WO2012035423A1

WO2012035423A1 - Anti-cancer activity of novel bicyclic heterocycles

Info

Publication number: WO2012035423A1
Application number: PCT/IB2011/002248
Authority: WO
Inventors: Jean Herman; Thierry Louat
Original assignee: Katholieke Universiteit Leuven, K.U. Leuven R&D
Priority date: 2010-09-15
Filing date: 2011-09-08
Publication date: 2012-03-22
Also published as: ES2604112T3; US20140088088A1; US9573966B2; EP2616077A1; GB201015411D0; EP2616077B1

Abstract

The present invention relates to compound of formula I, II, III, or IV, and/or a pharmaceutical acceptable addition salt thereof and/or a stereoisomer thereof and/or a solvate thereof, Formulas (I), (II), (III) and (IV) wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹, and R¹² are as defined in the claim 1 or as described in detail in the description of the invention, and to the use of said compounds to treat or prevent proliferative disorders and their use to manufacture a medicine to treat or prevent proliferative disorders, particularly cancer such as leukemia. The present invention also relates to pharmaceutical compositions of said compounds and the use of said pharmaceutical compositions to treat or prevent proliferative disorders. The present invention further relates to the use of said compounds as biologically active ingredients, more specifically as medicaments for the treatment of proliferative disorders and pathologic conditions such as, but not limited to, cancer such as leukemia.

Description

ANTI-CANCER ACTIVITY OF NOVEL BICYCLIC HETEROCYCLES

FIELD OF THE INVENTION

The present invention relates to a class of novel thiazolo[5 ,4-d]pyrimidine, oxazolo[5,4- d]pyrimidine, thieno[2,3-d]pyrimidine, their use to treat or prevent proliferative disorders such as cancer and their use to manufacture a medicine to treat or prevent said proliferative disorders, particularly cancer and more particular hematological cancers such as leukemias. BACKGROUND OF THE INVENTION

Thiazo!o[5,4-d]pyrimidines and oxazolo[5,4-d]pyrimidines can be considered as structural analogues of purines, in which the imidazole moiety is replaced by a 1 ,3-thiazole or 1 ,3- oxazole ring system. Although purine chemistry is extensively described in literature, the number of medicinal chemistry papers that describe the synthesis and biological evaluation of oxazolopyrimidines and thiazolopyrimidines is limited. Apparently, the oxazolopyrimidine and thiazolopyrimidine scaffold is not very frequently used in drug discovery programs.

However, biolog ica l activitie s of ce rta in th iazolo[5,4-d]pyrimidines and oxazolo[5,4- d]pyrimidines have been reported. 2,5-Diaminothiazolo[5,4-d]pyrimidin-7(6H)-one, a thio- isostere of 8-amino-guanine, was found to be a weak inhibitor of purine nucleoside phosphorylase (J. C. Sircar et al. J. Med. Chem. 1986, 29, 1804-1806). Thiazolo[5,4- d]pyrimidines were covered by several patent applications as activators of caspases and inducers of apoptosis (WO2008/057402), anti-angiogenic agents (WO2004/01314), growth factor receptor inhibitors (EP1731523), heat shock protein 90 inhibitors (WO2008/059368) and xanthine oxidase inhibitors (WO2007/004688). WO2008/152390 discloses thiazolo[5,4- d]pyrimidines and their use as inhibitors of phosphatidylinositol-3 kinase. WO 2008/005303 discloses vanilloid receptor 1 (TRPV1 ) modulating thiazo!o[5,4-d]pyrimidine analogues and their use for the treatment of diseases, such as pain, arthritis, itch, cough, asthma, or inflammatory bowel disease.

2-Ary!oxazolo[5,4-d]pyrimidines have been described as adenosine kinase inhibitors ( . Bauser; et al. Bioorg. Med. Chem. Lett. 2004, 14, 1997-2000). 7-Amino-5-phenylethylamino- 2-furyl-oxazolo[5,4-d]pyrimidines act as brain A∑A adenosine receptor (A_2AAR) antagonists (M. H. Holschbach, et al. Eur. J. Med. Chem. 2006, 41 , 7-15). 7-(Substituted- cyclopentyl)aminooxazolo[5,4-d]pyrimidines have been reported to possess tumor growth inhibitory activity (WO/2008/019124). However none of these documents teaches or suggests thiazolo[5,4-d]pyrimidine or oxazolo[5,4-d]pyrimidine derivatives having the substitution pattern disclosed by the present invention and their use as anti-cancer compounds.

A huge number of thieno[2,3-d]pyrirmidines is already known in the art. WO 2007/102679 discloses thienopyrimidines with at position 4 a pyrrole-2,5-dione substituent which strongly inhibits 1KB kinase-β (Ι ΚΚ-β) involved in the activation of a transcriptional factor, N F-KB, which is associated with inducing various immune and inflammatory diseases, whereby a composition comprising the compound is a useful therapeutic agent against inflammatory diseases, in particular, arthritis and cancer. WO 2007/084815 discloses 2-carboxamide substituted thieno(2,3-d)pyrimidines inhibitors of one or more of the EGFR, HER-2, c-Src, Lyn , c-Abl, Aurora-A or VEGF kinase proteins and the like possessing anti-tumor cell proliferation activity, and as such are useful in treating or ameliorating a EGFR, HER-2, c- Src, Lyn , c-Abl, Aurora-A or VEGF kinase receptor mediated, angiogenesis-mediated or hyperproliferative disorder.

WO 2006/071988 discloses certain 4,5-disubstituted thienopyrimidine derivatives which are useful for the inhibition of PDE10 enzymes, and thus are useful for treating psychiatric or neurological syndromes, such as psychoses, obsessive-compulsive disorder and/or Parkinson's disease. WO 2004/1 1 1057 discloses compounds which are particularly useful for inhibiting potassium channels Kv1.5, which are known targets for the treatment of cardiac arrhythmia in the atria such as atrial fibrillation. However, none of these documents teaches or suggests thieno(2,3-d)pyrimidine derivatives having the substitution pattern disclosed by the present invention and their use as anti-cancer compounds.

Marketed drugs with a purine based skeleton are known. Examples include theophylline (drug for the treatment of asthma) and azathioprine (drug for the treatment of transplant rejection). Anti-cancer drugs with a purine scaffold include 6-mercaptoguanine and thioguanine. Purines are also an important constituent of antiviral nucleosides such as acyclovir (used for the treatment of herpes virus infections) and ganciclovir (medication used for treatment of cytomegalovirus infections). Abacavir and dideoxyadenosine (ddA) are both purine nucleosides acting as reverse transcriptase inhibitors and both compounds are licensed as anti-HIV agents.

Purines display a broad range of biological activities and as a result a huge number of purine analogues is already known in the art. WO 2009/005687 discloses purine derivatives and their use as modulators of Toll-like receptor 7. Compounds and pharmaceutical compositions which selectively activate toll-like receptor 7 are useful for treating viral infections in patients. WO 2008/135232 relates to substituted purines and purine derivatives as inhibitors of Aurora A, Aurora B, Aurora C, CHK2, JNK1 a1 , JNK3 and abl kinase. These compounds possess antiproliferative properties and are useful in the treatment of proliferative disorders such as cancer, leukemia, psoriasis and the like. WO 2008/094737 discloses purine derivatives as inhibitors of calcium dependent protein kinase 1 (PfCDPKI). These purines are useful for treating malaria. WO 2008/090181 relates to a new series of purine derivatives as inhibitors of Janus kinases. JAK3 kinase inhibitors have been recognized as a new class of effective immunosuppressive agents useful for transplant rejection prevention and in the prevention or treatment of immune, autoimmune, inflammatory and proliferative diseases such as psoriasis, psoriatic arthritis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases, systemic lupus erythematosus, type I diabetes and complications from diabetes, allergic reactions and leukemia. WO 2008/060301 also discloses 7-substituted purine derivatives as immunosuppressive drugs useful for treatment of an autoimmune disease, an inflammatory disease, a mast cell mediated disease, hematological malignancy and organ transplant rejection. However none of these documents teaches or suggests purine derivatives having the substitution pattern disclosed by the present invention and their use as anti-cancer compounds.

However there is a continuous need in the art for specific and highly therapeutically active compounds, such as, but not limited to, drugs for treating cancer such as leukemia. In particular, there is a need in the art to provide anti-cancer compounds, which are active in a minor dose in order to replace existing drugs having significant side effects and to decrease treatment costs.

Accordingly, in view of the relatively few choices for anti-cancer agents effective in low doses with low toxicity profiles and manageable side effects, there exists a need in the art for identification of alternative agents for several proliferative disorders such as cancer.

SUMMARY OF THE INVENTION

The present invention is based on the unexpected finding that certain combinations of substituents at different positions of the thiazolo[5,4-d]pyrimidine, oxazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine and purine ring system, said combinations not being suggested by the prior art, are able to meet one or more of the medical needs recited herein above and to show unexpected biological properties, in particular have significant anti-cancer activity.

The present invention concerns the use of a compound of I, II, III or IV :

II III IV

wherein

- X is S or O;

- R¹ is selected from the group consisting of halogen, cyano, carboxylic acid, acyl, thioacyl, alkoxycarbonyl, acyloxy, carbonate, carbamate, aryl, amino, acetamido, A/-protected amino, (mono- or di) d-₇ alkylamino, (mono- or di) arylamino, (mono- or di) C₃-₁₀ cycloalkylamino, (mono- or di) hydroxy C1-7 alkylamino, (mono- or di) C1.4 alkyl-arylamino, mercapto C1.7 alkyl, C^.₇ alkyloxy; - R³ is selected from the group consisting of (mono- or di-) C₁.₁₂ alkylamino; monoarylamino; diarylamino; (mono- or di-) cycloalkylamino; (mono- or di-) hydroxy d alkylamino; (mono- or di-) C1 alkylarylamino; (mono- or di-) arylC_{1 4} alkylamino; morpholinyl; mercapto d alkyl; d alkoxy, aralkylthio, piperidinyl, pyrrolidinyl, homopiperazinyl and piperazinyl, wherein said piperidinyl, pyrrolidinyl, homopiperazinyl or piperazinyl is optionally N- substituted with a substituent R²⁰ selected from the group consisting of formyl, acyl, thioacyl, amide, thioamide, sulfonyl, sulfinyl, carboxylate, thiocarboxylate, amino-substituted acyl, alkoxyalkyl, C3.10 cy cloa Iky l-a Iky I , C₃. ₀ cycloalkyl, dialkylaminoalkyl, heterocyclic-substituted alkyl, acyl-substituted alkyl, thioacyl-substituted alkyl, amido-substituted alkyl, thioamido- substituted alkyl, carboxylato-substituted alkyl, thiocarboxylato-substituted alkyl, (amino- substituted acyl)alkyl, heterocyclic, carboxylic acid ester, ω-cyanoalkyl, ω-carboxylic ester- alkyl, halo d alkyl, C₂ alkenyl, d alkynyl, arylalkenyl, aryloxyalkyl, arylalkyl and aryl, wherein the aryl moiety of each of said arylalkenyl, aryloxyalkyl, arylalkyl and aryl radicals is optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci.₇ alkyl, C₂.₇ alkenyl, alkynyl, halo d alkyl, nitro, hydroxyl, sulfhydryl, amino, d-₇ alkoxy, C₃.₁₀ cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio d alkyl, thio C₃.₁₀ cycloalkyl, thioaryl, thio- heterocyclic, arylal kylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo- alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydrazino, alkylhydrazino and phenylhydrazino; and

- R^: is selected from the group consisting of heteroaryl and aryl groups; halogen; d alkyl, C2 alkenyl; C_{2 7} alkynyl; halo d alkyl; d-10 cycloalkyl; carboxy d alkyl; carboxyaryl; d alkoxy; d-₁₀ cycloalkoxy; aryloxy; arylalkyloxy; oxyheterocyclic; heterocyclic-substituted alkyloxy; thio d alkyl; thio C₃.₁₀ cycloalkyl; thioaryl; thioheterocyclic; arylalkylthio; heterocyclic-substituted alkylthio; hydroxylamino; thio-acylamino; alkoxyamino; thioalkylamino; acetal; thio-acetal; carboxylic acid; carboxylic acid esters, thiocarboxylic acid; thiocarboxylic acid esters, thioesters, halides, anhydrides, amides and thioamides; hydroxyl; sulfhydryl; nitro; cyano; carbamoyl; thiocarbamoyl; ureido; thioureido; amino; alkylamino; cycloalkylamino; alkenylamino; cyclo-alkenylamino; alkynylamino; arylamino; arylalkylamino; hydroxyalkylamino; mercaptoalkyl-amino; heterocyclic a m i n o; heterocyclic substituted arylamino; heterocyclic-substituted alkyl-amino; oximino; alkyloximino; hydrazino; alkylhydrazino; phenylhydrazino; esters, thioesters, halides, anhydrides, amides and thioamides thereof; aromatic or heterocyclic substituents substituted with an aliphatic spacer between the thiazolo(5,4-d)pyrimidine or oxazolo(5,4-d)pyrimidine ring and the aromatic or heterocyclic substituent, wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, d-7 alkyi, d-7 alkenyl, C₂.₇ alkynyl, halo d-7 alkyi, nitro, hydroxyl, sulfhydryl, amino, d-7 alkoxy, d-io cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio Ci.₇ alkyi, thio d-10 cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, a l ke nyla m i n o , cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino; wherein said aliphatic spacer is a branched or straight, saturated or unsaturated aliphatic chains of 1 to 7 carbon atoms optionally containing one or more functions, atoms or radicals independently selected from the group consisting of halogen, carbonyl, thiocarbonyl, hydroxyl, thiol, ether, thio-ether, acetal, thio-acetal, amino, imino, oximino, alkyloximino, aminoacid, cyano, acylamino, thioacylamino, carbamoyl, thiocarbamoyl, ureido, thio-ureido, carboxylic acid ester or halide or anhydride or amide , thiocarboxylic acid or ester or thioester or halide or anhydride or amide, nitro, thio d-7 alkyi, thio C₃.₁₀ cycloalkyl, hydroxylamino, mercaptoamino, alkyl-amino, cycloalkylamino, alkenylamino, cycloalkenylamino, alkynylamino, arylamino, arylalkyl-amino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic-substituted alkylamino, hetero-cyclic amino, heterocyclic-substituted arylamino, hydrazino, alkylhydrazino, phenylhydrazino, sulfonyl, sulfinyl and sulfonamido;

- R⁴ is selected from the group consisting of halogen, cyano, carboxylic acid, acyl, thioacyl, alkoxycarbonyl, acyloxy, carbonate, carbamate, aryl, amino, acetamido, /V-protected amino, (mono- or di) d-₇ alkylamino, (mono- or di) arylamino, (mono- or di) d-10 cycloalkylamino, (mono- or di) hydroxy d.₇ alkylamino, (mono- or di) d-₄ alkyl-arylamino, mercapto -7 alkyi, .7 alkyloxy;

- R⁶ is selected from the group consisting of (mono- or di-) d-12 alkylamino, monoarylamino, diarylamino, (mono- or di-) C3.10 cycloalkylamino, (mono- or di-) hydroxy d-7 alkylamino, (mono- or di-) d- alkylarylamino, (mono- or di-) aryld.₄ alkylamino, morpholinyl, mercapto .7 alkyi, d.₇ alkoxy, homopiperazinyl and piperazinyl, wherein said homopiperazinyl or piperazinyl is optionally N-substituted with a substituent R²¹ selected from the group consisting of formyl, acyl, thioacyl, amide, thioamide, sulfonyl, sulfinyl, carboxylate, thiocarboxylate, amino-substituted acyl, alkoxyalkyl, d-io cycloalkyl-alkyl, C₃.₁₀ cycloalkyl, dialkylaminoalkyi, heterocyclic-substituted alkyi, acyl-substituted alkyi, thioacyl-substituted alkyl, amido-substituted alkyl, thioamido-substituted alkyl, carboxylato-substituted alkyl, thiocarboxylato-substituted alkyl, (amino-substituted acyl)alkyl, heterocyclic, carboxylic acid ester, ω-cyanoalkyl, ω-carboxylic ester-alkyl, halo C1.7 alkyl, C2-7 alkenyl, C2.7 alkynyl, arylalkenyl, aryloxyalkyl , arylalkyl and aryl; wherein the aryl moiety of each of said arylalkenyl, aryloxyalkyl, arylalkyl and aryl radicals is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C ₇ alkyl, C₂.₇ alkenyl, C2.7 alkynyl, halo C1.7 alkyl, nitro, hydroxyl, sulfhydryl, amino, C_v7 alkoxy, C₃.₁₀ cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C,.₇ alkyl, thio C3.10 cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenyla mino , cyclo- alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydrazino, alkylhydrazino and phenylhydrazino;

- R⁵ is selected from the group consisting of heteroaryl and aryl groups, wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, C1.7 alkyl, C₂.7 alkenyl, C₂.₇ alkynyl, halo C1.7 alkyl, nitro, hydroxyl, sulfhydryl, amino, C ₇ alkoxy, C3.10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio d.₇ alkyl, thio C3.10 cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl , thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or ha lides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino; wherein R¹² is represented by the general formula V :

V

and wherein

schematically represents a saturated or partly unsaturated heterocyclic ring with at least two nitrogen atoms in the said heterocyclic ring and with a total of 5 to 7 atoms in the said heterocyclic ring, and optionally with one or more other heteroatoms in the said heterocyclic ring or attached to one or more carbon atoms of said heterocyclic ring, wherein one of said at least two nitrogen atoms in the heterocyclic ring is attached to a carbon atom 6 of the purine ring;

- each substituent R¹³ of the heterocyclic ring is a group independently selected from the group consisting of halogen, nitro, C,.₇ alkyl (optionally containing one or more functions or radicals selected from the group consisting of halogen, carbonyl, thiocarbonyl, hydroxyl, sulfhydryl, C1.7 alkoxy, thio d-7 alkyl, thio C3.10 cycloalkyl, acetal, thioacetal, imino, oximino, alkyloximino, amino-acid, cyano, (thio)carboxylic acid, (thio)carboxylic acid ester or amide, nitro, amino, d-7 alkylamino, cycloalkylamino , alkenylamino , cycloalkenyl-amino, alkynylamino, arylamino, arylalkyla mino, hydroxya lkylamino, merca pto-alkylamino, heterocyclic-substituted alkylamino, heterocyclic amino, heterocyclic-substituted arylamino, hydrazino, alkylhydrazino, phenylhydrazino, sulfonyl and sulfonamide), C3-7 alkenyl, d-7 alkynyl, halo d-7 alkyl, C3.10 cycloalkyl, aryl, arylalkyi, alkylaryl, alkylacyl, arylacyl, hydroxyl, sulfhydryl, amino, C1.7 alkylamino, cycloalkylamino, alkenylamino, cycloalkenylamino, alkynylamino, arylamino, arylalkyl-amino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic-substituted alkylamino, heterocyclic amino, heterocyclic-substituted arylamino, hydrazino, alkylhydrazino, phenylhydrazino, C1.7 alkoxy, C₃.₁₀ cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio d.7 alkyl, thio C3-10 cycloalkyl, thioaryl, thioheterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, hydroxylamino, cyano, (thio)carboxylic acid or esters or thioesters or amides or thioamides thereof;

- n is an integer from 0 to 6; for example n is an integer selected from 0, 1 , 3, 4 or 5, preferably, n is 0, 1 , 2, or 3, more preferably, n is 0 or 1 , yet more preferably n is 0;

- R¹⁰ is selected from the group consisting of formyl, acyl, thioacyl, amide, thioamide, sulfonyl, sulfinyl, carboxylate, thiocarboxylate, amino-substituted acyl, alkoxyalkyl, C₃.₁₀ cycloalkyl- alkyl, C₃.i₀ cycloalkyl, dialkylaminoalkyl, heterocyclic-substituted alkyl, acyl-substituted alkyl, thioacyl-substituted alkyl, amido-substituted alkyl, thioamido-substituted alkyl, carboxylato- substituted alkyl, thiocarboxylato-substituted alkyl, (amino-substituted acyl)alkyl, heterocyclic, carboxylic acid ester, ω-cyanoalkyl, ω-carboxylic ester-alkyl, halo d.₇ alkyl, 7 alkenyl, .7 alkynyl, arylalkenyl, aryloxyalkyi, arylalkyi and aryl; wherein the aryl moiety of each of said arylalkenyl, aryloxyalkyi, arylalkyi and aryl radicals is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1.7 alkyl, C₂.₇ alkenyl, C₂.₇ alkynyl, halo d.₇ alkyl, nitro, hydroxyl, sulfhydryl, amino, d.₇ alkoxy, C3.10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C1.7 alkyl, thio C₃.₁₀ cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, al kenyla mino , cyclo- alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydrazino, alkylhydrazino and phenylhydrazino; and

- R¹¹ is selected from the group consisting of halogen, cyano, carboxylic acid, acyl, thioacyl, alkoxycarbonyl, acyloxy, carbonate, carbamate, Ci-₇ alkyl, aryl, amino, acetamido, N- protected amino, (mono- or di) C ₇ alkylamino, (mono- or di) arylamino, (mono- or di) C₃-i₀ cycloalkylamino, (mono- or di) hydroxy C1-7 alkylamino, (mono- or di) d-₄ alkyl-arylamino, mercapto C1.7 alkyl, d.7 alkyloxy;

- R⁸ is selected from the group consisting of heteroaryl and aryl groups; halogen; C1.7 alkyl; C2.7 alkenyl; C₂.₇ alkynyl; halo d-7 alkyl; carboxy C1.7 alkyl; carboxyaryl; C1.7 alkoxy; C3.10 cycloalkoxy; aryloxy; arylalkyloxy; oxyheterocyclic; heterocyclic-substituted alkyloxy; thio C1.7 alkyl; thio C₃.,₀ cycloalkyl; thioaryl; thioheterocyclic; arylalkylthio; heterocyclic-substituted alkylthio; hydroxylamino; acylamino; thio-acylamino; alkoxyamino; thioalkyl-amino; acetal; thio-acetal; carboxylic acid; carboxylic acid esters, thioesters, halides, anhydrides, amides and thioamides; thiocarboxylic acid; thiocarboxylic acid esters, thioesters, halides, anhydrides, amides and thioamides ; hydroxyl ; sulfhydryl; nitro; cyano ; carbamoyl; thiocarbamoyl; ureido; thioureido; amino; alkylamino; cycloalkylamino; alkenylamino; cyclo- alkenylamino; alkynylamino; arylamino; arylalkylamino; hydroxyalkylamino; mercaptoalkylamino; heterocyclic amino; heterocyclic substituted arylamino; heterocyclic-substituted alkylamino; oximino; alkyloximino; hydrazino; alkylhydrazino; phenylhydrazino; esters, thioesters, halides, anhydrides, amides and thioamides thereof; aromatic or heterocyclic substituents substituted with an aliphatic spacer between the purine ring and the aromatic or heterocyclic substituent; wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, d.7 alkyl, C2-7 alkenyl, C2.7 alkynyl, halo d.₇ alkyl, nitro, hydroxyl, sulfhydryl, amino, d.7 alkoxy, C₃-io cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio d ₇ alkyl, thio C₃. ₁₀ cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino; and wherein said aliphatic spacer is a branched or straight, saturated or unsaturated aliphatic chain of 1 to 7 carbon atoms optionally containing one or more functions, atoms or radicals independently selected from the group consisting of halogen, carbonyl, thiocarbonyl, hydroxyl, thiol, ether, thio-ether, acetal, thio-acetal, amino, imino, oximino, alkyloximino, aminoacid, cyano, acylamino, thioacylamino, carbamoyl, thiocarbamoyl, ureido, thio-ureido, carboxylic acid ester or halide or anhydride or amide, thiocarboxylic acid or ester or thioester or halide or anhydride or amide, nitro, thio C_1-7 alkyl, thio C₃. ₀ cycloalkyl, hydroxylamino, mercaptoamino, alkyl-amino, cycloalkylamino, alkenylamino, cycloalkenylamino, alkynylamino, arylamino, arylalkyl-amino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic-substituted alkylamino, hetero-cyclic amino, heterocyclic-substituted arylamino, hydrazino, alkylhydrazino, phenylhydrazino, sulfonyl, sulfinyl and sulfonamido;

- R⁷ and R⁹ are selected from the group consisting of hydrogen, C₃.₇ alkenyl, C₂.7 alkynyl, halo Ci-7 alkyl, C₃. io cycloalkyl, aryl, arylalkyl, alkylaryl, acyl sulfonyl and d- alkyl , wherein said C1.7 alkyl is optionally containing one or more functions or radicals selected from the group consisting of halogen, carbonyl, thiocarbonyl, hydroxyl, sulfhydryl, d.7 alkoxy, thio -7 alkyl, thio C3-10 cycloalkyl, acetal, thioacetal, imino, oximino, alkyloximino, amino-acid, cyano, (thio)carboxylic acid, (thio)carboxylic acid ester or amide, nitro, amino, d-7 alkylamino, cycloalkylamino, alkenylamino, cycloalkenyl-amino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercapto-alkylamino, heterocyclic-substituted alkylamino, heterocyclic amino, heterocyclic-substituted arylamino, hydrazino, alkylhydrazino, phenylhydrazino, sulfonyl and sulfonamido),

wherein acyl group refers to a carbonyl group adjacent to a d-7 alkyl, a C₃.₁₀ cycloalkyl, an aryl, an arylalkyl or a heterocyclic group, or is selected from the group comprising alkanoyl, cycloalkanoyl, cycloalkyl-alkanoyl, alkenoyl, alkylthioalkanoyl, alkanesulfonyl, alkoxycarbonyl, alky!carbamoyl, alkylcarbamidoyl, alkoxalyl, aroyl, aralkanoyl, aralkenoyl, aryloxyalkanoyl, arylthioalkanoyl, arylaminoalkanoyl, aryloxycarbonyl, aralkoxycarbonyl, arylcarbamoyl, arylglyoxyloyl, arylthiocarbamoyl, arylcarbamidoyl, heterocyclic-carbonyl, heterocyclic- alkanoyl, wherein said heterocyclic group is an aromatic or non-aromatic 5- to 7-membered heterocyclic ring with one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur in said ring;

and/or a pharmaceutical acceptable addition salt thereof and/or a stereoisomer thereof and/or a solvate thereof; as a medicine for the prevention or treatment of a proliferative disorder such as cancer in an animal, mammal or human.

The present invention also concerns the use of a compound having formula I, II, III or IV, for use as a medicine for the prevention or treatment of proliferative disorders, including cancer, in an animal, preferably a mammal, and more preferably a human. The present invention also concerns the use of a compound having formula I, II, III or IV for the manufacture of a medicament for the prevention or treatment of a a proliferative disorder such as cancer in an animal, preferably a mammal, and more preferably a human.

In more specific embodiments of the invention, said proliferative disorder is cancer. In a more particular embodiment of the invention, said cancer is a hematological malignancy, such as leukemia (eg. Lymphoblastic T cell leukemia, Chronic myelogenous leukemia (CML), Chronic lymphocytic/lymphoid leukemia (CLL), Hairy-cell leukemia, acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (A L), myelodysplastic syndrome, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, Acute megakaryocytic leukemia, promyelocytic leukemia and Erythroleukemia) and lymphoma, more specifically malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma and follicular lymphoma, MALT1 lymphomas, Hodgkin lymphomas, B-cell non-Hodgkin lymphoma- and marginal zone lymphoma. In a more particular embodiment of the invention, said cancer is selected from the group of hematological malignancies comprising acute leukemia, chronic leukemia, lymphoma, multiple myeloma, myelodysplastic syndrome. In a more particular embodiment of the invention, said chronic leukemia is myeloid or lymphoid. In another more particular embodiment of the invention, said lymphoma is Hodgkin's or non-Hodgkin's lymphoma.

In another particular embodiment of the present invention, said cancer is a non- hematological cancer or solid tumor cancer such as cancer of the prostate, lung, breast, rectal, colon, lymph node, bladder, kidney, pancreatic, liver, ovarian, uterine, brain, skin, sarcoma, meningioma, glioblastoma , multiforme, skin , stomach , including all kinds of neuroblastoma, gastric carcinoma, renal cell carcinoma, neuroblastoma, gastric carcinoma, renal cell carcinoma, uterine cancer and muscle cancer. In another more particular embodiment of the present invention, said cancer proatate cancer.

The present invention also concern s a pharmaceutical composition comprising a therapeutically effective amount of a compound having formula I, II, III or IV, and one or more pharmaceutically acceptable exipients for use as a medicine for the prevention or treatment of a proliferative disorder such as cancer in an animal, mammal or human. Said composition may further comprise one or more biologically active drugs being selected from the group consisting of immunosuppressant and/or immunomodulator drugs, and/or antineoplastic drugs.

The present invention also concerns a method of prevention or treatment of proliferative disorder, including cancer such as hematological malignancies, including acute leukemia, chronic leukemia (myeloid or lymphoid), lymphoma (Hodgkin's or non-Hodgkin's), multiple myeloma, myelodysplastic syndrome, or non-hematological cancers such as prostate carcinoma, in an animal, comprising the administration of a therapeutically effective amount of a compound having formula I, II, III or IV, optionally in combination with one or more pharmaceutically acceptable excipients.

The present invention will now be further described. In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

DETAILED DESCRIPTION OF THE INVENTION

One embodiment of the present invention concerns a compound according to the invention, including the use of said compound according to the invention, wherein, R³ and R² have any of the values as described herein and R¹ is selected from the extended group consisting of hydrogen, C_R7 alkyl, amino, halogen, cyano, carboxylic acid, acyl, thioacyl, alkoxycarbonyl, acyloxy, carbonate, carbamate, aryl, acetamido, /V-protected amino, (mono- or di) C₁-7 alkylamino, (mono- or di) arylamino, (mono- or di) C3-10 cycloa!kylamino, (mono- or di) hydroxy C_r7 alkylamino, (mono- or di) d.₄ alkyl-arylamino, mercapto C1.7 alkyl, and C1.7 alkyloxy.

One embodiment of the present invention concerns a compound according to the invention, including the use of said compound according to the invention, wherein, R³ and R² have any of the values as described herein and R¹ is selected from the group comprising aryl, amino, acetamido, /V-protected amino, (mono- or di) C ₇ alkylamino, (mono- or di) arylamino, (mono- or di) C₃-₁₀ cycloalkylamino, (mono- or di) hydroxy C ₇ alkylamino, (mono- or di) d.₄ alkyl-arylamino; preferably, said R¹ is selected from the group comprising amino, /V-protected amino, (mono- or di) C ₇ alkylamino, (mono- or di) arylamino, (mono- or di) C₃- ₀ cycloalkylamino, (mono- or di) C- alkyl-arylamino; preferably, said R¹ is selected from the group comprising amino, (mono- or di) C ₇ alkylamino, (mono- or di) arylamino; preferably, said R¹ is selected from the group comprising amino, and (mono- or di) C1-7 alkylamino; more preferably R is amino.

One embodiment of the present invention concerns a compound according to the invention, including the use of said compound according to the invention, wherein, R⁶ and R⁵ have any of the values as described herein and R⁴ is selected from the extended group consisting of hydrogen, C ₇ alkyl, amino, halogen, cyano, carboxylic acid, acyl, thioacyl, alkoxycarbonyl, acyloxy, carbonate, carbamate, aryl, acetamido, /V-protected amino, (mono- o r di) d-7 alkylamino, (mono- or di) arylamino, (mono- or di) C₃-₁₀ cycloalkylamino, (mono- or di) hydroxy d-7 alkylamino, (mono- or di) d-o alkyl-arylamino, mercapto d-7 alkyl, and d-7 alkyloxy.

One embodiment of the present invention concerns a compound according to the invention, including the use of said compound according to the invention, wherein, R³ and R¹ have any of the values as described herein and R² is selected from the extended group consisting of hydrogen, acylamino, heteroaryl and aryl groups; halogen; C₁.7 alkyl; C₂.₇ alkenyl; C₂.₇ alkynyl; halo d-7 alkyl; C₃.₁₀ cycloalkyl; carboxy Ci_-7 alkyl; carboxyaryl; d^ alkoxy; C₃.₁₀ cycloalkoxy; aryloxy; arylalkyloxy; oxyheterocyclic; heterocyclic-substituted alkyloxy; thio d-7 alkyl; thio C₃. io cycloalkyl; thioaryl; thioheterocyclic; arylalkylthio; heterocyclic-substituted alkylthio; hydroxylamino; thio-acylamino; alkoxyamino; thioalkyl-amino; acetal; thio-acetal; carboxylic acid; carboxylic acid esters, tricarboxylic acid; tricarboxylic acid esters, thioesters, halides, anhydrides, amides and thioamides; hydroxyl; sulfhydryl; nitro; cyano; carbamoyl; thiocarbamoyl; ureido; thioureido; amino; alkylamino; cycloalkylamino; alkenylamino; cyclo- alkenylamino; alkynylamino; arylamino; arylalkylamino; hydroxyalkylamino; mercaptoalkyl- amino; heterocyclic amino; heterocyclic substituted arylamino; heterocyclic-substituted alkylamino; oximino; alkyloximino, hydrazine, alkylhydrazino; phenylhydrazino; esters, thioesters, halides, anhydrides, amides and thioamides thereof; aromatic or heterocyclic substituents substituted with an aliphatic spacer between the thiazolo(5,4-d)pyrimidine or oxazolo(5,4- d)pyrimidine ring and the aromatic or heterocyclic substituent, wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, -7 alkyl, d-7 alkenyl, C₂.7 alkynyl, halo d-₇ alkyl, nitro, hydroxyl, sulfhydryl, amino, -7 alkoxy, C_{3 10} cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio d-7 alkyl, thio d-10 cycloalkyl, thioaryl, thioheterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, a l kenyl a m i n o , cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino; wherein said aliphatic spacer is a branched or straight, saturated or unsaturated aliphatic chains of 1 to 7 carbon atoms optionally containing one or more functions, atoms or radicals independently selected from the group consisting of halogen, carbonyl, thiocarbonyl, hydroxyl, thiol, ether, thio-ether, acetal, thio-acetal, amino, imino, oximino, alkyloximino, aminoacid, cyano, acylamino, thioacylamino, carbamoyl, thiocarbamoyl, ureido, thio-ureido, carboxylic acid ester or halide or anhydride or amide, thiocarboxylic acid or ester or thioester or halide or anhydride or amide, nitro, thio Ch alky!, thio C3.10 cycloalkyl, hydroxylamino, mercaptoamino, alkyl-amino, cycloalkylamino, alkenylamino, cycloalkenylamino, alkynylamino, arylamino, arylalkyl-amino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic-substituted alkylamino, hetero-cyclic amino, heterocyclic-substituted arylamino, hydrazino, alkylhydrazino, phenylhydrazino, sulfonyl, sulfmyl and sulfonamido.

One embodiment of the present invention concerns a compound according to the invention, including the use of said compound according to the invention, wherein, R⁶ and R⁴ have any of the values as described herein and R⁵ is selected from the extended group consisting of hydrogen, heteroaryl and aryl groups, wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, d-_? alkyl, C₂.₇ alkenyl, C₂.y alkynyl, halo d-7 alkyl, nitro, hydroxyl, sulfhydryl, amino, C_{1 7} alkoxy, C3-10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C1.7 alkyl, thio C3.10 cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, and heterocyclic amino.

In an embodiment, the present invention concern a compound of formula I , II , III or IV, a pharmaceutical acceptable addition salt thereof and/or a stereoisomer thereof and/or a solvate thereof, including the use of said compound according to the invention, wherein R¹ , R⁴, and R¹¹ are each independently selected from the group consisting of amino, acetamido, A/-protected amino, (mono- or di) C ₇ alkylamino, (mono- or di) arylamino, (mono- or di) C₃-₁₀ cycloalkylamino, (mono- or di) hydroxy C1-7 alkylamino, (mono- or di) C1.4 alkyl-arylamino.

One embodiment of the present invention concerns a compound according to the invention, including the use of said compound according to the invention, wherein X is S. Another embodiment of the present invention concerns a compound according to the invention, including the use of said compound according to the invention, wherein X is O.

One embodiment of the present invention concerns a compound according to the invention, including the use of said compound according to the invention, wherein R¹ and R² have any of the values as described herein and R³ is selected from the group consisting of monoarylamino; diarylamino; (mono- or di-) aryld.₄ alkylamino; morpholinyl; d.7 alkoxy, aralkylthio, piperidinyl, pyrrolidinyl, homopiperazinyl and piperazinyl, wherein said piperidinyl, pyrrolidinyl, homopiperazinyl or piperazinyl is optionally N-substituted with a substituent R²⁰, wherein R²⁰ has the same meaning as defined herein.

One embodiment of the present invention concerns a compound according to the invention, including the use of said compound according to the invention, wherein R⁴ and R⁵ have any of the values as described herein and R⁶ is selected from the group consisting of (mono- or di-) Ci-12 alkylamino, monoarylamino, diarylamino, (mono- or di-) C3.10 cycloalkylamino, (mono- or di-) aryld o alkylamino, morpholinyl, C₁.7 alkoxy, homopiperazinyl and piperazinyl, wherein said homopiperazinyl or piperazinyl is optionally N-substituted with a substituent R²¹, wherein R²¹ has the same meaning as that defined in herein.

One embodiment of the present invention concerns a compound according to the invention, including the use of said compound according to the invention, wherein R ¹, R⁷, R⁸ and R⁹ have any of the values as described herein and n is 0 and R¹⁰ is selected from the group consisting of formyl, acyl, thioacyl, amide, thioamide, sulfonyl, sulfinyl, carboxylate, thiocarboxylate, amino-substituted acyl, alkoxyalkyl, C₃.,₀ cycloalkyl-alkyl, C3.10 cycloalkyl, dia!kylaminoalkyl, heterocyclic-substituted alkyl, acyl-substituted alky I, thioacyl-substituted alkyl, amido-substituted alkyl, thioamido-substituted alkyl, carboxylato-substituted alkyl, thiocarboxylato-substituted alkyl, (amino-substituted acyl)alkyl, heterocyclic, carboxylic acid ester, ω-carboxylic ester-alkyl, aryloxyalkyl, arylalkyl and aryl; wherein the aryl moiety of each of said aryloxyalkyl, arylalkyl and aryl radicals is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -7 alkyl, halo C₁.7 alkyl, nitro, hydroxy!, sulfhydryl, amino, d- alkoxy, C₃.i₀ cycloalkoxy, aryloxy, arylalkyloxy, fo rmy l , ca rba moyl , th i oca rba moyl , su lfo n am ide hydroxyla mino , a l koxy-amino, mercaptoamino, thioalkylamino, cyano, alkylamino, cycloalkylamino.

