 (d, 1H), 7.44 (t, 1H), 7.83 (d, 1H), 8.42 (s, 1H) .HPLC:RT=4.71min (methods: 5-100-7).

Embodiment 271 9-(2-bromo-ethyl)-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (271)

Step 1 8-bromine adenine is as preparation as described in reporting, referring to Collect.Czech.Chem.Commun.2000, and 65,1126-1144.

Step 2 8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine

According to embodiment 232, the identical process that provides in the step 4. ¹H NMR(DMSO)δ 8.23(s，1H)，8.10(t，1H)，7.90(d，1H)，7.82(bs，2H)，7.59(d，1H)。

Step 3 9-(2-bromo-ethyl)-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine

8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (200mg in DMF (10ml) at room temperature, 0.599mmol) and cesium carbonate (292.6mg, 0.898mmol) mixture in add 1,2-two bromo-ethane (168.7mg, 0.898mmol).This reactant mixture at room temperature stirred 16 hours, water (20ml) cancellation then.Precipitate is filtered, and dry under vacuum.Thick material is by the flash chromatography purification, and productive rate is 35%. ¹H NMR (CDCl ₃) δ 3.82 (t, 2H), 4.78 (t, 2H), 5.71 (s, 2H), 7.36 (d, 1H), 7.42 (t, 1H), 7.84 (d, 1H), 8.45 (s, 1H) .HPLC:RT=6.05min (methods: 5-100-7).

Embodiment 272 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-chloro-ethyl)-9H-purine-6-base amine (272)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-chloro-ethyl)-9H-purine-6-base amine by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 3.92 (t, 2H), 4.72 (t, 2H), 5.86 (s, 2H), 7.36 (d, 1H), 7.43 (t, 1H), 7.83 (d, 1H), 8.45 (s, 1H) .HPLC:RT=5.93min (methods: 5-100-7).

Embodiment 273 9-(3-bromo-propyl group)-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (273)

9-(3-bromo-propyl group)-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 2.49 (m, 2H), 3.89 (t, 2H), 4.51 (t, 2H), 5.67 (s, 2H), 7.37 (d, 1H), 7.44 (t, 1H), 7.83 (d, 1H), 8.43 (s, 1H) .HPLC:RT=6.261min (methods: 5-100-7).

Embodiment 274 8-(7-chloro-benzothiazole-2-base sulfane base)-9-[2, (2,5-dimethoxy-phenyl)-ethyl]-9H-purine-6-base amine (274)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-[2, (2,5-dimethoxy-phenyl)-ethyl]-9H-purine-6-base amine by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 3.15 (t, 2H), 3.61 (s, 3H), 3.62 (s, 3H), 4.60 (t, 2H), 5.7 (bs, 2H), 6.37 (s, 1H), 6.56 (d, 1H), 6.61 (d, 1H), 7.31 (d, 1H), 7.39 (t, 1H), 7.77 (d, 1H), 8.46 (s, 1H); HPLC:RT=6.515min (method: 5-100-7).

Embodiment 275 9-fourth-2-alkynyl-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (275)

9-fourth-2-alkynyl-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 1.54 (s, 3H), 5.09 (t, 2H), 6.00 (bs, 2H), 7.36 (d, 1H), 7.44 (t, 1H), 7.86 (d, 1H), 8.47 (s, 1H); HPLC:RT=5.964min (method: 5-100-7).

Embodiment 276 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(3,4,4-three fluoro-fourth-3-thiazolinyl)-9H-purine-6-base amine (276)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-(3,4,4-three fluoro-fourth-3-thiazolinyl)-9H-purine-6-base amine be by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 2.92 (m, 2H), 4.59 (t, 2H), 5.90 (bs, 2H), 7.35 (d, 1H), 7.44 (t, 1H), 7.84 (d, 1H), 8.45 (s, 1H) .HPLC:RT=6.29min (methods: 5-100-7).

Embodiment 277 6-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-own nitrile (277)

6-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-own nitrile by with embodiment 271 in the identical method preparation described. ¹HNMR (CDCl ₃) δ 1.52 (m, 2H), 1.72 (m, 2H), 1.94 (m, 2H), 2.33 (t, 2H), 4.41 (t, 2H), 7.42 (d, 1H), 7.47 (t, 1H), 7.86 (d, 1H), 8.40 (s, 1H) .HPLC:RT=5.879min (methods: 5-100-7).

Embodiment 278 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(3-methyl-Ding-3-thiazolinyl)-9H-purine-6-base amine (278)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-(3-methyl-Ding-3-thiazolinyl)-9H-purine-6-base amine by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 1.55 (s, 3H), 1.81 (s, 3H), 4.94 (d, 2H), 5.25 (t, 1H), 5.81 (bs, 2H), 7.35 (d, 1H), 7.44 (t, 1H), 7.84 (d, 1H), 8.45 (s, 1H) .HPLC:RT=6.524min (methods: 5-100-7).

Embodiment 279 4-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-butyronitrile (279)

4-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-butyronitrile by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 2.31 (m, 2H), 2.46 (t, 2H), 4.50 (t, 2H), 5.74 (bs, 2H), 7.36 (d, 1H), 7.43 (t, 1H), 7.83 (d, 1H), 8.44 (s, 1H) .HPLC:RT=5.516min (methods: 5-100-7).

Embodiment 280 8-(7-chloro-benzothiazole-2-base sulfane base)-9-oneself-5-alkynyl-9H-purine-6-base amine (280)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-oneself-5-alkynyl-9H-purine-6-base amine by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 1.57 (m, 2H), 1.84 (t, 2H), 2.18 (m, 2H), 2.22 (m, 2H), 4.39 (t, 2H), 5.71 (s, 2H), 7.36 (d, 1H), 7.44 (t, 1H), 7.84 (d, 1H), 8.45 (s, 1H) .HPLC:RT=6.276min (methods: 5-100-7).

Embodiment 281 8-(7-chloro-benzothiazole-2-base sulfane base)-9-[3-(tetrahydrochysene-furan-2-yl)-propyl group]-9H-purine-6-base amine (281)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-[3-(tetrahydrochysene-furan-2-yl)-propyl group]-9H-purine-6-base amine by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 1.48 (m, 4H), 2.21 (m, 2H), 3.42 (m, 2H), 3.81 (m, 2H), 4.52 (m, 3H), 5.92 (s, 2H), 7.37 (d, 1H), 7.44 (t, 1H), 7.83 (d, 1H), 8.44 (s, 1H) .HPLC:RT=6.395min (methods: 5-100-7).

Embodiment 282 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(tetrahydrochysene-furan-2-ylmethyl)-9H-purine-6-base amine (282)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-(tetrahydrochysene-furan-2-ylmethyl)-9H-purine-6-base amine by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 1.68 (m, 4H), 3.21 (t, 1H), 3.68 (m, 1H), 3.78 (d, 1H), 4.37 (d, 2H), 5.78 (s, 2H), 7.37 (d, 1H), 7.44 (t, 1H), 7.83 (d, 1H), 8.44 (s, 1H) .HPLC:RT=6.404min (methods: 5-100-7).

Embodiment 283 8-(7-chloro-benzothiazole-2-base sulfane base)-9-[2-(2-ethyoxyl-ethyoxyl-)-ethyl]-9H-purine-6-base amine (283)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-[2-(2-ethyoxyl-ethyoxyl-)-ethyl]-9H-purine-6-base amine by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 1.15 (t, 3H), 3.46 (m, 6H), 3.88 (t, 2H), 4.58 (t, 2H), 5.84 (s, 2H), 7.37 (d, 1H), 7.44 (t, 1H), 7.83 (d, 1H), 8.44 (s, 1H) .HPLC:RT=5.925min (methods: 5-100-7).

Embodiment 284 5-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-valeronitrile (284)

5-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-valeronitrile by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 1.71 (m, 2H) 2.05 (m, 2H), 2.42 (t, 2H), 4.41 (t, 2H), 5.88 (bs, 2H), 7.36 (d, 1H), 7.43 (t, 1H), 7.83 (d, 1H), 8.44 (s, 1H) .HPLC:RT=5.694min (methods: 5-100-7).

Embodiment 285 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-6-base amine (285)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-(4-methoxyl group-3,5-dimethyl-pyridine-2-ylmethyl)-9H-purine-6-base amine by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 2.08 (s, 3H), 2.35 (s, 3H), 3.71 (s, 3H), 5.60 (s, 2H), 5.82 (bs, 2H), 7.31 (d, 1H), 7.39 (t, 1H), 7.77 (d, 1H), 8.45 (s, 1H) .HPLC:RT=5.570min (methods: 5-100-7).

Embodiment 286 8-(7-chloro-benzothiazole-2-base sulfane base)-9-Propargyl-9H-purine-6-base amine (286)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-Propargyl-9H-purine-6-base amine by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 8.49 (s, 1H), 7.84 (d, J=1.08Hz, 1H), 7.46 (t, J=8.4Hz, 1H), 7.36 (d, J=1.08Hz, 1H), 5.83 (bs, 2H, NH ₂), 5.15 (s, 2H, CH ₂), 2.25 (s, 1H, CH) .HPLC:RT=5.700 (methods: 5-100-7).

Embodiment 287 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-piperidines-1-base-ethyl]-9H-purine-6-base amine (287)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-piperidines-1-base-ethyl)-9H-purine-6-base amine by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 8.44 (s, 1H), 7.83 (d, J=7.0Hz, 1H), 7.43 (t, J=7.9Hz, 1H), 7.38 (d, J=7.0Hz, 1H), 5.70 (bs, 2H, NH ₂), 4.44 (t, J=5.95Hz, 2H, CH ₂), 2.68 (t, J=5.95Hz, 2H, CH ₂), 2.42 (t, J=8.19Hz, 4H, 2CH ₂), 1.57 (t, J=8.19Hz, 4H, 2CH ₂), 1.40 (m, 2H, CH2) .HPLC:RT=4.923 (methods: 5-100-7).

Embodiment 288 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-methyl sulfophenyl-ethyl)-9H-purine-6-base amine (288)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-methyl sulfophenyl-ethyl)-9H-purine-6-base amine by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 2.15 (s, 3H), 2.99 (t, 2H), 4.57 (t, 2H), 5.72 (s, 2H), 7.35 (d, 1H), 7.43 (t, 1H), 7.84 (d, 1H), 8.43 (s, 1H) .HPLC:RT=6.04min (methods: 5-100-7).

Embodiment 289 3-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-9-yl]-propyl group }-diethyl phosphonate (289)

{ 3-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-9-yl]-propyl group }-diethyl phosphonate by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 8.43 (s, 1H), 7.83 (d, J=7.0Hz, 1H), 7.43 (t, J=7.9Hz, 1H), 7.38 (d, J=7.0Hz, 1H), 5.80 (bs, 2H, NH ₂), 4.45 (t, J=7.23Hz, 2H, CH ₂), 4.04 (m, 4H, 2CH ₂), 2.21 (m, 2H, CH ₂), 1.35 (m, 2H, CH ₂), 1.26 (t, J=7.06Hz, 6H, 2CH ₃) .HPLC:RT=5.696 (method: 5-100-7).

Embodiment 290 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-ethyl sulfane base-ethyl)-9H-purine-6-base amine (290)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-ethyl sulfane base-ethyl)-9H-purine-6-base amine by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 1.21 (t, 3H), 2.58 (m, 2H), 3.00 (t, 2H), 4.57 (t, 2H), 5.72 (s, 2H), 7.35 (d, 1H), 7.43 (t, 1H), 7.84 (d, 1H), 8.43 (s, 1H) .HPLC:RT=6.34min (methods: 5-100-7).

Embodiment 291 phosphoric acid 3-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-9-yl]-propyl ester diethylester (291)

Phosphoric acid 3-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-9-yl]-the propyl ester diethylester by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 8.43 (s, 1H), 7.83 (d, J=7.0Hz, 1H), 7.43 (t, J=7.9Hz, 1H), 7.38 (d, J=7.0Hz, 1H), 5.80 (bs, 2H, NH ₂), 4.50 (t, J=7.23Hz, 2H, CH ₂), 4.12 (m, 6H, 3CH ₂), 2.30 (m, 2H, CH ₂), 1.32 (t, J=7.06Hz, 6H, 2CH ₃) .HPLC:RT=5.834 (method: 5-100-7).

Embodiment 292 phosphoric acid 2-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-ester is two-and (2-chloro-ethyl ester) (292)

Phosphoric acid 2-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-ester is two-(2-chloro-ethyl ester) by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 8.43 (s, 1H), 7.83 (d, J=7.0Hz, 1H), 7.43 (t, J=7.9Hz, 1H), 7.38 (d, J=7.0Hz, 1H), 5.80 (bs, 2H, NH ₂), 4.70 (t, J=7.23Hz, 2H, CH ₂), 4.54 (t, J=7.23Hz, 2H, CH ₂), 4.19 (m, 4H, 2CH ₂), 3.62 (t, J=7.06Hz, 4H2CH ₂) .HPLC:RT=5.909 (method: 5-100-7).

Embodiment 293 3-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-acrylic }-diethyl phosphonate (293)

{ 3-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-acrylic }-diethyl phosphonate by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 8.43 (s, 1H), 7.83 (d, J=7.0Hz, 1H), 7.43 (t, J=7.9Hz, 1H), 7.38 (d, J=7.0Hz, 1H), 6.85 (t, J=8.0Hz, 1H, CH), 5.86 (bs, 2H, NH ₂), 5.56 (t, J=8.0Hz, 1H, CH), 5.13 (t, J=7.23Hz, 2H, CH ₂), 3.99 (m, 4H, 2CH ₂), 1.26 (t, J=7.06Hz, 6H, 2CH ₃) .HPLC:RT=5.622 (method: 5-100-7).

Embodiment 294 phosphoric acid 2-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-9-yl]-ethyl ester diethylester (294)

Phosphoric acid 2-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-9-yl]-the ethyl ester diethylester by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 8.43 (s, 1H), 7.83 (d, J=7.0Hz, 1H), 7.43 (t, J=7.9Hz, 1H), 7.38 (d, J=7.0Hz, 1H), 5.80 (bs, 2H, NH ₂), 4.66 (t, J=7.23Hz, 2H, CH ₂), 4.48 (m, 2H, CH ₂), 3.99 (m, 4H, 2CH ₂), 1.22 (t, J=7.06Hz, 6H, 2CH ₃) .HPLC:RT=5.713 (method: 5-100-7).

Embodiment 295 8-(7-chloro-benzothiazole-2-base sulfane base)-9-methyl-9H-purine-6-base amine (295)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-methyl-9H-purine-6-base amine by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 3.91 (s, 3H), 5.76 (s, 2H, NH ₂), 7.36 (d, 1H), 7.45 (t, 1H), 7.83 (d, 1H), 8.46 (s, 1H) .HPLC:RT=5.51min (methods: 5-100-7).

Embodiment 296 4-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-Ding-2-ketone (296)

4-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-Ding-2-ketone by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 2.1 (s, 3H), 3.10 (m, 2H), 4.61 (m, 2H), 5.84 (s, 2H), 7.35 (d, 1H), 7.43 (t, 1H), 7.84 (d, 1H), 8.43 (s, 1H) .HPLC:RT=5.60min (methods: 5-100-7).

Embodiment 297 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-ethylsulfinyl-1 base-ethyl)-9H-purine-6-base amine (297)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-ethylsulfinyl-1 base-ethyl)-9H-purine-6-base amine from 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-ethyl sulfane base-ethyl)-9H-purine-6-base amine (referring to embodiment 290) by at room temperature among HOAC, using H ₂O ₂Handle and preparation. ¹H NMR (CDCl ₃) δ 1.29 (t, 3H), 2.75 (m, 2H), 3.20 (m, 1H), 3.33 (m, 1H), 4.80 (m, 1H), 4.88 (m, 1H), 6.11 (s, 2H), 7.35 (d, 1H), 7.43 (t, 1H), 7.84 (d, 1H), 8.43 (s, 1H) .HPLC:RT=5.05min (methods: 5-100-7).

Embodiment 298 4-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-Ding-2-thioketone (298)

4-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-Ding-2-thioketone by with embodiment 297 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 2.6 (s, 3H), 3.22 (m, 1H), 3.43 (m, 1H), 4.81 (m, 1H), 4.92 (m, 1H), 5.77 (s, 2H), 7.35 (d, 1H), 7.43 (t, 1H), 7.84 (d, 1H), 8.63 (s, 1H) .HPLC:RT=4.87min (methods: 5-100-7).

Embodiment 299 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-ethylsulfonyl-ethyl)-9H-purine-6-base amine (299)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-ethylsulfonyl-ethyl)-9H-purine-6-base amine passes through at room temperature at CH from 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-ethyl sulfane base-ethyl)-9H-purine-6-base amine (referring to embodiment 290) ₂Cl ₂In handle and preparation with mCPBA. ¹H NMR (CDCl ₃) δ 1.37 (t, 3H), 3.00 (m, 2H), 3.28 (t, 2H), 4.86 (t, 2H), 5.76 (s, 2H), 7.35 (d, 1H), 7.43 (t, 1H), 7.84 (d, 1H), 8.43 (s, 1H) .HPLC:RT=5.39min (methods: 5-100-7).

Embodiment 300 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-mesyl-ethyl)-9H-purine-6-base amine (300)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-mesyl-ethyl)-9H-purine-6-base amine by with embodiment 299 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 2.96 (s, 3H), 3.76 (t, 2H), 4.87 (t, 2H), 5.76 (s, 2H), 7.37 (d, 1H), 7.43 (t, 1H), 7.84 (d, 1H), 8.43 (s, 1H) .HPLC:RT=5.30min (methods: 5-100-7).

Embodiment 301 [2-(6-amino-9-butyl-9H-purine-8-base sulfane base)-benzothiazole-7-yl]-methanol (301)

[2-(6-amino-9-butyl-9H-purine-8-base sulfane base)-benzothiazole-7-yl]-methanol passes through to prepare in 15 minutes with the HCl processing among MeOH under 65 ℃ from 9-butyl-8-(7-methoxymethoxy methyl-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (187). ¹H NMR (CDCl ₃) δ 0.90 (t, 3H), 1.33 (m, 2H), 1.84 (m, 2H), 4.33 (t, 2H), 4.89 (s, 2H), 6.19 (bs, 2H), 7.29 (d, 1H), 7.43 (t, 1H), 7.87 (d, 1H), 8.42 (s, 1H) .HPLC:RT=5.36min (methods: 5-100-7).

Embodiment 302 9-[2-isopropyl amino-ethyls]-8-(7-methoxyl group-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (302)

9-[2-isopropyl amino-ethyl]-8-(7-methoxyl group-benzothiazole-2-base sulfane base)-9H-purine-6-base amine by with embodiment 247 in the identical method preparation described. ¹H NMR (CD ₃OD) δ 8.29 (s, 1H), 7.50 (d, J=1.08Hz, 1H), 7.48 (t, J=8.4Hz, 1H), 6.99 (d, J=1.08Hz, 1H), 4.50 (t, J=5.09,2H, CH2), 3.97 (s, 3H, CH ₃), 3.07 (t, J=5.09,2H, CH ₂), 2.87 (m, 1H, CH), 1.00 (d, J=6.32,6H, 2CH ₃) .HPLC:RT=4.575 (method: 5-100-7).

Embodiment 303 9-[2-tert-butyl group amino-ethyls]-8-(7-methoxyl group-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (303)

9-[2-tert-butyl group amino-ethyl]-8-(7-methoxyl group-benzothiazole-2-base sulfane base)-9H-purine-6-base amine by with embodiment 247 in the identical method preparation described. ¹H NMR (CD ₃OD) δ 8.29 (s, 1H), 7.50 (d, J=1.08Hz, 1H), 7.48 (t, J=8.4Hz, 1H), 6.99 (d, J=1.08Hz, 1H), 4.47 (t, J=5.09,2H, CH2), 3.97 (s, 3H, CH ₃), 3.07 (t, J=5.09,2H, CH ₂), 2.87 (m, 1H, CH), 1.02 (s, 9H, 3CH ₃) .HPLC:RT=4.727 (method: 5-100-7).

Embodiment 304 9-(2-isobutylamino-ethyl)-8-(7-methoxyl group-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (304)

9-(2-isobutylamino-ethyl)-8-(7-methoxyl group-benzothiazole-2-base sulfane base)-9H-purine-6-base amine by with embodiment 247 in the identical method preparation described. ¹H NMR (CD ₃OD) δ 8.29 (s, 1H), 7.50 (d, J=1.08Hz, 1H), 7.48 (t, J=8.4Hz, 1H), 6.99 (d, J=1.08Hz, 1H), 4.507 (t, J=5.09,2H, CH ₂), 3.97 (s, 3H, CH ₃), 3.02 (t, J=5.09,2H, CH ₂), 2.38 (d, J=6.89,2H, CH ₂), 1.64 (m, 1H, CH), 0.83 (s, 6H, 2CH ₃) .HPLC:RT=4.869 (method: 5-100-7).

Embodiment 305 6-amino-8-(7-methyl-benzothiazole-2-base sulfane base)-purine-9-yl]-third-alcohol (305)

3-[6-amino-8-(7-methyl-benzothiazole-2-base sulfane base)-purine-9-yl]-third-alcohol by with embodiment 244 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 1.91 (m, 2H), 2.50 (s, 3H), 3.45 (t, 2H), 4.54 (t, 2H), 5.78 (bs, 2H), 7.02 (d, 1H), 7.40 (t, 1H), 7.79 (d, 1H), 8.42 (s, 1H); HPLC:RT=4.96min (method: 5-100-7).

Embodiment 306 9-fourth-3-thiazolinyl-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine (306)

9-fourth-3-thiazolinyl-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine by with embodiment 232 in the identical method preparation described. ¹H NMR (CDCl ₃)

2.14 (m, 2H), 4.36 (t, 2H), 5.04 (m, 2H), 5.74 (m, 1H), 5.90 (bs, 2H), 7.35 (d, 1H), 7.44 (t, 1H), 7.84 (d, 1H), 8.45 (s, 1H); HPLC:RT=6.185min (method: 5-100-7).

Embodiment 307 8-(7-chloro-benzothiazole-2-base sulfane base)-9-penta-4-thiazolinyl-9H-purine-6-base amine (307)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-penta-4-thiazolinyl-9H-purine-6-base amine by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 1.97 (m, 2H), 2.14 (m, 2H), 4.36 (t, 2H), 5.04 (m, 2H), 5.74 (m, 1H), 5.90 (bs, 2H), 7.35 (d, 1H), 7.44 (t, 1H), 7.84 (d, 1H), 8.45 (s, 1H); HPLC:RT=6.488min (method: 5-100-7).

Embodiment 308 8-(7-chloro-benzothiazole-2-base sulfane base)-9-oneself-5-thiazolinyl-9H-purine-6-base amine (308)

8-(7-chloro-benzothiazole-2-base sulfane base)-9-oneself-5-thiazolinyl-9H-purine-6-base amine by with embodiment 271 in the identical method preparation described. ¹H NMR (CDCl ₃) δ 1.41 (m, 2H), 1.83 (m, 2H), 2.02 (m, 2H), 4.33 (t, 2H), 4.92 (m2H), 5.64 (m, 1H), 5.75 (bs, 2H), 7.33 (d, 1H), 7.42 (t, 1H), 7.82 (d, 1H), 8.42 (s, 1H); HPLC:RT=6.761min (method: 5-100-7).

Embodiment 309 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine (309)

The preparation of 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-penta-4-alkynyl-9H-purine-6-base amine is described in other place.(referring to .JMed.Chem.2005 such as .WO such as Kasibhatla 3037860,2003 and Llauger, 48,2892-2905).

Embodiment 310 9-butyl-8-(3-methoxyl group-benzyl)-9H-purine-6-base amine (310)

Step 1 N-(5,6-diaminourea-pyrimidine-4-yl)-2-(3-methoxyl group-phenyl)-hydrochloric acid acetamide

Under 70 ℃ with 4,5, the 6-Triaminopyrimidine (6.25g, 50mmol) be dissolved in the N-N-methyl-2-2-pyrrolidone N-(NMP, 70mL).This solution is cooled to room temperature, and handles 3 hours with 3-methoxybenzene chloroacetic chloride (9.2g, 50mmol, 1.0 equivalents) down at 50 ℃, so the expectation product of HCl salt form is settled out.The collecting precipitation thing, with EtOAc and washing with acetone, and dry product (15.2g, 98%) to obtain the white solid form.HPLC purity: 97.4%.t _R.mp=286-288 ℃ of=4.13min (condition I). ¹H NMR (DMSO-d ₆) δ 9.22 (s, 1H), 8.20 (s, 1H), 6.75-7.58 (br.s, 4H), 7.21 (t, J=7.9Hz, 1H), 6.95 (d, J=1.3Hz, 1H), 6.90 (d, J=7.6Hz, 1H), 6.80 (dd, J=7.6 ﹠amp; 1.3Hz, 1H), 3.74 (s, 2H), 3.73 (s, 3H). ¹³C NMR (DMSO-d ₆) δ 170.9,159.4,156.4 (2C), 147.9,137.7,129.3,122.8,116.2,112.2,93.9,55.4,41.8

Step 2 8-(3-methoxyl group-benzyl)-9H-purine-6-base amine

Rough N-(5,6-diaminourea-pyrimidine-4-yl)-2-(3-methoxyl group-phenyl)-hydrochloric acid acetamide (17.6g, 57mmol) and MeONa (12.3g, 227mmol, refluxed 2 hours 4.0 n-BuOH equivalent) (150mL) solution is heated, be cooled to room temperature, and neutralize with HCl 2M.Add saline, it obtains two-phase mixture.Concentrated organic layer obtains the title compound (10.7g, 75%) of solid form.t _R.mp=252-254 ℃ of=4.70min (condition II) ¹H NMR (DMSO-d ₆) δ 8.06 (s, 1H), 7.43 (br.s, 1H), 7.21 (t, J=7.9Hz, 1H), 7.05 (s, 2H), 6.93 (s, 1H), 6.87 (d, J=7.6Hz, 1H), 6.79 (dd, J=8.1 ﹠amp; 2.3Hz, 1H), 4.09 (s, 2H), 3.73 (s, 3H). ¹³C NMR (DMSO-d ₆) δ 159.8,155.5,152.3,151.6,150.8,139.3,130.0,121.4,119.0.115.0,112.4,55.5,35.5.