One embodiment of the present invention concerns a compound according to the invention, including the use of said compound according to the invention, wherein R¹ and R³ have any of the values as described herein R² is selected from the group consisting of heteroaryl and aryl groups; d-7 alkyl; C3.10 cycloalkyl; halo -7 alkyl; carboxy C₁.7 alkyl; carboxyaryl; C1.7 alkoxy; C₃.₁₀ cycloalkoxy; aryloxy; arylalkyloxy; heterocyclic-substituted alkyloxy; thio C1.7 alkyl; thio C₃.₁₀ cycloalkyl; thioaryl; thioheterocyclic; arylalkylthio; heterocyclic-substituted alkylthio; hydroxylamino; acylamino; thio-acylamino; alkoxyamino; carbamoyl; thiocarbamoyl; aromatic or heterocyclic substituents substituted with an aliphatic spacer between the thiazolo(5,4-d)pyrimidine or oxazolo(5,4-d)pyrimidine ring and the aromatic or heterocyclic substituent, wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, d-7 alkyl, halo d-7 alkyl, nitro, hydroxyl, sulfhydryl, amino, d-7 alkoxy, C₃.₁₀ cycloalkoxy, aryloxy, arylalkyloxy, thio d-7 alkyl, thio C3.10 cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, carbamoyl, thiocarbamoyl, sulfonamido , hydroxyla mino , a lkoxy-amino , acylamino , thioacylamino, cyano, wherein said aliphatic spacer is a branched or straight, saturated or unsaturated aliphatic chains of 1 to 7 carbon atoms optionally containing one or more functions, atoms or radicals independently selected from the group consisting of halogen, thiol, ether, thio-ether, amino, cyano, acylamino, nitro, thio d.₇ alkyl.

One embodiment of the present invention concerns a compound according to the invention, including the use of said compound according to the invention, wherein R⁴ and R⁶ have any of the values as described herein and R⁵ is an aryl group, wherein said aryl group is optionally substituted with one or more substituents selected from the group consisting of halogen, C_{1 7} alkyl, halo -7 alkyl, nitro, hydroxyl, sulfhydryl, -7 alkoxy, thio C_h alky!, cyano. One embodiment of the present invention concerns a compound according to the invention, including the use of said compound according to the invention, wherein R¹¹, R⁷, R¹² and R⁹ have any of the values as described herein, and R⁸ is selected from the group consisting of heteroaryl and aryl groups; d.₇ alkyl; halo .? alkyl; d- alkoxy; C₃.₁₀ cycloalkoxy; aryloxy; arylalkyloxy; thio Ci.₇ alkyl; thio C₃.₁₀ cycloalkyl; thioaryl; thioheterocyclic; arylalkylthio; heterocyclic-substituted alkylthio; aromatic or heterocyclic substituents substituted with an aliphatic spacer between the purine ring and the aromatic or heterocyclic substituent; wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, Ci.₇ alkyl, halo d-7 alkyl, nitro, hydroxyl, sulfhydryl, amino, d-7 alkoxy, C₃.₁₀ cycloalkoxy, thio Ci. alkyl, and wherein said aliphatic spacer is a branched or straight, saturated or unsaturated aliphatic chain of 1 to 7 carbon atoms optionally containing one or more functions, atoms or radicals independently selected from the group consisting of halogen, carbonyl, hydroxyl, thiol, cyano, nitro, thio Ci.₇ alkyl, thio C₃.io cycloalkyl.

One embodiment of the present invention concerns a compound according to the invention, including the use of said compound according to the invention, wherein R³, R⁶ are each independently homopiperazinyl or piperazinyl, wherein said homopiperazinyl or piperazinyl is each respectively optionally N-substituted with a substituent R²⁰, R²¹, wherein R²⁰ and R²¹ have the same meaning as that defined herein.

One embodiment of the present invention concerns a compound according to the invention, including the use of said compound according to the invention, wherein R¹ , R⁴ and R¹¹ are each independently amino.

One embodiment of the present invention concerns a compound according to the invention, including the use of said compound according to the invention, wherein R¹ and R³ have any of the values as described herein and R² is selected from the group consisting of phenyl; pyridin-3-yl; pyridin-2-yl; pyridin-4-yl; 4-fluorophenethyl; 4-fluorophenyl; 4-bromophenethyl; pentyl; tolyl; (4-fluorophenyl)butyl; (4-fluorophenyl)propyl; 4-chlorophenyl; 4-methylphenethyl; 3,4-dimethoxyphenethyl; 3-methoxyphenethyl; furan-2-y I ; 2-phenylethyl; cyclohexyl; methoxylmethyl; cyclopropyl; 2-thiophen-2-ylethyl; cyclopentyl-(4-fluorophenyl)methyl; 1 -(4- fluorophenyl)propyl; 4-fluorophenylamino; methylsulfinyl; 1 -(4-chlorophenyl)ethyl; 3- methoxyphenyl; 4-chlorophenyl; 4-chlorophenylmethyl; N-oxopyridine-3-yl; 1 -(4- chlorophenyl)cyclopropyl; 3,4-dichlorophenyl; methylthio; 1 -phenylcyclopropyl; 1-(4- fluorophenyl)ethyl; 1-(4-fluorophenyl)-2-phenylethyl; 2-(4-fluorophenoxy)ethyl; moφholino; preferably 4-fluorophenyl, 4-fluorobenzyl, 4-fluorophenethyl, 2-(4-fluorophenoxy)ethyl, 1 -(4- fluorophenyl)ethyl, 1 -(4-fluorophenyl)-2-phenylethyl, 3-pyridyl, 3-methoxyphenyl, cyclopropyl, cyclohexyl, 3,4-dichlorophenyl, 1-phenylcyclopropyl, 1 -(4-chlorophenyl)cyclopropyl, 2- thiophen-2-ylethyl, pentyl, and 2-phenylethyl.

One embodiment of the present invention concerns a compound according to the invention, including the use of said compound according to the invention, wherein R⁴ and R⁶ have any of the values as described herein and R⁵ is phenyl or 4-fluorophenyl.

One embodiment of the present invention concerns a compound according to the invention, including the use of said compound according to the invention, wherein R¹ and R² have any of the values as described herein and R³ is selected from the group consisting of p-tolyl piperazinyl-1-carboxylate; N-methyl-N-p-tolylpiperazinyl-1-carboxamide; N-p-tolylpiperazinyl- 1-carbothioamide; -N-hexylpiperazinyl-1-c a r b o x a m i d e ; 4-(N-4- fluorophenylcarboxamide)piperazin-1-yl; N-cyclohexylpiperazinyl-1 -carboxamide; N- phenylpiperazinyl-1-carboxamide; N-(4-(trifluoromethyl)phenyl)piperazinyl-1 -carboxamide, piperazin-1 -yl-2-(4-chlorophenoxy)ethanone; piperazin-1 -yl-2-(4-methoxyphenoxy)ethanone; benzylsulfonylpiperazin-1 -yl; N-(4-cyanophenyl)piperazinyl-1 -carboxamide; N-(4- methoxybenzyl)piperazinyl-1-carboxamide; N-(4-chlorophenyl)piperazinyl-1 -carboxamide; N- m-tolylpiperazinyl-1 -carboxamide; piperazin-1 -yl-2-(m-tolyloxy)ethanone; piperazin-1-yl-2-(4- chlorophenoxy)-2-methylpropan-1-one; piperazin-1-yl-2-(4- trifluoromethoxyphenoxy)ethanone;piperazin-1 -yl-2-(4-fluorophenoxy)ethanone; piperazin-1 - yl-2-(4-bromophenoxy)ethanone; piperazin-1 -yl-3-(4-fluorophenyl)propan-1 -one; piperazin-1 - yl-2-(3-chlorophenoxy)ethanone; 4-acetylphenoxy-piperazin-1 -yl-ethanone; piperazin-1 -yl-2- oxoethoxy)benzoate; piperazin-1 -yl-2-(4-hydroxyphenoxy)ethanone; piperazin-1 -yl-3-(4- bromophenyl)propan-1-one; N-(2-methoxyphenyl)piperazinyl-carboxamide; N-(4- bromophenyl)piperazinyl-carboxamide; N-(2,4-difluorophenyl)piperazinyl-carboxamide; piperazin-1 -yl-2-(4-chloro-2-methylphenoxy)ethanone; piperazin-1 -yl-2-(2,4- dichlorophenoxy)ethanone; (methylphenyl-carbamoyl)methyl]piperazin-1-yl; phenoxyethyl)piperazin-1 -yl; ( 4-chlorophenyl)acetyl]-piperazin-1 -yl; (4-chlorophenyl)acetyl)- piperazin-1 -yl; [2-(3-nitrophenoxy)acetyl]-piperazin-1-yl; 4-(2-methoxyethyl)-piperazin-1 -yl; 4- acetylpiperazin-1 -yl; 4-isobutylpiperazin-1 -yl; 3-chloro-4-fluorophenyl-amino; 4-(2- phenoxyethyl)piperazin-1 -yl; 4-benzoylpiperidine-1 -yl; 4-chlorophenoxyacetyl)pyrrolidin-3- (S)-ylamino; 1 -tert-butoxycarbonylpyrrolidin-3-(S)-ylamino; 1 -benzyloxycarbonylpiperidin-3- y I a m i n o ; 3-(R)-(4-chlorobenzoylamino)-pyrrolidin-1-yl; 3-(R)-[2-(4-chlorophenoxy)- acetylamino]pyrrolidin-1-yl; 3-(R)-tert-butoxycarbonylamino; 4-(phenethylcarbamoyl- methyl)piperazin-1 -yl; 4-thiazol-2-yl-piperazine-1 -yl; 4-[(methylphenylcarbamoyl)- methyl]piperazin-1-yl; 4-chlorophenoxy)acetyl]homopiperazin-1 -yl; 4- phenylmethanesulfonylpiperazin-1-yl; 4-(3-phenylpropionyl)piperazin-1 -yl; 4-[2- phenoxyacetyl]piperazin-1 -yl; 4-[2-(4-chlorophenyl)acetyl]piperazin-1 -yl; 4-[2-(3- nitrophenoxy)acetyl]piperazin-1 -yl; 4-(phenylsulfonyl)piperazin-1 -yl; pyrimidin-7-yl- piperazinyl-1-carboxylate; 4-benzylpiperazin-1-yl; piperazin-1 -yl-1 -moφholinoethaπone; 4- pentylpiperazin-1 -yl; 4-(thiazol-2-yl)piperazin-1 -yl; 4-m-tolylpiperazin-1 -yl; 3- methoxypropylamino; ethoxy; 2-methoxyethoxy; benzylthio; benzyl amino; preferably methylthio, piperazin-1 -yl, ethoxy, moφholino, 4-m-tolylcarbamoyl-piperazin-1-yl, 4-(4- chlorophenoxyacetyl)piperazin-1 -yl, 4-[2-(4-bromophenoxy)acetyl]-piperazin-1-yl, 4-[2-(3- nitrophenoxy)acetyl]-piperazin-1 -yl, and 4-(2-phenoxyacetyl)-piperazin-1 -yl.

One embodiment of the present invention concerns a compound according to the invention, including the use of said compound according to the invention, wherein R² is selected from the group consisting of 4-fluorophenyl, 4-fluorobenzyl, 4-fluorophenethyl, 2-(4- fluorophenoxy)ethyl, 1 -(4-fluorophenyl)ethyl, 1 -(4-fluorophenyl)-2-phenylethyl, 3-pyridyl, 3- methoxyphenyl, cyclopropyl, cyclohexyl, 3,4-dichlorophenyl, 1 -phenylcyclopropyl, 1 -(4- chlorophenyl)cyclopropyl, 2-thiophen-2-ylethyl, pentyl, and 2-phenylethyl; R¹ and is amino; and R³ is selected from the group consisting of methylthio, piperazin-1 -yl, ethoxy, morpholino, 4-m-tolylcarbamoyl-piperazin-1-yl, 4-(4-chlorophenoxyacetyl)piperazin-1 -yl, 4-[2- (4-bromophenoxy)acetyl]-piperazin-1-yl, 4-[2-(3-nitrophenoxy)acetyl]-piperazin-1 -yl, and 4-(2- phenoxyacetyl)-piperazin-1 -yl.

One embodiment of the present invention concerns a compound according to the invention, including the use of said compound according to the invention, wherein R⁴ and R⁵ have any of the values as described herein and R⁶ is 4(rn-tolylcarbamoyl)piperazin-1-yl or 4-(2-(4- chlorophenoxy)acetyl)piperazin-1-yl.

One embodiment of the present invention concerns a compound according to the invention, including the use of said compound according to the invention, wherein R⁷, R⁸, R⁹, and R¹ have any of the values as described herein and R¹² is 4-(4-chlorophenoxy)acetylpiperazin-1 - yl or 4-(phenoxyacetyl)piperazin-1-yl.

One embodiment of the present invention concerns a compound according to the invention, including the use of said compound according to the invention, wherein R⁵ is phenyl or 4- fluorophenyl; R⁴ is amino; and R⁶ is (4(m-tolylcarbamoyl)piperazin-1 -y I o r ( 4-(2-(4- chlorophenoxy)acetyl)piperazin-1 -yl).

One embodiment of the present invention concerns a compound according to the invention, including the use of said compound according to the invention, wherein R⁷, R¹², R⁹, and R^{1 1} have any of the values as described herein and R⁸ is 4-fluorophenyl or methylthio.

One embodiment of the present invention concerns a compound according to the invention, including the use of said compound according to the invention, wherein R¹², R⁸, and R ¹ have any of the values as described herein R⁹ is hydrogen or methyl.

One embodiment of the present invention concerns a compound according to the invention, including the use of said compound according to the invention, wherein R⁸, R¹², and R^{1 1} have any of the values as described herein R⁷ is hydrogen or methyl.

One embodiment of the present invention concerns a compound according to the invention, including the use of said compound according to the invention, wherein R ¹ is amino, R ² is 4-(4-chlorophenoxy)acetylpiperazin-1 -yl or (4-phenoxyacetyl)piperazin-1 -yl, R⁸ is 4- fluorophenyl or methylthio, and R⁹ is hydrogen or methyl.

One embodiment of the present invention concerns a compound according to the invention , including the use of said compound according to the invention, wherein R¹¹ is amino, R¹² is 4-(4-chlorophenoxy)acetylpiperazin-1 -yl or 4-(phenoxyacetyl)piperazin-1 -yl, R⁸ is 4- fluorophenyl or methylthio, and R⁷ is hydrogen or methyl.

In an embodiment, the present invention encompasses a thiazolo(5,4-d)pyrimidine or oxazolo(5,4-d)pyrimidine derivative having the general formula I, including the use according to the invention of said thiazolo(5 ,4-d)pyrimidine or oxazolo(5,4-d)pyrimidine derivative having the general formula I, wherein

- X is S or O;

- R¹ is selected from the group consisting of hydrogen, halogen, cyano, carboxylic acid, acyl, thioacyl, alkoxycarbonyl, acyloxy, carbonate, carbamate, C₁-7 alkyl, aryl, amino, acetamido, /V-protected amino, (mono- or di) C₁-7 alkylamino, (mono- or di) arylamino, (mono- or di) C3-10 cycloalkylamino, (mono- or di) hydroxy C1-7 alkylamino, (mono- or di) alkyl-arylamino, mercapto C_1-7 alkyl, C₁.7 alkyloxy;

- R³ is selected from the group consisting of (mono- or di-) CM₂ alkylamino; monoarylamino; diarylamino; (mono- or di-) C₃.₁₀ cycloalkylamino; (mono- or di-) hydroxy C₁.7 alkylamino; (mono- or di-) C₁.₄ alkylarylamino; (mono- or di-)

alkylamino; morpholinyl; mercapto C 7 alkyl; C ₇ alkoxy, homopiperazinyl and piperazinyl,

wherein said homopiperazinyl or piperazinyl is optionally N-substituted with a substituent R²⁰ selected from the group consisting of formyl, acyl, thioacyl, amide, thioamide, sulfonyl, sulfinyl, carboxylate, thiocarboxylate, amino-substituted acyl, alkoxyalkyl, C₃.₁₀ cycloalkyl-alkyl, C₃.i₀ cycloalkyl, dialkylaminoalkyl, heterocyclic- substituted alkyl, acyl-substituted alkyl, thioacyl-substituted alkyl, amido-substituted alkyl, thioamido-substituted alkyl, carboxylato-substituted alkyl, thiocarboxylato- substituted alkyl, (amino-substituted acyl)alkyl, heterocyclic, carboxylic acid ester, ω- cyanoalkyl, ω-carboxylic ester-alkyl, halo d.₇ alkyl, C₂.₇ alkenyl, C₂.₇ alkynyl, arylalkenyl, aryloxyalkyl, arylalkyl and aryl,

wherein the aryl moiety of each of said arylalkenyl, aryloxyalkyl, arylalkyl and a ryl radica ls is optiona lly su bstituted with one or more su bstituents independently selected from the group consisting of halogen, Ci.₇ alkyl, C₂.₇ alkenyl, C₂.₇ alkynyl, halo C _l alkyl, nitro, hydroxyl, sulfhydryl, amino, C^.₁ alkoxy, C₃.io cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic- substituted alkyloxy, thio CL₇ alkyl, thio C₃-i₀ cycloalkyl, thioaryl, thio- heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo- alkenylamino, a lky ny l amino , aryla mino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydrazino, alkylhydrazino and phenylhydrazino; and

- R² is selected from the group consisting of heteroaryl and aryl groups; hydrogen; halogen; Ci.7 alkyl; C_{2 7} alkenyl; C₂.₇ alkynyl; halo C_{1 7} alkyl; carboxy d.₇ alkyl; carboxyaryl; alkoxy; C3.10 cycloalkoxy; aryloxy, arylalkyloxy; oxyheterocyclic; heterocyclic-substituted alkyloxy; thio C₁.7 alkyl; thio C3.10 cycloalkyl; thioaryl; thioheterocyclic; arylalkylthio; heterocyclic-substituted alkylthio; hydroxylamino; acylamino; thio-acylamino; alkoxyamino; thioalkyl-amino; acetal; thio-acetal; carboxylic acid; carboxylic acid esters, thioesters, halides, anhydrides, amides and thioamides; thiocarboxylic acid; thiocarboxylic acid esters, thioesters, halides, anhydrides, amides and thioamides; hydroxyl; sulfhydryl; n itro , cyano ; carbamoyl ; thiocarbamoyl; ureido; thioureido; amino; alkylamino; cycloalkylamino; alkenylamino; cyclo- alkenylamino; alkynylamino; arylamino; arylalkylamino; hydroxyalkylamino; mercaptoalkylamino; heterocyclic amino; heterocyclic substituted arylamino; heterocyclic-substituted alkylamino; oximino; alkyloximino; hydrazino; alkylhydrazino; phenylhydrazino; esters, thioesters, halides, anhydrides, amides and thioamides thereof ; aromatic or heterocyclic substituents substituted with an aliphatic spacer between the thiazolo(5,4-d)pyrimidine or oxazolo(5,4- d)pyrirmidine ring and the aromatic or heterocyclic substituent, - wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, C1.7 alkyl, C₂.7 alkenyl, C₂. 7 alkynyl, halo C1-7 alkyl, nitro, hydroxyl, sulfhydryl, amino, C1.7 alkoxy, C3.10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio CL_? alkyl, thio C₃.i₀ cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-su bstituted alkylthio , formyl , carbamoyl , th ioca rbamoyl , ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino; and

- wherein said aliphatic spacer is a branched or straight, saturated or unsaturated aliphatic chains of 1 to 7 carbon atoms optionally containing one or more functions, atoms or radicals independently selected from the group consisting of halogen, carbonyl, thiocarbonyl, hydroxyl, thiol, ether, thio-ether, acetal, thio-acetal, amino, imino, oximino, alkyloximino, aminoacid, cyano, acylamino, thioacylamino, carbamoyl, thiocarbamoyl, ureido, thio-ureido, carboxylic acid ester or halide or anhydride or amide, thiocarboxylic acid or ester or thioester or halide or anhydride or amide, nitro, thio C1.7 alkyl, thio C₃.₁₀ cycloalkyl, hydroxylamino, mercaptoamino, alkyl-amino, cycloalkylamino, alkenylamino, cycloalkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic-substituted alkylamino, hetero-cyclic amino, heterocyclic-substituted arylamino, hydrazino, alkylhydrazino, phenylhydrazino, sulfonyl, sulfinyl and sulfonamido; and/or

a pharmaceutical acceptable addition salt thereof and/or a stereoisomer thereof and/or a solvate thereof.

One embodiment of the present invention concerns thiazolo(5,4-d)pyrimidine or oxazolo(5,4- d)pyrimidine of formula I, any subgroup thereof, or stereoisomeric forms thereof, including the use according to the invention of said thiazolo(5,4-d)pyrimidine or oxazolo(5,4- d)pyrimidine of formula I, any subgroup thereof, or stereoisomeric forms thereof, wherein R² and R³ have any of the values as described herein and R¹ is selected from the group consisting of amino, acetamido, /V-protected amino, (mono- or di) C1-7 alkylamino, (mono- or di) arylamino, (mono- or di) C₃-i₀ cycloalkylamino, (mono- or di) hydroxy d-₇ alkylamino, (mono- or di) C alkyl-arylamino.

One embodiment of the present invention concerns thiazolo(5,4-d)pyrimidine or oxazolo(5,4- d)pyrimidine of formula I, any subgroup thereof, or stereoisomeric forms thereof, including the use according to the invention of said thiazolo(5,4-d)pyrimidine or oxazolo(5,4- d)pyrimidine of formula I, any subgroup thereof, or stereoisomeric forms thereof, wherein R² and R¹ have any of the values as described herein and R³ is homopiperazinyl or piperazinyl.

One embodiment of the present invention concerns thiazolo(5,4-d)pyrimidine or oxazolo(5,4- d)pyrimidine of formula I, any subgroup thereof, or stereoisomeric forms thereof, including the use according to the invention of said thiazolo(5,4-d)pyrimidine or oxazolo(5,4- d)pyrimidine of formula I, any subgroup thereof, or stereoisomeric forms thereof, wherein R¹ and R³ have any of the values as described herein and R² is selected from the group consisting of 4-fluorophenyl, 4-fluorobenzyl, 4-fluorophenethyl, 2-(4-fluorophenoxy)ethyl, 1 - (4-fluorophenyl)ethyl , 1 -(4-fluorophenyl)-2-phenylethyl, 3-pyridyl, 3-methoxyphenyl, cyclopropyl, cyclohexyl, 3,4-dichlorophenyl, 1 -phenylcyclopropyl, 1 -(4- chlorophenyl)cyclopropyl, 2-thiophen-2-ylethyl, pentyl, and 2-phenylethyl.

One embodiment of the present invention concerns thiazolo(5,4-d)pyrimidine or oxazolo(5,4- d)pyrimidine of formula I, any subgroup thereof, or stereoisomeric forms thereof, including the use according to the invention of said thiazolo(5,4-d)pyrimidine or oxazolo(5,4- d)pyrimidine of formula I, any subgroup thereof, or stereoisomeric forms thereof, wherein R² and R³ have any of the values as described herein and R¹ is selected from the group consisting of amino, methyl, and hydrogen.

One embodiment of the present invention concerns thiazolo(5,4-d)pyrimidine or oxazolo(5,4- d)pyrimidine of formula I, any subgroup thereof, or stereoisomeric forms thereof, including the use according to the invention of said thiazolo(5,4-d)pyrimidine or oxazolo(5,4- d)pyrimidine of formula I, any subgroup thereof, or stereoisomeric forms thereof, wherein R² and R have any of the values as described herein and R³ is selected from the group consisting of methylthio, piperazin-1-yl, ethoxy, morpholino, 4-m-tolylcarbamoyl-piperazin-1 - yl , 4-(4-chlorophenoxyacetyl)piperazin-1-yl, 4-[2-(4-bromophenoxy)acetyl]-piperazin-1 -yl, 4- [2-(3-nitrophenoxy)acetyl]-piperazin-1 -yl, and 4-(2-phenoxyacetyl)-piperazin-1-yl.

One embodiment of the present invention concerns thiazolo(5,4-d)pyrimidine or oxazolo(5,4- d)pyrimidine of formula I, any subgroup thereof, or stereoisomeric forms thereof, including the use according to the invention of said thiazolo(5,4-d)pyrimidine or oxazolo(5,4- d)pyrimidine of formula I, any subgroup thereof, or stereoisomeric forms thereof, wherein R² is selected from the group consisting of 4-fluorophenyl, 4-fluorobenzyl, 4-fluorophenethyl, 2- (4-fluorophenoxy)ethyl, 1-(4-fluorophenyl)ethyl, 1 -(4-fluorophenyl)-2-phenylethyl, 3-pyridyl, 3- methoxyphenyl, cyclopropyl, cyclohexyl, 3 ,4-dichlorophenyl, 1 -phenylcyclopropyl, 1 -(4- chlorophenyl)cyclopropyl, 2-thiophen-2-ylethyl, pentyl, and 2-phenylethyl; R⁵ is selected from the group consisting of amino, methyl, and hydrogen; and R⁷ is selected from the group consisting of methylthio, piperazin-1-yl, ethoxy, morpholino, 4-m-tolylcarbamoyl-piperazin-1 - yl , 4-(4-chlorophenoxyacetyl)piperazin-1-yl, 4-[2-(4-bromophenoxy)acetyl]-piperazin-1-yl, 4- [2-(3-nitrophenoxy)acetyl]-piperazin-1-yl, and 4-(2-phenoxyacetyl)-piperazin-1-yl. One embodiment of the present invention concerns thiazolo(5,4-d)pyrimidine or oxazolo(5,4- d)pyrimidine of formula I, any subgroup thereof, or stereoisomeric forms thereof, including the use according to the invention of said thiazolo(5,4-d)pyrimidine or oxazolo(5,4- d)pyrimidine of formula I, any subgroup thereof, or stereoisomeric forms thereof, wherein X is S. One embodiment of the present invention concerns thiazolo(5,4-d)pyrimidine or oxazolo(5,4-d)pyrimidine of formula I, any subgroup thereof, or stereoisomeric forms thereof, wherein X is O.

One embodiment of the present invention concerns thiazolo(5,4-d)pyrimidine or oxazolo(5,4- d)pyrimidine of formula I, any subgroup thereof, or stereoisomeric forms thereof, including the use according to the invention of said thiazolo(5,4-d)pyrimidine or oxazolo(5,4- d)pyrimidine of formula I, any subgroup thereof, or stereoisomeric forms thereof, being selected from the group consisting of: 2-(4-fluorophenyl)-7-(methylthio)thiazolo[5,4- d]pyrimidin-5-amine; 2-(4-fluorobenzyl)-7-(methylthio)thiazolo[5,4-d]pyrimidin-5-amine; 2-(4- fluorophenethyl)-7-methylthio-thiazolo[5,4-d]pyrimidin-5-amine; 2-(2-(4-fluorophenoxy)ethyl)- 7-(methylthio)thiazolo[5,4-d]pyrimidin-5-amine; 2-(4-fluorophenyl)-5-methyl-7-methylthio- thiazolo[5,4-d]pyrimidine; 2-(4-fluorophenyl)-7-(piperazin-1 -yl)-thiazolo[5,4-d]pyrimidin-5- amine; 2-(4-fluorobenzyl)-7-(piperazin-1 -yl)-thiazolo[5,4-d]pyrimidin-5-amine; 2-(4- fluorophenethyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine; 7-(benzylthio)-2-(4- fluorophenyl)thiazolo[5,4-d]pyrimidin-5-amine; 2-(4-fluorophenyl)-7-(2-methoxyethoxy)- thiazolo[5,4-d]pyrimidin-5-amine; 7-ethoxy-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-5- amine; 7-ethoxy-2-(4-fluorobenzyl)thiazolo[5,4-d]pyrimidin-5-amine; 2-(4-fluorophenyl)-N-7- (3-methoxypropyl)thiazolo[5,4-d]pyrimidine-5,7-diamine, 2-(4-fluorophenyl)-7-morpholino- thiazolo[5,4-d]pyrimidin-5-amine; 2-(4-fluorobenzyl)-7-morpholino-thiazolo[5,4-d]pyrimidin-5- amine; 2-(4-fluorophenyl)-7-(4-m-tolylpiperazin-1-yl)-thiazolo[5,4-d]pyrimidin-5-amine; 2-(4- fluorophenyl)-7-(4-(thiazol-2-yl)piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine; 2-(4- fluorophenyl)-7-(4-pentylpiperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine; 2-(4-(5-amino-2-(4- fluoΓophenyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-1-mo holinoethanone; 7-(4- benzylpiperazin-1-yl)-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-5-amine; benzyl-4-(5-amino- 2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazine-1-carboxylate; 2-(4-fluorophenyl)-7- (4-(phenylsulfonyl)piperazin-1 -yl)thiazolo[5,4-d]pyrimidin-5-amine; 4-(5-amino-2-(4- fluorophenyl)-thiazolo[5,4-d]pyrimidin-7-yl)-A/-p-tolylpiperazine-1-carboxamide; 4-(5-amino-2- (4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)-/V-m-tolylpiperazine-1-carboxamide; 4-(5-amino- 2-(4-fluorobenzyl)thiazolo[5,4-d]pyrimidin-7-yl)-/\ -m-tolylpiperazine-1 -carboxamide; 1 -(4-(5- amino-2-(4-fluorophenyl)thiazolo[5,4-dlpyrimidin-7-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone; 1 -(4-(5-amino-2-(4-fluorobenzyl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone; 2-(4-chlorophenoxy)-1 -(4-(2-(4- fluorophenyl)-5-methylthiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)ethanone; 1 -(4-(5-amino-2- (2-(4-fluorophenoxy)ethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(4- chloro phe n oxy)etha no n e ; 1 -(4-(5-amino-2-(4-fluorophenethyl)-thiazolol5,4-d]pyrinnidin-7- yl)piperazin-1-yl)-2-(4-chlorophenoxy)ethanone; 1 -(4-(5-amino-2-(4- fluorophenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(4-methoxyphenoxy)ethanone; 1 -(4-(5-amino-2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- fluorophenoxy)ethanone; 1-(4-(5-amino-2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1-yl)-2-(4-bromophenoxy)ethanone; 1-(4-(5-amino-2-(4- fluorophenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(m-tolyloxy)ethanone; 1-(4-(5- amino-2-(4-fluorophenethyl)thiazolo[5,4-d]pyrirnidin-7-yl)piperazin-1-yl)-2-(2,4- dichlorophenoxy)ethanone; 1 -(4-(5-amino-2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1-yl)-3-(4-fluorophenoxy)propan-1 -one; 2-(1 -(4-fluorophenyl)ethyl)-7-methylt io- thiazolo[5,4-d]pyrimidin-5-amine; 2-(1-(4-fluorophenyl)-2-phenylethyl)-7- (methylthio)thiazolo[5,4-d]pyrimidin-5-amine; 1 -(4-(5-amino-2-(1 -(4- fluorophenyl)ethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(4-chlorophenoxy)ethanone; 1 -(4-(5-amino-2-(1 -(4 luorophenyl)-2-phenylethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 ^ yl)-2-(4-chlorophenoxy)ethanone; 4-(5-amino-2-(1-(4-fluorophenyl)ethyl)thiazolo[5,4- d]pyrimidin-7-yl)-N-m-tolylpiperazine-1 -carboxamide; 2-(4-fluorophenyl)-5,7- bis(methylthio)thiazolo[5,4-d]pyrinnidine; 5J-bis(butylthio)-2-(4-fluorophenyl)thiazolo[5,4- d]pyrimidine; 5,7-bis(benzylthio)-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidine; 7-ethoxy-2-(4- fluorophenyl)-5-(methylthio)thiazolo[5,4-d]pyrimidine; 5-amino-2-cyclopropyl-7-methylthio- thiazolo[5,4-d]pyrimidine; 5-amino-2-(2-phenylethyl)-7-methylthiothiazolo[5,4-d]pyrimidine; 5- amino-2-cyclohexyl-7-methylthiothiazolo[5,4-d]pyrimidine; 5-amino-2-(3-pyridinyl)-7- methylthiothiazolo[5,4-d]pyrimidine; 5-amino-2-(4-chlorobenzyl)-7-methylthiothiazolo[5,4- d]pyrimidine; 5-amino-2-(3-nriethoxyphenyl)-7-methylthiothiazolo[5,4-d)pyrimidine; 5-amino-2- (4-chlorophenyl)-7-(methylthio)thiazolo[5,4-d]pyrimidine; 5-amino-2-cyclopropyl-7- methoxythiazolo[5,4-d]pyrimidine; 5-amino-2-cyclopropyl-7-/V-piperazino-thiazolo[5, 4- d]pyrimidine; 5-amino-2-(3,4-dichlorophenyl)-7-(N-piperazino)thiazolo[5,4-d]pyrinnidine; 5- arriino-2-(1-phenylcyclopropyl)-7-(N-piperazino)thiazolo[5,4-d]pyrimidine; 5-amino-2-(1-(4- chlorop enyl)cyclopropyl)-7-(N-piperazino)thiazolo[5,4-d]pyrimidine; 5-amino-7-/V-piperazino- 2-methylthio-thiazolo[5, 4-d]pyrimidine; 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]- 2-(1 -phenylcyclopropyl)thiazolo[5,4-d]pyrirriidine; 5-amino-7-[4-(4- chlorophenoxyacetyl)piperazin-1-yl]-2-methylthio-thiazolo[5,4-d]pyrimidine; 5-amino-7-[4-(4- chlorophenoxyacetyl)piperazin-1-yl]-2-(3,4-dichlorophenyl)thiazolo[5,4-d]pyrimidine; 5-amino- 7-[4-(4-chlorophenoxyacetyl)piperazin-1 -yl]-2-(1-(4-chlorophenyl)cyclopropyl)thiazolo[5,4- d]pyrimidine; 5-amino-7-[4-(4-chlorop enoxyacetyl)piperazin-1 -yl]-2-(2- phenylethyl)thiazolo[5, 4-d]pyrimidine; 5-amino-2-cyclopropyl-7-[4-(4- chlorophenoxyacetyl)pipenazin-1 -yl]-thiazolo[5,4-d]pyrinnidine; 5-amino-7-[4-(4- chlorophenoxyacetyl)piperazin-1 -yl]-2-cyclohexylthiazolo[5,4-d]pyrinriidine; 5-amino-7-[4-(4- c lorophenoxyacetyl)piperazin-1 -yl]-2-(pyridine-3-yl)thiazolo[5,4-d]pyrimidine; 5-amino-7-[4- (4-chlorophenoxyacetyl)piperazin-1-yl]-2-(N-oxopyridine-3-yl)thiazolo[5,4-d]pyrirriidine; 5- amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1 -yl]-2-(4-chlorophenylrriethyl)thiazolo[5,4- d]pyrimidine; 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1 -yl]-2-(4- c lorophenyl)thiazolo[5,4-d]pyrimidine; 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1 -yl]- 2-(3-methoxyphenyl)thiazolo[5,4-d]pyrimidine; 5-amino-7-[4-(4- chlorophenoxyacetyl)piperazin-1 -yl]-2-(1 -(4-chlorophenyl)ethyl)thiazolo[5,4-d]pyrimidine; 5- amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1 -yl]-2-(4-fluorophenylamino)-thiazolo[5,4- d]pyrimidine; 5-amino-2-(4-fluorophenyl)-7-(4-[2-(4-bromophenoxy)acetyl]-piperazin-1-yl)- thiazolo[5,4-d]pyrimidine; 5-amino-2-(4-fluorophenyl)-7-(4-[2-(3-nitrophenoxy)acetyl]- piperazin-1 -yl)-thiazolo[5,4-d]pyrimidine; 5-amino-2-(4-fluorophenyl)-7-(4-(2-phenoxyacetyl)- piperazin-1 -yl)-thiazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-[2-(3- nitrophenoxy)acetyl]piperazin-1-yl)-thiazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4- fluorop enyl)ethyl]-7-(4-[2-(4-chlorophenyl)acetyl]piperazin-1 -yl)-thiazolo[5,4-d]pyrimidine; 5- amino-2-[2-(4-fIuorophenyl)ethyl]-7-(4-m-tolylcarbamoylpiperazin-1-yl)-thiazolo[5,4- d]pyrimidine; 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-[2-phenoxyacetyl]piperazin-1-yl)- thiazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-[4-(4- chlorobenzoyl)piperazin-1 -yl]-thiazolo[5,4-d]pyrimidine, 5-amino-2-[2-(4-fluorophenyl)ethyl]-7- (4-(3-phenylpropionyl)piperazin-1 -y!]-thiazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4- fluorop enyl)ethyl]-7-[4- phenylmethanesulfonylpiperazin-1 -yl]-thiazolo[5,4-d]pyrimidine; 5- amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-[2-(4-chlorophenoxy)acetyl]homopiperazin-1 -yl)- thiazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-[(methylphenylcarbamoyl)- methyl]piperazin-1 -yl)-thiazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4- thiazol-2-yl-piperazine-1-yl)-thiazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4-fluorophenyl)ethyl]-7- (4-(phenethylcarbamoyl-methyl)piperazin-1-yl)-thiazolo[5₎4-d]pyrimidine; 5-amino-2-[2-(4- fluorophenyl)ethyl]-7-((3-(RHe/f-butoxycarbonylamino)pyrrolidin-1-yl)-thiazolo[5,4- d]pyrimidine; 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(3-( ?)-[2-(4-chlorophenoxy)- acetylamino]pyrrolidin-1-yl)-thiazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4-fluorophenyl)ethyl]-7- (3-(/?)-(4-chlorobenzoylamino)-pyrrolidin-1-yl)-thiazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4- fluorophenyl)ethyl]-7-(1 -benzyloxycar onylpiperidin-3-ylamino)-thiazolo[5,4-d]pyrimidine; 5- amino-2-[2-(4-fluorophenyl)ethyl]-7-(1 -tert-butoxycarbonylpyrTolidin-3-(S)-ylamino)- thiazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(1-(4- chlorophenoxyacetyl)pyrrolidin-3-(S)-ylamino)-thiazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4- fluorophenyl)ethyl]-7-(4-benzoylpiperidine-1-yl)-thiazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4- fluorophenyl)ethyl]-7-(4-(2-phenoxyethyl)piperazin-1-yl)-thiazolo[5,4-d]pyrimidine; 5-amino-2- [1-(4-fluorophenyl)propyl]-7-(4-[2-(4-chlorophenoxy)acetyl]piperazin-1-yl)thiazolo[5,4- d ] p y r i m i d i n e ; 5-amino-2-[cyclopentyl-(4-fluorophenyl)methyl]-7-(4-[2-(4- chlorophenoxy)acetyl]piperazin-1-yl)thiazolo[5,4-d]pyrimidine; 5-amine-7-piperazin-1-yl-2-(2- thiophen-2-yl-ethyl)-thiazolo[5,4-d]pyrimidine; 5-amino-2-(2-thiophen-2-ylethyl)-7-(4-[2-(4- chloro-phenoxy)acetyl]piperazin-1 -yl)thiazolo[5,4-d]pyrimidine; 5-amino-2-(2-thiophen-2- ylethyl)-7-(4-[2-(4-chloro^henyl)acetyl]piperazin-1-yl)thiazolo[5,4-d]pyrimidine; 5-amino-2-(2- thiophen-2-ylethyl)-7-(4-(4-chloro-benzoyl)piperazin-1-yl)thiazolo[5,4-d]pyrimidine 5-amino- 2-(2-thiophen-2-ylethyl)-7-(4-m- tolylcarbamoylpiperazin-1-yl)thiazolo[5,4-d]pyrimidine; 2-(4- chlorophenoxy)-1 -(4-(2-(4-fluorophenyl)oxazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)ethanone; 2-(4-chlorophenoxy)-1 -(4-(2-(4-fluorophenyl)-5-methyl-oxazolo[5,4-d]pyrimidin-7-yl)pi^ 1-yl)ethanone; 1-(4-(5-amino-2-(4-fluorophenyl)oxazolo[5,4-d]pyrirnidin-7-yl)piperazin-1-yl)-2- (4-chlorophenoxy)ethanone; 2-(4-chlorophenoxy)-1-(4-(2-(4-fluorobenzyl)oxazolo[5,4- d]pyrimidin-7-yl)piperazin-1 -yl)ethanone; 2-(4-chlorophenoxy)-1 -(4-(2-(4-fluorobenzyl)-5- methyloxazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)ethanone; 1 -(4-(5-amino-2-(4- fluorophenethyl)oxazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(4-chlorophenoxy)ethanon N- (3-chloro-4-fluorophenyl)-2-(4-f!uorophenyl)-oxazolo[5,4-d]pyrimidin-7-aniine; A/-7-(3-chloro- 4-fluorophenyl)-2-(4-fluorophenyl)-oxazolo[5,4-d]pyrimidine-5J-diamine; 5-amino-2- cyclopropyl-7-A -piperazino-oxazolo[5,4-d]pyrimidine; 5-amino-2-methoxymethyl-7-/\/- piperazino-oxazolo[5,4-d]pyrimidine; 5-amino-2-cyclohexyl-7-/V-piperazino- oxazolo[5,4- djpyrimidine, 5-amino-2-pentyl-7-N-piperazino- oxazolo[5,4-d]pyrimidine; 5-amino-2-(2- phenylethyl)-7-N-piperazino- oxazolo[5, 4-d]pyrimidine; 5-amino-2-cyclopropyl-7-[4-(4- chlorophenoxyacetyl)piperazin-1 -yl]-oxazolo[5,4-d]pyrimidine; 5-amino-7-[4-(4- chlorophenoxyacetyl)piperazin-1 -yl]-2-methoxylmethyloxazolo[5, 4-d]pyrimidine; 5-amino-2- cyclohexyl-7-[4-(4-chlorophenoxyacetyl)piperazin-1 -yl]oxazolo[5, 4-d]pyrimidine; 5-amino-7- [4-(4-chlorophenoxyacetyl)piperazin-1-yl]- 2-pentyloxazolo[5,4-d]pyrimidine; 5-amino-2-(2- phenylethyl)-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]oxazolo[5, 4-d]pyrimidine; 5-amino- 2-(4-fluorophenyl)-7-(4-isobutylpiperazin-1-yl)-oxazolo[5,4-d]pyrirriidine; 5-amino-2-(4- fluorophenyl)-7-(4-acetylpiperazin-1 -yl)-oxazolo[5,4-d]pyrimidine; 5-amino-2-(4-fluorophenyl)- 7-[4-(2-methoxyethyl)-piperazin-1 -yl]-oxazolo[5,4-d]pyrimidine; 5-amino-2-(4-fluorophenyl)-7- (4-[2-(3-nitrophenoxy)acetyl]-piperazin-1 -yl)-oxazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4- fluorophenyl)ethyl]-7-(4-[2-(4-chlorophenyl)acetyl]-piperazin-1-yl)-oxazolo[5,4-d]pyrimidin 5- amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-[4-chlorobenzoyl]piperazin-1 -yl)-oxazolo[5,4- d]pyrimidine; 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-m-tolylcarbamoylpiperazin-1 -yl)- oxazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-(2-phenoxyethyl)piperazin- 1 -yl)-oxazolo[5,4-d]pyrimidine; and 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-[(methylphenyl- carbamoyl)methyl]piperazin-1 -yl)-oxazolo[5,4-d]pyrimidine.

The present invention also concerns thiazolo(5,4-d)pyrimidine or oxazolo(5,4-d)pyrimidine of formula I, any subgroup thereof, or stereoisomeric forms thereof, for use as a medicine for the prevention or treatment of proliferative disorders including cancer in an animal. In an embodiment, said animal is a mammal. In an embodiment, said mammal is a human being.

The present invention also concerns the use of the thiazolo(5,4-d)pyrimidine or oxazolo(5,4- d)pyrimidine of formula I, any subgroup thereof, or stereoisomers forms thereof, for the manufacture of a medicament for the prevention or treatment of cancer in an animal, preferably a mammal, and more preferably a human. In more specific embodiments, said cancer is a hematological malignancy or a cancer of the blood-forming tissues. In more particular embodiments, said cancer is a leukemia or lymphoma. In a yet more particular embodiment said cancer is leukemia. In more particular embodiments, said cancer is selected from the group: acute leukemia, chronic leukemia (myeloid or lymphoid), multiple myeloma, and myelodysplastic syndrome. In yet another particular embodiment, said cancer is Hodgkin's lymphoma or non-Hodgkin's lymphoma. In another particular embodiment, said cancer is prostate cancer.

The present invention also concerns a pharmaceutical composition comprising a therapeutically effective amount of a thiazolo(5,4-d)pyrimidine or oxazolo(5,4-d)pyrimidine of formula I , any subgroup thereof, or stereoisomeric forms thereof, and one or more pharmaceutically acceptable exipients for use as a medicine for the prevention or treatment of cancer in an animal, a mammal or a human. In an embodiment, said pharmaceutical composition further comprises one or more biologically active drugs being selected from the group consisting of and/or immunosuppressant and/or immunomodulator drugs, and/or antineoplastic drugs, and/or antiviral drugs.

The present invention also concerns a method of prevention or treatment of cancer in an animal, comprising the administration of a therapeutically effective amount of a thiazolo(5,4- d)pyrimidine or oxazolo(5,4-d)pyrimidine derivative or formula I , optionally in combination with one or more pharmaceutically acceptable excipients. In an embodiment, said cancer is a hematological malignancy or a cancer of the blood-forming tissues. In more particular embodiments, said cancer is a leukemia or lymphoma. In a yet more particular embodiment said cancer is leukemia. In more particular embodiments, said cancer is selected from the group: acute leukemia, chronic leukemia (myeloid or lymphoid), multiple myeloma, and myelodysplastic syndrome. In yet another particular embodiment, said cancer is Hodgkin's lymphoma or non-Hodgkin's lymphoma. In another particular embodiment, said cancer is prostate cancer. In an embodiment, said animal is a mammal, preferably said mammal is a human being.

In an embodiment, the present invention encompasses a thieno(2,3-d)pyrimidine derivative having the general formula II, including the use according to the invention of said thieno(2,3- d)pyrimidine derivative having the general formula II,

wherein - R⁴ is selected from the group consisting of halogen, cyano, carboxylic acid, acyl, thioacyl, alkoxycarbonyl, acyloxy, carbonate, carbamate, C ₇ alkyl, aryl, amino, acetamido, N- protected amino, (mono- or di) Ci-₇ alkylamino, (mono- or di) arylamino, (mono- or di) C₃-₁₀ cycloalkylamino, (mono- or di) hydroxy d.₇ alkylamino, (mono- or di) d.₄ alkyl-arylamino, mercapto C₁.7 alkyl, Ci.₇ alkyloxy;

- R⁶ is selected from the group consisting of (mono- or di-) C₁.₁2 alkylamino, monoarylamino, diarylamino, (mono- or di-) C₃.₁₀ cycloalkylamino, (mono- or di-) hydroxy C₁-7 alkylamino, (mono- or di-) C1.4 alkylarylamino, (mono- or di-) aryld.₄ alkylamino, moφholinyl, mercapto d-7 alkyl, d.₇ alkoxy, homopiperazinyl and piperazinyl,

wherein said homopiperazinyl or piperazinyl is optionally N-substituted with a substituent R²¹ selected from the group consisting of formyl, acyl, thioacyl, amide, thioamide, sulfonyl, sulfinyl, carboxylate, thiocarboxylate, amino-substituted acyl, alkoxyalkyl, C_{3 10} cycloalkyl-alkyl, C₃.₁₀ cycloalkyl, dialkylaminoalkyl, heterocyclic- substituted alkyl, acyl-substituted alkyl, thioacyl-substituted alkyl, amido-substituted alkyl, thioamido-substituted alkyl, carboxylato-substituted alkyl, thiocarboxylato- substituted alkyl, (amino-substituted acyl)alkyl, heterocyclic, carboxylic acid ester, ω- cyanoalkyl, ω-carboxylic ester-alkyl, halo C,.₇ alkyl, C₂.₇ alkenyl, C₂.₇ alkynyl, arylalkenyl, aryloxyalkyl, arylalkyl and aryl,

wherein the aryl moiety of each of said arylalkenyl, aryloxyalkyl, arylalkyl and aryl radicals is optionally substituted with one or more substituents independently selected from the group consisting of halogen, d.₇ alkyl, C₂.₇ alkenyl, C₂.₇ alkynyl, halo C alkyl, nitro, hydroxyl, sulfhydryl, amino, d.₇ alkoxy, C₃.₁₀ cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic- substituted alkyloxy, thio C1.7 alkyl, thio C3.₁₀ cycloalkyl, thioaryl, thio- heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo- alkenylamino, a l ky ny l a mi n o , a ry l a m i n o , a ry !a l kyl a m i n o , hy d roxy a l ky l a m i n o , mercaptoalkylamino, heterocyclic amino, hydrazino, alkylhydrazino and phenylhydrazino; and

- R⁵ is selected from the group consisting of heteroaryl and aryl groups, wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, d.₇ alkyl, C₂.₇ alkenyl, C₂.₇ alkynyl, halo C_%7 alkyl, nitro, hydroxyl, sulfhydryl, amino, d.₇ alkoxy, C₃.₁₀ cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C^ alkyl, thio C₃.₁₀ cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxy lie acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, a l ke nyl a mi no , cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, or a pharmaceutical acceptable addition salt thereof, or a stereoisomer thereof, or a solvate thereof.

One embodiment of the present invention concerns thieno(2,3-d)pyrimidine derivative of formula II, any subgroup thereof, or stereoisomeric forms thereof, including the use according to the invention of said thieno(2,3-d)pyrimidine derivative having the general formula II, any subgroup thereof, or stereoisomeric forms thereof, wherein R⁵ and R⁶ have any of the values as described herein, and wherein R⁴ is selected from the group consisting of amino, acetamido, /V-protected amino, (mono- or di) C₁-7 alkylamino, (mono- or di) arylamino, (mono- or di) C₃-₁₀ cycloalkylamino, (mono- or di) hydroxy C1-7 alkylamino, (mono- or di) C†._A alky!-arylamino.

One embodiment of the present invention concerns thieno(2,3-d)pyrimidine derivative of formula II , any subgroup thereof, or stereoisomeric forms thereof, including the use according to the invention of said thieno(2,3-d)pyrimidine derivative, having the general formula II, any subgroup thereof, or stereoisomeric forms thereof, wherein R⁴ and R⁵ have any of the values as described herein and wherein R⁶ is homopiperazinyl or piperazinyl.

One embodiment of the present invention concerns thieno(2,3-d)pyrimidine derivative of formula II, any subgroup thereof, or stereoisomeric forms thereof, including the use according to the invention of said thieno(2,3-d)pyrimidine derivative, having the general formula II, any subgroup thereof, or stereoisomeric forms thereof, wherein R⁴ and R⁶ have any of the values as described herein and wherein R⁵ is phenyl or 4-fluorophenyl.

One embodiment of the present invention concerns thieno(2,3-d)pyrimidine derivative of formu la I I , any subgroup thereof, or stereoisomeric forms thereof, including the use according to the invention of said thieno(2,3-d)pyrimidine derivative, having the general formula II, any subgroup thereof, or stereoisomeric forms thereof, wherein R⁵ and R⁶ have any of the values as described herein and wherein R⁴ is butyl, methyl, or amino.

One embodiment of the present invention concerns thieno(2,3-d)pyrimidine derivative of formula II , any subgroup thereof, or stereoisomeric forms thereof, including the use according to the invention of said thieno(2,3-d)pyrimidine derivative, having the general formula II, any subgroup thereof, or stereoisomeric forms thereof, wherein R⁴ and R⁵ have any of the values as described herein and wherein R⁶ is 4(m-tolylcarbamoyl)piperazin-1 -yl or 4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl.

One embodiment of the present invention concerns thieno(2,3-d)pyrimidine derivative of formula II , any subgroup thereof, or stereoisomeric forms thereof, including the use according to the invention of said thieno(2,3-d)pyrimidine derivative, having the general formula II, any subgroup thereof, or stereoisomeric forms thereof, wherein R⁵ is phenyl or 4- fluorophenyl; R⁴ is butyl, methyl, or amino; and R⁶ is (4(m-tolylcarbamoyl)piperazin-1-yl or (4- (2-(4-chlorophenoxy)acetyl)piperazin-1-yl).

One embodiment of the present invention concerns thieno(2,3-d)pyrimidine derivative of formula II , any subgroup thereof, or stereoisomeric forms thereof, including the use according to the invention of said thieno(2,3-d)pyrimidine derivative, having the general formula II, any subgroup thereof, or stereoisomeric forms thereof, being selected from the group consisting of: 1-(4-(2-butyl-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)- 2-(4-chlorophenoxy)ethanone; 2-butyl-/V-(3-chloro-4-fluorophenyl)-6-(4- fluorophenyl)thieno[2,3-d]pyrimidin-4-amine; 2-(4-chlorophenoxy)-1 -(4-(6-(4-fluorophenyl)-2- methylthieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)ethanone; 1 -(4-(2-amino-6-(4- fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenoxy)ethanone; 2- amino-4-/V-benzylamino-6-(4-fluorophenyl)-thieno[2,3-d]pyrimidine; 2-amino-4-/V-piperazinyl- 6-phenyl-thieno[2,3-d]pyrimidine; 2-amino-4-(4-m-tolylcarbamoylpiperazin-1-yl)-6-phenyl- thieno[2,3-d]pyrimidine; 2-amino-4-(4-m-tolylcarbamoylpiperazin-1 -yl)-6-phenyl-thieno[2,3- d]pyrimidine; 2-amino-4-(4-p-chlorophenylcarbamoylpiperazin-1 -yl)-6-phenyl-thieno[2,3- d]pyrimidine; 2-amino-4-4-[2-phenoxy)acetyl]piperazin-1 -yl)-6-phenyl-thieno[2,3-d]pyrimidine; 2-amino-4-/V-homopiperazinyl-6-phenyl-thieno[2,3-d]pyrimidine; 2-amino-4-(4-[2-(4- chlorophenoxy)acetyl]homopiperazin-1-yl)-6-phenyl-thieno[2,3-d]pyrimidine; 2-amino-4-(4-[4- chlorobenzoyl]homopiperazin-1-yl)-6-phenyl-thieno[2,3-d]pyrimidine; 2-amino-4-(4- [(methylphenyl-carbamoyl)methyl]piperazin-1-yl)-6-phenyl-thieno[2,3-d]pyrimidine; 2-amino- 4-(4-(2-phenoxyethyl)piperazin-1 -yl)-6-phenyl-thieno[2,3-d]pyrimidine; 2-amino-4-(3-(/?)-fert- butoxycarbonylamino)pyrrolidin-1-yl)-6-phenyl-thieno[2,3-d]pyrimidine; 2-amino-4-(3-( )- amino)pyrrolidin-1-yl)-6-phenyl-thieno[2,3-d]pyrimidine; 2-amino-4-(3-(R)-[2-(4- chlorophenoxy)-acetylamino]pyrrolidin-1 -yl)-6-phenyl-thieno[2,3-d]pyrimidine; 2-amino-4--(3- (R)-(4-chlorobenzoylamino)-pyrrolidin-1-yl)-6-phenyl-thieno[2,3-d]pyrimidine; 2-amino-4-/V- piperazinyl-6-(4-fluorophenyl)-thieno[2,3-d]pyrimidine; 2-amino-4-[/\/-(hydrocinnamoyl)- piperazin-1 -yl]-6-(4-fluorophenyl)-thieno[2,3-d]pyrimidine; 2-amino-4-[4- phenylmethanesulfonylpiperazin-1 -yl]-6-(4-fluorophenyl)-thieno[2,3-d]pyrimidine; 2-amino-4- [A/-(cyclohexanoyl)-piperazinyl]-6-(4-fluorophenyl)-thieno[2,3-d]pyrimidine; 2-amino-4-[/V- (isonicotinoyl)-piperazinyl]-6-(4-fluorophenyl)-thieno[2,3-d]pyrimidine; 2-amino-4-[N- (diisopropylcarbamoyl)-piperazinyl-6-(4-fluorophenyl)-thieno[2,3-d]pyrimidine; 2-amino-4-(4- benzoylpiperidine-1 -yl)-6-(4-fluorophenyl)-thieno[2,3-d]pyrirnicline; 2-amino-4-/V-piperazino- thieno[2,3-d]pyrimidine; 2-amino-4-(4-[2-(4-chlorophenoxy)acetyl]piperazin-1-yl)-thieno[2,3- d]pyrimidin-4-(3H)-one; 2-(4-chlorophenoxy)-1 -(4-(6-(4-fluoraphenyl)-2-phenylthieno[2,3- d]pyrimidin-4-yl)piperazin-1 -yl)ethanone; 4-(4-(2-(4-chlorophenoxy)acetyl)piperazin-1 -yl)-6- (4-fluorophenyl)thieno[2,3-d]pyrimidine-2-carboxylate; ethyl 2-(4-(4-(2-(4- chlorophenoxy)acetyl)piperazin-1 -yl)-6^4-fluorophenyl)thieno[2,3-d]pyrimidin-2-yl)aceta 4- (4-(2-(4-chlorophenoxy)acetyl)piperazin-1 -yl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine-2- carboxamide; 4-(4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)-6-(4-fluorophenyl)-A -(2- methoxyethyl)thieno[2,3-d]pyrimidine-2-carboxamide; 4-(4-(2-(4- chlorophenoxy)ac^tyl)piperazin-1 -yl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine-2- ^ acid; 2-(4-(4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)-6-(4-fluorophenyl)thieno[2,3- d]pyrimidin-2-yl)acetamide; 4-(2-amino-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)-N-n7- tolylpiperazine-1-carboxamide; 4-(6-(4-fluorophenyl)-2-phenylthieno[2,3-d]pyrimidin-4-yl)-N- m-tolylpiperazine-1 -carboxamide; ethyl 6-(4-fluorophenyl)-4-(4-(m-tolylcarbamoyl)piperazin- 1-yl)thieno[2,3-d]pyrimidine-2-carboxylate; 6-(4-fluorophenyl)-4-(4-(n7- tolylcarbamoyl)piperazin-1 -yl)thieno[2,3-d]pyrimidine-2-carboxannidei 4-ethoxy-6-(4- fluorophenyl)thieno[2,3-d]pyrimidin-2 -amine; 6-(4-fluorophenyl)-4-morpholinothienoj2,3- d]pyrimidin-2-amine; A -(3-chloro-4-fluorophenyl)-6-(4-fluorophenyl)-2-methylthieno[2,3- d]pyrimidin-4-amine; and 4-(3-chloro-4-fluorophenylamino)-6-(4-fluorophenyl)thieno[2,3- d]pyrimidine-2-carboxylate.

The present invention also concerns thieno(2,3-d)pyrimidine derivative of formula II, any subgroup thereof, or stereoisomers forms thereof, for use as a medicine for the prevention or treatment of proliferative disorders including cancer in an animal. In an embodiment, said animal is a mammal. In an embodiment, said mammal is a human being.

The present invention also concerns the use of the thieno(2,3-d)pyrimidine derivative of formula II, any subgroup thereof, or stereoisomeric forms thereof, for the manufacture of a medicament for the prevention or treatment of proliferative disorders including cancer in an animal, preferably a mammal, and more preferably a human. In more specific embodiments, said cancer is a hematological malignancy or a cancer of the blood-forming tissues. In more particular embodiments, said cancer is a leukemia or lymphoma. In a yet more particular embodiment said cancer is leukemia. In more particular embodiments, said cancer is selected from the group: acute leukemia, chronic leukemia (myeloid or lymphoid), multiple myeloma, and myelodysplastic syndrome. In yet another particular embodiment, said cancer is Hodgkin's lymphoma or non-Hodgkin's lymphoma. In another particular embodiment, said cancer is prostate cancer.

The present invention also concerns a pharmaceutical composition comprising a therapeutically effective amount of a thieno(2,3-d)pyrimidine derivative of formula II, any subgroup thereof, or stereoisomer^ forms thereof, and one or more pharmaceutically acceptable exipients for use as a medicine for the prevention or treatment of cancer in an animal, a mammal or a human. In an embodiment, said pharmaceutical composition further comprises one or more biologically active drugs being selected from the group consisting of immunosuppressant and/or immunomodulator drugs, and/or antineoplastic drugs, and/or antiviral drugs.

The present invention also concerns a method of prevention or treatment of cancer in an animal, comprising the administration of a therapeutically effective amount of a thiazolo(5,4- d)pyrimidine or oxazolo(5,4-d)pyrimidine derivative or formula I, optionally in combination with one or more pharmaceutically acceptable excipients. In an embodiment, said cancer is a hematological malignancy or a cancer of the blood-forming tissues. In more particular embodiments, said cancer is a leukemia or lymphoma. In a yet more particular embodiment said cancer is leukemia. In more particular embodiments, said cancer is selected from the group: acute leukemia, chronic leukemia (myeloid or lymphoid), multiple myeloma, and myelodysplastic syndrome. In yet another particular embodiment, said cancer is Hodgkin's lymphoma or non-Hodgkin's lymphoma. In another particular embodiment, said cancer is prostate cancer. In an embodiment, said animal is a mammal, preferably said mammal is a human being.

In an embodiment, the present invention encompasses a purine derivative having the general formula III or IV, including the use according to the invention of said purine derivative having the general formula III or IV,

wherein substituent R¹² is represented by the general formula V :

V

and wherein

schematically represents a saturated or partly unsaturated heterocyclic ring with at least two nitrogen atoms in the said heterocyclic ring and with a total of 5 to 7 atoms in the said heterocyclic ring, and optionally with one or more other heteroatoms in the said heterocyclic ring or attached to one or more carbon atoms of said heterocyclic ring (for instance in the form of a carbonyl or thiocarbonyl group), wherein one of said at least two nitrogen atoms in the heterocyclic ring is attached to a carbon atom 6 of the purine ring;

- each substituent R¹³ of the heterocyclic ring is a group independently selected from the group consisting of halogen, nitro, d.₇ alkyl (optionally containing one or more functions or radicals selected from the group consisting of halogen, carbonyl, thiocarbonyl, hydroxyl, sulfhydryl, Ci.₇ alkoxy, thio C ₇ alkyl, thio C3.10 cycloalkyl, acetal, thioacetal, imino, oximino, alkyloximino, amino-acid, cyano, (thio)carboxylic acid, (thio)carboxylic acid ester or amide, nitro, amino, d.7 alkylamino, cycloalkylamino, alkenylamino, cycloalkenyl-amino, alkynylamino, arylamino, arylalkyiamino, hydroxyalkylamino, mercapto-alkylamino, heterocyclic-substituted alkylamino, heterocyclic amino, heterocyclic-substituted arylamino, hydrazino, alkylhydrazino, phenylhydrazino, sulfonyl and sulfonamido), C₃.₇ alkenyl, C₂.₇ alkynyl, halo C₁.7 alkyl, C3.10 cycloalkyl, aryl, arylalkyl, alkylaryl, alkylacyl, arylacyl, hydroxyl, sulfhydryl, amino, C₁.7 alkylamino, cycloalkylamino, alkenylamino, cycloalkenylamino, alkynylamino, arylamino , arylalkyl-amino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic-substituted alkylamino, heterocyclic amino, heterocyclic-substituted arylamino, hydrazino, alkylhydrazino, phenylhydrazino, C₁.7 alkoxy, C3.10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio - alkyl, thio C3.10 cycloalkyl, thioaryl, thioheterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, hydroxylamino, cyano, (thio)carboxylic acid or esters or thioesters or amides or thioamides thereof;

- n is an integer from 0 to 6;

- R¹⁰ is selected from the group consisting of formyl, acyl, thioacyl, amide, thioamide, sulfonyl, sulfinyl, carboxylate, thiocarboxylate, amino-substituted acyl, alkoxyalkyl, C₃.₁₀ cycloalkyl- alkyl, C3.10 cycloalkyl, dialkylaminoalkyl, heterocyclic-substituted alkyl, acyl-substituted alkyl, thioacyl-substituted alkyl, amido-substituted alkyl, thioamido-substituted alkyl, carboxylato- substituted alkyl, thiocarboxylato-substituted alkyl, (amino-substituted acyl)alkyl, heterocyclic, carboxylic acid ester, ω-cyanoalkyl, ω-carboxylic ester-alkyl, halo d-7 alkyl, C2-7 alkenyl, C2.7 alkynyl, arylalkenyl, aryloxyalkyl, arylalkyl and aryl,

wherein the aryl moiety of each of said arylalkenyl, aryloxyalkyl, arylalkyl and aryl radicals is optionally substituted with one or more substituents independently selected from the group consisting of halogen, d-7 alkyl, C₂.₇ alkenyl, C₂.₇ alkynyl, halo Ci.₇ alkyl, nitro, hydroxyl, sulfhydryl, amino, C1.7 alkoxy, C3.10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C₁.7 alkyl, thio C₃. 10 cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioa!kylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo- alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydrazino, alkylhydrazino and phenylhydrazino; and

- R ¹ is selected from the group consisting of halogen, cyano, carboxylic acid, acyl, thioacyl, alkoxycarbonyl, acyloxy, carbonate, carbamate, C1-7 alkyl, aryl, amino, acetamido, N- protected amino, (mono- or di) C1-7 alkylamino, (mono- or di) arylamino, (mono- or di) C3-10 cycloalkylamino, (mono- or di) hydroxy d-7 alkylamino, (mono- or di) d-4 alkyl-arylamino, mercapto C,.₇ alkyl, d-7 alkyloxy;

- R⁸ is selected from the group consisting of heteroaryl and aryl groups; halogen; d-7 alkyl; C2-7 alkenyl; C₂-₇ alkynyl; halo C1.7 alkyl; carboxy C1.7 alkyl; carboxyaryl; d- alkoxy; C₃- to cycloalkoxy; aryloxy; arylalkyloxy; oxyheterocyclic; heterocyclic-substituted alkyloxy; thio d-7 alkyl; thio C3-10 cycloalkyl; thioaryl; thioheterocyclic; arylalkylthio; heterocyclic-substituted alkylthio; hydroxylamino; acylamino; thio-acylamino; alkoxyamino; thioalkyl-amino; acetal; thio-acetal; carboxylic acid; carboxylic acid esters, thioesters, halides, anhydrides, amides and thioamides; thiocarboxylic acid; thiocarboxylic acid esters, thioesters, halides, anhydrides, amides and thioamides; hydroxyl; sulfhydryl; nitro; cyano; carbamoyl; thiocarbamoyl; ureido; thioureido; amino; alkylamino; cycloalkylamino; alkenylamino; cyclo- alkenylamino; alkynylamino; arylamino; arylalkylamino; hydroxyalkylamino; mercaptoalkyl- amino; heterocyclic amino; heterocyclic substituted arylamino; heterocyclic-substituted alkylamino; oximino; alkyloximino; hydrazino; alkylhydrazino; phenylhydrazino; esters, thioesters, halides, anhydrides, amides and thioamides thereof ; aromatic or heterocyclic substituents substituted with an aliphatic spacer between the purine ring and the aromatic or heterocyclic substituent,

- wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, d-7 alkyl- C2-7 alkenyl, C₂- 7 alkynyl, halo d. alkyl, nitro, hydroxyl, sulfhydryl, amino, d-7 alkoxy, C3.10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio d.7 alkyl, thio C3-10 cycloalkyl, thioaryl , thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl , ca rbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino; and - wherein said aliphatic spacer is a branched or straight, saturated or unsaturated aliphatic chain of 1 to 7 carbon atoms optionally containing one or more functions, atoms or radicals independently selected from the group consisting of halogen , carbonyl, thiocarbonyl, hydroxyl, thiol, ether, thio-ether, acetal, thio-acetal, amino, imino, oximino, alkyloximino, aminoacid, cyano, acylamino, thioacylamino, carbamoyl, thiocarbamoyl, ureido, thio-ureido, carboxylic acid ester or halide or anhydride or amide, thiocarboxylic acid or ester or thioester or halide or anhydride or amide, nitro, thio CL₇ alkyl, thio C₃.₁₀ cycloalkyl, hydroxylamino, mercaptoamino, alkyl-amino, cycloalkylamino, alkenylamino, cycloalkenylamino, alkynylamino, arylamino, arylalkyl- amino, hydroxyalky!amino, mercaptoalkylamino, heterocyclic-substituted alkylamino, hetero-cyclic amino, heterocyclic-substituted arylamino, hydrazino, alkylhydrazino, phenylhydrazino, sulfonyl, sulfinyl and sulfonamido;

- R⁷ and R⁹ are selected from the group consisting of hydrogen, Ci.₇ alkyl (optionally containing one or more functions or radicals selected from the group consisting of halogen, carbonyl, thiocarbonyl, hydroxyl, sulfhydryl, Ci.₇ alkoxy, thio d.₇ alkyl, thio C₃.i₀ cycloalkyl, acetal, thioacetal, imino, oximino, alkyloximino, amino-acid, cyano, (thio)carboxylic acid, (th io)ca rboxyl ic acid ester or a mide , nitro, amino , C_t.₇ alkylamino , cycloalkylamino, a l kenyla mi no , cycloa l ke nyl-amino, alkynylamino, arylamino, arylalkylamino, hydroxy alkylamino, mercapto-alkylamino, heterocyclic-substituted alkylamino, heterocyclic amino, heterocyclic-substituted arylamino, hydrazino, alkylhydrazino, phenylhydrazino, sulfonyl and sulfonamido), C₃.₇ alkenyl, C₂.₇ alkynyl, halo d.₇ alkyl, C3.10 cycloalkyl, aryl, arylalkyl, alkylaryl, acyl and sulfonyl;

or a pharmaceutical acceptable addition salt thereof, or a stereoisomer thereof, or a solvate thereof.

One embodiment of the present invention concerns a purine derivative of formula II I or IV, any subgroup thereof, or stereoisomeric forms thereof, including the use according to the inve ntion of said purine derivative of fo rm u l a I I I o r IV, a ny su bg rou p th ereof, o r stereoisomeric forms thereof, wherein R⁷, R⁸, R⁹, R¹² have any of the values as described herein and wherein R¹¹ is amino.

One embodiment of the present invention concerns a purine derivative of formula III or IV, any subgroup thereof, or stereoisomeric forms thereof, including the use according to the in vention of said purine derivative of fo rm u la I I I o r IV , a ny su bg rou p th e reof, o r stereoisomeric forms thereof, wherein R⁷, R⁸, R⁹, R^{1 1} have any of the values as described herein and wherein R¹² i s 4-(4-chlorophenoxy)acetylpiperazin-1 -yl or 4- (phenoxyacetyl)piperazin- 1 -yl.

One embodiment of the present invention concerns a purine derivative of formula II I or IV, any subgroup thereof, or stereoisomeric forms thereof, including the use according to the invention of said purine derivative of formula III or IV, any subgroup thereof, or stereoisomeric forms thereof, wherein R⁷, R¹ , R⁹, R¹² have any of the values as described herein and wherein R⁸ is 4-fluorophenyl or methylthio.

One embodiment of the present invention concerns a purine derivative of formula III or IV, any subgroup thereof, or stereoisomeric forms thereof, including the use according to the invention of said purine derivative of formu la I I I o r IV, any su bg ro u p thereof, or stereoisomeric forms thereof, wherein R⁷, R⁸, R¹¹, R¹² have any of the values as described herein and wherein R⁹ is hydrogen or methyl.

One embodiment of the present invention concerns a purine derivative of formula III or IV, any subgroup thereof, or stereoisomeric forms thereof, including the use according to the invention of said purine derivative of formula I I I or I V, any su bgroup th ereof, or stereoisomeric forms thereof, wherein R¹¹, R⁸, R⁹, R¹² have any of the values as described herein and wherein R⁷ is hydrogen or methyl.

One embodiment of the present invention concerns a purine derivative of formula III or IV, any subgroup thereof, or stereoisomeric forms thereof, including the use according to the invention of said purine derivative of formu l a I I I o r I V , a n y s ubgroup thereof, or stereoisomeric forms thereof, wherein R¹¹ is amino, R¹² is 4-(4- chlorophenoxy)acetylpiperazin-1 -yl or (4-phenoxyacetyl)piperazin-1 -yl, R⁸ is 4-fluorophenyl or methylthio, and R⁹ is hydrogen or methyl.

One embodiment of the present invention concerns a purine derivative of formula III or IV, any subgroup thereof, or stereoisomeric forms thereof, including the use according to the invention of said purine derivative of formula I I I o r IV, any su bgroup th ereof, or stereoisomeric forms thereof, wherein R¹¹ is amino, R¹² is 4-(4- chlorophenoxy)acetylpiperazin-1-yl or 4-(phenoxyacetyl)piperazin-1 -yl, R⁸ is 4-fluorophenyl or methylthio, and R⁷ is hydrogen or methyl.

One embodiment of the present invention concerns a purine derivative of formula III or IV, any subgroup thereof, or stereoisomeric forms thereof, including the use according to the invention of said purine derivative of fo rmula I I I o r IV, any su bgro up thereof, or stereoisomeric forms thereof, being selected from the group consisting of: 2-amino-6-[4-(4- chlorophenoxyacetyl)piperazin-1 -yl]-8-(4-fluorophenyl)-9H-purine; 2-amino-6-[4-(4- chlorophenoxyacetyl)piperazin-1 -yl]-8-(3,4-dimethoxyphenyl)-9H-purine; 2-amino-6-[4-(4- chlorophenoxyacetyl)piperazin-1 -yl]-8-(4-bromophenyl)-9H-purine; 2-amino-6-[4-(4- chlorophenoxyacetyl)piperazin-1 -yl]-8-(4-chlorophenyl)-9H-purine; 2-amino-6-[4-(4- chlorophenoxyacetyl)piperazin-1 -yl]-8-(3-chlorophenyl)-9H-purine; 2-amino-6-[4-(4- chlorophenoxyacetyl)piperazin-1-yl]-8-(4-trifluoromethylphenyl)-9H-purine; 2-amino-6-[4-(4- chlorophenoxyacetyl)piperazin-1 -yl]-8-(4-trifluoromethoxyphenyl)-9H-purine; 2-amino-6-[4-(4- chlorophenoxyacetyl)piperazin-1 -yl]-8-(4-methylphenyl)-9H-purine; 2-amino-6-[4-(4- chlorophenoxyacetyl)pjperazin-1 -yl]-8-propyl-9H-purine; 2-amino-6-[4-(4- chlorophenoxyacetyl)piperazin-1 -yl]-8-(cyclopropyl)-9H-purine; 2-amino-6-[4-(4- chlorophenoxyacetyl)piperazin-1 -yl]-8-(t-butyl)-9H-purine; 2-amino-6-[4-(4- chlorophenoxyacetyl)piperazin-1 -yl]-8-methyl-9H-purine; 2-amino-6-[4- (phenoxyacetyl)piperazin- 1 -yl]-8-(4-fluorophenyl)-9H-purine; 2-amino-6-[4-(3-methoxy- benzoyl)piperazin-1 -yl]-8-(4-fluorophenyl)-9H-purine; 2-amino-6-[4-(2-thiophene- acetyl)piperazin-1 -yl]-8-(4-fluorophenyl)-9H-purine; 2-amino-6-[4-(4-chloro-benzoyl)piperazin- 1 -yl]-8-(4-fluorophenyl)-9H-purine; 2-amino-6-[(4-a-toluenesulfonyl)piperazin-1 -yl]-8-(4- fluorophenyl)-9H-purine; 2-amino-6-[4-(1 -naphthoyl)piperazin-1 -yl]-8-(4-fluorophenyl)-9H- purine ; 2-amino-6-[4-acetylpiperazin-1 -yl]-8-(4-fluorophenyl)-9H-purine; 2-amino-6-[4- (thiazol-2-yl)piperazin- 1 -y!]-8-(4-fluorophenyl)-9H-p u r i n e ; 2-(4-(2-amino-8-(4-fluorophenyl)- 9H-purin-6-yl)piperazin-1 -yl)-1 -(pyrrolidin-1 -yl)ethanone; 2-(4-(2-amino-8-(4-fluorophenyl)- 9H-purin-6-yl)piperazin- 1 -yl)-1 -morpholino-ethanone; 2-(4-(2-amino-8-(4-fluorophenyl)-9H- purin-6-yl)piperazin-1 -yl)-A/-(pyridin-3-yl)acetamide; 2-(4-(2-amino-8-(4-fluorophenyl)-9H- purin-6-yl)piperazin-1 -yl)-A/-methyl-/\/-phenylacetamide; 2-amino-6-[4-(4- chlorophenyl)piperazin-1 -ylJ-8-(4-fluorophenyl)-9H-purine; 2-amino-6-[4-(4- fluorophenyl)piperazin-1 -yl]-8-(4-fluorophenyl)-9H-purine; 2-(4-(2-amino-8-(4-fluorophenyl)- 9H-purin-6-yl)piperazin- 1 -yl)-/V-(pyridin-2-yl)acetamide; 2-(4-(2-amino-8-(4-fluorophenyl)-9H- purin-6-yl)piperazin-1 -yl)-/\/-(thiazol-2-yl)acetannide; 2-amino-6-[4-(4-fluorobenzyl)piperazin-1 - yl]-8-(4-fluorophenyl)-9H-purine; 2-amino-6-[4-(4-pyridinyl)piperazin-1 -yl]-8-(4-fluorophenyl)- 9H-purine; 2-amino-6-(homopiperazin-1 -yl)-8-(4-fluorophenyl)-9H-purine; 2-amino-6-[4-(4- chlorophenoxyacetyl)homopiperazin-1 -yl]-8-(4-fluorophenyl)-9H-purine; 2-amino-6-[4-( \/-3- tolylcarbamoyl)-homopiperazin-1 -yl]-8-(4-fluorophenyl)-9H-purine; 2-amino-6-[4-(4- chlorophenoxyacetyl)piperazin-1 -yl]-8-methylthio-9H-purine; 2-amino-6-[4-(4- chlorophenoxyacetyl)piperazin-1 -yl]-8-propylthio-9H-purine; 2-amino-6-[4-(4- chlorophenoxyacetyl)piperazin-1 -yl]-8-benzylthio-9H-purine; 2-amino-6-[4-(4- chlorophenoxyacetyl)piperazin-1 -yl]-8-(2-phenylethylthio)-9H-purine; 2-amino-6-[4-(4- chlorophenoxyacetyl)piperazin-1 -yl]-9-methyl-8-methylthio-purine; 2-amino-6-[4-(4- chlorophenoxyacetyl)piperazin-1 -yl]-8-(cyclopentylthio)-9H-purine; 2-amino-6-[4-(4- chlorophenoxyacetyl)piperazin-1 -yl]-8-(4-f luorophenyl)-9-methy Ipurine; 2-amino-6-[4-(4- chlorophenoxyacetyl)piperazin-1 -yl]-8-(4-fluorophenyl)-9-benzylpurine; 2-amino-6-(piperazin- 1 -yl)-8-(4-fluorophenyl)-9H-purine; 2-amino-6-[4-(hydrocinnamoyl)-piperazin-1 -yl]-8-(4- fluorophenyl)-9H-purine.