Step 3 8-(3-methoxyl group-benzyl)-9H-purine-6-base amine (0.50g, 2.2mmol), BuI (0.30mL, 2.65mmol, 1.2 equivalents), Cs ₂CO ₃(1.43g, 4.4mmol, 2.0 equivalents) and mixture (2.5mL) at room temperature stirred 16 hours.Flash chromatography (MeOH:CH ₂Cl ₂5:95) obtain the title compound (370mg, 54%) of white solid form.HPLC purity: 91.0%.t _R.mp=163-165 ℃ of=6.92min (condition II). ¹HNMR (CDCl ₃: CD ₃OD 5:1) δ 8.13 (s, 1H), 7.16 (t, J=7.9Hz, 1H), 6.73-6.67 (m, 3H), 4.13 (s, 2H), 3.95 (t, J=7.7Hz, 2H), 3.68 (s, 3H), 1.48 (quintet, J=7.7Hz, 2H), 1.20 (sext., J=7.5Hz, 2H), 0.78 (t, J=7.4Hz, 3H). ¹³C NMR (CDCl ₃: CD ₃OD 5:1) δ 159.9,154.7,152.0,150.9,150.7,136.6,129.9,120.8,117.8,114.5,112.3,55.07,42.9,34.2,31.5,19.8,13.4.HRMS: calculate C ₁₇H ₂₂N ₅O (MH) ⁺M/z 312.1819, find 312.1817.

Embodiment 311 9-butyl-8-(2-chloro-5-methoxyl group-benzyl)-9H-purine-6-base amine (311)

9-butyl-8-(3-methoxyl group-benzyl)-9H-purine-(100mg, THF 0.32mmol) (4mL) solution is at room temperature used SO to 6-base amine (310) ₂Cl ₂(78 μ L, 0.96mmol, 3.0 equivalents) were handled 2 hours.Separation and purification operation and preparation type TLC (MeOH:CH ₂Cl ₂10:90) obtain title compound (60.2mg, 54%).Mp=138-139 ℃ of .HPLC purity: 92.4%.t _R=7.77min (condition II). ¹H NMR (CDCl ₃) δ 8.31 (s, 1H), 7.30 (d, J=8.8Hz, 1H), 6.75 (dd, J=8.8 ﹠amp; 3.0Hz, 1H), 6.67 (d, J=3.0Hz, 1H), 6.26 (s, 2H), 4.32 (s, 2H), 4.04 (t, J=7.7Hz, 2H), 3.67 (s, 3H), 1.62 (quintet, J=7.7Hz, 2H), 1.30 (sextet, J=7.5Hz, 2H), 0.87 (t, J=7.4Hz, 3H). ¹³C NMR (CDCl ₃) δ 157.1,153.6,150.9,149.8,148.4,133.1,128.8,123.4,117.3,114.7,112.5,54.0,41.5,30.4,30.2,18.6,12.2.HRMS: calculate C ₁₇H ₂₁N ₅ClO (MH) ⁺M/z 346.1429, find 346.1426

[0078] the test biology of chemical compound

[0079] embodiment 312 biotinylation geldanamycins are to the CBA based on fluorescence of the Hsp90 of purification

This test directly measurement biotinylation geldanamycin (Hsp90 of biotin-GM) and purification combines, and measures chemical compound thus to the competitiveness in conjunction with Hsp90.

(CA USA) by being applied on the 96-orifice plate at 37 ℃ of following incubations in 1 hour for Stressgen BiotechnologiesCorp., San Diego from the natural Hsp90 albumen (mixture of α and β) of the purification of HeLa cell.Remove Hsp90 and this hole washed twice in 1 * PBS (phosphate buffer) buffer of uncoated.Then biotin-GM is joined in the hole, reaction is further 37 ℃ of following incubations 1 hour.The hole adds 20ug/ml streptavidin-rhodophyll then with 1 * PBS washed twice, and 37 ℃ of following incubations 1 hour.1 * PBS washed twice is used in the hole once more.In Gemini spectrofluorophotometer (Molecular Devices), use 485nm exciting light and 580nm emission photo measure fluorescence then.

[0080] embodiment 313 screens the The compounds of this invention with HSP90 binding ability

Chemical compound in the following table prepares as mentioned above, and estimates the HSP90 binding ability based on above-mentioned test (embodiment 312).

Embodiment #	Chemical compound #	IC50μM
Embodiment #	Chemical compound #	IC50μM	1.1	1	10
2.1	2	2	1.1	1	10
2.1	2	2	2.2	3	1.1
2.4	5	2.0	2.2	3	1.1
2.4	5	2.0	3.2	8	6
3.4	10	2.8	3.2	8	6
3.4	10	2.8	4.7	26	1.1
4.8	27	0.9	4.7	26	1.1
4.8	27	0.9	4.9	28	2.3
4.10	29	0.9	4.9	28	2.3
4.10	29	0.9	9.4	44	1.5
9.5	45	1.8	9.4	44	1.5
9.5	45	1.8	9.6	46	0.9
9.7	47	0.8	9.6	46	0.9
9.7	47	0.8	11.3	57	4.0
11.10	63	1.3	11.3	57	4.0

[0081] embodiment 314 HER2 inhibition tests

The MCF-7 cell is seeded in 24 orifice plates with the density in about 30,000 cell number/add hole, and is allowed to condition among the DMEM that is supplemented with 10%FBS growth 16 hours.Medicine is added into the concentration of 100 μ M to 0.1 μ M then.Cell was by other 24 hours of incubation.The cell of drug treating and untreated control cells be by trypsinization, and at room temperature with the anti-Her-2neu Ab that is combined with rhodophyll (BectonDickinson, the San Jose CA of 0.25 μ g/ml concentration; Classification number 340552) or be combined with non-specific contrast IgGl (Becton Dickinson, the San Jose CA of rhodophyll; Classification number numbers 340761) incubation is 15 minutes.Sample is analyzed with the FACS Calibur flow cytometer (Becton Dickinson) that disposes argon ion laser, and the 488nm light of described argon ion laser emission 15mW is to excite the rhodophyll fluorochrome.Each sample collection 10,000 result.Produce a fluorescence block diagram, and measure the average fluorescent strength (mfi) of each sample with Cellquest software.Background is defined as the mfi that produces from the cell with contrast IgG incubation, and from being deducted painted each sample of HER-2/neuAb.The degraded percentage ratio of Her-2 is by following calculating:

%Her-2 degraded=(mfi HER-2 sample)/(the untreated cell of mfi HER-2) * 100

[0082] embodiment 315 screenings have the The compounds of this invention of Her-2 degradation capability

Chemical compound in the following table prepares as mentioned above, and estimates the Her-2 degradation capability based on above-mentioned test (embodiment 314).

Inhibition concentration 50 (the IC of this test ₅₀) be Her 2 expression (albumen) necessary concentration of degraded 50%.

Embodiment #	Chemical compound #	IC50μM
Embodiment #	Chemical compound #	IC50μM	1.1	1	6.0
2.1	2	0.6	1.1	1	6.0
2.1	2	0.6	2.2	3	0.5
2.4	5	1.0	2.2	3	0.5
2.4	5	1.0	3.2	8	1.5
3.4	10	1.5	3.2	8	1.5
3.4	10	1.5	4.7	26	1.5
4.8	27	0.8	4.7	26	1.5
4.8	27	0.8	4.9	28	1.0
4.10	29	0.8	4.9	28	1.0
4.10	29	0.8	9.4	44	1.5
9.5	45	2.0	9.4	44	1.5
9.5	45	2.0	9.6	46	0.3
9.7	47	0.3	9.6	46	0.3
9.7	47	0.3	11.3	57	1.4
11.10	63	0.7	11.3	57	1.4

The optimization of compound activity

[0083] one of strategy that improves purine radicals Hsp90 inhibitor activity is the characteristic of optimizing the substituent group on the 8-benzyladenine phenyl ring independently and crossing over the joint between phenyl ring and the purine ring.Optimize the preferred structure element that produces for two kinds and can combine then, and select to have the chemical compound that to accept the pharmacy characteristic.This plan makes us make full use of the method for the known 8-of preparation benzyladenine, is proved to be necessary although improve in some cases.

[0084] embodiment 316 HER-2 degraded test

The effectiveness of these chemical compounds is estimated with HER-2 degraded test, described HER-2 test be described in other place (Le Brazidec et.al.J.Med.Chem.2004,47,3865-3873).Briefly, chemical compound MCF-7 cell---breast cancer cell line of on the surface dielectric level of HER-2 receptor, expressing---incubation 16 hours, described HER-2 receptor is Hsp90 client.The HER-2 degraded is induced in the inhibition of Hsp90, and it is monitored with the antibody of rhodophyll labelling and the combination of flow cytometer.Because 17-AAG as one man provides the HER-2 IC of 12.9 ± 0.3nM ₅₀, this test has the height repeatability, and wherein error is meant mean standard deviation (SEM).

[0085] check of substituent effect on 317 pairs of phenyl ring of embodiment

2,5-dimethoxy substituent group form is than prototype 3,4, and 5-trimethoxy form has bigger effectiveness.Replace the 2-MeO group to reduce activity a little with Cl, but replace it to cause active increase with Br or I.Studied the effect of joint.Do not have activity with NH or O as the chemical compound of joint, and be considered to have only CH ₂Joint can be tolerated.Yet, behind the introducing S joint, observe sulphur atom and be better than primary CH ₂Joint.

Compound number L X HER-2 IC ₅₀[μ M]

PU3 3a CH ₂3,4,5-three MeO 40

18 CH ₂2,5-two MeO 12

311 12b CH ₂ 2-Cl，5-MeO 20

23 12c CH ₂ 2-Br，5-MeO 8.0

20 12d CH ₂ 2-I，5-MeO 5.0

43 18 S 2,5-two MeO 3.5

At least three of all value representations are the meansigma methods of observation independently.

Standard error of mean (SEM) is the 6-11% of meansigma methods.

[0086] check of the effect of embodiment 318 N (9) side chain

N (9) side chain then is optimized, and filters out more than 100 2, the analog of 5-dimethoxy-benzyl adduct.The high-isoprene base side chain is as the impartial optional form appearance of disclosed penta-4-alkynyl side chain, and two analog have HER-2 IC ₅₀=1.5 μ M.Therefore, (S-) and after side chain (high-isoprene base or penta-4-alkynyl) is optimized, we have checked these preferred structure combination of features to benzene ring substitution group (2-iodo-5-methoxyl group), joint respectively.High-isoprene base analog has similar effectiveness (HER-2 IC with penta-4-alkynyl analog ₅₀≈ 0.3 μ M).Yet the substituent adding of 2-F on the adenine ring---known favourable operation in 8-benzyladenine series brings extra activity for 8-sulfane base system row.

Entry number X R HER-2 IC ₅₀[μ M]

309 4 H, penta-4-alkynyl 0.28

46 23 H high-isoprene bases 0.37

68 28 F, penta-4-alkynyl 0.36

At least three of all value representations are the meansigma methods of observation independently.Standard error of mean (SEM) is the 6-11% of meansigma methods.

[0087] although these chemical compounds show to render a service than the Hsp90 inhibitor of previous report to be improved, they are proved poorly water-soluble, especially have the substituent chemical compound of 2-iodine.This has hindered their preparation, and makes that they can not be fully by oral utilization.Therefore we attempt in N (9) side chain at this inhibitor in conjunction with ionizable amino.Amino introducing has not only improved water solublity, and has increased effectiveness.When the amino N atom is separated with purine ring by 2 or 3 MU (methylene unit) and further replaced by big alkyl group, obtain maximum effectiveness.Active maximum chemical compound is proved to be tert-butylamine (HER-2 IC in 3 atom joint series ₅₀=140 ± 15nM), and in 2 atom joint series neopentyl amine (HER-2 IC ₅₀=90 ± 10nM) demonstrate best activity.