The present invention also concerns purine derivatives of formula I II or IV, any subgroup thereof, or stereoisomeric forms thereof, for use as a medicine for the prevention or treatment of proliferative disorders including cancer in an animal. In an embodiment, said animal is a mammal. In an embodiment, said mammal is a human being. The present invention also concerns the use of a purine derivative of formula III or IV, any subgroup thereof, or stereoisomeric forms thereof, for the manufacture of a medicament for the prevention or treatment of proliferative disorders including cancer in an animal, preferably a mammal, and more preferably a human. In more specific embodiments, said cancer is a hematological malignancy or a cancer of the blood-forming tissues. In more particular embodiments, said cancer is a leukemia or lymphoma. In a yet more particular embodiment said cancer is leukemia. In more particular embodiments, said cancer is selected from the group: acute leukemia, chronic leukemia (myeloid or lymphoid), multiple myeloma, and myelodysplastic syndrome. In yet another particular embodiment, said cancer is Hodgkin's lymphoma or non-Hodgkin's lymphoma. In another particular embodiment, said cancer is prostate cancer.

The present invention also concerns a pharmaceutical composition comprising a therapeutically effective amount of a purine derivative of formula III or IV, any subgroup thereof, or stereoisomeric forms thereof, and one or more pharmaceutically acceptable exipients for use as a medicine for the prevention or treatment of cancer in an animal, mammal or human. In an embodiment, said pharmaceutical composition further comprises one or more biologically active drugs being selected from the group consisting of immunosuppressant and/or immunomodulator drugs, and/or antineoplastic drugs, and/or antiviral drugs.

In a particular embodiment, the present invention also relates to the thiazolo(5,4- d)pyrimidine, oxazo!o(5,4-d)pyrimidine, thieno[2,3-d]pyrimidine and purine derivatives of formula I, II, III or IV, including the use according to the invention of said thiazolo(5,4- d)pyrimidine, oxazolo(5,4-d)pyrimidine, thieno[2,3-d]pyrimidine and purine derivatives of formula I, II, III or IV, being selected from the group consisting of:

- 2-(4-fluorophenyl)-7-(piperazin-1-yl)-thiazolo[5,4-d]pyrimidin-5-amine - 2-(4-fluorobenzyl)-7-(piperazin-1 -yl)-thiazolo[5,4-d]pyrimidin-5-arnine

- 2-(4-fluorophenethyl)-7-(piperazin-1 -yl)thiazolo[5,4-d]pyrimidin-5-amine

- 2-(4-fluorophenyl)-7-(2-methoxyethoxy)-thiazolo[5,4-d]pyrimidin-5-amine

- 7-ethoxy-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-5-amine

- 7-ethoxy-2-(4-fluorobenzyl)thiazolo[5,4-d]pyrimidin-5-amine

- 2-(4-fluorophenyl)-N-7-(3-rnethoxypropyl)thiazolo[5,4-d]pyrimidine-5,7-diamine

- 2-(4-fluorophenyl)-7-morpholino-t iazolo[5,4-d]pyrinnidin-5-amine

- 2-(4-fluorobenzyl)-7-morpholino-thiazolo[5,4-d]pyrimidin-5-amine

- 2-(4-fluorophenyl)-7-(4-m-tolylpiperazin-1 -yl) hiazolo[5,4-d]pyrimidin-5-amine

- 2-(4-fluorophenyl)-7-(4-(thiazol-2-yl)piperazin-1 -yl)thiazolo[5,4-d]pyrimidin-5-amine

- 2-(4-fluorophenyl)-7-(4-pentylpiperazin-1-yl)t iazolo[5,4-d]pyrimidin-5-amine

- 2-(4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7-y!)piperazin-1 -yl)-1 - morpholinoethanone

- 7-(4-benzylpiperazin-1-yl)-2-(4-fluorophenyl)thiazolo[5,4-d]pyrirnidin-5-amine

- benzyl-4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazine-1-carboxylate

- 2-(4-fluorophenyl)-7-(4-(phenylsulfonyl)piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine

- 4-(5-amino-2-(4-fluorophenyl)-thiazolo[5,4-d]pyrinriidin-7-yl)-N-p-toly!piperazine-1 - car oxamide

- 4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)-N-m-tolylpiperazine-1- carboxamide

- 4-(5-amino-2-(4-fluorobenzyl)thiazolo[5,4-d]pyrimidin-7-yl)-N-nri-tolylpiperazine-1- carboxamide

- 1 -(4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone

- 1 -(4-(5-amino-2-(4-fluorobenzyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone

- 2-(4-chlorophenoxy)-1 -(4-(2-(4-fluorophenyl)-5-methylthiazolo[5,4-d]pyrimidin-7- yl)piperazin-1-yl)ethanone

- 1-(4-(5-amino-2-(2-(4-fluorophenoxy)et yl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(4- chlorophenoxy)ethanone

- 1 -(4-(5-amino-2-(4-fluorophenethyl)-thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone

- 1 -(4-(5-amino-2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- methoxyphenoxy)ethanone - 1 -(4-(5-amino-2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(4- fluorophenoxy)ethanone

- 1 -(4-(5-amino-2-(4-fluorophenethyl)t iazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- bromophenoxy)ethanone

- 1 -(4-(5-amino-2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(m- tolyloxy)ethanone

- 1 -(4-(5-amino-2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(2,4- dichlorop enoxy)ethanone

- 1 -(4-(5-amino-2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-3-(4- fluorophenoxy)propan-1 -one

- 1 -(4-(5-amino-2-(1-(4-fluorop enyl)ethyl)t iazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(4- c lorop enoxy)ethanone

- 1-(4-(5-amino-2-(1-(4-fluorophenyl)-2-phenylethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1- yl)-2-(4-chlorophenoxy)ethanone

- 4-(5-amino-2-(1 -(4-fluorophenyl)ethyl)thiazolo[5,4-d]pyrimidin-7-yl)-N-m-tolylpiperazine-1 - car oxamide

- 5-amino-2-cyclopropyl-7-methoxythiazolo[5,4-d]pyrimidine

- 5-amino-2-cyclopropyl-7-N-piperazino-thiazolo[5, 4-d]pyrimidine

- 5-amino-2-(3,4-dichlorophenyl)-7-(N-piperazino)thiazolo[5,4-d]pyrimidine

- 5-amino-2-(1-phenylcyclopropyl)-7-(N-piperazino)thiazolo[5, 4-d]pyrimidine

- 5-amino-2-(1 -(4-chlorophenyl)cyclopropyl)-7-(N-piperazino)1hiazolo[5,4-d]pyrinnidine

- 5-amino-7-N-piperazino-2-methylthio-thiazolo[5, 4-d]pyrimidine

- 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2-(1 -phenylcyclopropyl)thiazolo[5,4- d]pyrimidine

- 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2-methylthio-thiazolo[5,4-d]pyrimidi^

- 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2-(3,4-dichlorophenyl)thiazolo[5,4- djpyrimidine

- 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2-(1 -(4- chlorophenyl)cyclopropyl)thiazolo[5,4-d]pyrimidine

- 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2-(2-phenylethyl)t iazolo[5,4- djpyrimidine

- 5-amino-2-cyclopropyl-7-[4-(4-chlorophenoxyacetyl)piperazin-1 -yl]-thiazolo[5,4-d]pyrimidine

- 5-amino-7^4-(4-chlorop enoxyacetyl)piperazin-1-yl]-2-cyclohe><ylthiazolo[5,4-d)pyrimidine - 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2-(pyridine-3-yl)thiazolo[5,4- d]pyrimidine

- 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2-(N-oxopyridine-3-yl)thiazolo[5,4- d]pyrimidine

- 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2-(4-chlorophenylmethy!)thiazolo[5,4- d]pyrimidine

- 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2-(4-chlorophenyl)thiazolo[5,4- d]pyrimidine

- 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2-(3-methoxyphenyl)thiazolo[5,4- djpyrimidine

- 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2-(1 -(4-chlorophenyl)ethyl)thiazolo[5,4- d]pyrimidine

- 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2-(4-fluorophenylamino)-thiazolo[5,4- d]pyrimidine

- 5-amino-2-(4-fluorophenyl)-7-(4-[2-(4-bromophenoxy)acetyl]-piperazin-1-yl)-thiazolo[5,4- d]pyrimidine

- 5-amino-2-(4-fluorophenyl)-7-(4-[2-(3-nitrophenoxy)acetyl]-piperazin-1 -yl)-thiazolo[5,4- djpyrimidine

- 5-amino-2-(4-fluorophenyl)-7-(4-(2-phenoxyacetyl)-piperazin-1 -yl)-thiazolo[5,4-d]pyrimidine - 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-[2-(3-nitrophenoxy)acetyl]piperazin-1 -yl)- thiazolo[5,4-d]pyrimidine

- 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-[2-(4-c lorophenyl)acetyl]piperazin-1 -yl)- thiazolo[5,4-d]pyrimidine

- 5-aiTiino-2-[2-(4-fluorophenyl)ethyl]-7-(4-rTi-tolylcarbamoylpiperazin-1-yl)-lhiazolo[5,4- djpyrimidine

- 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-[2-phenoxyacetyl]piperazin-1 -yl)-thiazolo[5,4- djpyrimidine

- 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-[4-(4-chlorobenzoyl)piperazin-1-yl]-thiazolo[5,4- djpyrimidine

- 5-amino-2-[2-(4-f!uorophenyl)ethyl]-7-[4-(3-phenylpropionyl)piperazin-1 -yl]-t iazolo[5,4- djpyrimidine

- 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-[4-phenylmet anesulfonylpiperazin-1 -yl]-thiazol^ djpyrimidine

- 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-[2-(4-chlorophenoxy)acetyl]homopiperazin-1 -yl)- thiazolo[5,4-d]pyrimidine - 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-[(methylpheny!carbarnoyl)-methyl]piperaziri-1-yl)- thiazolo[5,4-d]pyrimidine

- 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-thiazol-2-yl-piperazine-1 -yl)-thiazolo[5,4- d]pyrimidine

- 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-(phenethylcarbamoyl-rnethyl)piperazin-1 -yl)- thiazolo[5,4-d]pyrimidine

- 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-((3-(R)-tert-butoxycarbonylamino)pyrrolidin-1-yl)- thiazolo[5,4-d]pyrimidine

- 5-amino-2-[2-(4 luorophenyl)elhyl]-7-(3-(R)-[2-(4-chlorophenoxy)-acetylamino]pyrrolidin-1 - yl)-thiazolo[5,4-d]pyrimidine

- 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(3-(R)-(4-chlorobenzoylamino)-pyrrolidin-1-yl)- thiazolo[5,4-d]pyrimidine

- 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(1-benzyloxycarbonylpiperidin-3-ylamino)- thiazolo[5,4-d]pyrimidine

- 5-amino-2-[2-(4-fluorophenyl)ethy!]-7-(1 -tert-butoxycarbonylpyrrolidin-3-(S)-ylannino)- thiazolo[5,4-d]pyrimidine

- 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(1 -(4-chlorophenoxyacetyl)pyrrolidin-3-(S)-ylamino)- thiazolo[5,4-d]pyrimidine

- 5-amino-2-[2-(4 luorophenyl)ethyl]-7-(4-benzoylpiperidine-1-yl)-thiazolo[5,4-d]pyrimidine - 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-(2-phenoxyet yl)piperazin-1-yl)-thiazolo[5,4- d]pyrimidine

- 5-amino-2-[1 -(4-fluorophenyl)propyl]-7-(4-[2-(4-chlorophenoxy)acetyl]piperazin-1 - yl)thiazolo[5,4-d]pyrimidine

- 5-amino-2-[cyclopentyl-(4-fluorophenyl)methyl]-7-(4-[2-(4-chlorophenoxy)acetyl]piperazin-1- yl)thiazolo[5,4-d]pyrimidine

- 5-amino-7-piperazin-1-yl-2-(2-thiophen-2-yl-ethyl)-thiazolo[5,4-d]pyrimidine

- 5-amino-2-(2-thiophen-2-ylethyl)-7-(4-[2-(4-chloro-phenoxy)acetyl]piperazin-1- yl)thiazolo[5,4-d]pyrimidine

- 5-amino-2-(2-t iophen-2-ylethyl)-7-(4-[2-(4-chloro-phenyl)acetyl]piperazin-1 -yl)thiazolo[5,4- d]pyrimidine

- 5-amino-2-(2-thiophen-2-ylethyl)-7-(4-(4-chloro-benzoyl)piperazin-1 -yl)thiazolo[5,4- djpyrimidine

- 5-amino-2-(2-thiophen-2-ylethyl)-7-(4-m- tolylcarbamoylpiperazin-1 -yl)thiazolo[5,4- d]pyrimidine - 2-(4-chlorophenoxy)-1 -(4-(2-(4-fluorophenyl)oxa2olo[5,4-d]pyrirnidin-7-yl)piperazin-1- yl)ethanone

- 2-(4-chlorophenoxy)-1-(4-(2-(4-fluoropheny!)-5-methyl-oxa2olo[5,4-d]pyrimidin-7- yl)piperazin-1 -yl)ethanone

- 1-(4-(5-amino-2-(4-fIuorop enyl)oxazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone

- 2-(4-chlorophenoxy)-1 -(4-(2-(4-fluorobenzyl)oxazolo[5,4-d]pyrimidin-7-yl)piperazin-1- yl)ethanone

- 2-(4-chlorophenoxy)-1 -(4-(2-(4-fluorobenzyl)-5-methyloxazolo[5,4-d]pyrimidin-7- yl)piperazin-1 -yl)ethanone

- 1-(4-(5-amino-2-(4-fluorophenethyl)oxazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- chlorop enoxy)ethanone

- N-(3-chloro-4-fluorophenyl)-2-(4-fluorophenyl)-oxazolo[5,4-d]pyrimidin-7-amine

- N-7-(3-chloro -fluorophenyl)-2-(4-fluorophenyl)-oxazolo[5^-d]pyrinriidine-5,7-dianriine - 5-amino-2-cyclopropyl-7-N-piperazino-oxazolo[5,4-d]pyrimidine

- 5-amino-2-methoxyrnethyl-7-N-piperazino-oxazolo[5,4-d]pyrimidine

- 5-amino-2-cyclohexyl-7-N-piperazino-oxazolo[5,4-d]pyrimidine

- 5-amino-2-pentyl-7-N-piperazino-oxazolo[5,4-d]pyrimidine

- 5-amino-2-(2-phenylethyl)-7-N-piperazino-oxazolo[5,4-d]pyrimidine

- 5-amino-2-cyclopropyl-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yll-oxazolo[5,4-d]pyrinriidine

- 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2-methoxymethyloxazolo[5, 4- d]pyrimidine

- 5-amino-2-cyclohexyl-7-[4-(4-chlorophenoxyacetyl)piperazin-1 -yl]oxazolo[5,4-d]pyrimidine

- 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]- 2-pentyloxazolo[5,4-d]pyrimidine - 5-amino-2-(2-phenylethyl)-7-[4-(4-chlorophenoxyacetyl)piperazin-1 -yl]oxazolo[5,4- d]pyrimidine

- 5-amino-2-(4-fluorophenyl)-7-(4-isobutylpiperazin-1 -yl)-oxazolo[5,4-d]pyrimidine

- 5-amino-2-(4-fluorophenyl)-7-(4-acetylpiperazin-1 -yl)-oxazolo[5,4-d]pyrimidine

- 5-amino-2-(4-fluorophenyl)-7-[4-(2-methoxyethyl)-piperazin-1-yl]-oxazolo[5,4-d]pyrimidine - 5-amino-2-(4-fluorophenyl)-7-(4-[2-(3-nitrophenoxy)acetyl]-piperazin-1 -yl)-oxazolo[5,4- djpyrimidine

- 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-[2-(4-chlorophenyl)acetyl]-piperazin-1-yl)- oxazolo[5,4-d]pyrimidine - 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-[4-chlorobenzoyl]piperazin-1-yl)-oxazolo[5,4- d]pyrimidine

- 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-m-tolylcarbamoylpiperazin-1 -yl)-oxazolo[5,4- d]pyrimidine

- 5-amino-2-[2-(4-fluorophenyl)et yl]-7-(4-(2-p enoxyethyl)piperazin-1-yl)-oxazolo[5,4- d]pyrimidine

- 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-[(methylphenyl-carbamoyl)methyl]piperazin-1 -yl)- oxazolo[5,4-d]pyrimidine

- 5-amino-2-phenyl-7-N-piperazinyl-thiazolo[5,4-d]pyrimidine

- 5-amino-2-(2-furyl)-7-N-piperazinyl-thiazolo[5,4-d]pyrimidine

- 5-amino-2-(4-fluoro-p enyl)-7-N-piperazinyl-thiazolo[5,4-d]pyrimidine

-1-(4-(5-amino-2-phenylthiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- methoxyphenoxy)ethanone

- 1 -(4-(5-amino-2-(furan-2-yl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- fluorophenoxy)ethanone

- 1 -(4-(5-amino-2-(furan-2-yl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(m- tolyloxy)ethanone

- 1 -(4-(5-amino-2-(4-fIuorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(m- tolyloxy)ethanone

- 1-(4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(2,4- dichlorophenoxy)ethanone

- 1-(4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(4-chloro-2- methylphenoxy)ethanone

- 1 -(4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(3- chlorophenoxy)et anone

- 1-(4-(5-amino-2-phenylthiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(4- chlorophenoxy)ethanone

- 4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)-N-(4-cyanophenyl)piperazine-1- carboxamide

- 4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)-N-(2,4-difluorophenyl)piperazine- 1-carboxamide

- 4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)-N-(4-bromophenyl)piperazine-1- carboxamide

- 4-(5-amino-2-(4 luorophenyl)thiazolo[5,4-d]pyrinriidin-7-yl)-N-(2-methoxyphenyl)piperazine- 1-carboxamide - 4-(5-amino-2-phenylthia2olo[5,4-d]pyrimidin-7-yl)-N-m-tolylpiperazine-1-cait

- 5-amino-7-(N-piperazin-1 -yl)-2-(pyridin-3-yl)thiazolo[5, 4-d]pyrimidine

- 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N^-tolylpiperazine-1 -carboxam

- 1 -(4-(5-amino-2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-3-(4- bromophenyl)propan-1 -one

- 1 -(4-(5-amino-2-(4-fluorophenethyl)thiazolo[5,4-d]pyrirnidin-7-yl)piperazin-1 -yl)-2-(4- hydroxyphenoxy)ethanone

- methyl 4-(2-(4-(5-amino-2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2- oxoethoxy)benzoate

- 1 -(4-(5-amino-2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- (trifluoromethoxy)phenoxy)ethanone

- 2-(4-acetylphenoxy)-1 -(4-(5-amino-2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1 -yl)ethanone

- 1 -(4-(5-amino-2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(3- chlorophenoxy)ethanone

- 4-(5-amino-2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin-7-yl)-N-(4-cyanophenyl)piperazine- 1-carboxamide

- 1 -(4-(5-amino-2-(4-fluorobenzyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(4- methoxyphenoxy)ethanone

- 1 -(4-(5-amino-2-(4-fluorobenzyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- bromophenoxy)ethanone

- 4-(5-amino-2-(4-fluorobenzyl)thiazolo[5,4-d]pyrimidin-7-yl)-N-(4-cyanophenyl)piperazine-1 - carboxamide

- 1 -(4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- fluorophenoxy)ethanone

- 1 -(4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- methoxyphenoxy)ethanone

- 1-(4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- bromophenoxy)ethanone

- 1 -(4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-3-(4- fluorophenyl)propan-1 -one

- 1 -(4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(4- chlorophenoxy)-2-methylpropan-1-one

- 2-(3-methoxyphenethyl)-7-(piperazin-1 -yl)thiazolo[5,4-d]pyrimidin-5-amine - 2-(3^-dimethoxyphenethyl)-7-(piperazin-1 -yl)thiazolo[5^-d]pyrimidin-5-amine

- 2-(4-methylphenethyl)-7-(piperazin-1 -yl)thiazolo[5,4-d]pyrirnidin-5-arnine

- 1-(4-(5-amino-2-(3-methoxyphenet yl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(4- methoxyphenoxy)ethanone

- 1 -(4-(5-amino-2-(3-rriethoxyphenethyl)thiazolo[5,4-d]pyrirriidin-7-yl)piperazin-1 -yl)-2-(4- bromophenoxy)ethanone

- 1-(4-(5-amino-2-(3-melhoxyphenel yl)thiazo!o[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(4- chlorophenoxy)ethanone

- 1 -(4-(5-amino-2-(3,4-dimethoxyphenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- bromophenoxy)ethanone

- 1-(4-(5-amino-2-(3^-dimethoxyphenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4^ methoxyphenoxy)ethanone

- 1 -(4-(5-amino-2-(4-methylphenethyl)t iazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- bromophenoxy)ethanone

- 1-(4-(5-amino-2-(4-methylphenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- methoxyphenoxy)ethanone

- 1 -(4-(5-amino-2-(4-methylphenethyl)t iazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone

- 7-(piperazin-1 -yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-5-amine

- 7-(piperazin-1 -yl)-2-(pyridin-2-yl)thiazolo[5,4-d]pyrimidin-5-amine

- 7-(piperazin-1-yl)-2-(pyridin-4-yl)thiazolo[5,4-d]pyrimidin-5-amine

- 2-(4-chlorophenyl)-7-(piperazin-1 -yl)thiazolo[5,4-d]pyrimidin-5-amine

- 1-(4-(5-amino-2-(4-chlorophenyl)thiazolo[5,4-d]pyrirnidin-7-yl)piperazin-1 -yl)-2-(4- methoxyphenoxy)ethanone

- 1-(4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- methoxyphenoxy)ethanone

- 1 -(4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- fluorophenoxy)ethanone

- 1 -(4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- trifluoromethoxyphenoxy)ethanone

- 1 -(4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)-2-methylpropan-1-one

- 1 -(4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(m- tolyloxy)ethanone - 4-(5-amino-2-(pyridin-3-yl)thia2oloI5,4-d]pyrimidin-7-yl)-N-m-tolylpiperazine

- 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N-(4-chlorophenyl)piperazine-1 - carboxamide

- 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N-(4-methoxybenzyl)piperazine-1- carboxamide

- 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N-(4-cyanophenyl)piperazin carboxamide

- 1 -(4-(5-arnino-2-(4-c lorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- rnethoxyphenoxy)ethanone

- 1 -(4-(5-arnino-2-(pyridin-4-yl)thiazolo[5,4-d]pyrirnidin-7-yl)piperazin-1 -yl)-2-(4- ch!orophenoxy)ethanone

- 1 -(4-(5-amino-2-(pyridin-2-yl)thiazolo[5,4-d]pyrirnidin-7-yl)piperazin-1 -yl)-2-(4- chlorop enoxy)et anone

- 2-(4-fluorophenethyl)-7-(piperazin-1 -yl)thiazolo[5,4-d]pyrimidine

- 2-(4-fluorophenyl)-7-(piperazin-1 -yl)thiazolo[5,4-d]pyrimidine

- 2-(3-(4-fluorophenyl)propyl)-7-(piperazin-1 -yl)thiazolo[5,4-d]pyrimidin-5-arnine

- 2-(4-(4-fluorophenyl)butyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-arnine

- 2-(4-bromophenethyl)-7-(piperazin-1 -yl)thiazolo[5,4-d]pyrinriidin-5-arnine

- 2-pentyl-7-(piperazin-1 -yl)thiazolo[5,4-d]pyrimidin-5-amine

- 7-(piperazin-1 -yl)-2-p-tolylthiazolo[5,4-d]pyrimidin-5-amine

- 1 -(4-(5-amino-2-(3-(4-fluorophenyl)propyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone

- 1 -(4-(5-amino-2-(3-(4-fluorophenyl)propyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- methoxyphenoxy)ethanone

- 1-(4-(5-amino-2-(4-(4-fluorophenyl)butyl)thiazo

chlorophenoxy)ethanone

- 1 -(4-(5-amino-2-(4-(4-fluorophenyl)butyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- methoxyphenoxy)ethanone

- 1 -(4-(5-arnino-2-p-tolylthiazolo[5₎4-d]pyrirnidin-7-yl)piperazin-1 -yl)-2-(4- methoxyphenoxy)ethanone

- 1 -(4-(5-amino-2-p-tolylthiazolo[5,4-d]pyrirnidin-7-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone

- 1 -(4-(5-amino-2-pentylthiazolo(5,4-d]pyrirnidin-7-yl)piperazin-1 -yl)-2-(4- methoxyphenoxy)ethanone - 1-(4-(5-amino-2-pentylthiazolo[5,4-d]pyrirnidin-7-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone

- 1 -(4-(5-amino-2-(4-bromophenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- methoxyphenoxy)ethanone

- 1-(4-(5-amino-2-(4-bromophenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(4- chlorophenoxy)ethanone

- 1 -(4-(2-(4-fluorop enyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- methoxyphenoxy)ethanone

- 1 -(4-(2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone

- 1 -(4-(2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- methoxyphenoxy)ethanone

- 1 -(4-(2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone

- 2-(4-chlorophenoxy)-1-(4-(6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperazin-1- yl)ethanone

- 1-(4-(2-butyl-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)elhanone

- N-(3-chloro-4-fluorophenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-amine

- 2-butyl-N-(3-chloro-4-fluorophenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-amine

- 2-(4-chlorophenoxy)-1 -(4-(6-(4-fluorophenyl)-2-methylthieno[2,3-d]pyrimidin-4-yl)piperazin 1 -yl)ethanone

- 1 -(4-(2-amino^-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone

- 2-amino-4-N-benzylamino-6-(4-fluorophenyl)-thieno[2,3-d]pyrimidine

- 2-amino-4-N-piperazinyl-6-phenyl-thieno[2,3-d]pyrimidine

- 1 -(4-(2-amino-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone

- 4-(2-amino^-phenylthieno[2,3-d]pyrimidin-4-yl)-N-m-tolylpiperazine-1 -carboxamide - 4-(2-amino^-phenylthieno[2,3-d]pyrimidin-4-yl)-N-(4-chlorophenyl)piperazine-1- carboxamide

- 1 -(4-(2-amino^-phenylthieno[2,3-d]pyrimidin-4-yl)piperazin-1 -yl)-2-phenoxyethanone

- 2-amino-4-N-homopiperazinyl-6-phenyl-thieno[2,3-d]pyrimidine - 1 -(4-(2-amino-6-phenylthieno[2,3-d]pyrimidin-4-yl)-1 ,4-diazepan-1 -yl)-2-(4- ch1orophenoxy)ethanone

- 1 -(4-(2-amino-6-phenylthieno[2,3-d]pyrimidin-4-yl)-1 ,4-diazepan-1 -yl)(4- chlorophenyl)methanone

- 2-(4-(2-amino^-phenylthieno[2,3-d]pyrimidin-4-yl)piperazin-1 -yl)-N-rnethyl-N- phenylacetamide

- 4-(4-(2-phenoxyethyl)piperazin-1-yl)-6-phenylthieno[2,3-d]pyrimidin-2-amine

- (R)-tert-butyl 1-(2-amino-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)pyrrolidin-3- ylcarbamate

- (R)-4-(3-aminopyrrolidin-1 -yl)-6-(4-f)uorophenyl)lhieno[2₁3-d]pyrimidin-2-amine

- (R)-N-(1-(2-amino-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-2-(4- chlorophenoxy)acetamide

(R)-N-(1 -(2-amino-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)pyiTolidin-3-yl)-4- chlorobenzamide

- 2-amino-4-N-piperazinyl-6-(4-fluorophenyl)-thieno[2,3-d]pyrimidine

- 1-(4-(2-amino^-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperazin-1 -yl)-3-phenylpropan- 1 -one

- 4-(4-(benzylsulfonyl)piperazin-1-yl)-6-(4-fluorophenyl)thieno[2,3-d]pyrirnidin-2-amine

- (4-(2-amino-6-(4-fIuorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperazin-1 - yl)(cyclohexyl)methanone

- 4-(2-arnino-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)(pyridin-3- yl)methanone

- 4-(2-amino-6-(4-fluoropheny!)thieno[2,3-d]pyrimidin-4-yl)-N,N-diisopropylpiperazine-1- carboxamide

- (1 -(2-amino-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-yl)(phenyl)methan

- 2-amino-4-N-piperazino-thieno[2,3-d]pyrimidine

- 1 -(4-(2-aminothieno[2,3-d]pyrirriidin-4-yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone

- 2-(4-chlorophenoxy)-1 -(4-(6-(4-fluorophenyl)-2-phenylthieno[2,3-d]pyrimidin-4-yl)piperazin- 1-yl)ethanone

- ethyl 4-(4-(2-(4-chlorophenoxy)acety!)piperazin-1-yl)-6-(4-fluorophenyl)thieno[2,3- d]pyrimidine-2-carboxylate

- ethyl 2-(4-(4-(2-(4-chlorophenoxy)acetyl)piperazin-1 -yl)-6-(4-fluorophenyl)thieno[2,3- d]pyrimidin-2-yl)acetate - 4-(4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)-6-^

carboxamide

- 4-(4-(2-(4-chlorophenoxy)acetyl)piperazin-1 -yl)-6-(4-fluorophenyl)-N-(2- methoxyethyl)thieno[2,3-d]pyrimidine-2-carboxamide

- 4-(4-(2-(4-chlorophenoxy)acetyl)piperazin-1 -yl)-6-(4-fluorop enyl)thieno[2,3-d]pyrimidine-2- carboxylic acid

- 2-(4-(4-(2-(4-chlorophenoxy)acetyl)piperazin-1 -yl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin- 2-yl)acetamide

- 4-(2-amino^-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)-N-rri-tolylpiperazine-1- carboxamide

- 4-(6-(4-fluorophenyl)-2-phenylthieno[2,3-d]pyrimidin-4-yl)-N-m-tolylpiperazine-1- carboxamide

- ethyl 6-(4-fluorophenyl)-4-(4-(m-tolylcarbamoyl)piperazin-1 -yl)thieno[2,3-d]pyrimidine-2- carboxylate

- 6-(4-fluorophenyl)-4-(4-(m-tolylcarbamoyl)piperazin-1-yl)thieno[2,3-d]pyrimidine-2- carboxamide

- 4-ethoxy-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-2-amine

- 6-(4-fluorophenyl)-4-morpholinothieno[2,3-d]pyrimidin-2-arTiine

- N-(3-chloro-4-fluorophenyl)-6-(4-fluorophenyl)-2-methylthieno[2,3-d]pyrimidin-^

- ethyl 4-(3-chloro-4-fluorophenylamino)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine-2- carboxylate

- 1 -(4-(2-amino-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperazin-1 -yl)-2-(4- methoxyphenoxy)ethanone

- 1 -(4-(2-amino-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4- fluorophenoxy)ethanone

- 1-(4-(2-amino^^henylthieno[2,3-d]pyrimidin-4-yl)piperazin-1 -yl)-2-(m-tolyloxy)ethanon

- 1 -(4-(2-amino-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperazin-1 -yl)-2-(4- bromophenoxy)ethanone

- 1 -(4-(2-amino-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperazin-1 -yl)-2-(4-chlorophenoxy)-2- methylpropan-1 -one

-1-(4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1-yl)-2-(4-chlorophenoxy)ethanone

- 1-(4-(2-amino-8-(3,4-dimethoxyphenyl)-9H-purin-6-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone - 1 -(4-(2-amino-8-(4-bromophenyl)-9H-purin-6-yl)piperazin-1-yl)-2-(4- chlorophenoxy)ethanone

- 1 -(4-(2-amino-8-(4-chloropheny!)-9H-purin-6-yl)piperazin-1-yl)-2-(4- chlorophenoxy)et anone

- 1 -(4-(2-amino-8-(3-chlorophenyl)-9H-purin-6-yl)piperazin-1-yl)-2-(4- chlorophenoxy)ethanone

- 1 -(4-(2-amino-8-(4-(trifluoromethyl)p enyl)-9H-purin-6-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone

- 1 -(4-(2-amino-8-(4-(trifluoromethoxy)phenyl)-9H-purin-6-yl)piperazin-1-yl)-2-(4- chlorophenoxy)ethanone

- 1-(4-(2-amino-8-p-tolyl-9H-purin-6-yl)piperazin-1-yl)-2-(4-chlorophenoxy)ethanone

- 1-(4-(2-amino-8-propyl-9H-purin-6-yl)piperazin-1-yl)-2-(4-chlorophenoxy)ethanone

- 1 -(4-(2-amino-8-cyc!opropyl-9H-purin-6-yl)piperazin-1-yl)-2-(4-chlorophenoxy)ethanone - 1 -(4-(2-amino-8-tert-butyl-9H-purin-6-yl)piperazin-1 -yl)-2-(4-ch!orophenoxy)ethanone - 1-(4-(2-amino-8-methyl-9H-purin-6-yl)piperazin-1-yl)-2-(4-c lorophenoxy)ethanone

- 1-(4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1-yl)-2-phenoxyethanone

- 1 -(4-(2-amino-8-(4-fluorophenyl)-9H-purin^-yl)piperazin-1-yl)(3-rnethoxyphenyl)methanone

- 1 -(4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1-yl)-2-(thiophen-2-yl)ethanone

- (4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1-yl)(4-chlorophenyl)methanone - 6-(4-(benzylsulfonyl)piperazin-1 -yl)-8-(4-fluorophenyl)-9H-purin-2 -amine

- (4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1-yl)(naphthalen-1-yl)methanone - 1 -(4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1 -yl)ethanone

- 8-(4-f)uorophenyl)-6-(4-(thiazol-2-yl)piperazin-1 -yl)-9H-purin-2-amine

- 2-(4-(2-amino-8-(4-fluorophenyl)-9H^urin^-yl)piperazin-1-yl)-1 -(pyrrolidin-1-yl)ethanone - 2-(4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1-yl)-1 -morpholinoethanone

- 2-(4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1-yl)-N-(pyridin-3-yl)acetamide

- 2-(4-(2-amino-8-(4-fluorophenyl)-9H^urin^-yl)piperazin-1 -yl)-N-methyl-N-p enylacetamide

- 6-(4-(4-c lorophenyl)piperazin-1 -yl)-8-(4-fluorophenyl)-9H-purin-2-amine

- 8-(4-fIuorophenyl)-6-(4-(4-fluorophenyl)piperazin-1-yl)-9H-purin-2-amine

- 2-(4-(2-amino-8-(4-fluorophenyl)-9H^urin-6-yl)piperazin-1-yl)-N-(pyridin-2-yl)acetanriide

- 2-(4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetarriide

- 6-(4-(4-fIuorobenzyl)piperazin-1-yl)-8-(4-fluorophenyl)-9H-purin-2-amine

- 8-(4-fluorophenyl)-6-(4-(pyridin-4-yl)piperazin-1 -yl)-9H-purin-2-amine - 6-(1 ,4-diazepan-1 -yl)-8-(4-fiuorophenyl)-9H-purin-2-amine

- 1 -(4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)-1 ,4-diazepan-1-yl)-2-(4- chlorophenoxy)ethanone

- 4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)-N-m-tolyl-1 ,4-diazepane-1 -carboxamide - 1 -(4-(2-amino-8-thioxo-8,9-dihydro-7H-purin-6-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone

- 1 -(4-(2-amino-8-(methy!thio)-9H-purin-6-yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone

- 1-(4-(2-amino-8-(propylthio)-9H-purin-6-yl)piperazin-1-yl)-2-(4-chlorophenoxy)ethanone - 1 -(4-(2-amino-8-(benzylthio)-9H-purin-6-yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone - 1 -(4-(2-amino-8-(phenethylthio)-9H-purin-6-yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone

- 1 -(4-(2-amino-9-methyl-8-(methylthio)-9H-purin-6-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone

- 1 -(4-(2-amino-8-(cyclopentylthio)-9H-purin-6-yl)piperazin-1 -yl)-2-(4- c lorophenoxy)ethanone

- 1 -(4-(2-amino-8-(4-fluorophenyl)-9-methyl-9H-purin-6-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone

- 1 -(4-(2-amino-9-benzyl-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1-yl)-2-(4- chlorophenoxy)ethanone

- 2-amino-6-(piperazin-1-yl)-8-(4-fluorophenyl)-9H-purine

- 1 -(4-(2-arnino-8-(4-fluorophenyl)-9H-purin-€-yl)piperazin-1-yl)-3-phenylpropan-1 -one

4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N-(4- (trifluoromethyl)phenyl)piperazine-1 -carboxamide

- 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N-phenylpiperazine-1-carbox

4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N-cyclohexylpiperazine-1- carboxamide

- 5-amino-7-[4-(N-4-fluorop enylcarboxamide)piperazin-1 -yl]-2-(pyridine-3-yl)thiazolo[5, 4- d]pyrimidine

- 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrim^

4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N-p-tolylpiperazine-1- carbothioamide

4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N-methyl-N-p-tolylpiperazine^ carboxamide

- p-tolyl 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)piperazine-1 -carboxylate. I n another particular embodiment, the invention relates to thiazolo[5,4-d]pyrimidine, oxazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine and purine derivatives of formula I, II, III, or IV, as well as pharmaceutical compositions for use as a medicine for the prevention or treatment of proliferative disorders including cancer in an animal, mammal or human, said pharmaceutical compositions comprising such thiazolo[5,4-d]pyrimidine, oxazolo[5,4- d]pyrimidine, thieno[2,3-d]pyrimidine and purine derivatives as active principle, represented by the above mentioned structural formula I, II, III, or IV and being in the form of a pharmaceutically acceptable salt. The latter include any therapeutically active nontoxic addition salt which compounds represented by structural formula I, II , III, or IV are able to form with a salt-forming agent. Such addition salts may conveniently be obtained by treating the thiazolo[5,4-d]pyrimidine, oxazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine and purine derivatives of the invention with an appropriate salt-forming acid or base. For instance, thiazolo[5,4-d]pyrimidine , oxazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine and purine derivatives having basic properties may be converted into the corresponding therapeutically active, non-toxic acid addition salt form by treating the free base form with a suitable amount of an appropriate acid following conventional procedures. Examples of such appropriate salt- forming acids include, for instance, inorganic acids resulting in forming salts such as but not limited to hydrohalides (e.g. hydrochloride and hydrobromide), sulfate, nitrate, phosphate, diphosphate , carbonate, bicarbonate, and the like; and organic monocarboxylic or dicarboxylic acids resulting in forming salts such as, for example, acetate, propanoate, hydroxy acetate, 2-hydroxypropanoate, 2-oxopropanoate, lactate, pyruvate, oxalate, malonate, succinate, maleate, fumarate, malate, tartrate, citrate, methanesulfonate, ethanesulfonate, benzoate, 2-hydroxybenzoate, 4-amino-2-hydroxybenzoate, benzene- su lfo na te , p-toluenesulfonate, salicylate, p-aminosalicylate, palmoate, bitartrate, camphorsulfonate, edetate, 1 ,2-ethanedisulfonate, fumarate, glucoheptonate, gluconate, glutamate, hexylresorcinate, hydroxynaphthoate, hydroxyethanesulfonate, mandelate, methylsulfate, pantothenate, stearate, as well as salts derived from ethanedioic, propanediol, butanedioic, (Z)-2-butenedioic, (E)2- butenedioic, 2-hydroxybutanedioic, 2,3- dihydroxybutane-dioic, 2-hydroxy-1 ,2,3- propanetricarboxylic and cyclohexanesulfamic acids and the like. Thiazolo[5,4-d]pyrimidine, oxazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine and purine derivatives of this invention, including the ones represented by the structural formula I, I I , I I I , or IV, having acidic properties may be converted in a similar manner into the corresponding therapeutically active, non-toxic base addition salt form. Examples of appropriate salt-forming bases include, for instance, inorganic bases like metallic hydroxides such as but not limited to those of alkali and alkaline- earth metals like calcium, lithium, magnesium, potassium and sodium, or zinc, resulting in the corresponding metal salt; organic bases such as but not limited to ammonia, alkylamines, benzathine, hydrabamine, arginine, lysine, NiN¹- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylene-diamine, N-methylglucamine, procaine and the like.

Reaction conditions for treating the thiazolo[5,4-d]pyrimidine, oxazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine or purine derivatives of this invention, including the ones represented by the structural formula I, II, III, or IV, with an appropriate salt-forming acid or base are similar to standard conditions involving the same acid or base but different organic compounds with basic or acidic properties, respectively. Preferably, in view of its use in a pharmaceutical composition or in the manufacture of a medicament for treating specific diseases, the pharmaceutically acceptable salt will be designed, i.e. the salt-forming acid or base will be selected so as to impart greater water-solubility, lower toxicity, greater stability and/or slower dissolution rate to the thiazolo(5,4-d)pyrimidine or oxazolo(5,4-d)pyrimidine derivative of this invention.

Another aspect of the present invention relates to the thiazolo[5,4-d]pyrimidine oxazolo[5,4- djpyrimidine, thieno[2,3-d]pyrimidine and purine derivatives of the invention, including the thiazolo[5,4-d]pyrimidine, oxazolo(5,4-d)pyrimidine, thieno[2,3-d]pyrimidine and purine derivatives of formula I, II, III and IV, for use as a medicine and to the use of said thiazolo[5,4-d]pyrimidine, oxazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine or purine derivatives as a medicine to treat or prevent proliferative disorders including cancer in an animal, more specifically a mammal such as a human being. In more specific embodiments, said cancer is a hematological malignancy or a cancer of the blood-forming tissues. In more particular embodiments, said cancer is a leukemia or lymphoma. In a yet more particular embodiment said cancer is leukemia. In more particular embodiments, said cancer is selected from the group: acute leukemia, chronic leukemia (myeloid or lymphoid), multiple myeloma, and myelodysplastic syndrome. In yet another particular embodiment, said cancer is Hodgkin's lymphoma or non-Hodgkin's lymphoma. In another particular embodiment, said cancer is prostate cancer.

The present invention further relates to a method for preventing or treating cancer in a subject or patient by administering to the patient in need thereof a therapeutically effective amount of the compounds of the present invention, including the thiazolo[5,4-d]pyrimidine oxazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine and purine derivatives of the invention, including the thiazolo[5,4-d]pyrimidine, oxazolo(5,4-d)pyrimidine, thieno[2,3-d]pyrimidine and purine derivatives of formula I, II, III and IV. The therapeutically effective amount of said compound(s), especially for the treatment of proliferative disorders including cancer in humans and other mammals, preferably is a proliferation inhibiting amount. More preferably, it is a proliferation inhibiting amount of the derivative(s) of formula I, II, III and IV as defined herein. Depending upon the pathologic condition to be treated and the patient's condition, the said effective amount may be divided into several sub-units per day or may be administered at more than one day intervals.

Another aspect of the present invention relates to the pharmaceutical composition of the invention for use as a medicine and to the use of said pharmaceutical composition as a medicine to treat or prevent proliferative disorders including cancer in an animal, more specifically a mammal such as a human being. In more specific embodiments, said cancer is a hematological malignancy or a cancer of the blood-forming tissues. In more particular embodiments, said cancer is a leukemia or lymphoma. In a yet more particular embodiment said cancer is leukemia. In more particular embodiments, said cancer is selected from the group: acute leukemia, chronic leukemia (myeloid or lymphoid), multiple myeloma, and myelodysplastic syndrome. In yet another particular embodiment, said cancer is Hodgkin's lymphoma or non-Hodgkin's lymphoma. In another particular embodiment, said cancer is prostate cancer.

The present invention further provides the use of thiazolo[5,4-d]pyrimidine, oxazolo[5,4- djpyrimidine, thieno[2,3-d]pyrimidine and purine derivatives of this invention, including the ones represented by the structural formula I, I I, III, or IV, or a pharmaceutically acceptable salt or a solvate thereof, as a biologically active ingredient, i.e. active principle, especially as a medicine or a diagnostic agent or for the manufacture of a medicament or a diagnostic kit. In a particular embodiment, said medicament may be for the prevention or treatment of proliferative disorders including cancer in an animal, preferably a mammal, and more preferably a human In more specific embodiments, said cancer is a hematological malignancy or a cancer of the blood-forming tissues. In more particular embodiments, said cancer is a leukemia or lymphoma. In a yet more particular embodiment said cancer is leukemia. In more particular embodiments, said cancer is selected from the group: acute leukemia, chronic leukemia (myeloid or lymphoid), multiple myeloma, and myelodysplastic syndrome. In yet another particular embodiment, said cancer is Hodgkin's lymphoma or non- Hodgkin's lymphoma. In another particular embodiment, said cancer is prostate cancer.

The present invention further provides the use of thiazolo[5,4-d]pyrimidine, oxazolo[5,4- d]pyrimidine, thieno[2,3-d]pyrimidine and purine derivatives of this invention, including the ones represented by the structural formula I, II, III, or IV, or a pharmaceutically acceptable salt or a solvate thereof, as a biologically active ingredient, i.e. active principle such as a proliferation inhibiting amount of the thiazolo[5,4-d]pyrimidine, oxazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine and purine derivatives of this invention including the ones represented by the structural formula I, II, III, or IV, or a pharmaceutically acceptable salt or a solvate thereof.

The present invention further provides the use of the thiazo!o[5,4-d]pyrimidine, oxazolo[5,4- djpyrimidine, thieno[2,3-d]pyrimidine and purine derivatives of this invention, including the ones represented by the structural formula I, II, III, or IV, or a pharmaceutically acceptable salt or a solvate thereof, as a biologically active ingredient, i.e. active principle, especially as a medicine or for the manufacture of a medicament for treating a proliferative disorder, including cancer in an animal, preferably a mammal, and more preferably a human. In more specific embodiments, said cancer is a hematological malignancy or a cancer of the blood- forming tissues. In more particular embodiments, said cancer is a leukemia or lymphoma. In a yet more particular embodiment said cancer is leukemia. In more particular embodiments, said cancer is selected from the group: acute leukemia, chronic leukemia (myeloid or lymphoid), multiple myeloma, and myelodysplasia syndrome. In yet another particular embodiment, said cancer is Hodgkin's lymphoma or non-Hodgkin's lymphoma. In another particular embodiment, said cancer is prostate cancer.

The pathologic conditions and disorders concerned by the said use, and the corresponding methods of prevention or treatment, are detailed herein below. Any of the uses mentioned with respect to the present invention may be restricted to a nonmedical use (e.g. in a cosmetic composition), a non-therapeutic use, a non-diagnostic use, a non-human use (e.g. in a veterinary composition), or exclusively an in-vitro use, or a use with cells remote from an animal. The invention further relates to a pharmaceutical composition comprising: (a) one or more thiazolo[5,4-d]pyrimidine, oxazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine and/or purine derivatives of this invention, including the ones represented by the structural formula I, II, III, or IV, and (b) one or more pharmaceutically acceptable earners.

The invention also relates to the compounds of the formulas described herein, including the thiazolo[5,4-d]pyrimidine, oxazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine and purine derivatives of this invention, including the ones represented by the structural formula I, II, III, or IV, or a pharmaceutically acceptable salt or a solvate thereof, being used for inhibition of the proliferation of other cancers than cancers of the blood-forming tissues, particularly for the inhibition of members of the solid tumors, including but not limited to cancer of the prostate, lung, breast, rectal, colon, lymph node, bladder, kidney, pancreatic, liver, ovarian, uterine, brain, skin, sarcoma, meningioma, glioblastoma, multiforme, skin, stomach, muscle, including all kinds of neuroblastoma, gastric carcinoma, renal cell carcinoma, neuroblastoma, gastric carcinoma, renal cell carcinoma, and uterine cancer.

In another embodiment, this invention provides combinations, preferably synergistic combinations, of one or more thiazolo[5,4-d]pyrimidine, oxazolo[5,4-d]pyrimidine, thieno[2,3- djpyrimidine and/or purine derivatives of this invention with one or more biologically active drugs being preferably selected from the group consisting of antineoplastic drugs. In another embodiment said one or more biologically active drugs are selected from the group consisting of antiviral drugs and/or immunosuppressant and/or immunomodulator drugs and/or antineoplastic drugs. Suitable anti-viral agents for inclusion into the antiviral compositions or combined preparations of this invention include for instance, inhibitors of HIV replication, entoroviral replication (such as replication of Rhinovirus, Polioviru s or Coxsackievirus), Dengue virus replication or HCV replication, such as interferon-alfa (either pegylated or not), ribavirin and other selective inhibitors of the replication of HCV, such as a compound falling within the scope of disclosure EP1162196, WO 03/010141 , WO 03/007945 and WO 03/010140, a compound falling within the scope of disclosure WO 00/204425, and other patents or patent applications within their patent families or all the foregoing filings.

As is conventional in the art, the evaluation of a synergistic effect in a drug combination may be made by analyzing the quantification of the interactions between individual drugs, using the median effect principle described by Chou et al. in Adv. Enzyme Reg. (1984) 22:27. Briefly, this principle states that interactions (synergism, additivity, antagonism) between two drugs can be quantified using the combination index (hereinafter referred as CI) defined by the following equation: wherein ED_X is the dose of the first or respectively second drug used alone (1a, 2a), or in combination with the second or respectively first drug (1c, 2c), which is needed to produce a given effect. The said first and second drug have synergistic or additive or antagonistic effects depending upon CI < 1 , CI = 1 , or CI > 1 , respectively. As will be explained in more detail herein below, this principle may be applied to a number of desirable effects such as, but not limited to, an activity against tumor cell proliferation, an activity against viral infection or viral replication, an activity against transplant rejection, an activity against immunosuppression or immunomodulation. For instance the present invention relates to a pharmaceutical composition or combined preparation having synergistic effects against a proliferative disorder such as cancer and containing: (a) one or more antineoplastic drugs, and (b) at least one thiazolo[5,4-d]pyrimidine, oxazo!o[5,4-d]pyrimidine, thieno[2,3- djpyrimidine and/or purine derivative of the invention, including the ones represented by the structural formula I, II, III, or IV and (c) optionally one or more pharmaceutical excipients or pharmaceutically acceptable carriers, for simultaneous, separate or sequential use in the treatment or prevention of cancer.

Suitable immunosuppressant drugs for inclusion in the synergistic compositions or combined preparations of this invention belong to a well known therapeutic class. They are preferably selected from the group consisting of cyclosporine A, su bstituted xanth ines (e. g. methylxanthines such as pentoxyfylline), daltroban, sirolimus, tacrolimus, rapamycin (and derivatives thereof such as defined below), leflunomide (or its main active metabolite A771726, or analogs thereof called malononitrilamides), mycophenolic acid and salts thereof (including the sodium salt marketed under the trade name Mofetil^®), adrenocortical steroids, azathioprine, brequinar, gusperimus, 6-mercaptopurine, mizoribine, chloroquine, hydroxychloroquine and monoclonal antibodies with immunosuppressive properties (e.g. etanercept, infliximab or kineret). Adrenocortical steroids within the meaning of this invention mainly include glucocorticoids such as but not limited to ciprocinonide, desoxycorticosterone, fludrocortisone, flumoxonide, hydrocortisone, naflocort, procinonide, timobesone, tipredane, dexamethasone, methylprednisolone, methotrexate, prednisone, prednisolone, triamcinolone and pharmaceutically acceptable salts thereof. Rapamycin derivatives as referred herein include O-alkylated derivatives, particularly 9-deoxorapamycins, 26-dihydrorapamycins, 40- O-substituted rapamycin s and 28,40-0,0-disubstituted rapamycins (as disclosed in U.S. Patent No. 5,665,772) such as 40-O-(2-hydroxy) ethyl rapamycin - also known as SDZ-RAD -, pegylated rapamycin (as disclosed in U.S. Patent No. 5,780,462), ethers of 7- desmethylrapamycin (as disclosed in U.S. Patent No. 6,440,991 ) and polyethylene glycol esters of SDZ-RAD (as disclosed in U.S. Patent No. 6,331 ,547).

Suitable immunomodulator drugs for inclusion into the synergistic immunomodulating pharmaceutical compositions or combined preparations of this invention are preferably selected from the group consisting of acemannan, amiprilose, bucillamine, dimepranol, ditiocarb sodium, imiquimod, Inosine Pranobex, interferon-β, interferon-γ, lentinan, levamisole, lisophylline, pidotimod, romurtide, platonin, procodazole, propagermanium, thymomodulin, thymopentin and ubenimex.

Synergistic activity of the pharmaceutical compositions or combined preparations of this invention against immunosuppression or immuno-modulation may be readily determined by means of one or more lymphocyte activation tests. Usually activation is measured via lymphocyte proliferation. Inhibition of proliferation thus always means immunosuppression under the experimental conditions applied. There exist different stimuli for lymphocyte activation, in particular: a) co-culture of lymphocytes of different species (mixed lymphocyte reaction , hereinafter referred as M LR) in a so-called mixed lymphocyte culture test: lymphocytes expressing different minor and major antigens of the HLA-DR type (= alloantigens) activate each other non-specifically; b) a CD3 assay wherein there is an activation of the T-lymphocytes via an exogenously added antibody (OKT3). This antibody reacts against a CD3 molecule located on the lymphocyte membrane which has a co- stimulatory function. Interaction between OKT3 and CD3 results in T-cell activation which proceeds via the Ca²+/calmodulin/calcineurin system and can be inhibited e.g. by cyclosporine A (hereinafter referred as CyA); and c) a CD28 assay wherein specific activation of the T-lymphocyte proceeds via an exogenously added antibody against a CD28 molecule which is also located on the lymphocyte membrane and delivers strong co- stimulatory signals. This activation is Ca²+-independent and thus cannot be inhibited by CyA. Determination of the immunosuppressing or immunomodulating activity of the thiazolo[5,4- d]pyrimidine, oxazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine or purine derivatives of this invention, as well as synergistic combinations comprising them, is preferably based on the determination of one or more, preferably at least three lymphocyte activation in vitro tests, more preferably including at least one of the MLR test, CD3 assay and CD28 assay referred above. Preferably the lymphocyte activation in vitro tests used include at least two assays for two different clusters of differentiation preferably belonging to the same general type of such clusters and more preferably belonging to type I transmembrane proteins. Optionally the determination of the immuno-suppressing or immunomodulating activity may be performed on the basis of other lymphocyte activation in vitro tests, for instance by performing a TNF-a assay or an IL-1 assay or an IL-6 assay or an IL-10 assay or an !L-12 assay or an assay for a cluster of differentiation belonging to a further general type of such clusters and more preferably belonging to type II transmembrane proteins such as, but not limited to, CD69, CD71 or CD134.

The synergistic effect may be evaluated by the median effect analysis method described herein before. Such tests may for instance, according to standard practice in the art, involve the use of equipment, such as flow cytometer, being able to separate and sort a number of cell subcategories at the end of the analysis, before these purified batches can be analyzed further.

Synergistic activity of the pharmaceutical compositions or combined preparations of this invention in the prevention or treatment of transplant rejection may be readily determined by means of one or more leukocyte activation tests performed in a Whole Blood Assay (hereinafter referred as WBA) described for instance by Lin et al. in Transplantation (1997) 63:1734-1738. WBA used herein is a lymphoproliferation assay performed in vitro using lymphocytes present in the whole blood, taken from animals that were previously given the thiazolo[5,4-d]pyrimidine, oxazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine or purine derivative of this invention, and optionally the other immunosuppressant drug, in vivo. Hence this assay reflects the in vivo effect of substances as assessed by an in vitro read-out assay. The synergistic effect may be evaluated by the median effect analysis method described herein before. Various organ transplantation models in animals are also available in vivo, which are strongly influenced by different immunogenicities, depending on the donor and recipient species used and depending on the nature of the transplanted organ. The survival time of transplanted organs can thus be used to measure the suppression of the immune response.

The pharmaceutical composition or combined preparation with synergistic activity against a proliferative disorder (such as cancer) and/or a viral infection and/or immunosuppression or immunomodulation according to this invention may contain the thiazolo[5,4-d]pyrimidine, oxazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine and/or purine derivative of this invention, including the ones represented by the structural formulae I, II, III, or IV over a broad content range depending on the contemplated use and the expected effect of the preparation . Typically, the thiazolo[5,4-d]pyrimidine, oxazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine and/or purine derivative content in the combined preparation is within the range of 0.1 to 99.9 % by weight, preferably from 1 to 99 % by weight, more preferably from about 5 to 95 % by weight.

Auto-immune disorders to be prevented or treated by the pharmaceutical compositions or combined preparations of this invention include both:

- systemic auto-immune diseases such as, but not limited to, lupus erythematosus, psoriasis, vasculitis, polymyositis, scleroderma, multiple sclerosis, ankylosing spondilytis, rheumatoid arthritis and Sjogren syndrome; auto-immune endocrine disorders such as thyroiditis; and

organ-specific auto-immune diseases such as, but not limited to, Addison disease, hemolytic or pernicious anemia, Goodpasture syndrome, Graves disease, idiopathic thrombocytopenic purpura, insulin-dependent diabetes mellitus, juvenile diabetes, uveitis, Crohn's disease, ulcerative colitis, pemphigus, atopic dermatitis, autoimmune hepatitis, primary biliary cirrhosis, autoimmune pneumonitis, autoimmune carditis, myasthenia gravis, glomerulonephritis and spontaneous infertility.

Transplant rejections to be prevented or treated by the pharmaceutical compositions or combined preparations of this invention include the rejection of transplanted or grafted organs or cells (both allografts and xenografts), such as but not limited to host versus graft reaction disease. The term "organ" as used herein means all organs or parts of organs in mammals, in particular humans, such as but not limited to kidney, lung, bone marrow, hair, cornea, eye (vitreous), heart, heart valve, liver, pancreas, blood vessel, skin, muscle, bone, intestine or stomach. The term "rejection" as used herein means all reactions of the recipient body or the transplanted organ which in the end lead to cell or tissue death in the transplanted organ or adversely affect the functional ability and viability of the transplanted organ or the recipient. In particular, this means acute and chronic rejection reactions. Also included in this invention is preventing or treating the rejection of cell transplants and xenotransplantation. The major hurdle for xenotransplantation is that even before the T lymphocytes, responsible for the rejection of allografts, are activated, the innate immune system, especially T-independent B lymphocytes and macrophages are activated. This provokes two types of severe and early acute rejection called hyperacute rejection and vascular rejection , respectively. The present invention addresses the problem that conventional immunosuppressant drugs like cyclosporine A are ineffective in xeno- transplantation. The ability of the compounds of this invention to suppress T-independent xeno-antibody production as well as macrophage activation may be evaluated in the ability to prevent xenograft rejection in athymic, T-deficient mice receiving xenogenic hamster-heart grafts.

The term "pharmaceutically acceptable carrier or excipient" as used herein in relation to pharmaceutical compositions and combined preparations means any material or substance with which the active principle, i.e. the thiazolo[5,4-d]pyrimidine, oxazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine and purine derivative of this invention, including the ones represented by the structural formula I, II, III, or IV, and optionally an antineoplastic drug and/or antiviral agent and/or an immunosuppressant or immunomodulator may be formulated in order to facilitate its application or dissemination to the locus to be treated, for instance by dissolving, dispersing or diffusing said composition, and/or to facilitate its storage, transport or handling without impairing its effectiveness. The pharmaceutically acceptable carrier may be a solid or a liquid or a gas which has been compressed to form a liquid, i.e. the compositions of this invention can suitably be used as concentrates, emulsions, solutions, granulates, dusts, sprays, aerosols, pellets or powders. Suitable pharmaceutical carriers for use in said pharmaceutical compositions and their formulation are well known to those skilled in the art. There is no particular restriction to their selection within the present invention although, due to the usually low or very low water-solubility of the thiazolo[5,4-d]pyrimidine, oxazolo[5,4- d]pyrimidine, thieno[2,3-d]pyrimidine and purine derivatives of this invention, special attention will be paid to the selection of suitable carrier combinations that can assist in properly formulating them in view of the expected time release profile. Suitable pharmaceutical carriers include additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying or surface-active agents, thickening agents, complexing agents, gelling agents, solvents, coatings, antibacterial and antifungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, i.e. earners and additives which do not create permanent damage to mammals.

The pharmaceutical compositions of the present invention may be prepared in any known manner, for instance by homogeneously mixing, dissolving, spray-drying, coating and/or grinding the active ingredients, in a one-step or a multi-steps procedure, with the selected carrier material and, where appropriate, the other additives such as surface-active agents, may also be prepared by micronisation, for instance in view to obtain them in the form of microspheres usually having a diameter of about 1 to 10 pm, namely for the manufacture of microcapsules for controlled or sustained release of the biologically active ingredient(s).

Suitable surface-active agents to be used in the pharmaceutical compositions of the present invention are non-ionic, cationic and/or anionic surfactants having good emulsifying, dispersing and/or wetting properties. Suitable anionic surfactants include both water-soluble soaps and water-soluble synthetic surface-active agents. Suitable soaps are alkaline or alkaline-earth metal salts, unsubstituted or substituted ammonium salts of higher fatty acids (C10-C22) , e.g. the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures obtainable form coconut oil or tallow oil. Synthetic surfactants include sodium or calcium salts of polyacrylic acids; fatty sulphonates and sul phates; sulphonated benzimidazole derivatives and alkylarylsulphonates. Fatty sulphonates or sulphates are usually in the form of alkaline or alkaline-earth metal salts, unsubstituted ammonium salts or ammonium salts substituted with an alkyl or acyl radical having from 8 to 22 carbon atoms, e.g. the sodium or calcium salt of lignosulphonic acid or dodecylsulphonic acid or a mixture of fatty alcohol sulphates obtained from natural fatty acids, alkaline or alkaline-earth metal salts of sulphuric or sulphonic acid esters (such as sodium lauryl sulphate) and sulphonic acids of fatty alcohol/ethylene oxide adducts. Suitable sulphonated benzimidazole derivatives preferably contain 8 to 22 carbon atoms. Examples of alkylarylsulphonates are the sodium, ca l ci um o r a l ca no la min e sa lts of d od ecy l be n zen e s u l ph o n ic a cid o r d i bu ty l- naphtalenesulphonic acid or a naphthalene-sulphonic acid/formaldehyde condensation product. Also suitable are the corresponding phosphates, e.g. salts of phosphoric acid ester and an adduct of p-nonylphenol with ethylene and/or propylene oxide, or phospholipids. Suitable phospholipids for this purpose are the natural (originating from animal or plant cells) or synthetic phospholipids of the cephalin or lecithin type such as e.g. phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine, lysolecithin, cardiolipin, dioctanyl-phosphatidylcholine, dipalmitoylphoshatidylcholine and their mixtures.

Suitable non-ionic surfactants include polyethoxylated and polypropoxylated derivatives of alkylphenols, fatty alcohols, fatty acids, aliphatic amines or amides containing at least 12 carbon atoms in the molecule, alkylarenesulphonates and dialkylsulphosuccinates, such as polyglycol ether derivatives of aliphatic and cycloaliphatic alcohols, saturated and unsaturated fatty acids and alkylphenols, said derivatives preferably containing 3 to 10 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenol. Further suitable non-ionic surfactants are water-soluble adducts of polyethylene oxide with poylypropylene glycol, ethylenediamino- polypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250 ethyleneglycol ether groups and / or 10 to 100 propyleneglycol ether grou ps . Such compou nds usua lly contain from 1 to 5 ethyleneglycol units per propyleneglycol unit. Representative examples of non-ionic surfactants are nonylphenol- polyethoxyethanol, castor oil polyglycolic ethers, polypropylene/polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, polyethyleneglycol and octylphenoxypolyethoxyethanol. Fatty acid esters of polyethylene sorbitan (such as polyoxyethylene sorbitan trioleate), glycerol, sorbitan, sucrose and pentaerythritol are also suitable non-ionic surfactants. Suitable cationic surfactants include quaternary ammonium salts, preferably halides, having four hydrocarbon radicals optionally substituted with halo, phenyl, substituted phenyl or hydroxy; for instance quaternary ammonium salts containing as N-substituent at least one C₈-C₂₂ alkyl radical (e.g. cetyl, lauryl, palmityl, myristyl, oleyl and the like) and, as further substituents, unsubstituted or halogenated lower alkyl, benzyl and/or hydroxy-C^ alkyl radicals. A more detailed description of surface-active agents suitable for this purpose may be found for instance in " cCutcheon's Detergents and Emulsifiers Annual " (MC Publishing Crop., Ridgewood, New Jersey, 1981 ), " Tensid-Taschenbuch ", 2^nd ed. (Hanser Verlag, Vienna, 1981 ) and " Encyclopaedia of Surfactants " (Chemical Publishing Co., New York, 1981 ). Structure-forming, thickening or gel-forming agents may be included into the pharmaceutical compositions and combined preparations of the invention. Suitable such agents are in particular highly dispersed silicic acid, such as the product commercially available under the trade name Aerosil; bentonites; tetraalkyl ammonium salts of montmorillonites (e.g., products commercially available under the trade name Bentone), wherein each of the alkyl groups may contain from 1 to 20 carbon atoms; cetostearyl alcohol and modified castor oil products (e.g. the product commercially available under the trade name Antisettle).

Gelling agents which may be included into the pharmaceutical compositions and combined preparations of the present invention include, but are not limited to, cellulose derivatives such as carboxymethylcellulose, cellulose acetate and the like; natural gums such as arabic gum, xanthum gum, tragacanth gum, guar gum and the like; gelatin; silicon dioxide; synthetic polymers such as carbomers, and mixtures thereof. Gelatin and modified celluloses represent a preferred class of gelling agents.

Other optional excipients which may be included in the pharmaceutical compositions and combined preparations of the present invention include additives such as magnesium oxide; azo dyes; organic and inorganic pigments such as titanium dioxide ; UV-absorbers; stabilisers; odor masking agents; viscosity enhancers; antioxidants such as, for example, ascorbyl palmitate, sodium bisulfite, sodium metabisulfite and the like, and mixtures thereof; preservatives such as, for example, potassium sorbate, sodium benzoate, sorbic acid, propyl gallate, benzylalcohol, methyl paraben, propyl paraben and the like; sequestering agents such as ethylene-diamine tetraacetic acid; flavoring agents such as natural vanillin; buffers such as citric acid and acetic acid ; extenders or bulking agents such as silicates, diatomaceous earth, magnesium oxide or aluminum oxide; densification agents such as magnesium salts; and mixtures thereof. Additional ingredients may be included in order to control the duration of action of the biologically-active ingredient in the compositions and combined preparations of the invention. Control release compositions may thus be achieved by selecting appropriate polymer carriers such as for example polyesters, polyamino-acids, polyvinyl-pyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose , carboxy- methylcellulose, protamine sulfate and the like. The rate of drug release and duration of action may also be controlled by incorporating the active ingredient into particles, e.g. microcapsules, of a polymeric substance such as hydrogels, polylactic acid, hydroxymethyl- cellulose, polymethyl methacrylate and the other above-described polymers. Such methods include colloid drug delivery systems including, but not limited to liposomes, microspheres, microemulsions, nanoparticles, nanocapsules and so on . Depending on the route of administration, the pharmaceutical composition or combined preparation of the invention may also require protective coatings.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation thereof. Typical carriers fo r thi s purpose therefore include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol, complexing agents such as cyclodextrins and the like, and mixtures thereof.

Other modes of local drug administration can also be used. For example, the selected active agent may be administered by way of intracavernosal injection, or may be administered topically, in an ointment, gel or the like, or transdermal, including transscrotally, using a conventional transdermal drug delivery system. Intracavernosal injection can be carried out by use of a syringe or any other suitable device. An example of a hypodermic syringe useful herein is described in U.S. Patent No. 4, 127,1 18, injection being made on the dorsum of the penis by placement of the needle to the side of each dorsal vein and inserting it deep into the corpora.

Since, in the ca se of combined preparations including the thiazolo[5,4-d]pyrimidine, oxazolo[5,4-d]pyrimidine, thieno(2,3-d]pyrimidine and purine derivative of this invention and an antineoplastic drug and/or an antiviral agent and/or an immunosuppressant or immunomodulator the ingredients do not necessarily bring out their synergistic therapeutic effect directly at the same time in the patient to be treated, the said combined preparation may be in the form of a medical kit or package containing the two ingredients in separate but adjacent form. In the latter context, each ingredient may therefore be formulated in a way suitable for an administration route different from that of the other ingredient, e.g. one of them may be in the form of an oral or parenteral formulation whereas the other is in the form of an ampoule for intravenous injection or an aerosol.

The present invention further relates to a method for preventing or treating at least one disease selected from the group consisting of a proliferative disorder such as cancer, a viral disorder, immune and auto-immune disorders, transplant rejections, in a patient, preferably a mammal , more preferably a human being. The method of this invention consists of administering to the patient in need thereof an effective amount of a thiazolo[5 ,4- djpyrimidine, oxazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine and/or purine derivative of this invention, including the ones represented by the structural formula I, II, III, or IV, optionally together with an effective amount of another immunosuppressant or immunomodulator or antineoplastic drug or antiviral agent or phosphodiesterase-4 inhibitor, or a pharmaceutical composition comprising the same, such as disclosed above in extensive details. The effective amount is usually in the range of about 0.01 mg to 20 mg, preferably about 0.1 mg to 5 mg, per day per kg bodyweight for humans. Depending upon the pathologic condition to be treated and the patient's condition, the said effective amount may be divided into several sub-units per day or may be administered at more than one day intervals. The patient to be treated may be any warm-blooded animal, preferably a mammal, more preferably a human being, suffering from said pathologic condition.

The preferred compounds of the present invention are non-sedating. In other words, a dose of such compounds that is twice the minimum dose sufficient to provide analgesia in an animal model for determining pain relief causes only transient (i. e. lasting for no more than half the time that pain relief lasts) or preferably no statistically significant sedation in an animal model assay of sedation (using the method described by Fitzgerald et al. in Toxicology (1988) 49:433-9). Preferably, a dose that is five times the minimum dose sufficient to provide analgesia does not produce statistically significant sedation. More preferably, a compound provided herein does not produce sedation at intravenous doses of less than 10 mg/kg per day or at oral doses of less than 30 mg/kg per day. If desired, compounds provided herein may be evaluated for toxicity (a preferred compound is non-toxic when an immunomodulating amount or a cell anti-proliferative amount is administered to a subject) and/or side effects (a preferred compound produces side effects comparable to placebo when a therapeutically effective amount of the compound is administered to a subject). Toxicity and side effects may be assessed using any standard method. In general, the term "non-toxic" as used herein shall be understood as referring to any substance that, in keeping with established criteria, is susceptible to approval by the United States Federal Drug Administration for administration to mammals, preferably humans. Toxicity may be also evaluated using assays including bacterial reverse mutation assays, such as an Ames test, as well as standard teratogenicity and tumorogenicity assays. Preferably, administration of compounds provided herein within the therapeutic dose ranges disclosed hereinabove does not result in prolongation of heart QT intervals (e.g. as determined by electrocardiography in guinea pigs, minipigs or dogs). When administered daily, such doses also do not cause liver enlargement resulting in an increase of liver to body weight ratio of more than 50 % over matched controls in laboratory rodents (e. g. mice or rats). Such doses also preferably do not cause liver enlargement resulting in an increase of liver to body weight ratio of more than 10 % over matched untreated controls in dogs or other non-rodent mammals. The preferred compounds of the present invention also do not promote substantial release of liver enzymes from hepatocytes in vivo, i.e. the therapeutic doses do not elevate serum levels of such enzymes by more than 50% over matched untreated controls in vivo in laboratory rodents.

Another embodiment of this invention includes the various precursor or "prodrug" forms of the compounds of the present invention. It may be desirable to formulate the compounds of the present invention in the form of a chemical species which itself is not significantly biologically active, but which when delivered to the body of a human being or higher mammal will undergo a chemical reaction catalyzed by the normal function of the body, inter alia, enzymes present in the stomach or in blood serum, said chemical reaction having the effect of releasing a compound as defined herein. The term "prodrug" or "pro-drug" thus relates to these species which are converted in vivo into the active pharmaceutical ingredient.

The pro-drugs of the present invention can have any form suitable to the formulator, for example, esters are non-limiting common pro-drug forms. In the present case, however, the pro-drug may necessarily exist in a form wherein a covalent bond is cleaved by the action of an enzyme present at the target locus. For example, a C-C covalent bond may be selectively cleaved by one or more enzymes at said target locus and, therefore, a pro-drug in a form other than an easily hydrolysable precursor, inter alia an ester, an amide, and the like, may be used.

For the purposes of the present invention the term "therapeutically suitable pro-drug" is defined herein as a compound modified in such a way as to be transformed in vivo to the therapeutically active form, whether by way of a single or by multiple biological transformations, when in contact with the tissues of humans or mammals to which the prodrug has been administered, and without undue toxicity, irritation, or allergic response, and achieving the intended therapeutic outcome. The present invention will be further described with reference to certain more specific embodiments and examples, but the present invention is not limited thereto. The following examples are given by way of illustration only.

Definitions

When describing the compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless a context dictates otherwise.

It is to be noticed that the term "comprising", used in the claims, should not be interpreted as being restricted to the means listed thereafter; it does not exclude other elements or steps. Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to one of ordinary skill in the art from this disclosure, in one or more embodiments. Where an indefinite or definite article is used when referring to a singular noun e.g. "a" or "an", "the", this includes a plural of that noun unless something else is specifically stated.

Similarly it should be appreciated that in the description of exemplary embodiments of the invention , various features of the invention are sometimes grouped together in a single embodiment, figure, or description thereof for the purpose of streamlining the disclosure and aiding in the understanding of one or more of the various inventive aspects.

As used herein with respect to a substituting radical, and unless otherwise stated, the term " Ci -7 alkyl " means straight and branched chain saturated acyclic hydrocarbon monovalent radicals having from 1 to 7 carbon atoms such as, for example, methyl, ethyl, propyl, n-butyl, 1 -methylethyi (isopropyl) , 2-methylpropyl (isobutyl) , 1 , 1 -dimethylethyl (ter-butyl), 2- methylbutyl, n-pentyl, dimethylpropyl, n- hexyl, 2-methylpentyl, 3-methylpentyl, n-heptyl and the like. By analogy, the term " C1-12 alkyl " refers to such radicals having from 1 to 12 carbon atoms, i.e. up to and including dodecyl.

As used herein with respect to a substituting radical, and unless otherwise stated, the term " acyl " broadly refers to a substituent derived from an acid such as an organic monocarboxylic acid, a carbonic acid, a carbamic acid (resulting into a carbamoyl substituent) or the thioacid or imidic acid (resulting into a carbamidoyl substituent) corresponding to said acids, and the term " sulfonyl " refers to a substituent derived from an organic sulfonic acid, wherein said acids comprise an aliphatic, aromatic or heterocyclic group in the molecule. In a more specific embodiment of the invention said acyl grou p, within the scope of th e above definition, refers to a carbonyl (oxo) group adjacent to a C ₇ alkyl, a C₃.₁₀ cycloalkyl, an aryl, an arylalkyl or a heterocyclic group, all of them being such as herein defined. Suitable examples of acyl groups are to be found below. I n a more specific embodiment of the invention said " sulfonyl " group, within the scope of the above definition, refers to a sulfonyl group adjacent to a C1.7 alkyl, a C₃ i₀ cycloalkyl, an aryl, an arylalkyl or a heterocyclic group, all of them being such as herein defined.

Acyl and sulfonyl groups originating from aliphatic or cycloaliphatic monocarboxylic acids or sulfonic acids are designated herein as aliphatic or cycloaliphatic acyl and sulfonyl groups and include, but are not limited to, the following:

- alkanoyl (for example formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and the like);

cyclo a l ka n oy l (fo r exa mple cyclo bu ta n eca rbo n yl , cyclo pe n ta n eca rbo n y l , cyclohexanecarbonyl, 1 -adamantanecarbonyl and the like);

- cycloalkyl-alkanoyl (for example cyclohexylacetyl, cyclopentylacetyl and the like); - alkenoyl (for example acryloyl, methacryloyl, crotonoyl and the like);

- alkylthioalkanoyl (for example methylthioacetyl, ethylthioacetyl and the like);

- alkanesulfonyl (for example mesyl, ethanesulfonyl, propanesulfonyl and the like);

- alkoxycarbonyl (for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl and the like);

- alkylcarbamoyl (for example methylcarbamoyl and the like);

- (N-alkyl)-thiocarbamoyl (for example (N-methyl)-thiocarbamoyl and the like);

- alkylcarbamidoyl (for example methylcarbamidoyl and the like); and

- alkoxalyl (for example methoxalyl, ethoxalyl, propoxalyl and the like);

Acyl and sulfonyl groups may also originate from aromatic monocarboxylic acids and include, but are not limited to, the following:

- aroyl (for example benzoyl, toluoyl, xyloyl, 1 -naphthoyl, 2-naphthoyl and the like);

- aralkanoyl (for example phenylacetyl and the like);

- aralkenoyl (for example cinnamoyl and the like);

- aryloxyalkanoyl (for example phenoxyacetyl and the like);

- arylthioalkanoyl (for example phenylthioacetyl and the like);

- arylaminoa!kanoyl (for example N-phenylglycyl, and the like);

- arylsulfonyl (for example benzenesulfonyl, toluenesulfonyl, naphthalene sulfonyl and the like);

- aryloxycarbonyl (for example phenoxycarbonyl, naphthyloxycarbonyl and the like);

- aralkoxycarbonyl (for example benzyloxycarbonyl and the like);

- arylcarbamoyl (for example phenylcarbamoyl, naphthylcarbamoyl and the like);

-arylglyoxyloyl (for example phenylglyoxyloyl and the like).