[0088] check of embodiment 319 amine derivative cell growth inhibiting abilities

Adopt previously described cell proliferation quantitative test, tested the cytostatic ability of amine.Briefly, the MCF-7 breast cancer cell is with this test compounds incubation 5 days, and uses MTS (3-(4,5-dimethylthiazole-2-yl)-5-(3-carboxyl methoxyphenyl)-2-(4-sulfane base)-2H-tetrazole) to handle then.The cell that MTS reagent is only had metabolic activities is reduced into first

Dyestuff, and the quantity of living cells is derived by spectrophotometer (490nm).MTS IC ₅₀Be defined as comparing and produce the Hsp90 inhibitor concentration that is lower than 50% new living cells with the culture medium that is untreated.In this test, contrast 17-AAG has the MTS IC of 32 ± 4nm ₅₀, and mean standard deviation (SEM) scope relevant with this test is at the 9-21% of this meansigma methods.8-(sulfane base) adenine is proved cell growth inhibiting, wherein MTS IC ₅₀Typically in the 200-500nm scope, it is greatly in 1 log unit of goldstandard 17-AAG for value.

HER-2 MTS

Chemical compound # numbering n R IC ₅₀[μ M] ^aIC ₅₀[μ M] ^b

PU24FCl 3b 1.7 1.2

309 4 0.29 0.7

108 37 3 Et ₂CH- 0.21 0.2

109 38 3 EtMeCH- 0.21 0.2

126 39 3 i-Pr- 0.18 0.6

95 40 3 t-Bu- 0.14 0.2

89 41 2 i-Bu- 0.10 0.2

132 42 2 t-BuCH ₂- 0.09 0.5

(a) for HER-2 degraded test, at least three of these value representations are the meansigma methods of observation independently, and standard error of mean (SEM) is the 6-11% of meansigma methods.(b) for growth inhibition test, at least three of these value representations are the meansigma methods of observation independently, and standard error of mean (SEM) is the 9-21% of meansigma methods.

[0089] embodiment 320 selective evaluations

Conjugated protein with respect to other ATP, the selectivity of 132 couples of Hsp90 is estimated with series of human kinases (Aurora-A, CHK2, IKK α, MAPK1, MAPK2, MEK1, PDK1, P1k3, PI-3K, c-Raf, c-Src), and wherein neither one is obviously suppressed at 10 μ M.

[0090] embodiment 321 drug disposition dynamic metabolisms

May be except rendeing a service, the amines most important characteristic is the water solublity that they significantly increase.In case be transformed into its H ₃PO ₄Salt, these amine provide fabulous water solublity (〉 10mg/mL), and taken with standard water solution easily.For zooscopy, they are formulated in lecithin/aqueous dispersions.The pharmacokinetics of these chemical compounds is measured in the Balb/C mice.When these chemical compounds are oral with 100mg/kg, reach the peak serum concentration (C between the 4.8 and 9.7 μ g/mL (10-19 μ M) _Max).Peak plasma concentration is at T _Max=30min shows fast Absorption, and drops to after 1-4 hour and detect under the limit value (0.5 μ g/mL, 1 μ M), to obtain 240 to the 680min μ g/mL AUC value of (being equivalent to 8-22 μ Mhr) when combined 4 hours.Dissolubility is significant to the effect of oral bioavailability, and %F from the pentyne derivant＜10% increase to the 14-97% of amine 95,89,108,109,126,132 and 132.When taking with the 10mg/kg intravenous, these amine are eliminated with the speed of 33-131mL/min/kg, and it is (for mice, 90mL/min/kg) very high with respect to total liver blood flow.Yet we do not determine that this removing is because metabolism, distribution or the insufficient cause of protein binding.Analogize by the adenine with structurally associated, it also is possible that inhibitor 95,89,108,109,126,132 is accumulate in this tumor above the concentration in the blood plasma.Although the high definition of their 10mg/kg is removed, the chemical compound 126,95 of 100mg/kg and 132 oral bioavailability rate are equal to or greater than 50%, show that it is saturated removing with 100mg/kg.

The pharmacokinetic parameter of selected amine.

IV parameter PO parameter

Chemical compound # Compound C l T _1/2V _SsC _MaxT _MaxAUC T _1/2%F

[mL/min/kg] [h] [L/kg] [μg/mL] [h] [min·μg/mL] [h] [％]

108 37 69 0.5 2.4 5.8 0.5 590 0.6 42

109 38 33 1.3 3.4 4.8 0.5 380 0.7 28

126 39 62 4.2 22 4.7 0.5 450 1.5 55

95 40 131 1.6 24 6.7 0.5 680 0.9 97

89 41 47 0.3 0.4 6.7 0.5 290 0.3 14

132 4264 0.4 1.6 9.5 0.5 760 0.5 50

These chemical compounds are as H ₃PO ₄Salt is formulated into lecithin/aqueous dispersions, and with (IV) administration of 10mg/kg intravenous or with 100mg/kg oral (PO) administration.In 4 hours, on six time points, measure plasma concentration, and pharmacokinetic parameter adopts non-compartmentation method (non-compartmentalmethod) (WinNonlin Professional, Version 4.1) to measure.T1/2 adopts 3-4 data point to calculate.

[0091] at first we know the Hsp90 inhibitor pharmacology's related concentrations by oral route reach, and these results show that these inhibitor can have Orally active.For instance, C _Max=5.8 μ g/mL (108) are equivalent to the concentration of 12 μ M, and it is than inducing required concentration (the HER-2 IC of HER-2 degraded in the MCF-7 cell ₅₀=0.21 μ M) or suppress required concentration (the MTS IC of MCF-7 hyperplasia ₅₀=0.2 μ M) high about 50 times.The plasma concentration of amine 95,89,108,109,126,132 remains on and detects more than the limit value 1 μ M 1-4 hour.

[0092] induces in the body of embodiment 322 Hsp90 clients degraded

These amine provide the good combination of effectiveness, preparation easiness and bioavailability, but present high relatively removing value in mice.Next we confirm the ability of Hsp90 client's degraded in optional amine 89 inductors.The implanted A549 lung carcinoma cell of nude mice---depend on the cell line that Hsp90 client Raf-1 and Akt carry out cell proliferation, and with single oral dose 89H ₃PO ₄(200mg/kg) administration.Mice was killed at 6,14 or 48 hours, the results tumor, and Hsp90 client's albumen is observed by Western blotting.The level of Hsp90 client HER-2 and pHER-2 significantly descended in the time of 6 hours, and (Fig. 1 a) to reach its normal value then after 24-48 hour gradually.The level of Hsp90 client pAKT and pRaf and downstream kinases pERK descends so not significantly, and minimum at 24 hours.The response characteristic that the up regulation of chaperone Hsp70---Hsp90 suppresses is significant and lasting 24-48 hour.As expect kinases PI-3K---it is not Hsp90 client---be not affected.These pharmacodynamics data have emphasized that target decides the benefit that Hsp90 increases, and are enough to induce the proteic degraded of client in several hours because make tumor cell be exposed to the Hsp90 cell.In case degraded, its normal level is got back in those client's protein requirements 6-48 hour accumulation, even and the Hsp90 inhibitor as 89, removed fast, its pharmacotoxicological effect can continue for a long time.The behavior is significantly different with the behavior of the competitive inhibitors of kinases of most of ATP-, and in a single day the competitive inhibitors of kinases of ATP-is eliminated their target of permission restore funcitons at once.

[0093] embodiment 323 heteroplastic transplantation models

The pharmacodynamics of amine 126 acts on detected in the N78 heteroplastic transplantation model (Fig. 1 b), and wherein N78 is the stomach cancer cell system of expressing high-level HER-2.Mice is with two kinds of different schemes (2 * 100 or 2 * 200mg/kg/ days) oral administration 126H ₃PO ₄Three days, and be killed in 24 hours behind the dosage the last time.With 2 * 200mg/kg/ days oral administration 26H ₃PO ₄Induce Hsp90 client Akt, pAkt, Raf-1, pRaf, cdk6 and pRb degraded to such level, this level can be with the level of peritoneal injection 17-AAG gained be comparable once a day with 90mg/kg/ days.The level of HER-2 and pHER-2 just part reduces, and may reflect such fact---HER-2 and pHER-2 than other Hsp90 client's degraded and express again fast (＜24h).2 * 100mg/kg/ days 126H ₃PO ₄Dosage still degrade effectively Akt, pAkt, Raf-1, pMEK, cdk6 and pRb, but seldom promote or do not promote the degraded of HER-2, pHER-2 and pRaf.

[0094] one of embodiment 324 tumor growths suppresses

Next, it is detected that the ability of the subclass of amine (109,126 and 132) inhibition tumor growth adopts the N87 stomach cancer cell to tie up in the murine heteroplastic transplantation model, and described N87 stomach cancer cell is better than A549 cell line growth and breeding in mice.In same test, chemical compound 109H ₃PO ₄With] 126H ₃PO ₄(Fig. 2 a) for oral administration with 200mg/kg/ days (5 days/week once a day).Two kinds of chemical compounds are all observed tumor growth and are suppressed, but compare 126H ₃PO ₄(p=0.03), 109H ₃PO ₄(p=0.07) has lower significance,statistical.Under these dosage, both do not observed the mortality rate reduction and do not observed the body weight reduction yet.Equally, the active chemical compound 132H of tool in HER-2 degraded test ₃PO ₄With 200mg/kg/ days but have in the routine tests of different schemes (2 * 100mg/kg/ days, 5 days/week) testedly, and also show significant (p=0.02) tumor growth of statistics and suppress, and do not have tangible toxicity.Chaperone Hsp90 is because its center regulating action is the target target of treatment cancer.The proteic degraded of several clients has been induced in the inhibition of Hsp90, and has closed a plurality of carcinogenic paths, and it has influenced a plurality of committed steps (propagation, angiogenesis, acquired immortality, escape apoptosis and transfer) that relate to conversely in tumor takes place.Regulate in the time of various carcinogenesis and should reduce tumor and obtain probability Hsp90 inhibitor resistance.In addition, the existence of the Hsp90 of activated form provides exploitation that malignant cell is had the optionally possibility of inhibitor in the cancerous cell.The compounds of this invention as the Hsp90 inhibitor of purine radicals is optimised, and reaches effectiveness and the 200nM in the growth in vitro inhibition test as 90nM in HER-2 degraded test.In side chain, introduce the amino water solublity that has significantly improved them (to its H ₃PO ₄Salt,〉10mg/kg), this has made things convenient for its preparation to be used for oral administration widely.In mice, the oral bioavailability rate scope of The compounds of this invention is at 14-97%.These amine reach high plasma concentration (C _Max=10-19 μ M; The oral dose of 100mg/kg) still removed (Cl=33-131mL/min/kg rapidly; The intravenous dosages of 10mg/kg).When the mice oral administration (200mg/kg) of A549 tumor xenogeneic graft is arranged to growth, chemical compound of the present invention has been induced the pharmacodynamics response that the Hsp90 inhibitor is expected: the degraded of client's albumen HER-2, pHER-2, pAKT and pRaf and the up regulation of Hsp70.Equally, in murine N87 heteroplastic transplantation model, (but 2 * 200mg/kg/day) induce Hsp90 client's degraded do not cause the degraded of PI-3K the oral administration of The compounds of this invention.In addition, in the N87 model, chemical compound of the present invention has suppressed tumor growth with 200mg/kg/ days oral administrations.These are Hsp90 inhibitor that suppress tumor growth when oral administration of reported first, but high dose is necessary at present.Further work must improve the effectiveness of these chemical compounds and the property removed, and detects optional heteroplastic transplantation model.

[0095] optimization of embodiment 325 benzo thio-purine (benzolothiopurine) analog

The structure-activity relationship data of the benzimidazole thiophanate of replacement have been summarized below for purine analogue.7 '-substituent group is necessary for suppressing activity.When 7 '-Cl (5) was moved to optional site (6 '-Cl (179) or 5 '-Cl (2) or 4 '-Cl (3)) on the aryl rings, active to reduce to 20nM from 200nM so much.In addition, with various parts replace 7 '-position the appreciable impact of Cl-substituent group the degraded of Her-2 render a service.For instance, 7 '-halogen, 7 '-OCH ₃With 7 '-CH ₃180 to 330nM, wherein 7 '-chlorine presents best activity to the benzimidazole thiophanate that replaces for the HER-2 degrading activity scope of purine analogue.With longer alkyl ether as 7 '-OCH ₂CH ₃Replace 7 '-OCH ₃Base has reduced active 500 times.Equally, replace 7 '-Cl with 7 '-H and reduced active 25 times.With respect to single analog that replaces, disubstitution (6 ', 7 '-dichloro) causes 140 times loss of activity.All these results show, the ATP-binding site of Hsp90 is very responsive to the delicate variation of 7 '-position.

The structure-activity relationship of benzothiazole part

Chemical compound #	Chemical compound #	R＂	HER-2 IC ₅₀(nM)
Chemical compound #	Chemical compound #	R＂	HER-2 IC ₅₀(nM)	178	1	H	5000
181	3	4’-Cl	15000	178	1	H	5000
181	3	4’-Cl	15000	180	2	5’-Cl	20000
179	4	6’-Cl	7000	180	2	5’-Cl	20000
179	4	6’-Cl	7000	232	5	7’-Cl	180
171	6	7’-Br	330	232	5	7’-Cl	180
171	6	7’-Br	330	175	7	7’-F	200
172	8	7’-Me	300	175	7	7’-F	200
172	8	7’-Me	300	185	9	7’Cl，6’-Cl	25000
173	10	7’-OCH ₃	190	185	9	7’Cl，6’-Cl	25000
173	10	7’-OCH ₃	190	174	11	7’-OCH ₂CH ₃	100000

[0096] optimization of embodiment 326 9-N-alkyl substituents

The analysis of N-alkyl substituent shows, the chemical property of 9-position joint with and the effect length biological activity.The chemical compound that the 9-position has 2-or 4-carbon joint shows similar activity, even when the various functional groups that comprised alcohol, ester and some amine replace.Increase the alkyl length of said joint and surpass 4 carbon atoms reduction activity.Surprisingly, in these amine substituent groups, compare other amine substituent group, tert-butyl group methylamine is added to 2-carbon joint causes HER-2 degrading activity (35nM) to significantly improve.In addition, the diethyl bound phosphate groups is added to also demonstrate the similar raising of HER-2 degrading activity (30nM) on the 2-carbon alcohol.As if two kinds of carbon joints provide best support.

The structure-activity relationship of 9-N-alkyl position

Chemical compound #	Chemical compound #	R	HER-2
Chemical compound #	Chemical compound #	R	HER-2	229	12	-CH ₂CH ₃	200

231	13	-CH ₂CH ₂CH ₃	250
231	13	-CH ₂CH ₂CH ₃	250	232	5	-CH ₂CH ₂CH ₂CH ₃	180
233	14	-CH ₂CH ₂CH ₂CH ₂CH ₃	700	232	5	-CH ₂CH ₂CH ₂CH ₃	180
233	14	-CH ₂CH ₂CH ₂CH ₂CH ₃	700	244	15	-CH ₂CH ₂OH	300
245	16	-CH ₂CH ₂CH ₂OH	150	244	15	-CH ₂CH ₂OH	300
245	16	-CH ₂CH ₂CH ₂OH	150	246	17	-CH ₂CH ₂CH ₂CH ₂OH	150
241	18	-CH ₂CH ₂O ₂CCH ₃	150	246	17	-CH ₂CH ₂CH ₂CH ₂OH	150
241	18	-CH ₂CH ₂O ₂CCH ₃	150	242	19	-CH ₂CH ₂CH ₂O ₂CCH ₃	90
243	20	-CH ₂CH ₂CH ₂CH ₂O ₂CCH ₃	130	242	19	-CH ₂CH ₂CH ₂O ₂CCH ₃	90
243	20	-CH ₂CH ₂CH ₂CH ₂O ₂CCH ₃	130	204	21	-CH ₂CH ₂PO(OCH ₂CH ₃) ₂	30
284	22	-CH ₂CH ₂CH ₂CH ₂CN	110	204	21	-CH ₂CH ₂PO(OCH ₂CH ₃) ₂	30
284	22	-CH ₂CH ₂CH ₂CH ₂CN	110	270	23	-CH ₂CH ₂-morpholine	250
265	24	-CH ₂CH ₂NHC(CH ₃) ₃	140	270	23	-CH ₂CH ₂-morpholine	250
265	24	-CH ₂CH ₂NHC(CH ₃) ₃	140	247	25	-CH ₂CH ₂NHCH ₂C(CH ₃) ₃	35
264	26	-CH ₂CH ₂NHCHCH ₂CH ₂	110	247	25	-CH ₂CH ₂NHCH ₂C(CH ₃) ₃	35
264	26	-CH ₂CH ₂NHCHCH ₂CH ₂	110	266	27	-CH ₂CH ₂CH ₂NHCH(CH ₃) ₂	170
253	28	-CH ₂CH ₂CH ₂NHC(CH ₃) ₃	150	266	27	-CH ₂CH ₂CH ₂NHCH(CH ₃) ₂	170

[0097] embodiment 327 usefulness pyrido thiazole rings replace benzothiazole

Although benzothiazole compound presents receivable effectiveness as a class in HER-2 degraded test, they are poorly soluble and therefore show and have low oral bioavailability rate in aqueous medium.In the trial of the whole oral bioavailability rate that increases this compounds, we introduce other ionizable part by replacing benzothiazole with the pyrido thiazole.This most of active member's of series HER-2 degrading activity is determined.For the shown SAR data of series, best analog comprises the 2-carbon joint that replaces with the diethyl phosphonate moiety according to benzimidazole thiophanate.

The structure-activity relationship of pyrido thiazole part

	Chemical compound #	R′	R＂	HER-2
	Chemical compound #	R′	R＂	HER-2	207	29	-CH ₂CH ₂CH ₂CH ₃	Br	400
202	30	-CH ₂CH ₂PO(OCH ₂CH ₃) ₂	Br	28	207	29	-CH ₂CH ₂CH ₂CH ₃	Br	400
202	30	-CH ₂CH ₂PO(OCH ₂CH ₃) ₂	Br	28	177	31	-CH ₂CH ₂CH ₂CH ₃	Cl	280
206	32	-CH ₂CH ₂PO(OCH ₂CH ₃) ₂	Cl	30	177	31	-CH ₂CH ₂CH ₂CH ₃	Cl	280
206	32	-CH ₂CH ₂PO(OCH ₂CH ₃) ₂	Cl	30	205	33	-CH ₂CH ₂CH ₂O ₂CCH ₃	Cl	170

[0098] embodiment 328 dissolubility analyses

To compare in comprising one group of solubility parameter of simulating the dissolubility in stomach fluid, simulation intestinal fluid and the blood plasma with the similar thing 204 of its benzothiazole from the ethyl-diethyl phosphate ester analog 206 of pyrido thiazole series, pyrido thiazole dissolubility in three kinds of all solution is bigger significantly.

	Chemical compound #	Stomach (PH2.0) μ g/ml	Intestinal (PH6.5) μ g/ml	Serum (PH7.4) μ g/ml
	Chemical compound #	Stomach (PH2.0) μ g/ml	Intestinal (PH6.5) μ g/ml	Serum (PH7.4) μ g/ml	204	21	98.5	*	*
206	32	124	38.3	14	204	21	98.5	*	*
206	32	124	38.3	14	242	19	220	16	9
243	20	46	3	*	242	19	220	16	9
243	20	46	3	*	253	28	*	137.7	198.7
173	10	35	2	18	253	28	*	137.7	198.7
173	10	35	2	18	284	22	58.7	4.4	31.3
247	25	*	6	4.9	284	22	58.7	4.4	31.3
247	25	*	6	4.9	270	23	*	*	*
264	26	245	21	59	270	23	*	*	*

^*-owing to the cause of degraded be can not determine

[0099] drug effect kinetic measurement value in the body of embodiment 329 main compound

Chemical compound 242 demonstrates biologically relevant concentration with 264 in simulation stomach, intestinal and plasma solutions, and therefore, 242,264 and 206 selected further detections in vivo.Below being presented at the pharmacodynamics measured value that in mice, obtains behind the 100mg/Kg oral administration.

	Chemical compound #	Mice PK POCmax, 100mg/kgng/mL	Mice PK POAUC, 100mg/kg PO (ng/mL*min)
	Chemical compound #	Mice PK POCmax, 100mg/kgng/mL	Mice PK POAUC, 100mg/kg PO (ng/mL*min)	206	32	BLD	BLD
242	19	603	62592	206	32	BLD	BLD
242	19	603	62592	264	26	4479	430511

Under the BLD-detection level

After the administration, chemical compound 264 was reached C-max 4513ng/ml (referring to Fig. 3) in 30 minutes by fast Absorption, and its half-life was estimated at 90 minutes.The concentration ratio 264 of chemical compound 242 is much lower.Surprisingly, increase although compare the similar thing dissolubility of benzothiazole, 206 concentration does not increase and remains under the detection level, may be because the cause of Penetration Signature difference.

[00100] renders a service in the body in the N87 heteroplastic transplantation model of embodiment 330 human gastric cancer

Find out in the summation of structure-activity data and pharmacy characteristic that from above-mentioned research chemical compound 264 is significant, this is because it is effectively in HER-2 degraded test, can oral utilization and have in mice the rational half-life.Therefore it is selected in the N87 heteroplastic transplantation model of human gastric cancer and carries out effect evaluation in the further body.Briefly, N87 tumor segment by subcutaneous transplantation in the rib abdomen of nude mouse.When this tumor reaches mean size 100mm ³The time, mice is become 10 groups by random alignment.Chemical compound 264 is with 200mg/kg5 days/all oral administrations, and 39 days of this research, and than matched group, observing 264 has 56% tumor growth to suppress (referring to Fig. 4).When analyzing with the t test, observed tumor growth suppresses to have significance,statistical (p＜0.05).

Confirm as many nearest reports that [00101] the Hsp90 inhibitor has become the target target of treatment cancer rapidly.The ATP-binding site of Hsp90 is modified to carry out chemical compound optimization and drug development.Chemical compound of the present invention shows that the phosphate binding pocket of ATP-binding site enough can hold the dicyclo member ring systems greatly.Yet it is very special that ring replaces requirement, and wherein 7 '-halogen is all better than all other replacement forms.The dicyclo loop section provides the increase of the necessary effectiveness of effective inhibition growth of tumour cell, and the raising of the required pharmacy characteristic of the activity in vivo of oral administration route also is provided simultaneously.Because Hsp90 not only plays pivotal role in regulating the albumen relevant with the tumor approach but also in neuropathy and aspect of inflammation, this class Hsp90 inhibitor as herein described may have other effectiveness.

***

[00102] embodiment of front is not determinate and just illustrates various aspects of the present invention and embodiment.All documents that this paper quoted have shown one of ordinary skill in the art's of the present invention level, and all are introduced into this paper as a reference with it.Yet there is not one piece to be recognized as prior art.

[00103] those of ordinary skills will readily appreciate that the present invention be suitable for realizing these purposes well and obtain described result and advantage and wherein inherent those.Described method and composition has been illustrated preferred embodiment, is illustrative, and is not intended to as limiting the scope of the invention.Those of ordinary skills will expect that some modifies and other application, and be included in the spirit of the present invention, as claims scope limited.

[00104] this paper the present invention of describing illustratively can be suitable for not having concrete disclosed any key element (one or more) at this paper, limiting under (one or more) non-existent situation and implement.Already used term and express and to be used as descriptive term but not determinate, and when using these terms and expressing, be not intended to get rid of any equivalent form of value or its part of shown and the feature described.Will be appreciated that various modifications all may be in the present invention for required protection scope.Therefore, be to be understood that, although the present invention has passed through preferred embodiment by specifically open, the optional feature of notion disclosed herein, modification and variation all may be adopted by those skilled in the art, and these modifications and change all are considered in the scope of the invention that description and appended claims are limited.

[00105] in addition, feature of the present invention or aspect according to Ma Kushi group or other situation that optionally grouping is described under, one of skill in the art will recognize that, therefore the present invention also is described according to any single composition or member's subgroup of this Ma Kushi group or other group, and has got rid of single member suitably or by collateral condition.

[00106] other embodiment is in following claim.

Claims

1. formula I chemical compound:

Formula I

Or its tautomer or pharmaceutically acceptable salt, wherein

R ^sIndependently be selected from H and F;

R ^yIndependently be selected from O, NR ¹And key;

2. according to the chemical compound of claim 1, R wherein ^a, R ^b, R ^cAnd R ^dIn at least two independently be selected from halogen and OR ³

3. according to the chemical compound of claim 1, R wherein ^a, R ^b, R ^cAnd R ^dIn at least two independently be selected from halogen and methoxyl group.

4. according to the chemical compound of claim 1, R wherein ^a, R ^b, R ^c, and R ^dIn at least three independently be selected from halogen and OR ³

5. according to the chemical compound of claim 1, R wherein ^a, R ^b, R ^c, and R ^dIn at least three independently be selected from halogen and methoxyl group.

6. according to the chemical compound of claim 1, wherein

R ^aBe halogen, and

R ^dBe OR ³

7. according to each the chemical compound of claim 1-5, wherein

R ^xBe the optional C that replaces ₂-C ₃Alkyl, the optional C that replaces ₂-C ₃Thiazolinyl or the optional C that replaces ₂-C ₃Alkynyl,

R ^yBe NR ¹And

R ^zBe C ₁-C ₆Alkyl.