- arylthiocarbamoyl (for example phenylthiocarbamoyl and the like); and

- arylcarbamidoyl (for example phenylcarbamidoyl and the like).

Acyl groups may also originate from an heterocyclic monocarboxylic acids and include, but are not limited to, the following:

- heterocyclic-carbonyl, in which said heterocyclic group is as defined herein, preferably an aromatic or non-aromatic 5- to 7-membered heterocyclic ring with one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur in said ring (for example thiophenoyl, furoyl, pyrrolecarbonyl, nicotinoyl and the like); and

- heterocyclic-alkanoyl in which said heterocyclic group is as defined herein, preferably an aromatic or non-aromatic 5- to 7-membered heterocyclic ring with one or more heteroatoms selected from the group consisting of nitrogen, oxygen a nd su lfu r in sa id ri ng (fo r exa mple th io phe n e nea cetyl , fu ryl a cetyl , imidazolylpropionyl, tetrazolylacetyl, 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl and the like).

- As used herein with respect to a substituting radical, and unless otherwise stated, the term " thioacyl " refers to an acyl group as defined herein-above but wherein a sulfur atom replaces the oxygen atom of the carbonyl (oxo) moiety.

As used herein with respect to a substituting radical, and unless otherwise stated, the term " C1.7 alkylene " means the divalent hydrocarbon radical corresponding to the above defined C1.7 alkyl, such as methylene, bis(methylene), tris(methylene), tetramethylene, hexamethylene and the like.

As used herein with respect to a substituting radical, and unless otherwise stated, the term " C3.10 cycloalkyl " means a mono- or polycyclic saturated hydrocarbon monovalent radical having from 3 to 10 carbon atoms, such as for instance cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, or a C7.10 polycyclic saturated hydrocarbon monovalent radical having from 7 to 10 carbon atoms such as, for instance, norbornyl, fenchyl, trimethyltricycloheptyl or adamantyl.

As used herein with respect to a substituting radical, and unless otherwise stated, the term " C3-10 cycloalkyl-alkyl " refers to an aliphatic saturated hydrocarbon monovalent radical (preferably a C1.7 alkyl such as defined above) to which a C3.10 cycloalkyl (such as defined above) is already linked such as, but not limited to, cyclohexylmethyl, cyclopentylmethyl and the like.

As used herein with respect to a substituting radical, and unless otherwise stated, the term " C3-10 cycloalkylene" means the divalent hydrocarbon radical corresponding to the above defined C3.10 cycloalkyl.

As used herein with respect to a substituting radical, and unless otherwise stated, the term " aryl " designate any mono- or polycyclic aromatic monovalent hydrocarbon radical having from 6 up to 30 carbon atoms such as but not limited to phenyl, naphthyl, anthracenyl, phenantracyl, fluoranthenyl, chrysenyl, pyrenyl, biphenylyl, terphenyl, picenyl, indenyl, biphenyl, indacenyl, benzocyclobutenyl, benzocyclooctenyl and the like, including fused benzo-C.p cycloalkyl radicals (the latter being as defined above) such as, for instance, indanyl, tetrahydronaphthyl, fluorenyl and the like, all of the said radicals being optionally substituted with one or more substituents independently selected from the group consisting of halogen, amino, trifluoromethyl, hydroxyl, sulfhydryl and nitro, such as for instance 4- fluorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-cyanophenyl, 2,6-dichlorophenyl, 2- fluorophenyl, 3-chlorophenyl, 3,5-dichlorophenyl and the like. As used herein, e.g. with respect to a substituting radical such as the combination of substituents in certain positions of the thiazolo[5,4-d]pyrimidine, oxazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine or purine ring together with the carbon atoms in the same positions of said ring, and unless otherwise stated, the term "homocyc!ic" means a mono- or polycyclic, saturated or mono-unsaturated or polyunsaturated hydrocarbon radical having from 4 up to 15 carbon atoms but including no heteroatom in the said ring; for instance said combination of substituents may form a C_{2 6} alkylene radical, such as tetramethylene, which cyclizes with the ca rbon atoms in certain positions of the th iazolo[5 ,4-d]pyrimidine, oxazolo[5,4- djpyrimidine, thieno[2,3-d]pyrimidine or purine ring.

As used herein with respect to a substituting radical (including the combination of substituents in certain positions of the thiazolo[5,4-d]pyrimidine, oxazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine or purine ring together with the carbon atoms in the same positions of said ring), and unless otherwise stated, the term " heterocyclic " means a mono- or polycyclic, saturated or mono-unsaturated or polyunsaturated monovalent hydrocarbon radical having from 2 up to 15 carbon atoms and including one or more heteroatoms in one or more heterocyclic rings, each of said rings having from 3 to 10 atoms (and optionally further including one or more heteroatoms attached to one or more carbon atoms of said ring, for instance in the form of a carbonyl or thiocarbonyl or selenocarbonyl group, and/or to one or more heteroatoms of said ring, for instance in the form of a sulfone, sulfoxide, N- oxide, phosphate, phosphonate or selenium oxide group), each of said heteroatoms being independently selected from the group consisting of nitrogen, oxygen, sulfur, selenium and phosphorus, also including radicals wherein a heterocyclic ring is fused to one or more aromatic hydrocarbon rings for instance in the form of benzo-fused, dibenzo-fused and naphtho-fused heterocyclic radicals; within this definition are included heterocyclic radicals such as, but not limited to, diazepinyl, oxadiazinyl, thiadiazinyl, dithiazinyl, triazolonyl, diazepinonyl, triazepinyl, triazepinonyl, tetrazepinonyl, benzoquinolinyl, benzothiazinyl, benzothiazinonyl , benzoxa-thiinyl, benzodioxinyl, benzodithiinyl, benzoxazepinyl, benzothiazepinyl, benzodiazepine, benzodioxepinyl, benzodithiepinyl, be zo azocinyl, benzo- thiazocinyl, benzodiazocinyl, benzoxathiocinyl, benzodioxocinyl, benzotrioxepinyl, benzoxathiazepinyl , be nzoxadiaze pi nyl , benzothia-diazepinyl, benzotriazepinyl, benzoxathiepinyl, benzotriazinonyl, benzoxazolinonyl, azetidinonyl, azaspiroundecyl, dithiaspirodecyl, selenazinyl, selenazolyl, selenophenyl, hypoxanthinyl, azahypo- xanthinyl, bipyrazinyl, bipyridinyl, oxazolidinyl, diselenopyrimidinyl, benzodioxocinyl, benzopyrenyl, benzopyranonyl, benzophenazinyl, benzoquinolizinyl, dibenzo- carbazolyl, dibenzoacridinyl, dibenzophenazinyl, dibenzothiepinyl, dibenzoxepinyl, dibenzopyranonyl, dibenzoquinoxalinyl, dibenzothiazepinyl, dibenzisoquinolinyl, tetraazaadamantyl, thiatetraazaadamantyl, oxauracil, oxazinyl, dibenzothiophenyl, dibenzofuranyl, oxazolinyl, oxazolonyl, azaindolyl, azolonyl, thiazolinyl, thiazolonyl, thiazolidinyl, thiazanyl, pyrimidonyl, thiopyrimidonyl, thiamorpholinyl, azlactonyl, naphtindazolyl, naphtindolyl, naphtothiazolyl, naphtothioxolyl, naphtoxindolyl, naphto- triazolyl, naphtopyranyl, oxabicycloheptyl, azabenzimidazolyl, azacycloheptyl, azacyclooctyl, azacyclononyl, azabicyclononyl, tetrahydrofuryl, tetrahydropyra yl, tetrahydro- pyronyl, tetrahydroquinoleinyl, tetrahydrothienyl and dioxide thereof, dihydrothienyl dioxide, dioxindolyl, dioxinyl, dioxenyl, dioxazinyl, thioxanyl, thioxolyl, thiourazolyl, thiotriazolyl, thiopyranyl, thiopyronyl, coumarinyl, quinoleinyl, oxyquinoleinyl, quinuclidinyl, xanthinyl, dihydropyranyl, benzodihydrofuryl, benzothiopyronyl, benzothiopyranyl, benzoxazinyl, benzoxazolyl , benzodioxo lyl , benzodioxanyl , benzoth iadiazolyl , benzotriazinyl , benzothiazolyl, benzoxazolyl, phenothioxinyl, phenothiazolyl, phenothienyl (benzothiofuranyl), phenopyronyl, phenoxazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl, piperidinyl, morpholinyl, thiomoφholinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, triazolyl, benzotriazolyl, tetrazolyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, pyrrolyl, furyl, dihydrofutyl, furoyl, hydantoinyl, dioxolanyl, dioxolyl, dithianyl, dithienyl, dithiinyl, thienyl, indolyl, indazolyl, benzofutyl, quinolyl, quinazolinyl, quinoxalinyl, carbazolyl, phenoxazinyl, phenothiazinyl, xanthenyl, purinyl, benzothienyl, naphtothienyl, thianthrenyl, pyranyl, pyronyl, benzopyronyl, isobenzofuranyl, chromenyl, phenoxathiinyl, indolizinyl, quinolizinyl, isoquinolyl, phthalaziTryl, naphthiridinyl, cinnolinyl, pteridinyl, carbolinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, imidazolinyl, imidazolidinyl, benzimidazolyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, piperazinyl, uridinyl, thymidinyl, cytidinyl, azirinyl, aziridinyl, diazirinyl , diaziridinyl, oxiranyl, oxaziridinyl, dioxiranyl, thiiranyl, azetyl , dihydroazetyl, azetidinyl, oxetyl, oxetanyl, oxetanonyl, homopiperazinyl, homopiperidinyl, thietyl, thietanyl, diazabicyclooctyl, diazetyl, diaziridinonyl, diaziridinethionyl, . chromanyl, chromanonyl, thiochromanyl, thiochromanonyl, thiochromenyl, benzofuranyl, benzisothiazolyl, benzocarbazolyl, benzochromonyl, benzisoalloxazinyl, benzocoumarinyl, thiocoumarinyl, pheno- metoxazinyl, phenoparoxazinyl, phentriazinyl, thiodiazinyl, thiodiazolyl, indoxyl, thioindoxyl, benzodiazinyl (e.g. phtalazinyl), phtalidyl, phtalimidinyl, phtalazonyl, alloxazinyl, dibenzopyronyl (i.e. xanthonyl), xanthionyl, isatyl, isopyrazolyl, isopyrazolonyl, urazolyl, urazinyl, uretinyl, uretidinyl, succinyl, succinimido, benzylsultimyl, benzylsultamyl and the like, including all possible isomeric forms thereof, wherein each carbon atom of said heterocyclic ring may furthermore be independently substituted with a substituent selected from the group consisting of halogen, nitro, C ₇ alkyl (optionally containing one or more functions or radicals selected from the group consisting of carbonyl (oxo), alcohol (hydroxyl), ether (alkoxy), acetal, amino, imino, oximino, alkyloximino, amino- acid, cyano, carboxylic acid ester or amide, nitro, thio C1.7 alkyl, thio C₃.₁₀ cycloalkyl, C1.7 alkylamino, cycloalkylamino, alkenylamino, cyc!oalkenylamino, alkynylamino, arylamino, arylalkyl- amino, hydroxylalkylamino, mercaptoalkylamino, heterocyclic-substituted alkylamino, heterocyclic amino, heterocyclic-substituted arylamino, hydrazino, alkylhydrazino, phenylhydrazino, sulfonyl, sulfonamido and halogen), C₃.₇ alkenyl, C₂-₇ alkynyl, halo C1.7 alkyl, C₃.₁₀ cycloalkyl, aryl, arylalkyl, alkylaryl, alkylacyl, arylacyl, hydroxyl, amino, C1.7 alkylamino, cycloalkylamino, alkenylamino, cycloalkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic- substituted a l kyl am i n o , h ete rocycl i c a mi no , h eterocyclic-substituted arylamino, hydrazino, alkylhydrazino, phenylhydrazino, sulfhydryl, C1.7 alkoxy, C3.10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C1.7 alkyl, thio C3.10 cycloalkyl, thioaryl, thioheterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, hydroxylamino, cyano, carboxylic acid or esters or thioesters or amides thereof, tricarboxylic acid or esters or thioesters or amides thereof; depending upon the number of unsaturations in the 3 to 10 atoms ring, heterocyclic radicals may be sub-divided into heteroaromatic (or " heteroaryl ") radicals and non- aromatic heterocyclic radicals; when a heteroatom of said non-aromatic heterocyclic radical is nitrogen, the latter may be substituted with a substituent selected from the group consisting of d.7 alkyl, C3.10 cycloalkyl, aryl, arylalkyl and alkylaryl.

As used herein with respect to a substituting radical, and unless otherwise stated, the terms " C1-7 alkoxy ", " C3.10 cycloalkoxy ", " aryloxy ", " arylalkyloxy ", " oxyheterocyclic ", " thio C1.7 alkyl ", " thio C3.10 cycloalkyl ", " arylthio ", " arylalkylthio " and " thioheterocyclic" refer to substituents wherein a carbon atom of a Ci ₇ alkyl, respectively a C₃.i₀ cycloalkyl, aryl, arylalkyl or heterocyclic radical (each of them such as defined herein), is attached to an oxygen atom or a divalent sulfur atom through a single bond such as, but not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, thiomethyl, thioethyl, thiopropyl, thiobutyl, thiopentyl, thiocyclopropyl, thiocyclobutyl, thiocyclopentyl, thiophenyl, phenyloxy, benzyloxy, mercaptobenzyl, cresoxy, and the like.

As used herein with respect to a substituting atom, and unless otherwise stated, the term "halogen" or "halo" means any atom selected from the group consisting of fluorine, chlorine, bromine and iodine.

As used herein with respect to a substituting radical, and unless otherwise stated, the term " halo C1. alkyl " means a C,.₇ alkyl radical (such as above defined) in which one or more hydrogen atoms are independently replaced by one or more halogens (preferably fluorine, chlorine or bromine), such as but not limited to difluoromethyl, trifluoromethyl, trifluoroeth l, octafluoropentyl, dodecafluoroheptyl, dichloromethyl and the like.

As used herein with respect to a substituting radical, and unless otherwise stated, the terms " C₂-7 alkenyl " designate a straight and branched acyclic hydrocarbon monovalent radical having one or more ethylenic unsaturations and having from 2 to 7 carbon atoms such as, for example, vinyl, 1-propenyl, 2-propenyl (ally I), 1-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3- methyl-2-butenyl, 3-hexenyl, 2-hexenyl, 2-heptenyl, 1 ,3-butadienyl, pentadienyl, hexadienyl, heptadienyl, heptatrienyl and the like, including all possible isomers thereof.

As used herein with respect to a substituting radical, and unless otherwise stated, the term " C₃.,o cycloalkenyl " means a monocyclic mono- or polyunsaturated hydrocarbon monovalent radical having from 3 to 8 carbon atoms, such as for instance cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclohepta- dienyl, cycloheptatrienyl, cyclooctenyl, cyclooctadienyl and the like, or a C₇.₁₀ polycyclic mono- or polyunsaturated hydrocarbon monovalent radical having from 7 to 10 carbon atoms such as dicyclopentadienyl, fenchenyl (including all isomers thereof, such as a-pinolenyl), bicyclo[2.2.1]hept-2-enyl, bicyclo[2.2.1 ]hepta-2,5-dienyl, cyclo-fenchenyl and the like.

As used herein with respect to a substituting radical, and unless otherwise stated, the term " C₂.7 alkynyl " defines straight and branched chain hydrocarbon radicals containing one or more triple bonds and optionally at least one double bond and having from 2 to 7 carbon atoms such as, for example, acetylenyl, 1-propynyl, 2- propynyl, 1 -butynyl, 2-butynyl, 2- pentynyl, 1-pentynyl, 3-methyl-2-butynyl, 3-hexynyl, 2-hexynyl, 1-penten-4-ynyl, 3-penten-1 - ynyl, 1 ,3-hexadien-1 -ynyl and the like.

As used herein with respect to a substituting radical, and unless otherwise stated, the terms " arylalkyl ", " arylalkenyl " and " heterocyclic-substituted alkyl " refer to an aliphatic saturated or ethylenically unsaturated hydrocarbon monovalent radical (preferably a d.7 alkyl or C₂.i alkenyl radical such as defined above) onto which an aryl or heterocyclic radical (such as defined above) is already bonded via a carbon atom, and wherein the said aliphatic radical and/or the said aryl or heterocyclic radical may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, amino, hydroxyl, sulfhydryl, C_v7 alkyl, C ₇ alkoxy, trifluoromethyl and nitro, such as but not limited to benzyl, 4-chlorobenzyl, 4-fluorobenzyl, 2-fluorobenzyl, 3,4-dichlorobenzyl, 2,6- dichlorobenzyl, 3- methyl benzyl , 4-methylbenzyl, 4-ter-butylbenzyl, phenylpropyl, 1- naphthylmethyl, phenylethyl, 1 -amino-2-phenylethyl, 1-amino-2-[4-hydroxy- phenyl]ethyl, 1 -amino-2-[indo!-2- yljethyl, styryl, pyridylmethyl (including all isomers thereof), pyridylethyl, 2-(2- pyridy isopropyl, oxazolylbutyl, 2-thienylmethyl, pyrrolylethyl, morpholinylethyl, imidazol-1 -yl- ethyl, benzodioxolylmethyl and 2- furylmethyl.

As used herein with respect to a substituting radical, and unless otherwise stated, the terms " alkylaryl " and " alkyl-substituted heterocyclic " refer to an aryl or, respectively, heterocyclic radical (such as defined above) onto which are bonded one or more aliphatic saturated or unsaturated hydrocarbon monovalent radicals, preferably one or more C1.7 alkyl, C₂._? alkenyl or C₃.₁₀ cycloalkyl radicals as defined above such as, but not limited to, o-toluyl, m-toluyl, p- toluyl, 2,3-xylyl, 2,4-xylyl, 3,4- xylyl , o-cumenyl, m-cumenyl , p-cumenyl, o-cymenyl, m- cymenyl, p-cymenyl, mesityl, ter-butylphenyl, lutidinyl (i.e. dimethylpyridyl), 2-methylaziridinyl, methyl- benzimidazolyl, methylbenzofuranyl, methylbenzothiazolyl, methylbenzotriazolyl, methylbenzoxazolyl and methylbenzselenazolyl.

As used herein with respect to a substituting radical, and unless otherwise stated, the term " alkoxyaryl " refers to an aryl radical (such as defined above) onto which is (are) bonded one or more C₁.7 alkoxy radicals as defined above, preferably one or more methoxy radicals, such a s , but n ot li m ited to , 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4- dimethoxyphenyl, 2,4,6-trimethoxyphenyl, methoxynaphtyl and the like.

As used herein with respect to a substituting radical, and unless otherwise stated, the terms " alkylamino ", " cycloalkylamino ", '.' alkenylamino ", " cyclo- alkenylamino " , " arylamino ", " arylalkylamino ", " heterocyclic-substituted alkylamino ", " heterocyclic-substituted arylamino ", " heterocyclic amino ", " hydroxy- alkylamino ", " mercaptoalkylamino " and " alkynylamino " mean that respectively one (thus monosubstituted amino) or even two (thus disubstituted amino) d.₇ alkyl, C₃.|₀ cycloalkyl, C₂.₇ alkenyl, C3.10 cycloalkenyl, aryl, arylalkyl, heterocyclic- substituted alkyl, heterocyclic-substituted aryl, heterocyclic (provided in this case the nitrogen atom is attached to a carbon atom of the heterocyclic ring), mono- or polyhydroxy C₁.7 alkyl, mono- or polymercapto d.₇ alkyl, or C₂.₇ alkynyl radical(s) (each of them as defined herein, respectively, and including the presence of optional substituents independently selected from the group consisting of halogen, amino, hydroxyl, sulfhydryl, d.₇ alkyl, C₁.7 alkoxy, trifluoromethyl and nitro) is/are attached to a nitrogen atom through a single bond such as, but not limited to, anilino, 2- bromoanilino, 4-bromoanilino, 2-chloroanilino, 3-chloroanilino, 4- chloroanilino, 3- chloro-4-methoxyanilino, 5-chloro-2-methoxyanilino, 2,3-dimethylanilino, 2,4- dimethylanilino, 2,5-dimethylanilino, 2,6-dimethylanilino, 3,4-dimethylanilino, 2- fluoroanilino,

3- fluoroanilino, 4-fluoroanilino, 3-fluoro-2-methoxyanilino, 3-fluoro-4-methoxyanilino, 2-fluoro- 4-methylanilino, 2-fluoro-5-methylanilino, 3-fluoro-2- methylanilino, 3-fluoro-4-methylanilino,

4- fluoro-2-methylanilino, 5-fluoro-2- methylanilino, 2-iodoanilino, 3-iodoanilino, 4-iodoanilino, 2-methoxy-5-methylanilino , 4-methoxy-2-methylanilino, 5-methoxy-2-methylanilino, 2- ethoxyanilino, 3-ethoxy- anilino, 4-ethoxyanilino, benzylamino, 2-methoxybenzylamino, 3- methoxybenzylamino, 4-methoxybenzylamino, 2-fluorobenzylamino, 3-fluorobenzylamino, 4- fluoro- benzylamino, 2-chlorobenzylamino, 3-chlorobenzylamino, 4-chlorobenzylamino, 2- aminobenzylamino, diphenylmethylamino, a-naphthylamino, methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, propenylamino, n- butylamino, ter-butylamino, dibutylamino, 1 ,2-diaminopropyl, 1 ,3-diaminopropyl, 1 ,4-diaminobutyl, 1 ,5-diaminopentyl, 1 ,6-diaminohexyl, morpholinomethylamino, 4-morpholinoanilino, hydroxymethylamino, β- hydroxyethylamino and ethynylamino; this definition also includes mixed disubstituted amino radicals wherein the nitrogen atom is attached to two such radicals belonging to two different sub-sets of radicals, e.g. an alkyl radical and an alkenyl radical, or to two different radicals within the same subset of radicals, e.g. methylethylamino; among di-substituted amino radicals, symmetrically-substituted amino radicals are more easily accessible and thus usually preferred from a standpoint of ease of preparation.

As used herein with respect to a substituting radical, and unless otherwise stated, the terms " (thio)carboxylic acid-ester ", " (thio)carboxylic acid thioester " and " (thio)carboxylic acid amide" refer to radicals wherein the carboxyl or thiocarboxyl group is bonded to the hydrocarbonyl residue of an alcohol, a thiol, a polyol, a phenol, a thiophenol, a primary or secondary amine, a polyamine, an amino-alcohol or ammonia, the said hydrocarbonyl residue being selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, alkylaryl, alkylamino, cycloalkylamino, alkenylamino, cycloalkenylamino, aryla mino , aryla l kylamin o , h eterocycl ic-substituted alkylamino, heterocyclic amino, heterocyclic-substituted arylamino, hydroxyalkylamino, mercapto- alkylamino or alkynylamino (such as above defined, respectively). As used herein with respect to a substituting radical, and unless otherwise stated, the term " amino-acid " refers to a radical derived from a molecule having the chemical formula HbN-CHR-COOH_! wherein R is the side group of atoms characterizing the amino-acid type; said molecule may be one of the 20 naturally- occurring amino-acids or any similar non naturally-occurring amino-acid.

As used herein and unless otherwise stated, the term " stereoisomer " refers to all possible different isomeric as well as conformational forms which the compounds of formula I, II, III, or IV may possess, in particular all possible stereochemical and conformationally isomeric forms, all diastereomers, enantiomers and/or conformers of the basic molecular structure. Some compounds of the present invention may exist in different tautomeric forms, all of the latter being included within the scope of the present invention.

As used herein and unless otherwise stated, the term " enantiomer " means each individual optically active form of a compound of the invention, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e. at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.

As used herein and unless otherwise stated, the term " solvate " includes any combination which may be formed by a thiazolo[5,4-d]pyrimidine, oxazolo[5,4-d]pyrimidine, thieno(2,3- d]pyrimidine or purine derivative of this invention with a suitable inorganic solvent (e.g. hydrates) or organic solvent, such as but not limited to alcohols, ketones, esters, ethers, nitriles and the like.

As used herein and unless otherwise stated, the term " proliferative disorder " includes cancer or carcinoma's of any type, including soft tissue cancers and solid tissue cancers.

The term "cancer" or "tumor formation" refers to a mass of abnormal tissue that arises without obvious cause from pre-existing body cells, has no purposeful function, and is characterized by a tendency to autonomous and unrestrained growth. Examples of tumors or cancers envisaged in the context of the present invention include non-hematological cancers and hematological malignancies and such cancers/malignancies include but are not limited to cancer of the prostate, lung, breast, rectal, colon, lymph node, bladder, kidney, pancreatic, liver, ovarian, uterine, brain, skin, sarcoma, meningioma, glioblastoma, multiforme, skin, stomach, including all kinds of neuroblastoma, gastric carcinoma, renal cell carcinoma, neuroblastoma, gastric carcinoma, renal cell carcinoma, uterine cancer, muscle cancer or other tumors such as leukemia. The term "solid tumor" refers to non-metastased cancers or benign cancers (for a detailed description see below).

Particularly envisaged by the present invention are "hematological malignancies" or "cancers of the blood-forming tissues" such as leukemias (Lymphoblastic T cell leukemia, Chronic myelogenous leukemia (CML), Chronic lymphocytic/lymphoid leukemia (CLL), Hairy-cell leukemia, acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AM L), myelodysplastic syndrome, Chronic neutrophilic leukemia , Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, Acute megakaryocytic leukemia, promyelocytic leukemia and Erythroleukemia) and lymphomas, more specifically malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma and follicular lymphoma, MALT1 lymphomas, Hodgkin lymphomas, B-cell non-Hodgkin lymphoma- and marginal zone lymphoma, among others.

The compounds of the invention have been shown to inhibit cancer or tumor formation. Current research suggests that each tumor arises from a single cell that has been transformed by one or more events. Such events include the activation of oncogenes and the absence or inactivation of specific tumor-suppressor genes. These transformed cells can form small clones, initially co-opting normal host vessels, growing to only several millimeters in size before their supply of nutrients becomes limited. At this point, the tumor may lie dormant for prolonged periods (from months to years) until ultimately undergoing destruction by the immune system or switching to an angiogenic phenotype. This "switch" involves a shift in the local equilibrium between negative and positive endogenous regulators of angiogenesis. The tumor cells may achieve this shift in several ways, including the overexpression of angiogenic factors, the recruitment of host cells (such as macrophages) that can produce their own angiogenic factors, the mobilization of angiogenic proteins from the extracellular matrix (ECM), or a combination of these processes. If the production of proangiogenic factors is sufficiently robust, neighboring endothelial cells will be activated, leading to the sprouting of new capillaries.

Tumors are quite different from inflammatory or other swellings because the cells in tumors are abnormal in their appearance and other characteristics. Abnormal cells - the kind that generally make up tumors - differ from normal cells in having undergone one or more of the following alterations: (1 ) hypertrophy, or an increase in the size of individual cells; this feature is occasionally encountered in tumors but occurs commonly in other conditions; (2) hyperplasia or an increase in the number of cells within a given zone; in some instances it may constitute the only criterion of tumor formation; (3) anaplasia, or a regression of the physical characteristics of a cell toward a more primitive or undifferentiated type; this is an almost constant feature of malignant tumors, though it occurs in other instances both in health and in disease. In some instances the cells of a tumor are normal in appearance and are faithful reproductions of their parent types so that the differences between them and normal body cells are difficult to discern. Such tumors are also often benign. Other tumors are composed of cells that appear different from normal adult types in size, shape, and structure. They usually belong to tumors that are malignant. Such cells may be bizarre in form or be arranged in a distorted manner. In more extreme cases, the cells of malignant tumors are described as primitive, or u ndifferentiated, because they have lost the appearance and functions of the particular type of (normal) specialized cell that was their predecessor. As a rule, the less differentiated malignant tumor cells are, the more quickly that tumor may grow. Malignancy refers to the ability of a tumor to ultimately cause death. Any tumor, either benign or malignant in type, may produce death by local effects.

The common and more specific definition of malignancy implies an inherent tendency of the tumor's cells to metastasize (invade the body widely and become disseminated by subtle means) and eventually to kill the patient unless all the malignant cells can be eradicated. Metastasis is thus the outstanding characteristic of malignancy. Metastasis is the tendency of tumor cells to be carried from their site of origin by way of the circulatory system and other channels, which may eventually establish these cells in almost every tissue and organ of the body. The amount of new blood vessel growth can correlate with poor prognosis in several tumor types. Since the shedding of large numbers of tumor cells from the primary tumor may not begin until after the tumor has a sufficient network of blood vessels, angiogenesis may also correlate with metastatic potential. Destruction of the ECM is probably necessary to initiate the metastatic process. Microvessel density has been correlated with cancer invasion and metastasis in a number of human tumors including breast, prostate, lung, esophageal, colorectal, endometrial and cervical.

In contrast to malignant tumor cells, the cells of a benign tumor invariably remain in contact with each other in one solid mass centered on the site of origin ("solid tumors"). Because of the physical continuity of benign tumor cells, they may be removed completely by surgery if the location is suitable. But the dissemination of malignant cells, each one individually possessing (through cell division) the ability to give rise to new masses of cells (new tumors) in new and distant sites, precludes complete eradication by a single surgical procedure in all but the earliest period of growth. A benign tumor may undergo malignant transformation, but the cause of such change is unknown. It is also possible for a malignant tumor to remain quiescent, mimicking a benign one clinically, for a long time. All benign tumors tend to remain localized at the site of origin. Many benign tumors are encapsulated. The capsule consists of connective tissue derived from the structures immediately surrounding the tumor.

Well-encapsulated tumors are not anchored to their surrounding tissues. These benign tumors enlarge by accretion, pushing aside the adjacent tissues without involving them intimately.

Among the major types of benign tumors are the following: lipomas, which are composed of fat cells; angiomas, which are composed of blood or lymphatic vessels; osteomas, which arise from bone; chondromas, which arise from cartilage; and adenomas, which arise from glands. For malignant tumors, examples comprise carcinomas (occur in epithelial tissues, which cover the body (the skin) and line the inner cavitary structures of organs (such as the breast, the respiratory and gastrointestinal tracts, the endocrine glands, and the genitourinary system). Sarcomas develop in connective tissues, including fibrous tissues, adipose (fat) tissues, muscle, blood vessels, bone, and cartilage. A cancer can also develop in both epithelial and connective tissue and is called a carcinosarcoma. Cancers of the blood- forming tissues (such as leukemias and lymphomas), tumors of nerve tissues (including the brain), and melanoma (a cancer of the pigmented skin cells) are classified separately.

The following examples illustrate the present invention.

Examples

General

For all reactions, analytical grade solvents were used. All moisture-sensitive reactions were earned out in oven-dried glass-ware (135 °C). ¹H and ¹³C N R spectra were recorded with a Bruker Advance 300 (^ΊΗ NMR: 300 MHz, ¹³C NMR: 75 MHz), using tetramethy!silane as internal standard for ¹H NMR spectra and DMSO-d₆ (39.5 ppm) or CDCI₃ (77.2 ppm) for ¹³C NMR spectra. Abbreviations used are: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br s = broad signal. Coupling constants are expressed in Hertz. Mass spectra are obtained with a Finnigan LCQ advantage Max (ion trap) mass spectrophotometer from Thermo Finnigan, San Jose, CA, USA. Exact mass measurements are performed on a quadrupole time-of-flight mass spectrometer (Q-tof-2, Micromass, Manchester, UK) equipped with a standard electrospray-ionization (ESI) interface. Samples were infused in /-PrOH/H₂0 (1 : 1 ) at 3 μΙ/min. Melting points are determined on a Barnstead IA 9200 apparatus and are uncorrected. Precoated aluminum sheets (Fluka Silica gel TLC-cards, 254 nm) were used for TLC. Column chromatography was performed on ICN silica gel 63-200, 60 A. Example 1 : Synthesis of diethyl 2-(4-fluorobenzamido)malonate

To a solution of diethyl aminomalonate hydrochloride (5.0 g, 23.6 mmol) in pyridine (7.64 ml, 94.5 mmol) and dimethylformamide (60 ml) was added p-fluorobenzoyl chloride (4.19 ml, 35.4 mmol). The reaction mixture was stirred at room temperature for 15 hours. After removing the solvents, the residue was redissolved in dichloromethane, washed with water, brine and dried over Na₂S0₄. After removing the solvents, the crude residue was purified by flash chromatography on silica (CH₂CI₂/MeOH 30:1 ) to yield the title compound as a white solid (4.9 g, 70 %).

¹H NMR (300 MHz, DMSO, 25 °C): δ = 9.37 (d, J= 7.5 Hz, 1 H, NH), 7.96-8.01 (m, 2H, PhH), 7.33 (t, J= 8.8 Hz, 2H, PhH), 5.30 (d, J= 7.5 Hz, 1 H, CH), 4.12-4.28 (m, 4H, CH₂), 1.22 (t, J= 7.1 Hz, 6H, CH₃) ppm.

HRMS: calcd for Ci₄Hi₇FN0₅ 298.1091 , found 298.1092.

Example 2 : Synthesis of diethyl 2-(2-(4-fluorophenyl)acetamido)malonate

To a solution of 4-fluorophenylacetic acid (4.5 g, 29.3 mmol) and 1-hydroxybenzotriazole (4.35 g, 32.2 mmol) in dichloromethane (140 ml) was added dicyclohexylcarbodiimide (6.65 g, 32.2 mmol). The reaction mixture was stirred at room temperature for 2 hours. The resulting solution was cooled to 0°C, and then a solution of diethyl aminomalonate hydrochloride (6.2 g, 29.3 mmol) in pyridine (4.5 ml, 29.3 mmol) and DMF (10 ml) was added. The temperature was allowed to rise to ambient temperature. After 1 hour, the reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and a 5% NaHC0₃ solution. The organic layer was washed with water, brine and dried over Na₂S0₄. After removing the solvents, the crude residue was purified by flash chromatography on silica (CH₂CI₂/MeOH 50:1 ) to yield the title compound as a white solid (8.5 g, 93 %).

1H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.26-7.29 (m, 2H, PhH), 7.05 (t, J= 8.7 Hz, 2H, PhH), 6.44 (d, J= 6.9 Hz, 1 H, NH), 5.12 (d, J= 6.9 Hz, 1 H, CH), 4.16-4.32 (m, 4H, CH₂), 3.61 (s, 2H, CH^Ph), 1.27 (t, J= 7.1 Hz, 6H, CH₃) ppm.

HRMS: calcd for C₁₅H₁₉FN0₅ 312.1247, found 312.1247.

Example 3: Synthesis of dimethyl 2-(3-(4-fluorophenyl)propanamido)malonate

This compound was synthesized from dimethyl aminomalonate according to the procedure for the preparation of example 2 using 4-fluorophenylpropionic acid. The crude residue was purified by flash chromatography on silica (CH₂CI₂/MeOH 50:1 ) to yield the title compound as a white solid (53 %).

¹H NMR (300 MHz, CDCI_3l 25 °C): δ = 7.13-7.18 (m, 2H, PhH), 6.96 (t, J= 8.7 Hz, 2H, PhH), 6.50 (d, J= 6.7 Hz, 1 H, NH), 5.19 (d, J= 6.7 Hz, 1 H, CH), 3.80 (s, 6H, CH₃), 2.95 (t, J= 7.4 Hz, 2H, CH₂), 2.58 (t, J= 7.4 Hz, 2H, CH₂) ppm. HRMS: calcd for C₁₄Hi₇FN0₅ 298.10908, found 298.10827.

Example 4 : Synthesis of dimethyl 2-(3-(4-fluorophenoxy)propanamido)malonate

This compound was synthesized from dimethyl aminomalonate according to the procedure for the preparation of example 2 using 3-(4-fIuorophenoxy)propionic acid. The crude residue was purified by flash chromatography on silica (CH₂CI₂/ eOH 50:1 ) to yield the title compound as a white solid (80 %).

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.01 (br s, 1 H, NH), 6.96 (t, J= 9.1 Hz, 2H, PhH), 6.86-6.91 (m, 2H, PhH), 5.22 (d, J= 6.8 Hz, 1 H, CH), 4.23 (t, J= 5.9 Hz, 2H, OCH₂), 3.82 (s, 6H, CH₃), 2.76 (t, J= 5.9 Hz, 2H, CH₂) ppm.

HRMS: calcd for C₁₄Hi₇FNO_s 314.10399, found 314.10315.

Example 5 : Synthesis of rV-(2-amino-4,6-dihydroxypyrimidin-5-yl)-4-fluorobenzamide

Guanidine hydrochloride (1 .35 g, 14.1 mmol) and diethyl 2-(4-fluonobenzamido)malonate (example 1 , 3.0 g, 10.1 mmol) were added to a solution of sodium (0.46 g, 20.2 mmol) in ethanol (50 ml). The reaction mixture was refluxed for 3 hours. The reaction was cooled down to room temperature. The solid product was filtered off and washed with ethanol. The product was dissolved in a minimal volume of water and acidified to pH 4-5 with 5M HCI. The precipitate was collected, washed with water and dried to give the title compound as a white solid (1.41 g, 53 %).

¹H NMR (300 MHz, DMSO, 25 °C): 6 = 10.62 (s, 2H, OH), 8.81 (s, 1 H, NH), 7.96-8.01 (m, 2H, PhH), 7.28 (t, J= 8.8 Hz, 2H, PhH), 6.63 (s, 2H, NH₂) ppm.

HRMS: calcd for CnHi₀FN,O₃ 265.07369, found 265.07148.

Example 6 Synthesis of A -(2-amino-4,6-dihydroxypyrimidin-5-yl)-2-(4- fluorophenyl)acetamide

This compound was synthesized from example 2 (yield of 77%) using a similar procedure as for the preparation of example 5.

H NMR (300 MHz, DMSO, 25 °C): δ = 10.61 (s, 2H, OH), 8.57 (s, 1 H, NH), 7.32-7.36 (m, 2H, PhH), 7.10 (t, J= 8.8 Hz, 2H, PhH), 6.57 (s, 2H, NH₂), 3.50 (s, 2H, CH₂) ppm.

HRMS: calcd for C₁₂H₁₂FN₄0₃ 279.08934, found 279.08846.

Example 7 Synthesis of W-(2-amino-4,6-dihydroxypyrimidin-5-yl)-3-(4- fluorophenyl)propanamide

This compound was prepared from example 3 in a yield of 76%, according to the procedure for the synthesis of example 5.

¹H NMR (300 MHz, DMSO, 25 °C): δ = 10.67 (s, 2H, OH), 8.41 (s, 1 H, NH), 7-26-7.31 (m, 2H, PhH), 7.07 (t, J= 8.8 Hz, 2H, PhH), 6.61 (s, 2H, NH₂), 2.82 (t, J= 7.2 Hz, 2H, CH₂), 2,50 (t, J= 7.2 Hz, 2H, CH₂) ppm. HRMS: calcd for C₁₃H₁₄FN₄0₃293.10499, found 293.10424

Example 8 Synthesis of A -{2-amino-4,6-clihydroxypyrimidin-5-yl)-3-(4- fluorophenoxy)propanamide

This compound was prepared from example 4 in a yield of 34%, according to the procedure for the synthesis of example 5.

¹H N R (300 MHz, DMSO, 25 °C): δ = 10.65 (s, 2H, OH), 8.51 (s, 1 H, NH), 7.10 (t, J= 8.7 Hz, 2H, PhH), 6.90-6.97 (m, 2H, PhH), 6.55 (s, 2H, NH₂), 4.15 (t, J= 6.2 Hz, 2H, OCH₂), 2.66 (t, J= 6.2 Hz, 2H, CH₂) ppm.

MS 307 [M-H]

Example 9 : Synthesis of yV-(4,6-dihydroxy-2-methylpyrimidin-5-yl)-4-fluorobenzamide

Acetamidine hydrochloride (1 .05 g, 11.1 mmol) and dimethyl 2-(4-fluorobenzamido)malonate (1.0 g, 3.71 mmol) were added to a solution of sodium (0.26 g, 1 1 .1 mmol) in ethanol (37 ml). The reaction mixture was refluxed for 3 hours. Then, after cooling, the solid product was collected and washed with ethanol. The product was dissolved in a minimal volume of water and acidified to pH 4-5 with 5M HCI. The precipitate was collected, washed with water and dried to give the title compound as a white solid (0.77 g, 79 %).

¹H NMR (300 MHz, DMSO, 25 °C): δ = 12.0 (s, 2H, OH), 9.09 (s, 1 H, NH), 8.00 (br s, 2H, PhH), 7.30 (t, J= 8.0 Hz, 2H, PhH), 2.28 (s, 3H, CH₃) ppm.

MS: 261.8 [M-H]

Example 10 Synthesis of N-(4,6-dihydroxy-2-mercaptopyrimidin-5-yl)-4- fluorobenzamide

Thiourea (0.72 g, 9.4 mmol) and diethyl 2-(4-fluorobenzamido)malonate (example 1 , 2.0 g, 6.7 mmol) were added to a solution of sodium (0.16 g, 6.7 mmol) in ethanol (50 ml). The reaction mixture was refluxed for 3 hours and then cooled down to room temperature. The precipitate was filtered off and washed with ethanol. The product was dissolved in a minimal volume of water and acidified to pH 4-5 with 5M HCI. The precipitate was collected, washed with water and dried, furnishing the title compound as a white solid (0.78 g, 41 %).

¹H NMR (300 MHz, DMSO, 25 °C): δ = 12.47 (s, 1 H, SH), 12.32 (s, 2H, OH), 9.15 (s, 1 H, NH), 8.00 (br s, 2H, PhH), 7.31 (t, J= 6.8 Hz, 2H, PhH) ppm.

HRMS: calcd for CnHgFNsOaS 282.03487, found 282.03402.

Example 11 : Synthesis of 5-amino-2-{4-fluorophenyl)thiazolo[5,4-d]pyrimidine-7 -thiol

A solution of A/-(2-amino-4,6-dihydroxypyrimidin-5-yl)-4-fluorobenzamide (example 5, 1.3 g, 4.92 mmol) and phosphorus pentasulfide (2.19 g, 9.84 mmol) in dry pyridine (25 ml) was refluxed for 6 hours. The solvents were evaporated in vacuo. The crude residue was purified by flash chromatography on silica (CH₂CI₂/MeOH 30:1 ), yielding the title compound as a yellow solid (1.28 g, 93 %).

¹H NMR (300 MHz, DMSO, 25 °C): δ = 12.51 (s, 1 H, SH), 7.96-8.01 (m, 2H, PhH), 7.38 (t, J= 8.8 Hz, 2H, PhH), 7.10 (s, 2H, NH₂) ppm.

HRMS: calcd for C^HeFN^ 279.0174, found 279.0165.

Example 12 : Synthesis of 5-amino-2-(4-fluorobenzyl)thiazolo[5,4-d]pyrimidine-7 -thiol

This compound was prepared from example 6 in a yield of 76%, according to the procedure for the synthesis of example 1 1.

¹H NMR (300 MHz, DMSO, 25 °C): δ = 12.40 (s, 1 H, SH), 7.37-7.42 (m, 2H, PhH), 7.19 (t, J= 8.9 Hz, 2H, PhH), 6.98 (s, 2H, NH₂), 4.29 (s, 2H, CH₂) ppm.

HRMS: calcd for C₁₂H₁₀FN₄S₂ 293.03309, found 293.03260.

Example 13 : Synthesis of 5-amino-2-(4-fluorophenethyl)-thiazolo[5₎4-d]pyrimidine-7- thiol

This compound was prepared from example 7 in a yield of 76%, according to the procedure for the synthesis of example 1 1.

¹H NMR (300 MHz, DMSO, 25 °C): δ = 12.39 (s, 1 H, SH), 7.31 -7.36 (m, 2H, PhH), 7.1 1 (t, J= 8.8 Hz, 2H, PhH), 6.96 (s, 2H, NH₂), 3.23 (t, J= 7.4, 2H, CH₂), 3.03 (t, J= 7.4, 2H, CH₂) ppm.

HRMS: calcd for C₁₃H₁₂FN₄S₂ 307.04874, found 307.04792.

Example 14 : Synthesis of 2-(4-fluorophenyl)-5-methyl-thiazolo[5,4-d]pyrimidine-7 -thiol This compound was prepared from example 9 in a yield of 73%, according to the procedure for the synthesis of example 11 .

¹H NMR (300 MHz, DMSO, 25 °C): δ = 14.09 (s, 1 H, SH), 8.07-8.15 (m, 2H, PhH), 7.42 (t, J= 8.8 Hz, 2H, PhH), 2.50 (s, 3H, CH₃) ppm.

MS 278.1 [Μ+ΗΓ

Example 15 : Synthesis of 2-(4-fluorophenyl)-thiazolo[5,4-d]pyrimidine-5,7-dithiol

This compound was prepared from example 10 in a yield of 57%, according to the procedure for the synthesis of example 11 .

H NMR (300 MHz, DMSO, 25 °C): δ = 13.62 (s, 1 H, SH), 8.00-8.05 (m, 2H, PhH), 7.39 (t, J= 8.7 Hz, 2H, PhH) ppm.

HRMS: calcd for C11 H7FN3S3 295.97861 , found 295.97777.

Example 16 : Synthesis of 2-(4-fluorophenyl)-7-(methylthio)thiazolo[5,4-d]pyrimidin-5- amine

To a sol ution of 5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidine-7-th iol ( 1 .2 g , 4.31 mmol) and triethylamine (1 .50 ml, 10.8 mmol) in DMSO (25 ml) was added iodomethane (0.54 ml, 8.62 mmol). The reaction mixture was stirred for 12 h under N₂ at 25°C. The mixture was poured into water and extracted with EtOAc. The organic extracts were dried over Na₂S0₄ and the solvents were removed under reduced pressure. The crude residue was purified by flash chromatography on silica (CH₂CI₂/MeOH 80:1 ), yielding the title compound as a light yellow solid (0.76 g, 60 %).

¹H NMR (300 MHz, DMSO, 25 °C): δ = 7.98-8.03 (m, 2H, PhH), 7.39 (t, J= 8.8 Hz, 2H, PhH), 7.09 (s, 2H, NH₂), 2.59 (s, 3H, CH₃) ppm.

HRMS: calcd for C₁₂H₁₀FN₄S₂ 293.0331 , found 293.0328.

Example 17 : Synthesis of 2-(4-fluorobenzyl)-7-(methylthio)thiazolo[5,4-d]pyrimidin-5- amine

This compound was prepared from example 12 in a yield of 87%, according to the procedure for the synthesis of example 16.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.27-7.32 (m, 2H, PhH), 7.03 (t, J= 8.6 Hz, 2H, PhH), 5.02 (s, 2H, NH₂), 4.31 (s, 2H, CH₂), 2.61 (s, 3H, CH₃) ppm.

HRMS: calcd for C₁₃H₁₂FN₄S₂ 307.0487, found 307.0482.

Example 18 : Synthesis of 2- 4-fluorophenethyl)-7-methylthio-thiazolo[5,4-d]pyrimidin- 5-amine

This compound was prepared from example 13 in a yield of 61%, according to the procedure for the synthesis of example 16.

1H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.16-7.21 (m, 2H, PhH), 6.97 (t, J= 8.7 Hz, 2H, PhH), 5.30 (s, 2H, NH₂), 3.30 (t, J= 8.3, 2H, CH₂), 3.11 (t, J= 8.3, 2H, CH₂) ppm.

HRMS: calcd for C₁₄H₁₄FN₄S₂ 321.06439, found 321 .06362.

Exa mple 1 9 : Synthesi s of 2-(2-(4-fluorophenoxy)ethyl)-7-(methylthio)thiazolo[5,4- d]pyrimidin-5 -amine

A solution of /V-(2-amino-4,6-dihydroxypyrimidin-5-yl)-3-(4-fluorophenoxy)propanamide (2.5 g, 8.1 1 mmol) and phosphorus pentasulfide (3.60 g, 16.2 mmol) in dry pyridine (40 ml) was refluxed for 6 hours. After cooling down to room temperature, the precipitate was filtered off, washed with ethylacetate and dried. The crude 5-amino-2-(2-(4-fluorophenoxy)ethyl)- thiazolo[5,4-d]pyrimidine-7-thiol (2.0 g, 6.20 mmol) was redissolved in DMSO (30 ml). Triethylamine (0.85 ml, 6.12 mmol) and iodomethane (0.31 ml, 4.90 mmol) were added. The reaction mixture was stirred for 12 hours at room temperature under a nitrogen atmosphere. The mixture was poured into water and extracted with EtOAc. The combined organic layers were dried over Na2S0₄ and the solvents were removed under reduced pressure. The crude residue was purified by chromatography on silica gel (CH₂CI₂/MeOH 100: 1 ), yielding the title compound as a light yellow solid (0.45 g, 15 % over 2 steps). ¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 6.96 (t, J= 9.1 Hz, 2H, PhH), 6.34-6.88 (m, 2H, PhH), 5.19 (s, 2H, NH₂), 4.31 (t, J= 6.2, 2H, CH₂), 3.48 (t, J= 6.2, 2H, CH₂) ppm.

HRMS: calcd for C₁₄H₁₄FN₄OS₂337.0593, found 337.05827.

Example 20 : Synthesis of 2-(4-fluorophenyl)-5-methyl-7-methylthio-thiazolo[5,4- d]pyrimidine

This compound was prepared from example 14 in a yield of 95%, according to the procedure for the synthesis of example 16.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.07-8.11 (m, 2H, PhH), 7.19 (t, J= 8.7 Hz, 2H, PhH), 2.78 (s, 3H, CH₃), 2.71 (s, 3H, CH₃) ppm.

Example 21 : Synthesis of 2-(4-fluorophenyl)-7-methylsulfonyl-thiazolo[5,4- d]pyrimidin-5 -amine

To a solution of 2-(4-fluorophenyl)-7-methylthio)-thiazolo[5,4-d]pyrimidin-5-amine (0.30 g, 1.03 mmol) in dichloromethane (5 ml) was added mCPBA (70 %, 0.44 g, 2.57 mmol) at 0°C. The reaction mixture was stirred for 3 hours, whereby the reaction temperature was gradually increased from 0°C to room temperature. The reaction mixture was diluted with CHCI₃ and was washed with a saturated NaHC0₃ solution, brine and dried over Na₂S0₄. After removing the solvents under reduced pressure, the residue was purified by flash chromatography on silica (CH₂CI₂/MeOH 50:1), affording the title compound as a white solid (0.31 g, 93 %).

H NMR (300 MHz, DMSO, 25 °C): δ = 8.11-8.16 (m, 2H, PhH), 7.12 (s, 2H, NH₂), 7.44 (t, J= 8.8 Hz, 2H, PhH), 3.58 (s, 3H, CH₃) ppm.

HRMS: calcd for Ci₂H₁₀FN₄O₂S₂325.02292, found 325.02221.

Example 22 : Synthesis of 2-(4-fluorobenzyl)-7-methylsulfonyl-thiazolo[5,4-d]pyrimidin- 5 -a mine

This compound was prepared from example 17 in a yield of 71%, according to the procedure for the synthesis of example 21.

¹H NMR (300 MHz, DMSO, 25 °C): δ = 7.58 (s, 2H, NH₂), 7.43-7.48 (m, 2H, PhH), 7.22 (t, J= 6.8 Hz, 2H, PhH), 4.47 (s, 2H, CH₂), 3.51 (s, 3H, CH₃) ppm.

HRMS: calcd for C₁₃Hi₂FN₄0₂S₂339.03857, found 339.03804.

Example 23 : Synthesis of 2-(4-fluorophenethyl)-7-methylsulfonyl-thiazolo[5,4- d]pyrimidin-5-amine

This compound was prepared from example 18 in a yield of 35%, according to the procedure for the synthesis of example 21.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.17-7.22 (m, 2H, PhH), 6.98 (t, J= 8.6 Hz, 2H, PhH), 5.43 (s, 2H, NH₂), 3.43 (s, 3H, CH₃), 3.41 (t, J= 7.9, 2H, CH₂), 3.17 (t, J= 7.9, 2H, CH₂) ppm. HRMS: calcd for C₁₄H₁₄FN₄0₂S₂353.05422, found 353.05363. Example 24 : Synthesis of 2-{2-{4-fluorophenoxy)ethyl)-7-methylsulfonyl-thiazo!o[5,4- dJpyrimidin-5 -amine

This compound was prepared from example 19 in a yield of 28%, according to the procedure for the synthesis of example 21.

H NMR (300 MHz, DMSO, 25 °C): δ = 7.57 (s, 2H, NH₂), 7.13 (t, J= 8.9 Hz, 2H, PhH), 6.98- 7.03 (m, 2H, PhH), 4.39 (t, J= 5.9, 2H, CH₂), 3.55 (t, J= 5.9, 2H, CH₂) 3.49 (s, 3H, CH₃) ppm. HRMS: calcd for C₁₄H,₄FN₄0₃S₂369.04913, found 369.04842.

Example 25 : Synthesis of 2-(4-fluorophenyl)-7-(piperazin-1-yl)-thiazolo[5,4- d]pyrimidin-5 -amine

To a solution of 2-(4-fluorophenyl)-7-methylsulfonyl-thiazolo[5,4-d]pyrimidin-5-amine (0.40 g, 1.23 mmol) and triethylamine (0.26 ml, 1.85 mmol) in dioxane (6 ml) was added piperazine (0.16 g, 1.85 mmol). The reaction mixture was heated at 60 °C for 5 hours. After cooling, the volatiles were removed under reduced pressure. The crude residue was purified by flash chromatography on silica (CH₂CI₂/ eOH 15:1), fumishing the title compound as a light yellow solid (0.27 g, 67 %).

¹H NMR (300 MHz, DMSO, 25 °C): δ = 9.09 (t, J= 9.2 Hz, 1H, NH), 7.98-8.03 (m, 2H, PhH), 7.37 (t, J= 8.8 Hz, 2H, PhH), 6.58 (s, 2H, NH₂), 4.45 (br s, 4H, N(CH₂)₂), 3.26 (br s, 4H, NHiCti^) ppm.

HRMS: calcd for C₁₅H₁₆FN₆S 331.11412, found 331.11290.

Example 26 : Synthesis of 2-(4-fluorobenzyl)-7-(piperazin-1-yl)-thiazolo[5,4- d]pyrimidin-5 -amine

This compound was prepared from example 22 in a yield of 50%, according to the procedure for the synthesis of example 25.

¹H NMR (300 MHz, DMSO, 25 °C): δ = 7.36-7.41 (m, 2H, PhH), 7.17 (t, J= 8.9 Hz, 2H, PhH), 6.26 (s, 2H, NH₂), 4.27 (s, 2H, CH₂), 4.14 (br s, 4H, N(CH₂)₂), 2.85 (t, J= 4.7 Hz, 4H, NHiCH^) ppm.

HRMS: calcd for C₁₆Hi₈FN₆S 345.12977, found 345.12883.

Example 27 : Synthesis of 2-(4-fluorophenethyl)-7-(piperazin-1-yl)thiazolo[5,4- d]pyrimidin-5-amine

This compound was prepared from example 23 in a yield of 76%, according to the procedure for the synthesis of example 25.

¹H NMR (300 MHz, DMSO, 25 °C): δ = 7.26-7.31 (m, 2H, PhH), 7.08 (t, J= 8.9 Hz, 2H, PhH), 6.19 (s, 2H, NH₂) 3.95 (br s, 4H, N(CH₂)₂), 3.23 (t, J= 7.4, 2H, CH₂), 3.02 (t, J= 7.4, 2H, CH₂), 2.74 (br s, 4H, HNiCH^) ppm.

HRMS: calcd for C₁₇H₂oFN₆S 359.14542, found 359.14456. Example 28 : Synthesis of 7-(benzylthio)-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-5- amine

To a so lution of 5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidine-7-thiol (50 mg, 0.18 mmol) and triethylamine (63 μΙ, 0.45 mmol) in DMSO (1 ml) was added benzyl bromide (43 μΙ, 0.36 mmol). The reaction mixture was stirred under N₂ at 25°C for 3 hours. The mixture was poured onto water and extracted with EtOAc. The organic extracts were dried over Na₂S0₄ and the solvents were removed under reduced pressure. The residue was purified by flash chromatography on silica (CH₂CI₂/MeOH 100: 1 ) to yield the title compound as a light yellow solid (40 mg, 60 %).

1H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.95-7.98 (m, 2H, PhH), 7.44 (d, J= 6.6 Hz, 2H, PhH), 7.28-7.35 (m, 3H, PhH), 7.15 (t, J= 8.6 Hz, 2H, PhH), 5.09 (s, 2H, NH₂), 4.53 (s, 2H, CH₂) ppm.

HRMS: calcd for C₁₈H₁₄FN_<,S₂ 369.06439, found 369.06332.

E x a m p l e 29 : S yn th e s i s of 2-(4-fluorophenyl)-7-(2-methoxyethoxy)-thiazolo[5,4- d]pyrimidin-5-amine

To a solution of Na (2.0 mg, 0.07 mmol) in 2-methoxyethanol (1 ml) was added 2-(4- fluorophenyl)-7-methylthio-thiazolo[5,4-d]pyrimidin-5-amine (40 mg, 0.14 mmol). The reaction mixture was heated at 80 °C for 20 hours. After cooling, the mixture was neutralized with 1 N HCI and the solvent was removed under reduced pressure. The crude residue was extracted by ethyl acetate, brine and dried over Na₂S0₄. After removing the solvents under reduced pressure, the residue was purified by flash chromatography on silica (CH₂CI₂/MeOH 100: 1 ) to yield the title compound as a white solid (35 mg, 80 %).

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.98-8.02 (m, 2H, PhH), 7.14 (t, J= 8.5 Hz, 2H, PhH), 5.02 (s, 2H, NH₂), 4.70 (t, J= 5.0 Hz, 2H, OCH₂), 3.85 (t, J= 5.0 Hz, 2H, CJiOCH^, 3.46 (s, 3H, CH₃) ppm.

HRMS: calcd for C₁₄H₁₄FN₄0₂S 321.0821 , found 321.0812.

Example 30 : Synthesis of 7-ethoxy-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-5-amine

This compound was synthesized according to the procedure for the synthesis of example 29 using ethanol . The crude residue was purified by chromatography on silica gel (ethyl acetate/heptane 1 :10) to yield the title compound as a white solid (67 %).

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.97-8.02 (m, 2H, PhH), 7.14 (t, J= 8.6 Hz, 2H, PhH), 5.04 (s, 2H, NH₂), 4.61 (q, J= 7.1 Hz, 2H, CH₂), 1.51 (t, J= 7.1 Hz, 3H, CH₃) ppm.

HRMS: calcd for C₁₃H₁₂FN₄OS 291.0716, found 291.0717.

Example 31 : Synthesis of 7-ethoxy-2-(4-fluorobenzyl)thiazolo[5,4-d]pyrimidin-5-amine This compound was synthesized from example 17 in a yield of 36%, according to the procedure for the synthesis of example 29.

¹H N R (300 MHz, CDCI₃, 25 °C): 6 = 7.26-7.31 (m, 2H, PhH), 7.02 (t, J= 9.0 Hz, 2H, PhH), 4.95 (s, 2H, NH₂), 4.58 (q, J= 7.1 Hz, 2H, CH₂), 4.32 (s, 2H, CH₂), 1 .50 (t, J= 7.1 Hz, 3H, CH₃) ppm.

HRMS: calcd for C₁₄H₁₄FN₄OS 305.08723, found 305.08635.

Exa mple 32 : Synth es i s of 2-(4-fluorophenyl)-N-7-(3-methoxypropyl)thiazolo[5,4- d]pyrimidine-5,7-diamine

To a solution of 2-(4-fluorophenyl)-7-methylsulfonyl-thiazolo[5,4-d]pyrimidin-5-amine (50 mg, 0.15 mmol) and triethylamine (32 μΙ, 0.23 mmol) in dioxane (1 ml) was added 3- methoxypropylamine (21 μΙ, 0.20 mmol). The reaction mixture was heated at 60 °C for 5 hours. After cooling, the volatiles were removed under reduced pressure. The crude residue was purified by flash chromatography on silica (CH₂CI₂/MeOH 70: 1 ), yielding the title compound as a white solid (32 mg, 62 %).

1H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.89-7.94 (m, 2H, PhH), 7.13 (t, J= 8.7 Hz, 2H, PhH), 6.37 (br s, 1 H, NH), 4.84 (s, 2H, NH₂), 3.68 (q, J= 6.3, 2H, NHCH?), 3.56 (t, J= 5.9 Hz, 2H, OCH₂), 3.41 (s, 3H, OCH₃), 1.97 (quint, J= 6.3, 2H, CH₂) ppm.

HRMS: calcd for C₁₅H₁₇FN₆OS 334.1 138, found 334.1 121.

Example 33 : Synthesis of 2-(4-fluorophenyl)-7-morpholino-thiazolo[5,4-d]pyrimidin-5- amine

This compound was synthesized from example 21 using morpholine, according to the procedure for the synthesis of example 32. The crude residue was purified by flash chromatography on silica (CH₂CI₂/MeOH 50: 1 ) to yield the title compound as a light yellow solid (77 %).

1H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.86-7.90 (m, 2H, PhH), 7.14 (t, J= 8.6 Hz, 2H, PhH), 4.77 (s, 2H, NH₂), 4.35 (br s, 4H, 0(CH₂)₂), 3.85 (t, J= 3.9 Hz, 4H, N(CH₂)₂) ppm.

HRMS: calcd for C₁₅Hi₅FN₅OS 332.0981 , found 332.0975.

Example 34 : Synthesis of 2-(4-fluorobenzyl)-7-morpholino-thiazolo[5,4-d]pyrimidin-5- amine

This compound was synthesized from example 22 in a yield of 67%, according to the procedure for the synthesis of example 32.

H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.24-7.28 (m, 2H, PhH), 7.02 (t, J= 8.7 Hz, 2H, PhH), 4.69 (s, 2H, NH₂), 4.27 (br s, 4H, 0(CH₂)₂), 4.21 (s, 2H, CH₂), 3.80 (t, J= 5.0 Hz, 4H, N(CH₂)₂) ppm.

HRMS: calcd for C₁₆H₁₇FN₅OS 346.1 138, found 346.1 125. Example 35 : Synthesis of 2-(4-fluorophenyl)-7-(4-m-tolylpiperazin-1 -yl)-thiazolo[5,4- d]pyrimidin-5 -amine

This compound was synthesized according to the procedure for the preparation of example 32, using 1 -m-tolylpiperazine. The crude residue was purified by flash chromatography on silica (CH₂CI₂/MeOH 40:1 ) to yield the title compound as a white solid (60 %).

H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.89-7.93 (m, 2H, PhH), 7.12-7.22 (m, 4H, PhH, tolyl H), 6.72-6.82 (m, 3H, tolyl H), 4.77 (s, 2H, NH₂), 4.51 (br s, 4H, N(CH₂)₂), 3.33 (t, J= 5.0 Hz, 4H, N(CH₂)₂), 2.34 (s, 3H, CH₃) ppm.

HRMS: calcd for C₂₂H₂₂FN₆S 421.16107, found 421.15992.

E x a m p l e 3 6 : S y n t h e s i s o f 2-(4-fluorophenyl)-7-(4-(thiazol-2-yl)piperazin-1- yl)thiazolo[5,4-d]pyrimidin-5-amine

This compound was synthesized according to the procedure for example 32, using 1 -(thiazol- 2-yl)piperazine. The crude residue was purified by flash ch romatography on silica (CH₂CI₂/MeOH 50:1 ), yielding the pure title compound as a white solid (43 %).

H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.87-7.92 (m, 2H, PhH), 7.24 (d, J= 3.6 Hz, 1 H, thiazolyl H), 7.15 (t, J= 8.6 Hz, 2H, PhH), 6.63 (d, J= 3.6 Hz, 1 H, thiazolyl H), 4.81 (s, 2H, NH₂), 4.50 (br s, 4H, N(CH₂)₂), 3.66 (t, J= 5.3 Hz, 4H, N(CH₂)₂) ppm.

HRMS: calcd for C₁₈H₁₇FN₇S₂ 414.09709, found 414.09592.

Exa mple 37 : Synthesis of 2-(4-fluorophenyl)-7-(4-pentylpiperazin-1-yl)thiazolo[5,4- d]pyrimidin-5-amine

This compound was synthesized using a similar procedure as for the preparation of example 32, using 1-pentylpiperazine. The crude residue was purified by flash chromatography on silica (CH₂CI₂/MeOH 50:1 ) to yield the title compound as a white solid (40 %).

¹H NMR (300 MHz, CDCI₃₎ 25 °C): δ = 7.86-7.91 (m, 2H, PhH), 7.14 (t, J= 8.6 Hz, 2H, PhH), 4.77 (s, 2H, NH₂), 4.38 (br s, 4H, N(CH₂)₂), 2.61 (br s, 4H, pentylNiCH^), 2.41 (t, J= 7.8 Hz, 2H, NCH2CH₂CH₂CH₂CH₃), 2.00 (br s, 2H, NCH₂Cii>CH₂CH₂CH₃), 1.56 (quint, J= 6.7 Hz, 2H, NCH₂CH₂CH CH₂CH₃), 1.28-1.34 (m, 2H, NCH₂CH₂CH₂CJiCH3), 0.91 (t, J= 6.5 Hz, 3H, NCH₂CH₂CH₂CH₂Cli₃) ppm.

HRMS: calcd for C₂₀H₂₆FN₆S 401.19237, found 401.19102.

Example 38 : Synthesis of 2-(4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1 -yl)-1 -morpholinoethanone

This compound was synthesized according to the procedure for the synthesis of example 32, using 1 -morpholino-2-(piperazin-1 -yl)ethanone. The crude residue was purified by flash chromatography on silica (CH₂CI₂/MeOH 60:1 ), affording the title compound as a light yellow solid (48 %). H N R (300 MHz, CDCI₃, 25 °C): δ = 7.85-7.89 (m, 2H, PhH), 7.13 (t, J= 8.4 Hz, 2H, PhH), 4.75 (s, 2H, NH₂), 4.37 (br s, 4H, N(CH₂)₂), 3.71 (br s, 4H, morpholinyl H), 3.66 (br s, 4H, morpholinyl H), 3.25 (S, 2H,CH₂), 2.67 (t, J= 4.9 Hz, 4H, CH₂N(CH2» Ppm.

HRMS: calcd for C₂₁H₂₅FN70₂S 458.17745, found 458.17603.

Example 39 : Synthesis of 7-(4-benzylpiperazin-1 -yl)-2-(4-fluorophenyl)thiazolo[5,4- d]pyrimidin-5 -amine

This compound was synthesized according to the procedure for the preparation of example 32, using 1-benzylpiperazine. The crude residue was purified by flash chromatography on silica (CH₂CI₂/MeOH 60:1 ) to yield the title compound as a white solid (81 %).

1H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.84-7.88 (m, 2H, PhH), 7.26-7.37 (m, 5H, PhH), 7.12 (t, J= 8.4 Hz, 2H, PhH), 4.73 (s, 2H, NH₂), 4.36 (br s, 4H, N(CH₂)₂), 3.57 (s, 2H, CH₂), 2.59 (t, J= 4.7 Hz, 4H, CH₂N(CH2)₂) ppm.

HRMS: calcd for C₂₂H₂₂FN₆S 421 .16107, found 421 .15986.

E x a m p l e 40 : S y n th e s i s of b e n z y l-4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazine-1-carboxylate

To a solution of 2-(4-fluorophenyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine (50 mg, 0.15 mmol) and pyridine (18 μΙ, 0.23 mmol) in DMF (1 ml) was added benzyl chloroformate (24 μΙ, 0.17 mmol). The reaction mixture was stiffed for 3 hours at room temperature. The reaction mixture was quenched with water, extracted with EtOAc, brine and dried over Na₂S0₄. After removing the solvents, the crude residue was purified by flash chromatography on silica (CH₂CI₂/MeOH 100:1 ) to yield the title compound as a white solid (54 mg, 77 %). H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.85-7.89 (m, 2H, PhH), 7.40-7.35 (m, 5H, PhH), 7.13 (t, J= 8.6 Hz, 2H, PhH), 5.19 (s, 2H, CH₂), 4.82 (s, 2H, NH₂), 4.34 (br s, 4H, N(CH₂)₂), 3.66 (br s, 4H, CON(CH₂)₂) ppm.

HRMS: calcd for C₂₃H₂₂FN₆0₂S 465.15090, found 465.15005.

E x a m p l e 41 : S y n t h e s i s of 2-(4-fluorophenyl)-7-(4-(phenylsulfonyl)piperazin-1- yl)thiazolo[5,4-d]pyrimidin-5 -amine

To a solution of 2-(4-fluorophenyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine (50 mg, 0.15 mmol) and pyridine (18 pi, 0.23 mmol) in DMF (1 ml) was added benzenesulfonyl chloride (21 μΙ, 0.17 mmol). The reaction mixture was stirred for 3 hours at room temperature. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na₂S0₄. After removing the solvents, the crude residue was purified by flash chromatography on silica (CH₂CI₂/MeOH 80:1 ) to yield the title compound as a white solid (32 mg, 45 %). ¹H N R (300 MHz, DMSO, 25 °C): 0 = 7.94-7.98 (m, 2H, PhH), 7.64-7.79 (m, 5H, PhH), 7.35 (t, J= 8.6 Hz, 2H, PhH), 6.48 (s, 2H, NH₂), 4.35 (br s, 4H, N(CH₂)₂), 3.06 (br s, 4H, S-

HRMS: calcd for C₂iH₂₀FN₆O₂S₂ 471.10732, found 471 .10694.

Example 42 : Synthesis of 4-(5-amino-2-(4-fluorophenyl)-thiazolo[5,4-d]pyrimidin-7-yl)- W-p-tolylpiperazine-1 -carboxamide

To a solution of 2-(4-fluorophenyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine (50 mg, 0.15 mmol) in DMF (1 ml) was added p-tolyl isocyanate (21 μΙ, 0.17 mmol) in DMF (0.3 ml). The reaction mixture was stirred for 2 hours at room temperature. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na₂SO„. After removing the solvents in vacuo, the crude residue was purified by flash chromatography on silica (CH₂CI₂/MeOH 100:1 ) to yield the title compound as a white solid (31 mg, 44 %).

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.86-7.91 (m, 2H, PhH), 7.26 (d, J=1 .6 Hz, 2H, tolyl H), 7.10-7.23 (m, 4H, PhH, tolyl H), 6.34 (s, 1 H, NH), 4.81 (s, 2H, NH₂), 4.42 (br s, 4H, N(CH₂)₂), 3.28 (t, J= 5.3 Hz, 4H, CON(Ch_2)₂), 2.31 (s, 3H, CH₃) ppm.

HRMS: calcd for C₂₃H₂₃FN₇OS 464.1669, found 464.1671.

Example 43 : Synthesis of 4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)- A/-m-tolylpiperazine-1 -carboxamide

This compound was prepared according to the procedure for the synthesis of example 42, using m-tolylisocyanate in a yield of 57%.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.86-7.91 (m, 2H, PhH), 7.25 (s, 1 H, tolyl H), 7.12- 7.22 (m, 4H, PhH, tolyl H), 6.88 (d, J= 7.2 Hz, 1 H, tolyl H), 6.41 (s, 1 H, NH), 4.84 (s, 2H, NH₂), 4.42 (br s, 4H, N(CH₂)₂), 3.68 (t, J= 5.3 Hz, 4H,

2.33 (s, 3H, CH₃) ppm. HRMS: calcd for C₂₃H₂₃FN₇OS 464.1669, found 464.1673.

Example 44 : Synthesis of 4-(5-amino-2-(4-fluorobenzyl)thiazolo[5,4-d]pyrimidin-7-yl)- /V-m-tolylpiperazine-1 -carboxamide

This compound was prepared from example 26 in a yield of 72%, according to the procedure for the synthesis of example 42.

1H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.06-7.29 (m, 5H, PhH, tolyl H), 7.04 (d, J= 4.7 Hz, 2H, PhH), 6.89 (d, J= 6.2 Hz, 1 H, tolyl H), 6.30 (s, 1 H, NH), 4.71 (s, 2H, NH₂), 4.34 (br s, 4H, N(CH₂)₂), 4.23 (s, 2H, CH₂), 3.61 -3.65 (m, 4H, CON(CH2)₂), 2.34 (s, 3H, CH₃) ppm.

HRMS: calcd for C₂₄H₂₅FN₇OS 478.1825, found 478.1823.

Example 45 : Synthesis of 1 -(4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone To a solution of 2-(4-fluorophenyl)-7-(pipera2in-1-yl)thiazolo[5,4-d]pyrimidin-5-amine (40 mg, 0.12 mmol) and pyridine (15 μΙ, 0.18 mmol) in DMF (1 ml) was added 4-chlorophenoxyacetyl chloride (27 mg, 0.13 mmol). The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was quenched with water, extracted with EtOAc, brine and was dried over Na₂S0₄. After removing the solvents, the crude residue was purified by flash chromatography on silica (CH₂CI₂/ eOH 100:1) to yield the title compound as a white solid (32 mg, 53 %).

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.86-7.91 (m, 2H, PhH), 7.26 (d, J= 9.0 Hz, 2H, tolyl H), 7.15 (t, J= 8.4 Hz, 2H, PhH), 6.93 (d, J= 9.0 Hz, 2H, tolyl H), 4.81 (s, 2H, NH₂), 4.75 (s, 2H, CH₂), 4.32 (br s, 4H, N(CH₂)₂), 3.75 (quint, J= 5.0 Hz, 4H, CONiCH^) ppm.

HRMS: calcd for C₂₃H₂₁CIFN₆0₂S 499.1119, found 499.1130

Example 46 : Synthesis of 1-(4-(5-amino-2-(4-fluorobenzyl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1-yl)-2-(4-chlorophenoxy)ethanone

This compound was prepared from example 26 in a yield of 31%, according to the procedure for the synthesis of example 45.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.23-7.28 (m, 4H, PhH), 7.02 (t, J= 8.7 Hz, 2H, PhH), 6.92 (d, J= 9.1 Hz, 2H, PhH), 4.74 (s, 2H, OCH₂), 4.71 (s, 2H, NH₂), 4.23-4.28 (br s, 4H, N(CH₂)₂), 4.22 (s, 2H, CH₂), 3.67-3.75 (m, 4H, CONiCH^) ppm.

HRMS: calcd for C₂₄H₂₃CIFN₆0₂S 513.12758, found 513.12732.

Example 47 : Synthesis of 2-(4-chlorophenoxy)-1 -(4-(2-(4-fluorophenyl)-5- methylthiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)ethanone

To a solution of 7-chloro-2-(4-fluorophenyl)-5-methylthiazolo[5,4-d]pyrimidine (30 mg, 0.11 mmol) and triethylamine (22 μΙ, 0.16 mmol) in dioxane (1 ml) was added 2-(4- chlorophenoxy)-1-(piperazin-1-yl)ethanone (38 mg, 0.16 mmol). The reaction mixture was heated at 70°C for 3 hours. After cooling, the volatiles were removed under reduced pressure. The crude residue was purified by chromatography on silica gel (CH₂CI₂/MeOH 70:1) to yield the title compound as a white solid (40 mg, 75 %).

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.93-7.97 (m, 2H, PhH), 7.26 (d, J= 9.1 Hz, 2H, tolyl H), 7.17 (t, J= 8.7 Hz, 2H, PhH), 6.93 (d, J= 9.1 Hz, 2H, tolyl H), 4.76 (s, 2H, CH₂), 4.42 (br s, 4H, N(CH₂)₂), 3.79 (br s, 4H, CON(CI½)₂) ppm.

HRMS: calcd for C₂₄H₂₂CIFN₅0₂S 498.11668, found 498.11541.

Example 48 : Synthesis of 1-(4-(5-amino-2-(2-(4-fluorophenoxy)ethyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1-yl)-2-(4-chlorophenoxy)ethanone

This compound was prepared from example 24 in a yield of 72%, according to the procedure for the synthesis of example 47. ¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.25 (d, J= 5.3 Hz, 2H, PhH), 6.83-7.00 (m, 6H, PhH), 4.72 (s, 2H, CH₂), 4.31 (t, J= 6.2 Hz, 2H, CH₂), 4.23 (br s, 4H, NCH₂), 3.71 (br s, 2H , CONCH,), 3.65 (br s, 2H, CONCH^), 3.40 (t, J= 6.2, 2H, CH₂) ppm.

HRMS: calcd for C₂5H₂₅CIFN₆0₃S 543.13814, found 543.13690.

Example 49 : Synthesis of 1-(4-(5-amino-2-(4-fluorophenethyl)-thia2olo[5,4-d]pyrimidin- 7-yl)piperazin-1-yl)-2-{4-chlorophenoxy)ethanone

To a solution of 2-(4-fluorophenethyl)-7-(methylsulfonyl)thiazolo[5,4-d]pyrimidin-5-amine (50 mg, 0.14 mmol) and triethylamine (30 μΙ, 0.21 mmol) in dioxane (1 ml) was added 2-(4- chlorophenoxy)-1 -(piperazin-1-yl)ethanone (51 mg, 0.21 mmol). The reaction mixture was heated at 70°C for 3 hours. After cooling, the volatiles were removed under reduced pressure. The crude residue was purified by chromatography on silica gel (CH₂CI₂/MeOH 70:1 ) to yield the title compound as a light yellow solid (64 mg, 85 %).