8. according to each the chemical compound of claim 1-5, wherein

R ^xBe the optional C that replaces ₂-C ₃Alkyl, the optional C that replaces ₂-C ₃Thiazolinyl or the optional C that replaces ₂-C ₃Alkynyl;

R ^yIt is key; And

R ^zBe H.

9. according to each the chemical compound of claim 1-5, wherein

R ^yBe NR ¹And

R ^zBe C (O) R ²

10. according to each the chemical compound of claim 1-5, wherein

R ^yBe NH; And

R ^zBe H.

11. according to each the chemical compound of claim 1-5, wherein

R ^yBe NH; And

R ^zBe C ₁-C ₆Alkyl.

12. according to each the chemical compound of claim 1-5, wherein

R ^xBe the optional C that replaces ₂-C ₃Alkyl;

R ^yBe NH; And

R ^zBe C ₁-C ₆Alkyl.

13. formula II chemical compound:

Formula II

Or its tautomer or pharmaceutically acceptable salt, wherein

R ^sIndependently be selected from H and F;

R ^yIndependently be selected from O, NR ¹Or key;

14. according to the chemical compound of claim 13, wherein

R ^a, R ^b, R ^cAnd R ^dIn at least one be halogen;

R ^xBe the optional C that replaces ₂-C ₃Alkyl;

R ^yIt is key; With

R ^zBe H.

15. according to the chemical compound of claim 13, wherein

R ^a, R ^b, R ^cAnd R ^dIn at least one be halogen;

R ^xBe the optional C that replaces ₂-C ₃Alkyl;

R ^yBe NR ¹With

R ^zBe H.

16. according to the chemical compound of claim 13, wherein

R ^a, R ^b, R ^cAnd R ^dIn at least one be halogen;

R ^xBe the optional C that replaces ₂-C ₃Alkyl;

R ^yBe NR ¹With

R ^zBe C ₁-C ₆Alkyl.

17. according to the chemical compound of claim 13, wherein

R ^a, R ^b, R ^cAnd R ^dIn at least one be halogen;

R ^xBe the optional C that replaces ₂-C ₃Alkyl;

R ^yIt is key; With

R ^zBe-P (O) (OR ⁴) ₂

18. according to the chemical compound of claim 13, wherein

R ^a, R ^b, R ^cAnd R ^dIn at least one be methoxyl group;

R ^xBe the optional C that replaces ₂-C ₃Alkyl;

R ^yIt is key; With

R ^zBe H.

19. formula III chemical compound:

Formula III

Or its tautomer or pharmaceutically acceptable salt, wherein

R ^sIndependently be selected from H and F;

R ^xIndependently be selected from the optional C that replaces ₂-C ₄Alkyl, the optional C that replaces ₂-C ₄Thiazolinyl and the optional C that replaces ₂-C ₄Alkynyl;

R ^yIndependently be selected from O, NR ¹And key; With

20. according to the chemical compound of claim 19, wherein

R ^a, R ^cAnd R ^dIn at least one be halogen;

R ^xBe the optional C that replaces ₂-C ₃Alkyl;

R ^yIt is key; With

R ^zBe H.

21. according to the chemical compound of claim 19, wherein

R ^a, R ^cAnd R ^dIn at least one be halogen;

R ^xBe the optional C that replaces ₂-C ₃Alkyl;

R ^yBe NR ¹With

R ^zBe H.

22. according to the chemical compound of claim 19, wherein

R ^a, R ^cAnd R ^dIn at least one be halogen;

R ^xBe the optional C that replaces ₂-C ₃Alkyl;

R ^yIt is key; With

R ^zBe C ₁-C ₆Alkyl.

23. according to the chemical compound of claim 19, wherein

R ^a, R ^cAnd R ^dIn at least one be halogen;

R ^xBe the optional C that replaces ₂-C ₃Alkyl;

R ^yIt is key; With

R ^zBe-P (O) (OR ⁴) ₂

24. formula IV chemical compound:

Formula IV

Or its tautomer or pharmaceutically acceptable salt, wherein

Y independently is selected from the optional alkyl that replaces, the optional thiazolinyl that replaces, the optional alkynyl that replaces, the optional aryl that replaces, the optional alicyclic ring that replaces, the optional aralkyl that replaces, the optional aryloxy alkyl that replaces, the optional alkoxyalkyl that replaces, the optional heterocyclic radical that replaces, optional alkyl amino the alkyl ((CH that replaces ₂) _n-NHR ²), optional alkyl amino the dialkyl group ((CH that replaces ₂) _n-NR ²R ²), the optional alkyl-carbonyl-amino alkyl that replaces ,-(CH ₂) _n-C (O)-NR ⁴R ⁴), optional alkyl carbonyl oxy the alkyl ((CH that replaces ₂) _n-C (O)-O-R ⁴), hydroxy alkyl ((CH ₂) _n-OH), haloalkyl ((CH ₂) _n-halogen), perhaloalkyl radical, aminoalkyl ((CH ₂) _n-NH ₂), C (O) R ², S (O) ₂R ², C (O) NR ⁴ ₂And C (O) OR ²

Z independently is selected from H and halogen;

N is 1 to 3.

25. formula V chemical compound:

Formula V

Or its tautomer or pharmaceutically acceptable salt, wherein

Z independently is selected from H and halogen;

N is 1 to 3.

26. formula VI chemical compound:

Formula VI

Or its tautomer or pharmaceutically acceptable salt, wherein

Z independently is selected from H and halogen;

R ¹Independently be selected from H, the optional alkyl that replaces, the optional cycloalkyl that replaces, the optional assorted alkyl that replaces, the optional aryl that replaces, optional heterocyclic radical, C (O) R that replaces ²,-C (O) OR ², C (O) NR ⁴ ₂, C (S) OR ², C (S) NR ⁴ ₂, P (O) (OR ⁴) ₂And SO ²R ²

N is 1 to 3.

27. pharmaceutical composition, it comprises claim 1,13,19,24,25 or 26 each described chemical compound, tautomer or pharmaceutically acceptable salt, and one or more pharmaceutical carriers or excipient.

28. prodrug according to claim 1,13,19,24, each described chemical compound of 25 or 26.

29. prodrug, it changes in vivo according to claim 1,13,19,24, each described chemical compound of 25 or 26.

30. the described prodrug of claim 29, wherein said prodrug is changed by hydrolysis in blood or in digestive tract.

31. suppress the method for HSP90, comprising:

Make cell and contact according to claim 1,13,19,24,25 or 26 each described chemical compound, tautomer or pharmaceutically acceptable salt or pharmaceutical composition with HSP90.

32. according to the application in treatment inflammation, infectious disease, autoimmune disease, sacred disease, cancer and ischemia one or more of claim 1,13,19,24,25 or 26 each described chemical compound, tautomer or pharmaceutically acceptable salt.

33. the method for claim 31, wherein said contact realizes by the oral object that is administered to.

34. the method for claim 31, wherein said contact realizes for object by local application.

35. the method for claim 31, wherein said cell is a mammalian cell.

36. the method for claim 35, wherein said mammalian cell is the people.

37. the method for claim 31, wherein said contact is in external generation.

38. the method for claim 31, wherein said contact takes place in vivo.

39. the method for claim 31, wherein said contact are the parts of the method that exsomatizes.

40. the method for claim 31, wherein said contact realizes for object by intravenous administration.

41. the method for claim 31, wherein said contact is administered to object outward by intestinal and realizes.

42. the method for claim 31, wherein said contact is carried out in position.

43. the method for claim 31, wherein said contact are the parts at the treatment of cancerous cell.

44. the method for claim 43, wherein said cancerous cell is selected from breast cancer cell and melanoma cells.

45. pharmaceutical composition, it comprises claim 1,13,19,24,25 or 26 each described chemical compound, tautomer or pharmaceutically acceptable salt, and at least a other chemical compound.

46. the pharmaceutical composition of claim 45, at least a in wherein said at least a other chemical compound is the inhibitor of HSP90.

47. the pharmaceutical composition of claim 45, at least a in wherein said at least a other chemical compound is the inhibitor of people HSP90.

48. claim 1,13,19,24,25 or 26 each described chemical compound, tautomer or the application of pharmaceutically acceptable salt in chemotherapy regimen.

49. the application of claim 48, wherein said scheme is to use the part of the conjoint therapy of one or more other medicaments, and described medicament is selected from: radiosiotope, antibody, recombinant product, micromolecule, antineoplastic agent, Trastuzumab, paclitaxel, taxane and Taxane derivative, gleevec, alkylating agent, antimetabolite, epidophylltoxin, antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological response modifier/growth inhibitor; Hormone/hormone antagonist therapeutic agent and hemopoietic growth factor, anthracycline antibiotics, Vinca, mitomycin, bleomycin, the cytotoxicity nucleoside, tepothilones, discodermolide, the pteridine medicine, diynyl, podophyllotoxin, Carubicin, daunorubicin, aminopterin, methotrexate, methopterin, dichioromethotrexate, ametycin, porfiromycin, 5-fluorouracil, the 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin, podophyllotoxin derivative, etoposide, phosphoric acid etoposide or teniposide, alkeran, vinblastine, vincristine, leurosidine, vindesine, leurosine, paclitaxel, estramustine phosphate, carboplatin, cyclophosphamide, bleomycin, gemcitabine, ifosfamide, alkeran, altretamine, plug is for group, cytosine arabinoside, idatrexate, Trimetrexate, Dacarbazine, the altheine enzyme, camptothecine, CPT-11, hycamtin, ara-C, bicalutamide, Drogenil, leuprorelin, pyridine benzindole derivant, interferon and interleukin.

50. chemical compound is selected from:

9 - (tert-butyl - dimethyl - silyloxy methyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - Ylamine; 9 - (2 - chloro - ethyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 9 - (3 - chloro - third Yl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 9 - (4 - chloro - butyl) -8 - (2 - iodo - 5 - methoxy- Yl - phenylsulfanyl)-9H-purin-6 - amine; 8-( 2 - iodo-5 - methoxy - phenylsulfanyl) -9 - [3 - (4 - methyl - piperazine Triazine-1 - yl) - propyl]-9H-purin-6 - amine; 9 - (3 - dimethylamino - propyl) -8 - (2 - iodo-5 - methoxy - phenyl sulfide Alkyl)-9H-purin-6 - amine; 8-( 2 - iodo-5 - methoxy - phenylsulfanyl) -9 - (3 - piperidin-1 - yl - propyl)-9H - Purin-6 - amine; 9 - (3 - cyclopropylamino - propyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - Ylamine; 8-( 2 - iodo-5 - methoxy - phenylsulfanyl) -9 - (3 - morpholin-4 - yl - propyl)-9H-purin-6 - amine; 8-( 2 - iodo-5 - methoxy - phenylsulfanyl) -9 - (3 - methylamino - propyl)-9H-purin-6 - amine; 9 - (3 - ethylamino Yl - propyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 8-( 2 - iodo-5 - methoxy - phenyl Sulfanyl) -9 - [2 - (4 - methyl - piperazin-1 - yl) - ethyl]-9H-purin-6 - amine; 8-( 2 - iodo-5 - methoxy - phenyl sulfide Alkyl) -9 - (2 - piperidin-1 - yl - ethyl)-9H-purin-6 - amine; 8-( 2 - iodo-5 - methoxy - phenylsulfanyl)-9 - (2 - Propyl-amino - ethyl)-9H-purin-6 - amine; 8-( 2,5 - dimethoxy - phenylsulfanyl) -9 - (3 - dimethylamino - Propyl)-9H-purin-6 - amine; 8-( 2 - iodo-5 - methoxy - phenylsulfanyl) -9 - (2 - isopropyl-amino - ethyl)-9H- Purin-6 - amine; 9 - (2 - butylamino - ethyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - yl Amine; 9 - (2 - sec-butylamino - ethyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 9 - [2 - (1 - ethyl - propyl-amino) - ethyl]-8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 9 - (2 - cyclopropylamino - ethyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 8-( 2 - iodo - 5 - Methoxy - phenylsulfanyl) -9 - [2 - (3 - methyl - butylamino) - ethyl]-9H-purin-6 - amine; 9 - [2 - (3,3 - two Methyl - butylamino) - ethyl]-8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; {2 - [6 - amino- -8 - (2 - iodo-5 - methoxy - phenylsulfanyl) - purin-9 - yl] - ethylamino} - acetonitrile; 2 - {2 - [6 - amino-8 - (2 - Iodo-5 - methoxy - phenylsulfanyl) - purin-9 - yl] - ethylamino} - ethanol; 8-( 2 - iodo-5 - methoxy - phenyl sulfide Alkyl) -9 - [2 - (2 - methoxy - ethylamino) - ethyl]-9H-purin-6 - amine; 9 - (2 - cyclopentyl-amino - ethyl Yl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 9 - (2 - cyclohexyl-amino - ethyl) -8 - (2 - Iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 9 - (2 - cycloheptyl-amino - ethyl) -8 - (2 - iodo-5 - methoxy- Yl - phenylsulfanyl)-9H-purin-6 - amine; 9 - (2 - amino cyclooctyl - ethyl) -8 - (2 - iodo-5 - methoxy - phenyl Sulfanyl)-9H-purin-6 - amine; 9 - [2 - (cyclopropylmethyl - amino) - ethyl]-8 - (2 - iodo-5 - methoxy - phenyl sulfide Alkyl)-9H-purin-6 - amine; 8-( 2 - iodo-5 - methoxy - phenylsulfanyl) -9 - [2 - (2 - methyl - allyl-amino) - Ethyl]-9H-purin-6 - amine; 9 - (2 - tert-butyl-amino - ethyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H- Purin-6 - amine; 9 - (3 - amino - propyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 9 - (2 - cyclopropylamino - ethyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 9 - (2 - allyl Amino - ethyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 8-( 2 - iodo-5 - methoxy - Phenylsulfanyl) -9 - (2 - morpholin-4 - yl - ethyl)-9H-purin-6 - amine; 8-( 2 - iodo-5 - methoxy - phenyl thioalkoxy Yl) -9 - (3 - propylamino - propyl)-9H-purin-6 - amine; 9 - (3 - heptyl-amino - propyl) -8 - (2 - iodo-5 - methoxy- - Phenylsulfanyl)-9H-purin-6 - amine; 9 - (3 - cyclopentyl-amino - propyl) -8 - (2 - iodo-5 - methoxy - phenyl thioalkoxy Yl)-9H-purin-6 - amine; 9 - (3 - amino cyclooctyl - propyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H- Purin-6 - amine; 8-( 2 - iodo-5 - methoxy - phenylsulfanyl) -9 - (3 - isobutyl-amino - propyl)-9H-purin-6 - Ylamine; 8-( 2 - iodo-5 - methoxy - phenylsulfanyl) -9 - [3 - (1,2,2 - trimethyl - propylamino) - propyl]-9H- purine -6 - Ylamine; 4 - {3 - [6 - amino-8 - (2 - iodo-5 - methoxy - phenylsulfanyl) - purin-9 - yl] - propyl-amino} - piperidine 1 - carboxylic acid tert-butyl ester; 9 - (2 - benzylamino - ethyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - yl Amine; 9 - [3 - (1,1 - dimethyl - propyl-amino) - propyl]-8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - Ylamine; 9 - (3 - cyclobutylamino - propyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 9 - (3 - amino - propyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; {2 - [6 - amino-8 - (2 - Iodo-5 - methoxy - phenylsulfanyl) - purin-9 - yl] - ethyl} - carbamic acid tert-butyl ester; 9 - (2 - amino - B Yl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 2 - [6 - amino-8 - (2 - iodo-5 - methoxy- base - Phenylsulfanyl) - purin-9 - yl] - acetamide; 1 - [6 - amino-8 - (2 - iodo-5 - methoxy - phenylsulfanyl) - purine -9 - Yl] - propan-2 - one; N-{2 - [6 - amino-8 - (2 - iodo-5 - methoxy - phenylsulfanyl) - purin-9 - yl] - acetic yl} - Acetamide; N-{2 - [6 - amino-8 - (2 - iodo-5 - methoxy - phenylsulfanyl) - purin-9 - yl] - ethyl} - methanesulfonyl Amine; N-{2 - [6 - amino-8 - (2 - iodo-5 - methoxy - phenylsulfanyl) - purin-9 - yl] - ethyl}-N-isobutyl - acetyl Amine; N-{2 - [6 - amino-8 - (2 - iodo-5 - methoxy - phenylsulfanyl) - purin-9 - yl] - ethyl}-N-isobutyl - A sulfur Amide; 8-( 3 - bromo-2 ,5 - dimethoxy - phenylsulfanyl) -9 - (4 - methyl - pent-3 - enyl)-9H-purin-6 - amine; 8-( 3 - bromo-2 ,5 - dimethoxy - phenylsulfanyl) -9 - pent-4 - ynyl-9H-purin-6 - amine; 8-( 2,5 - dimethyl oxy - Biphenyl-3 - yl sulfanyl) -9 - pent-4 - ynyl-9H-purin-6 - amine; 9 - (4 - methyl - pent-3 - enyl) -8 - ( thiazole -2 - Yl sulfanyl)-9H-purin-6 - amine; 8-( benzothiazol-2 - yl sulfanyl) -9 - (4 - methyl - pent-3 - ene Yl)-9H-purin-6 - amine; 8-( 1H-benzimidazol-2 - yl sulfanyl) -9 - (4 - methyl - pent-3 - enyl)-9H-purine -6 - Ylamine; 2 - [6 - amino-8 - (naphth-2 - yl sulfanyl) - purin-9 - yl] - acetate; 2 - [6 - amino-8 - (naphthalen-1 - Ylsulfanyl) - purin-9 - yl] - acetate; 2 - [6 - amino-8 - (quinolin-8 - yl sulfanyl) - purin-9 - yl] - acetic acid Ester; 2 - [6 - amino -8 - (1H-indol-2 - yl sulfanyl) - purin-9 - yl] - acetate; 2 - [6 - amino-8 - (2,5- - Dimethoxy - phenylsulfanyl) - purin-9 - yl] - acetate; 2 - [6 - amino-8 - (benzo [b] thiophen-2 - yl thioalkoxy Yl) - purin-9 - yl] - acetate; 8-( benzothiazol-2 - yl sulfanyl) -9 - pent-4 - ynyl-9H-purin-6 - amine; 9 - pent-4 - alkynyl-8 - (quinolin-2 - yl sulfanyl)-9H-purin-6 - amine; 8-( 1 - allyl-1H-benzimidazol-2 - Ylsulfanyl) -9 - (4 - methyl - pent-3 - enyl)-9H-purin-6 - amine; 8-( 1 - methyl-1H-benzimidazol-2 - ylthio Alkyl) -9 - (4 - methyl - pent-3 - enyl)-9H-purin-6 - amine; 2 - [6 - amino-8 - (naphth-2 - yl sulfanyl) - purine -9 - Yl] - ethanol; 2 - [6 - amino-8 - (naphthalen-1 - yl sulfanyl) - purin-9 - yl] - ethanol; 2 - [6 - amino-8 - (quinolin-8 - yl Sulfanyl) - purin-9 - yl] - ethanol; 2 - [6 - amino-8 - (3 - chloro-1H-indol-2 - yl sulfanyl) - purin-9 - yl] - acetic Ethyl; 2 - [6 - amino-8 - (3 - bromo-1H-indol-2 - yl sulfanyl) - purin-9 - yl] - acetate; 2 - [6 - amino- -8 - (3 - iodo-1H-indol-2 - yl sulfanyl) - purin-9 - yl] - acetate; 2 - [6 - amino-8 - (1 - propyl-1H-indole indole -2 - Yl sulfanyl) - purin-9 - yl] - acetate; 2 - [6 - amino-8 - (3 - iodo-1 - propyl-1H-indol-2 - yl thioalkoxy Yl) - purin-9 - yl] - acetate; 2 - [6 - amino-8 - (1,4 - dimethoxy - naphthalene-2 - yl sulfanyl) - purin-9 - yl] - Acetate; 3 - [6 - amino-8 - (Benzo [1,3] dioxol-5 - yl sulfanyl) - purin-9 - yl] -1 - C Alcohol; 3 - [6 - amino-8 - (2,3 - dihydro - benzo [1,4] dioxin -6 - yl sulfanyl) - purin-9 - yl] -1 - propanol; 9 - D -8 - (7 - chloro - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 9 - ethyl-8 - (7 - chloro - benzothiazol-2 - Ylsulfanyl)-9H-purin-6 - amine; 9 - propyl-8 - (7 - chloro - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - yl Amine; 9 - pentyl-8 - (7 - chloro - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 8-( 7 - bromo - benzothiazol-2 - Ylsulfanyl) -9 - butyl-9H-purin-6 - amine; 9 - butyl-8 - (7 - methyl - benzothiazol-2 - yl sulfanyl)-9H- Purin-6 - amine; 9 - butyl-8 - (7 - methoxy - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 9 - butyl -8 - (7 - ethoxy - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 9 - butyl-8 - (7 - fluoro - benzothiazol-2 - Ylsulfanyl)-9H-purin-6 - amine; 9 - butyl-8 - (7 - (Trifluoromethoxy) - benzothiazol-2 - yl sulfanyl)-9H- Purin-6 - amine; 8-( benzothiazol-2 - yl sulfanyl) -9 - butyl-9H-purin-6 - amine; 9 - butyl-8 - (6 - chloro - Benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 9 - butyl-8 - (5 - chloro - benzothiazol-2 - yl thioalkoxy Yl)-9H-purin-6 - amine; 9 - butyl-8 - (4 - chloro - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 9 - Butyl-8 - (4 - chloro - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl thioalkoxy Yl) -9 - pent-4 - ynyl-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - (2 - methoxy - B Yl)-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - (2 - vinyloxy - ethyl)-9H- Purin-6 - amine; 9 - butyl-8 - (thiazolo [5,4-b] pyridin-2 - yl sulfanyl)-9H-purin-6 - amine; 4 - [6 - amino- -8 - (7 - fluoro - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] - Titanium Dioxide; 8-( 4 - bromo-6 ,7 - difluoro - benzothiazole -2 - Yl sulfanyl) -9 - butyl-9H-purin-6 - amine; 9 - butyl-8 - (6,7 - dichloro - benzothiazol-2 - yl thioalkoxy Yl)-9H-purin-6 - amine; 9 - butyl-8 - (6,7 - difluoro - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 8-( 6,7 - dichloro - benzothiazol-2 - yl sulfanyl) -9 - pent-4 - ynyl-9H-purin-6 - amine; 3 - [6 - amino-8 - ( 6,7 - Dichloro - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] - propyl acetate; 9 - t -3 - en-8 - (7 - chloro - benzothiazole -2 - Yl sulfanyl)-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - pent-4 - ynyl-9H-purine Methotrexate -6 - ylamine; 8-( 7 - methoxy - benzothiazol-2 - yl sulfanyl) -9 - pent-4 - ynyl-9H-purin-6 - amine; 8-( 7 - Methyl - benzothiazol-2 - yl sulfanyl) -9 - pent-4 - ynyl-9H-purin-6 - amine; 9 - butyl-8 - (7 - methoxymethyl Oxymethyl - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 3 - [6 - amino-8 - (7 - methoxy - benzothiazol Oxazol-2 - yl sulfanyl) - purin-9 - yl] - propyl acetate; 3 - [6 - amino-8 - (7 - methyl - benzothiazol-2 - yl thioalkoxy Yl) - purin-9 - yl] - propyl acetate; 8-( 4 - amino-7 - fluoro - benzothiazol-2 - yl sulfanyl) -9 - pent-4 - ynyl-9H- Purin-6 - amine; 8-( 7 - ethoxy - benzothiazol-2 - yl sulfanyl) -9 - pent-4 - ynyl-9H-purin-6 - amine; 2 - [6 - amino-8 - (7 - methoxy - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] - acetate; 8-( 7 - chloro - benzo Thiazol-2 - yl sulfanyl) -9 - ethyl-9H-purin-6 - yl amine China; - chloro-8 - (7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - Methyl-9H-purin-6 - amine; 8-( 7 - bromo - thiazolo [5,4-b] pyridin-2 - yl sulfanyl) -9 - butyl-9H-purin-6 - Ylamine; 8-( 7 - bromo - thiazolo [4,5-c] pyridin-2 - yl sulfanyl) -2 - chloro-9 - methyl-9H-purin-6 - amine; 2 - [6 - Amino-8 - (7 - bromo - thiazolo [4,5-c] pyridin-2 - yl sulfanyl) - purin-9 - yl] - acetate; 8-( 7 - bromo - thiazolo [5,4-b] pyridin-2 - yl sulfanyl) -9 - butyl-9H-purin-6 - amine; 3 - [6 - amino-8 - (7 - bromo - thiazolo [4,5 -c] Pyridin-2 - yl sulfanyl) - purin-9 - yl] - propyl acetate; 8-( 7 - bromo - thiazolo [4,5-c] pyridin-2 - yl thioalkoxy Yl) -9 - (4 - methyl - pent-3 - enyl)-9H-purin-6 - amine; 2 - [6 - amino-8 - (7 - bromo - thiazolo [4,5-c] pyridine-2 - Ylsulfanyl) - purin-9 - yl] - acetate; 8-( 7 - bromo - thiazolo [5,4-b] pyridin-2 - yl sulfanyl) -2 - chloro-9 - Methyl-9H-purin-6 - amine; 3 - [6 - amino-8 - (7 - chloro - thiazolo [4,5-c] pyridin-2 - yl sulfanyl) - purin-9 - Yl] - propyl acetate; 9 - butyl-8 - (7 - chloro - benzoxazol-2 - yl sulfanyl)-9H-purin-6 - amine; 2 - [6 - amino- -8 - (7 - chloro - benzoxazol-2 - yl sulfanyl) - purin-9 - yl] - acetate; 3 - [6 - amino-8 - (7 - chloro - benzoxazin Oxazol-2 - yl sulfanyl) - purin-9 - yl] - propyl acetate; 9 - butyl-8 - (7 - fluoro - benzoxazol-2 - yl sulfanyl)-9H- Purin-6 - amine; 2 - [6 - amino-8 - (7 - chloro - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] - acetate; 2 - [6 - Amino-8 - (7 - fluoro - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] - acetate; 4 - [6 - amino-8 - (7 - chloro - benzo Thiazol-2 - yl sulfanyl) - purin-9 - yl] - Titanium Dioxide; 3 - [6 - amino-8 - (7 - fluoro - benzothiazol-2 - yl thioalkoxy Yl) - purin-9 - yl] - propyl acetate; 3 - [6 - amino-8 - (7 - bromo - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] - Propyl acetate; 2 - [6 - amino-8 - (7 - chloro - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] - ethanol; 2 - [6 - amino- -8 - (7 - fluoro - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] - ethanol; 2 - [6 - amino-8 - (7 - chloro - benzothiazol-2 - Ylsulfanyl) - purin-9 - yl] -1 - propanol; 4 - [6 - amino-8 - (7 - chloro - benzothiazol-2 - yl sulfanyl) - purin-9 - Yl] -1 - butanol; 4 - [6 - amino-8 - (7 - fluoro - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] -1 - butanol; 3 - [6 - Ammonia -8 - (7 - fluoro - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] -1 - propanol; 3 - [6 - amino-8 - (6,7 - dichloro - benzo Thiazol-2 - yl sulfanyl) - purin-9 - yl] -1 - propanol; 3 - [6 - amino-8 - (7 - bromo - benzothiazol-2 - yl sulfanyl) - Purin-9 - yl] -1 - propanol; 3 - [6 - amino-8 - (7 - methoxy - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] -1 - Propanol; 2 - [6 - amino-8 - (7 - methoxy - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] - ethanol; 3 - [6 - amino- -8 - (7 - methyl - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] -1 - propanol; 2 - [6 - amino-8 - (7 - bromo - thiazolo [4,5-c] pyridin-2 - yl sulfanyl) - purin-9 - yl] - ethanol; 2 - [6 - amino-8 - (7 - chloro - thiazolo [5,4-b] pyridine -2 - Ylsulfanyl) - purin-9 - yl] - ethanol; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - [3 - (1 - ethyl - propyl-amino Yl) - propyl]-9H-purin-6 - amine; 9 - (3 - tert-butylamino - propyl) -8 - (7 - chloro - benzothiazol-2 - yl thioalkoxy Yl)-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - (3 - isobutyl-amino - propyl)-9H- Purin-6 - amine; 9 - (3 - sec-butylamino - propyl) -8 - (7 - chloro - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - Ylamine; 9 - [2 - (2,2 - dimethyl - propyl-amino) - ethyl]-8 - (7 - chloro - benzothiazol-2 - yl sulfanyl)-9H-purine -6 - Ylamine; 9 - [2 - isopropylamino - ethyl]-8 - (7 - methoxy - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - Ylamine; 9 - [2 - tert-butylamino - ethyl]-8 - (7 - methoxy - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - yl Amine; 9 - (2 - isobutyl-amino - ethyl) -8 - (7 - methoxy - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - [3 - (2,2 - dimethyl - propyl-amino) - propyl]-9H-purin-6 - yl Amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - (2 - prop-2 - ynyl-amino - ethyl)-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - (2 - cyclopentyl-amino - ethyl)-9H-purin-6 - amine; 8-( 7 - chloro - Benzothiazol-2 - yl sulfanyl) -9 - [2 - (3 - methyl - butylamino) - ethyl]-9H-purin-6 - amine; 8-( 7 - chloro - benzene And thiazol-2 - yl sulfanyl) -9 - [2 - (1,1 - dimethyl - propyl-amino) - ethyl]-9H-purin-6 - amine; 9 - (2 - ene Propyl-amino - ethyl) -8 - (7 - chloro - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol Oxazol-2 - yl sulfanyl) -9 - (3 - isopropylamino - propyl) 9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - ylthio Alkyl) -9 - (3 - pyrrol-1 - yl - propyl)-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl thioalkoxy Yl) -9 - [2 - (3,3 - dimethyl - butylamino) - ethyl]-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - ylthio Alkyl) -9 - (3 - morpholin-4 - yl - propyl)-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl thioalkoxy Yl) -9 - (2 - morpholin-4 - yl - ethyl)-9H-purin-6 - amine; 9 - (2 - bromo - ethyl) -8 - (7 - chloro - benzothiazole -2 - Ylsulfanyl)-9H-purin-6 - amine; 8-( 7 - fluoro - benzothiazol-2 - yl sulfanyl) -9 - (2 - vinyl group - B Yl)-9H-purin-6 - amine; 8-( 7 - fluoro - benzothiazol-2 - yl sulfanyl) -9 - pent-4 - ynyl-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - (2 - chloro - ethyl)-9H-purin-6 - amine; 9 - (3 - bromo - propyl) - 8-( 7 - Chloro - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - pent-4 - Enyl-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - hex-5 - enyl-9H-purin-6 - yl Amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - [2, (2,5 - dimethoxy - phenyl) - ethyl]-9H-purin-6 - base Amine; 9 - butan-2 - yn-8 - (7 - chloro - benzothiazol-2 - yl sulfanyl)-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol Oxazol-2 - yl sulfanyl) -9 - (3,4,4 - trifluoro - but-3 - enyl)-9H-purin-6 - amine; 6 - [6 - amino-8 - (7 - Chlorine - benzo Thiazol-2 - yl sulfanyl) - purin-9 - yl] - has carbonitrile; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - (3 - methyl - D -3 - Enyl)-9H-purin-6 - amine; 4 - [6 - amino-8 - (7 - chloro - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] - Nitrile; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - hex-5 - ynyl-9H-purin-6 - amine; 8-( 7 - chloro - benzo Thiazol-2 - yl sulfanyl) -9 - [3 - (tetrahydro - furan-2 - yl) - propyl]-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazole -2 - Yl sulfanyl) -9 - (tetrahydro - furan-2 - ylmethyl)-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - ylthio Alkyl) -9 - [2 - (2 - ethoxy - ethoxy) - ethyl]-9H-purin-6 - amine; 5 - [6 - amino-8 - (7 - chloro - benzo thiazole -2 - Yl sulfanyl) - purin-9 - yl] - pentanenitrile; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - (4 - methoxy-3 ,5 - two Methyl - pyridin-2 - ylmethyl)-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - prop-2 - ynyl -9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - (2 - piperidin-1 - yl - ethyl]-9H-purin-6 - Ylamine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - (2 - methylsulfanyl - ethyl)-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - (2 - ethyl-sulfanyl - ethyl)-9H-purin-6 - amine; 3 - [6 - amino- -8 - (7 - chloro - benzothiazol-2 - yl sulfanyl)-9 - yl] - propyl phosphate, diethyl ester; 2 - [6 - amino-8 - (7 - chloro - benzothiazol Oxazol-2 - yl sulfanyl) - purin-9 - yl] - ethyl-II - (2 - chloro - ethyl) phosphate; {3 - [6 - amino-8 - (7 - chloro - benzothiazol Oxazol-2 - yl sulfanyl) - purin-9 - yl] - propenyl} - phosphonic acid diethyl ester; 2 - [6 - amino-8 - (7 - chloro - benzothiazol-2 - Ylsulfanyl)-9 - yl] - acid diethyl ester; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl)-9 - methyl-9H-purine -6 - Ylamine; 4 - [6 - amino-8 - (7 - chloro - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] - butan-2 - one; 8-( 7 - Chlorine - Benzothiazol-2 - yl sulfanyl) -9 - (2 - ethylsulfinyl - ethyl)-9H-purin-6 - amine; 4 - [6 - amino-8 - (7 - Chloro - benzothiazol-2 - yl sulfanyl) - purin-9 - yl] - D - 2 - thione; 8-( 7 - chloro - benzothiazol-2 - yl thioalkoxy Yl) -9 - (2 - ethylsulfonyl - ethyl)-9H-purin-6 - amine; 8-( 7 - chloro - benzothiazol-2 - yl sulfanyl) -9 - (2 - methyl Sulfonyl - ethyl)-9H-purin-6 - yl amine; (6 - amino-9 - butyl-9H-purin-8 - yl sulfanyl) - benzothiazole-7 - Yl] - methanol; 9 - (2 - dimethylamino - ethyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 9 - (2 - diethylamino - ethyl) -8 - (2 - iodo-5 - methoxy - phenylsulfanyl)-9H-purin-6 - amine; 8-( 2 - iodo - 5 - Methoxy - phenylsulfanyl) -9 - (2 - pyrrolidin-1 - yl - ethyl)-9H-purin-6 - amine; 8-( 2 - iodo-5 - methoxy - Phenylsulfanyl) -9 - (2 - vinyloxy - ethyl)-9H-purin-6 - amine; 8-( 2 - iodo-5 - methoxy - phenyl thioalkoxy Yl) -9 - (2 - isopropoxy - ethyl)-9H-purin-6 - amine; {3 - [6 - amino-8 - (2 - iodo-5 - methoxy - phenyl sulfide alkyl Yl) - purin-9 - yl] - propyl} - methyl - carbamic acid tert-butyl ester; 8-( 2 - iodo-5 - methoxy - phenylsulfanyl) -9 - (3 - Pyrrol-1 - yl - propyl)-9H-purin-6 - yl amine; (2,4 - iodo-5 - methoxy - phenylsulfanyl) -9 - pent-4 - ynyl -9H-purin-6 - amine; {3 - [6 - amino-8 - (2 - iodo-5 - methoxy - phenylsulfanyl) - purin-9 - yl] - propyl} - amino Carboxylic acid tert-butyl ester; 8-( 2 - iodo-5 - (Trifluoromethoxy) - phenylsulfanyl) -9 - pent-4 - ynyl-9H-purin-6 - yl amine And 8-( 2 - iodo-5 - (Trifluoromethoxy) - phenylsulfanyl) -9 - pent-4 - ynyl-9H-purin-6 - amine. ...

51. chemical compound is selected from:

8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-(2-isobutyl amino-ethyl)-9H-purine-6-base amine; 9-(uncle's 3-fourth amino-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine; 9-[3-(1-ethyl-third amino)-propyl group]-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine; 9-(3-Zhong Ding amino-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine (racemic modification); (R)-9-(3-Zhong Ding amino-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine; (S)-9-(3-Zhong Ding amino-propyl group)-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine; 8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9-(3-isopropylamino-propyl group)-9H-purine-6-base amine; 9-[2-(2,2-dimethyl-third amino)-ethyl]-8-(2-iodo-5-methoxyl group-phenyl sulfane base)-9H-purine-6-base amine; 2-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-ethyl }-diethyl phosphate; 2-[6-amino-8-(7-chloro-thiazole is [4,5-c] pyridine-2-base sulfane base also)-purine-9-yl]-ethyl }-diethyl phosphate; 2-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-ethyl }-diethyl phosphonate; 2-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-ethyl }-the phosphoramidic acid diethylester; 2-[6-amino-8-(7-bromo-thiazole [4,5-c] pyridine-2-base sulfane base)-purine-9-yl]-ethyl }-diethyl phosphonate; 3-[6-amino-8-(7-bromo-thiazole [4,5-c] pyridine-2-base sulfane base)-purine-9-yl]-ethyl }-diethyl phosphonate; 4{3-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-9-yl]-propyl group }-diethyl phosphonate; 3-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-acrylic }-diethyl phosphonate; 8-(7-chloro-benzothiazole-2-base sulfane base)-9-[2-(2,2-dimethyl-third amino)-ethyl]-9H-purine-6-base amine; 8-(7-chloro-benzothiazole-2-base sulfane base)-9-[2-(cyclopropyl methyl-amino)-ethyl]-9H-purine-6-base amine; 8-(7-chloro-benzothiazole-2-base sulfane base)-9-(2-cyclopropylamino)-ethyl)-9H-purine-6-base amine; 9-(uncle's 2-fourth amino-ethyl)-8-(7-chloro-benzothiazole-2-base sulfane base)-9H-purine-6-base amine and 2-[6-amino-8-(7-chloro-benzothiazole-2-base sulfane base)-purine-9-yl]-propyl acetate.

52. pharmaceutical composition, it comprises the described chemical compound of claim 51, tautomer or pharmaceutically acceptable salt and one or more pharmaceutical carriers or excipient.

53. suppress the method for HSP90, comprising:

Cell with HSP90 is contacted with the described chemical compound of claim 51, tautomer or pharmaceutically acceptable salt or pharmaceutical composition.