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.26 (d, J= 8.9 Hz, 2H, PhH), 7.13-7.18 (m, 2H, PhH), 6.68 (d, J= 8.9, 2H PhH), 6.93 (t, J= 9.1 Hz, 2H, PhH), 4.73 (br s, 4H, NH₂, OCH₂), 4.23 (br s, 4H, N(CH₂)₂), 3.71 (br s, 2H , CONChy, 3.70 (br s, 2H , CONCH^), 3.23 (t, J= 7.0, 2H, CH₂), 3.07 (t, J= 7.0, 2H, CH₂) ppm.

HRMS: calcd for C₂₅H₂₅CIFN₆0₂S 527.14323, found 527.14215.

Example 50 : Synthesis of 1 -(4-{5-amino-2- 4-fluorophenethyl)thiazolo[5,4-d]pyrimidin- 7-yl)piperazin-1-yl)-2-(4-methoxyphenoxy)ethanone

To a solution of 2-(4-fluorophenethyl)-7-(methylsulfonyl)thiazolo[5,4-d]pyrimidin-5-amine (40 mg, 0.11 mmol) and 4-methoxyphenoxyacetic acid (30 mg, 0.17 mmol) in DMF (2 ml) was added TBTU (/V,/V,/\/',/\/'-tetramethyl-0-(benzotriazol-1 -yl)uronium tetrafluoroborate, 54 mg, 0.17 mmol), followed by DIPEA (29 μΙ, 0.17 mmol. The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine and dried over Na₂S0₄. After removing the solvents under reduced pressure, the crude residue was purified by flash chromatography on silica (CH₂CI₂/MeOH 40: 1 ), yielding the title compound as a white solid (40 mg, 69 %).

H NMR (300 MHz, DMSO, 25 °C): δ = 7.27-7.32 (m, 2H, PhH), 7.09 (t, J= 8.9 Hz, 2H, PhH), 6.84-6.91 (m, 4H, PhH), 6.31 (br s, 2H, NH₂), 4.79 (s, 2H, CH₂), 4.22 (br s, 2H, NCH₂), 4.10 (br s, 2H, NCH₂), 3.69 (s, 3H, CH₃), 3.56 (br s, 4H, CONiCH^), 3.25 (t, J= 7.4, 2H, CH₂), 3.04 (t, J= 7.4, 2H, CH₂) ppm.

HRMS: calcd for C_2SH₂₈FN₆0₃S 523.19276, found 523.19218.

Example 51 : Synthesis of 1-(4-{5-amino-2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin- 7-yl)piperazin-1 -yl)-2-(4-fluorophenoxy)ethanone This compound was prepared from example 27 using 4-fluorophenoxyacetic acid in a yield of 56%, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, DMSO, 25 °C): δ = 7.27-7.32 (m, 2H, PhH), 7.12 (t, J= 8.9 Hz, 2H, PhH), 7.09 (t, J= 8.6 Hz, 2H, PhH), 6.94-6.98 (m, 2H, PhH), 6.31 (br s, 2H, NH₂), 4.87 (s, 2H, CH₂), 4.23 (br s, 2H, NCH₂), 4.10 (br s, 2H, NCH₂), 3.56 (br s, 4H, CONKCH^), 3.25 (t, J= 7.3, 2H, CH₂), 3.05 (t, J= 7.3, 2H, CH₂) ppm.

HRMS: calcd for C₂₅H₂₅F₂N₆0₂S 51 1.17278, found 51 1.17170.

Example 52 : Synthesis of 1 -(4-(5-amino-2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin- 7-yl)piperazin-1 -yl)-2-(4-bromophenoxy)ethanone

This compound was prepared from example 27 using 4-bromophenoxyacetic acid in a yield of 47%, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, DMSO, 25 °C): δ = 7.44 (d, J= 8.9 Hz, 2H, PhH), 7.27-7.32 (m, 2H, PhH), 7.09 (t, J= 8.9 Hz, 2H, PhH), 6.92 (d, J= 8.9 Hz, 2H, PhH), 6.31 (br s, 2H, NH₂), 4.91 (s, 2H, CH₂), 4.24 (br s, 2H, NCH₂), 4.10 (br s, 2H, NCH₂), 3.55 (br s, 4H, CONKCH^), 3.25 (t, J= 7.4, 2H, CH₂), 3.04 (t, J= 7.4, 2H, CH₂) ppm.

Example 53 : Synthesis of 1 -(4-(5-amino-2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin- 7-yl)piperazin-1-yl)-2-(m-tolyloxy)ethanone

This compound was prepared from example 27 using 3-methylphenoxyacetic acid in a yield of 44%, according to the procedure for the synthesis of example 50.

1H NMR (300 MHz, DMSO, 25 °C): δ 7.28-7.32 (m, 2H, PhH), 7.16 (t, J= 7.7 Hz, 1 H, PhH), 7.09 (t, J= 8.9 Hz, 2H, PhH), 6.73-6.78 (m, 3H, PhH), 6.31 (br s, 2H, NH₂), 4.84 (s, 2H, CH₂), 4.24 (br s, 2H, NCH₂), 4.10 (br s, 2H, NCH₂), 3.57 (br s, 4H, CON(CI½)₂), 3.25 (t, J= 7.4, 2H, CH₂), 3.05 (t, J= 7.4, 2H, CH₂), 2.27 (s, 3H, CH₃) ppm.

HRMS: calcd for C₂₆H₂8FN₆0₂S 507.19785, found 507.19725.

Example 54 : Synthesis of 1 -(4-(5-amino-2^4-fluorophenethyl)thiazolo[5,4-d]pyrimidin- 7-yl)piperazin-1 -yl)-2-(2,4-dichlorophenoxy)ethanone

This compound was prepared from example 27 using 2,4-dichlorophenoxyacetic acid in a yield of 43%, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, DMSO, 25 °C): δ = 7.58 (d, J 2.6 Hz, 1 H, PhH), 7.28-7.37 (m, 3H, PhH), 7.07-7.12 (m, 3H, PhH), 6.32 (br s, 2H, NH₂), 5.07 (s, 2H, CH₂), 4.25 (br s, 2H, NCH₂), 4.11 (br s, 2H, NCH₂), 3.56 (br s, 4H, CON(Cli>)₂), 3.25 (t, J= 7.5, 2H, CH₂), 3.04 (t, J= 7.5, 2H, CH₂) ppm.

HRMS: calcd for C₂5H₂,CI₂FN₆0₂S 561.10425, found 561 .10335.

Example 55 : Synthesis of 1 -(4-(5-amino-2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin- 7-yl)piperazin-1-yl)-3-(4-fluorophenoxy)propan-1 -one This compound was prepared from example 27 using 3-(4-fluorophenoxy)propionic acid in a yield of 43%, according to the procedure for the synthesis of example 50.

¹H N MR (300 MHz, DMSO, 25 °C): δ = 7.27-7.33 (m, 2H, PhH), 7.06-7.14 (m, 4H, PhH), 6.92-6.97 (m, 2H, PhH), 6.30 (br s, 2H, NH₂), 4.19 (t, J= 5.8 Hz, 2H, OCH₂), 4.17 (br s, 2H, NCH₂), 4.09 (br s, 2H, NCH₂), 3.59 (br s, 4H , CON{CH ₂), 3.25 (t, J= 7.4, 2H, CH₂), 3.05 (t, J= 7.4, 2H, CH₂), 2.86 (t, J= 5.8, 2H, CH₂) ppm.

Example 56 : Synthesis of 2-(4-fluorophenyl)-5-methyl-thiazolo[5,4-d]pyrimidin-7(6H)- one

To a solution of 2-(4-fluorophenyl)-7-(methylthio)thiazolo[5,4-d]pyrimidin-5-amine (0.15 g, 0.51 mmol) in dichloromethane (3 ml) was added mCPBA (70 %, 0.32 g, 1 .29 mmol) at 0°C. The temperature was gradually raised from 0°C to room temperature and the reaction was stirred for another 3 hours. The reaction mixture was diluted with CHCI₃ and washed with a saturated NaHC0₃ solution, brine and dried over Na₂SO_.. After removing the solvents under reduced pressure, the residue was purified by chromatography on silica gel (CH₂CI₂/MeOH 50:1 ) to yield the title compound as a white solid (0.10 g, 75 %).

H N MR (300 MHz, DMSO, 25 °C): δ = 12.80 (s, 1 H, NH), 8.03-8.08 (m, 2H, PhH), 7.40 (t, J= 8.8 Hz, 2H, PhH), 2.41 (s, 3H, CH₃) ppm.

HRMS: calcd for Ci₂H₉FN₃OS 262.04504, found 262.04433.

E x a m p l e 5 7 : S y n t h e s i s o f 7-chloro-2-(4-fluorophenyl)-5-methyl-thiazolo[5,4- djpyrimidine

To a solution of 2-(4-fluorophenyl)-5-methyl-thiazolo[5,4-d]pyrimidin-7(6H)-one (0.40 g, 1 .23 mmol) in POCI₃ was added diisopropylethylamine (0.13 ml, 0.77 mmol). The reaction mixture was stirred under N₂ at 90°C for 3.5 hours. After cooling down to room temperature, the reaction mixture was poured into ice-water and the aqueous phase was extracted with diethyl ether. The combined organic layers were washed with a saturated NaHC0₃ solution and brine, dried over Na₂S0₄ and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (hexane/EtOAc 10: 1 ) to yield the title compound as a white solid (42.8 mg, 40 %).

¹ H N MR (300 MHz, CDCI₃, 25 °C): δ = 8.09-8.14 (m, 2H, PhH), 7.22 (t, J= 8.5 Hz, 2H, PhH), 2.83 (s, 3H, CH₃) ppm.

HRMS: calcd for C₁₂H₈CIFN₃S 280.01 1 15, found 280.01063.

Example 58 : Synthesis of ferf-butyl 4-(2-(4-chlorophenoxy)acetyl)piperazine-1 - carboxylate

To a solution of terf-butyl piperazine-1 -carboxylate (0.30 g, 0.16 mmol) and triethylamine (0.34 ml, 2.42 mmol) in dichloromethane (8 ml) was added p-chlorophenoxyacetyl chloride (0.36 mg, 1.77 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and washed with water, brine and dried over Na₂S0₄. After removing the solvents, the crude residue was purified by chromatography on silica gel (CH₂CI₂/MeOH 80:1 ) to yield the title compound as a white solid (0.57g, 100 %). ¹H N R (300 MHz, CDCI₃₎ 25 °C): δ = 7.25 (d, J= 8.9 Hz, 2H, PhH), 6.88 (d, J= 8.9 Hz, 2H, PhH), 4.68 (s, 2H, CH₂), 3.57 (br s, 4H, CON CH^), 3.41 (br s, 4H, CONiCH^). 1.46 (s, 3H, CH₃) ppm.

HRMS: calcd for C₁₇H₂4CIN₂0₄ 355.14246, found 355.14167.

Example 59 : Synthesis of ethyl 4-(m-tolylcarbamoyl)piperazine-1 -carboxylate

To a solution of ethyl piperazine-1 -carboxylate (1.0 g, 6.32 mmol) in dichloromethane (30 ml) was added m-tolylisocyanate (0.90 mg, 6.95 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane and washed with water, brine and dried over Na₂S0₄. After removing the solvents, the residue was purified by chromatography on silica gel (CH₂CI₂/MeOH 50:1 ) to yield the title compound as a white solid (1 .6 g, 87 %).

1H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.18 (s, 1 H, PhH), 7.10-7.15 (m, 2H, PhH), 6.83 (d, J= 6.4 Hz, 1 H, PhH), 4.14 (q, J= 7.1 Hz, 2H, OCH^CHs), 3.42 (br s, 8H, NKCH^), 2.27 (s, 3H, CH₃), 1 .26 (t, J= 7.1 Hz, 3H, OCH₂CHa) ppm.

MS 289.7 [M-H]

Example 60 : Synthesis of 2-(4-chlorophenoxy)-1-(piperazin-1-yl)ethanone

A suspension of terf-butyl 4-(2-(4-chlorophenoxy)acetyl)piperazine-1 -carboxylate (example 58, 0.58g, 0.16 mmol) in dichloromethane (8 ml) was treated dropwise at room temperature with TFA until the solid completely dissolved. The reaction mixture was stirred under nitrogen at room temperature overnight. The volatiles were evaporated to dryness, diluted with water and the solid was collected by filtration. The solid was washed with water and dried to yield the title compound as a white solid (0.30 g, 72 %).

¹H NMR (300 MHz, DMSO, 25 °C): δ = 9.02 (s, 1 H, NH), 7.32 (d, J= 8.8 Hz, 2H, PhH), 6.96 (d, J= 8.8 Hz, 2H, PhH), 4.90 (s, 2H, CH₂), 3.65 (br s, 4H, CONiCKfe)), 3.18 (br s, 2H, NCH₂), 3.10 (br s, 2H, NCH₂) ppm.

HRMS: calcd for C₁₂H₁₆CIN₂0₂ 255.09003, found 255.08913.

Example 61 : Synthesis of A -m-tolylpiperazine-1 -carboxamide

A suspension of ethyl 4-(m-tolylcarbamoyl)piperazine-1-carboxylate (example 59, 1.5 g, 5.15 mmol) in dichloromethane (25 ml) was treated dropwise at room temperature with iodotrimethylsilane (1.6 ml, 1 1 .3 mmol). The reaction mixture was stirred under nitrogen at room temperature overnight. The volatiles were evaporated to dryness, diluted with methanol and the solid was filtered off. The solid was washed with methanol and dichloromethane and dried under vacuum to yield the title compound as a yellow solid (1 .1 g, 100 %). ¹H N R (300 MHz, DMSO, 25 °C): δ = 8.62 (s, 1H, NH), 7.29 (s, 1H, PhH), 7.27 (d, J= 7.3 Hz, 1 H, PhH), 7.13 (1, J= 7.3 Hz, 1H, PhH), 6.79 (d, J= 7.3 Hz, 1H PhH), 3.65 (br s, 4H, CON(CI½)), 3.17 (br s, 4H, N(CH₂)₂), 2.26 (s, 3H, CH₃) ppm.

MS 227.8 [M-H]

Example 62 : Synthesis of 2-(1-(4-fluorophenyl)ethyl)-7-methylthio-thiazolo[5,4- d]pyrimidin-5 -amine

To a solution of 2-(4-fluorobenzyl)-7-(methylthio)thiazolo[5,4-d]pyrimidin-5-amine (0.4 g, 1.31 mmol) and 2N NaOH (0.65 ml, 1.31 mmol) in DMSO (7 ml) was added iodomethane (81 μΙ, 1.31 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into water and extracted with ethyl acetate, brine and dried over Na₂S0₄. After removing the solvents under reduced pressure, the residue was purified by chromatography on silica gel (hexane/EtOAc 5:1) yielding the title compound as a white solid (0.29 g, 69 %).

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.31(br s, 2H, PhH), 7.02 (br s, 2H, PhH), 5.16 (s, 2H, NH₂), 4.47 (br s, 1H, CH), 2.58 (s, 3H, CH₃), 1.76 (d, J= 6.6Hz, 3H, CHCh ) ppm.

HRMS: calcd for Ci₄H₁₄FN₄S₂321.06439, found 321.06377.

E x a m p l e 63 S y n t h e s i s o f 2-(1-{4-fluorophenyl)-2-phenylethyl)-7- (methylthio)thiazolo[5,4-d]pyrimidin-5 -amine

This compound was synthesized according to the procedure for the preparation of example 62, using benzyl bromide. The crude residue was purified by flash chromatography on silica gel (hexane/EtOAc 5:1 ) to yield the title compound as a white solid (67 %).

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.13-7.25(m, 5H, PhH), 7.07 (d, J= 6.8 Hz, 2H, PhH), 6.96 (t, J= 8.5 Hz, 2H, PhH), 5.05 (s, 2H, NH₂), 4.52 (t, J= 7.8 Hz, 1 H, CH), 3.74 (dd, J= 13.8, 7.8 Hz, 1H, benzylH), 3.30 (dd, J= 13.8, 7.8 Hz, 1H, benzylH), 2.59 (s, 3H, CH₃) ppm.

HRMS: calcd for C₂₀Hi₈FN₄S₂397.09569, found 397.09495.

Example 64 : Synthesis of 2-(1-(4-fluorophenyl)ethyl)-7-(methylsulfonyl)thiazolo[5,4- d]pyrimidin-5 -amine

This compound was synthesized from example 62 according to the procedure for the preparation of example 21. The crude residue was purified by flash chromatography on silica (CH₂CI₂/MeOH 100:1) to yield the title compound as a white solid (77 %).

1H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.35-7.30 (m, 2H, PhH), 7.05 (t, J= 8.6 Hz, 2H, PhH), 5.49 (s, 2H, NH₂), 4.54 (q, J= 7.1, 1H, CH), 3.49 (s, 3H, CH₃), 1.83 (d, J= 7.1 Hz, 3H, CHCHaj ppm.

HRMS: calcd for Ci₄H₁₄FN₄0₂S₂353.05422, found 353.05356.

E x a m p l e 65 : S y n t h e s i s o f 2-(1-{4-fluorophenyl)-2-phenylethyl)-7- (methylsulfonyl)thiazolo[5,4-d]pyrimidin-5-amine This compound was synthesized from example 63 according to the procedure for the preparation of example 21. The crude residue was purified by flash chromatography on silica (CH₂CI₂/MeOH 100:1) to yield the title compound as a white solid (85 %).

H NMR (300 MHz, DMSO, 25 °C): δ = 7.59 (s, 2H, NH₂), 7.44-7.49 (m, 2H, PhH), 7.11-7.24 (m, 7H, PhH), 4.96 (t, J= 7.8 Hz, 1H, CH), 3.67 (dd, J= 13.8, 7.8 Hz, 1H, benzylH), 3.53 (s, 3H, CH₃), 3.35 (dd, J= 13.8, 7.8 Hz, 1H, benzylH) ppm.

HRMS: calcd for C₂₀Hi₈FN₄O₂S₂429.08552, found 429.08481.

Example 66 : Synthesis of 1-(4-(5-amino-2-(1-(4-fluorophenyl)ethyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1-yl)-2-(4-chlorophenoxy)ethanone

To a solution of 2-(1-(4-fluorophenyl)ethyl)-7-(methylsulfonyl)thiazolo[5,4-d]pyrimidin-5-amine (50 mg, 0.14 mmol) and triethylamine (30 μΙ, 0.21 mmol) in dioxane (1 ml) was added 2-(4- chlorophenoxy)-1-(piperazin-1-yl)ethanone (51 mg, 0.21 mmol). The reaction mixture was heated at 70°C for 3 hours. After cooling down to room temperature, the volatiles were removed under reduced pressure. The crude residue was purified by chromatography on silica gel (CH₂CI₂/MeOH 70:1 ) furnishing the title compound as a white solid (50 mg, 67 %). H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.29-7.25 (m, 4H, PhH), 7.02 (t, J= 8.1 Hz, 2H, PhH), 6.92 (d, J= 8.9 Hz, 2H, PhH), 4.74 (s, 4H, OCH₂, NH₂), 4.33 (q, J= 7.3 Hz, 1H, CH), 4.27 (br s, 4H, N(CH₂)₂), 3.71 (br s, 4H, CON(CI½)₂), 1.73 (d, J= 7.3 Hz, 3H, CHCHaJ ppm.

HRMS: calcd for C₂5H₂5CIFN₆0₂S 527.14323, found 527.14230.

E x a m p l e 67 S y n t h e s i s o f 1-(4-(5-amino-2-(1-(4-fluorophenyl)-2- phenylethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(4-chlorophenoxy)ethanone

This compound was synthesized from example 65 according to the procedure for the preparation of example 66. The crude residue was purified by flash chromatography on silica (CH₂CI₂/MeOH 70:1) to yield the title compound as a white solid (60 mg, 83 %).

1H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.17-7.28 (m, 7H, PhH), 6.91-7.05 (m, 6H, PhH), 4.74 (s, 2H, OCH₂), 4.70 (s, 2H, NH₂), 4.48 (t, J= 7.7 Hz, 1H, CH), 4.24 (br s, 4H, N(CH₂)₂), 3.72 (brs, 2H, CONChb), 366 (br s, 2H, CONChy, 3.62 (dd, J= 13.8, 7.7 Hz, 1H, benzylH), 3.26 (dd, J= 13.8, 7.8 Hz, 1H, benzylH) ppm.

HRMS: calcd for C₃₁H₂₉CIFN₆0₂S 603.17453, found 603.17371.

Example 68 : Synthesis of 4-(5-amino-2-(1-(4-fluorophenyl)ethyl)thiazolo[5,4- d]pyrimidin-7-yl)-N-m-tolylpiperazine-1-carboxamide

This compound was synthesized according to the procedure for the preparation of example 66, using N-m-tolylpiperazine-1-carboxamide. The crude residue was purified by flash chromatography on silica gel (CH₂CI₂/MeOH 50:1) furnishing the title compound as a white solid (76 %). ¹H NMR (300 MHz, DMSO, 25 °C): δ = 8.50 (s, 1H, NH), 7.38-7.43 (m, 2H, PhH), 7.32 (s, 1H, PhH), 7.28 (d, J= 8.5 Hz, 1H, PhH), 7.18 (t, J= 8.9 Hz, 2H, PhH), 7.12 (t, J= 7.8 Hz, 1H, PhH), 6.76 (d, J= 7.4 Hz, 1H, PhH), 6.33 (s, 2H, NH₂), 4.51 (q, J= 7.1 Hz, 1H, CH), 4.22 (br s, 4H, N(CH₂)₂), 3.57 (br s, 4H, CON(CH₂)₂), 2.25 (s, 3H, CH₃), 1.67 (d, J= 7.1 Hz, 3H, CHChy ppm.

Example 69 : Synthesis of 2-(4-fluorophenyl)-5,7-bis(methylthio)thiazolo[5,4- d]pyrimidine

To a solution of 2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidine-5,7-dithiol (0.20 g, 0.68 mmol) and triethylamine (0.33 ml, 2.37 mmol) in DMSO (3 ml) was added iodomethane (0.13 ml, 2.03 mmol). The reaction mixture was stirred for 12 hours under N₂ at 25°C. The mixture was poured into water and extracted with EtOAc. The organic extracts were dried over Na₂SO,₁ and the solvent was removed under reduced pressure. The crude residue was purified by flash chromatography on silica (EtOAc/Hex 1:40), yielding the title compound as a light yellow solid (0.19 g, 87 %).

1H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.04-8.09 (m, 2H, PhH), 7.18 (t, J= 8.6 Hz, 2H, PhH), 2.70 (s, 3H, CH₃), 2.66 (s, 3H, CH₃) ppm.

HRMS: calcdforCi₃HnFN₃S₃324.00991, found 324.00908.

Example 70 : Synthesis of 5, 7-bis(butylthio)-2-(4-fluorophenyl)thiazolo[5,4- d]pyrimidine

This compound was synthesized according to a procedure for the preparation of example 69, using n-butyl bromide. The crude residue was purified by flash chromatography on silica (EtOAc/Hex 1:100) to yield the title compound as a white solid (53 %).

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.03-8.08 (m, 2H, PhH), 7.18 (t, J= 8.6 Hz, 2H, PhH), 3.34 (t, J =7.3 Hz, 2H, SCH₂), 3.24 (t, J =7.3 Hz, 2H, SCH₂), 1.73-1.82 (m, 4H, SCHsCH^CHzCHs), 1.48-1.55 (m, 4H, SCH₂CH₂CI½CH₃), 0.98 (t, J= 7.4 Hz, 3H, CH₃), 0.97 (t, J=7.4 Hz, 3H, CH₃) ppm.

HRMS: calcd for Ci₉H₂₃FN₃S₃408.10381, found 408.10259.

Example 71 : Synthesis of 5 , 7-bis(benzylthio)-2-(4-fluorophenyl)thiazolo[5,4- d]pyrimidine

This compound was synthesized according to a procedure for the preparation of example 69, using benzyl bromide. The crude residue was purified by flash chromatography on silica (EtOAc/Hex 1:100) to yield the title compound as a white solid (97 %).

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.01-8.04 (m, 2H, PhH), 7.41-7.45 (m, 4H, PhH), 7.28- 7.32 (m, 6H, PhH), 7.17 (t, J= 8.5 Hz, 2H, PhH), 4.54 (s, 2H, CH₂), 4.49 (s, 2H, CH₂) ppm. HRMS: calcd for C₂₅H₁₉FN₃S₃476.0725, found 476.3023. Exa mp le 72 : Sy nthes is of 7-ethoxy-2-(4-fluorophenyl)-5-(methylthio)thiazolo[5,4- djpyrimidine

To a solution of Na (2.0 mg, 0.08 mmol) in ethanol (1 ml) was added 2-(4-fluorophenyl)-5,7- bis(methylthio)thiazolo[5,4-d]pyrimidine (50 mg, 0.15 mmol). The reaction mixture was heated at 80°C for 3 hours. After cooling, the mixture was neutralized with 1 /V HCI and the solvent was removed under reduced pressure. The crude residue was redissolved in ethyl acetate, extracted with brine and dried over Na₂S0₄. After removing the solvents in vacuo, the residue was purified by flash chromatography on silica (EtOAc/Hex 1 :50), yielding the title compound as a white solid (30 mg, 60 %).

1H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.02-8.07 (m, 2H, PhH), 7.17 (t, J= 8.6 Hz, 2H, PhH), 4.71 (q, J= 7.1 Hz, 2H, OCH₂), 2.63 (s, 3H, SCH₃) 1.54 (t, J= 7.1 Hz, 3H, CH₃) ppm.

HRMS: calcd for Ci4H₁₃FN₃OS₂ 322.04841 , found 322.04753.

Example 73 : Synthesis of 7-«thoxy-2-(4-fluorophenyl)-5-methylsulfonyl-thiazolo[5,4- d]pyrimidine

This compound was synthesized according to a procedure for the preparation of example 21. The crude residue was purified by flash chromatography on silica (EtOAc/Hex 1 :30) to yield the title compound as a white solid (61 %).

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.1 1 -8.16 (m, 2H, PhH), 7.23 (t, J= 8.6 Hz, 2H, PhH), 4.84 (q, J= 7.1 Hz, 2H, CH₂), 1 .61 (t, J= 7.1 Hz, 3H, CH₃) ppm.

HRMS: calcd for C^H^FNsOsSz 354.03824, found 354.03748.

Examples 74 - 76 : Synthesis of diethyl 2-(acylamino)malonate analogues

General procedure

To a solution of diethyl 2-aminomalonate hydrochloride (4.23 g, 20 mmol) in pyridine (50 ml) was added an acid ch loride (20 mmol) . The resu lting mixture was stirred at room temperature for 1 hour. The solvents were evaporated in vacuo. The residue was collected, washed with water and dried over P2O5, yielding the title compound.

The following compounds were synthesized according to this procedure:

Example 74 : Synthesis of diethyl 2-(cvclopropanecarboxamido)malonate

This compound was synthesized in 91 % yield, using cyclopropanecarbonyl chloride.

MS m/z (%): 244 ([M+H]⁺, 100)

Example 75 : Synthesis of diethyl 2-(2-methoxyacetamido)malonate

This compound was synthesized from 2-methoxyacetyl chloride in 97 % yield.

MS m/z (%): 248 ([M+H]⁺, 100)

Example 76 : Synthesis of diethyl 2-hexanamidomalonate This compound was synthesized from hexanoyl chloride in 95 % yield.

MS m/z (%): 274 ([Μ+ΗΓ, 100)

Examples 77 - 79 : Synthesis of 2-amino-4,6-dihydroxy-5-(acylamino)pyrimidine analogues

General procedure

Sodium (0.58 g, 25 mmol) was added to absolute ethanol (50 ml). After sodium was completely dissolved, diethyl 2-(acylamino)malonate (2.43 g, 10 mmol) and guanidine hydrochloride (1 .20 g, 12.5 mmol) were added. The resulting mixture was heated under reflux for 1 .5 h. The reaction mixture was cooled down to room temperature. The precipitate was collected by filtration, and washed with ethanol. The precipitate was then dissolved in a small amount of water and neutralized to pH = 3-4 with acetic acid. The precipitate was collected, washed with water and dried over P₂0₅, yielding the title compounds

The following compounds were synthesized according to this procedure :

Example 77 : Synthesis of 2-amino-4,6-dihvdroxy-5-(cvclopropanamido)pyrimidine

This compound was synthesized from diethyl 2-(cyclopropanecarboxamido)malonate in 91 % yield.

MS m/z (%): 209 ([M-H]^", 100)

Example 78 : Synthesis of 2-amino-4.6-dihvdroxy-5-(2-methoxyacetamido)pyrimidine

This compound was synthesized from diethyl 2-(2-methoxyacetamido)malonate in 65 % yield.

MS m/z (%): 213 ([M-H]^", 100)

Example 79 . Synthesis of 2-amino-4,6-dihydroxy-5-hexanamidopyrimidine

This compound was synthesized from diethyl 2-hexanamidomalonate (2.73 g, 10 mmol) in 83% yield.

MS m/z (%): 239 ([M-H]^", 100)

Examples 80 - 86 : Synthesis o f 2-amino-5-acylamino-4,6-dihydroxypyrimidine analogues

General procedure

To an ice-cooled solution of 2,5-diaminopyrimidine-4,6-diol (1 .78 g, 10 mmol) in 1 N NaOH (25 ml), was added slowly an appropriate acid chloride (10 mmol). The resulting mixture was stirred and warmed to room temperature over 1 hour. The reaction mixture was neutralized with HCI to pH 5. The precipitate was filtered off, washed with water and dried over P₂0₅, yielding the title compound.

The following compounds were synthesized according to this general procedure: Example 80 : Synthesis of 2-amino-5-cvclohexanecarboxamido-4,6-dihvdroxypyrirnidine This compound was synthesized from cyclohexane carbonyl chloride in 87 % yield.

MS m/z (%): 253 ([M+H]⁺, 100)

Example 81 : Synthesis of 2-amino-4,6-dihydroxy-5-nicotinamidopyrimidine

This compound was synthesized from nicotinoyl chloride hydrochloride in 81 % yield.

MS m/z (%): 248 ([M+H]⁺, 100)

Example 82: Synthesis of 2-amino-4,6-dihydroxy-5-(3-phenylpropanamido)pyrimidine

This compound was synthesized from 3-phenylpropanoyl chloride in 96 % yield.

MS m/z (%): 275 ([M+H]⁺, 100)

Example 83: Synthesis of 2-amino-4,6-dihydroxy-5-(4-chlorophenylacetamido)pyrimidine

This compound was synthesized from 4-chlorophenylacetyl chloride yielding the title compound in 95 % yield.

MS m/z (%): 295 ([M+H]⁺, 100)

Example 84: Synthesis of 2-amino-4,6-dihydroxy-5-(3,4-dichlorobenzamido)pyrimidine

This compound was synthesized from 3,4-dichlorobenzoyl chloride yielding the title compound in 89 % yield.

WIS m/z (%): 315 ([M+H]⁺, 100)

Example 85: Synthesis of 2-amino-4.6-dihvdroxy-5-(3-methoxybenzamido)pyrimidine

This compound was synthesized from 3-methoxybenzoyl chloride, yielding the title compound in 94 % yield.

MS m/z (%): 277 ([M+H]⁺, 100)

Example 86: Synthesis of ethyl 2-amino-4, 6-dihydroxypyrimidin-5-ylcarbamate

This compound was synthesized from ethyl chloroformate yielding the title compound in 89 % yield.

Examples 87 - 88: Synthesis of 2-amino-4,6-dihydroxy-5-(acylamino)pyrimidine analogues

General procedure

A suspension of 1 -phenylcyclopropanecarboxylic acid (973 mg, 6.0 mmol) in SOCI₂ (5 ml) was heated under reflux for 1 h. After concentration under reduced pressure, the residue was re d isso lved i n d i oxa n e (5 ml ) a nd added to a sti rri ng so lu tio n of 2 , 5-diamino-4,6- dihydroxypyrimidine (893 mg, 5.0 mmol) in 1 N NaOH (20 ml) at 0°C. The mixture was stirred and warmed to room temperature in 1 h. After neutralization with 1 N hydrochloride to pH = 5, the precipitate was filtered off, washed with water and dried over P₂0₅, yielding the title compound. The following compounds were synthesized according to this procedure:

Example 87 ; Synthesis of. 2-amino-4,6-dihydroxy-5-( 1 - phenylcvclopropanecarboxamido)py midine

This compound was synthesized using 1 -phenylcyclopropanecarboxylic acid, yielding the title compound in 87% yield.

MS m/z (%): 285 ([M-H]\ 100)

Example 88: Synthesis of. 2-a mino-4 ,6-dihydroxy-5-( 1 -(4- chlorophenyl)cyclopropanecarboxamido)pyrimidine

This compound was synthesized from 1 -(4-chlorophenyl)cyclopropanecarboxylic acid yielding the title compound in 84 % yield.

MS m/z (%): 321 ([M+H]⁺, 100)

Examples 89 - 98: Synthesis of 5-amino-2-substituted-thiazolo[5,4-d]pyrimidine-7 -thiol analogues

General procedure

A suspension of the appropriate 2-amino-4,6-dihydroxy-5-(acylamino)pyrimidine analogue (630 mg, 3 mmol) and P₂S₅ (1.33 g, 6 mmol) in pyridine (15 ml) was heated under reflux for 6 hours. After concentration under reduced pressure, the residue was resuspended in 20 ml water. Sodium carbonate (1 .27 g, 9 mmol) was added and the mixture was stirred at room temperature for 1 h . The precipitate was collected by filtration and washed with water, yielding the crude title compound which was used without further purification (450 mg, 67%).

The following compounds were synthesized according to this procedure :

Example 89 : Synthesis of 5-amino-2-cyclopropylthiazolor5,4-dlpyrimidine-7-thiol

This compound was synthesized from 2-amino-4,6-dihydroxy-5-(acylamino)pyrimidine in 67 % yield.

MS m/z (%): 223 ([M-H] , 100)

Example 90: Synthesis of 5-amino-2-(2-phenylethyl)thiazolo[5,4-dlpyrimidine-7 -thiol

This compound was synthesized from 2-amino-4,6-dihydroxy-5-(3- phenylpropanamido)pyrimidine (550 mg, 2.0 mmol), yielding the title compound (530 mg, 92%).

MS m/z (%): 289 ([M+H]⁺, 100)

Example 91 : Synthesis of 5-amino-2-(3-pyridinyl)thtazolof5,4-dlpyrimidine-7-thiol

This compound was synthesized from 2-amino-4,6-dihydroxy-5-(3-nicotinamido)pyrimidine (494 mg, 2.0 mmol), yielding the title compound (260 mg, 50%).

MS m/z (%): 262 ([M+H]\ 100) Example 92: Synthesis of 5-amino-2-(cvclohexyl)thiazolof5,4-dlpyrimidine-7-thiol

This compound was synthesized from 2-amino-4,6-dihydroxy-5- cyclohexanecarboxamidopyrimidine (504 mg, 2.0 mmol), yielding the title compound (400 mg, 75%).

MS m/z (%): 267 ([M+H]\ 100)

Example 93: Synthesis of 5-amino-2-(4-chlorobenzyl)thiazolof5,4-dlpyrimidine-7-thiol

This compound was synthesized from 2-amino-4,6-dihydroxy-5-(4- chlorophenylacetamido)pyrimidine (589 mg, 2.0 mmol), yielding the title compound (500 mg, 81 %).

MS m/z (%): 309 ([M+H]⁺, 100)

Example 94: Synthesis of 5-amino-2-(4-chlorophenyl)thiazolo[5,4-dlpyrimidine-7-thiol

This compound was synthesized from 2-amino-4,6-dihydroxy-5(4- chlorobenzamido)pyrimidine (560 mg, 2.0 mmol), yielding the title compound (450 mg, 76%).

MS m/z (%): 295 ([M+H]⁺, 100)

Example 95: Synthesis of 5-amino-2-(3-methoxyphenyl)thiazolo[5,4-dlpyrimidine-7 -thiol

This compound was synthesized from 2-amino-4,6-dihydroxy-5(4- methoxybenzamido)pyrimidine (1 .10 g, 4.0 mmol), yielding the title compound (1.0 g, 86%).

MS m/z (%): 291 ([Μ+Η , 100)

Example 96: Synthesis of 5-amino-2-(3,4-dichlorophenyl)thiazolo[5,4-dlpyrimidine-7-thiol This compound was synthesized from 2-amino-4,6-dihydroxy-5-(3,4- dichlorobenzamido)pyrimidine (1.26 g, 4.0 mmol), yielding the title compound (1.1 g, 83%).

MS m/z (%): 329 ([M+H]⁺, 100)

Example 97: Synthesis of 5-amino-2-(1-phenylcyclopropyl)thiazolo[5,4-d1pyrimidine-7-thiol

This compound was synthesized from 2-amino-4,6-dihydroxy-5-(1- phenylcyclopropanecarboxamido)pyrimidine (1 .15 g, 4.0 mmol), yielding the title compound (1 .1 g, 92%).

MS m/z (%): 301 ([M+H]⁺, 100)

Example 98: Synthesis of 5-amino-2-(1-(4-chlorophenyl)cyclopropyl)thiazolof5, 4- dlpyrimidine-7-thiol

This compound was synthesized from 2-amino-4,6-dihydroxy-5-(1 - phenylcyclopropanecarboxamido)pyrimidine (1 .28 g, 4.0 mmol), yielding the title compound (1 .1 g, 82%).

MS m/z (%): 335 ([M+H]⁺, 100) Examples 99 - 105: Synthesis of 5-amino-2-substituted-7-methylthio-thiazolot5,4- d]pyrimidine analogues

General procedure

To a suspension of an appropriate 5-amino-2-substituted-thiazolo[5,4-d]pyrimidine-7 -thiol (340 mg, 1 .5 mmol) in 1 N NaOH (10 ml), was added Mel (1 12 μΙ, 1 .8 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with dichloromethane and washed with water and brine. The organic layer was evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/50), yielding the pure title compounds.

The following compounds were synthesized according to this procedure :

Example 99 : Synthesis of 5-amino-2-cvclopropyl-7-methylthio-thiazolof5,4-dlpyrimidine

This compound was synthesized from 5-amino-2-cyclopropyl-thiazolo[5,4-d]pyrimidine-7-thiol in 92 % yield.

MS m/z (%): 239 ([M+H]⁺, 100)

Example 100: Synthesis of 5-amino-2-(2-phenylethyl)-7-methylthiothiazolof5,4-dlpyrimidine This compound was synthesized from 5-amino-2-(2-phenylethyl)thiazolo[5,4-d]pyrimidine-7- thiol (288 mg, 1.0 mmol), yielding the pure title compound (190 mg, 63%).

MS m/z (%): 303 ([M+H]\ 100)

Example 101 : Synthesis of 5-amino-2-cvclohexyl-7-methylthiothiazolof5,4-dlpyrimidine

This compound was synthesized from 5-amino-2-cyclohexylthiazolo[5,4-d]pyrimidine-7-thiol (133 mg, 0.5 mmol), yielding the pure title compound (80 mg, 57%).

MS m/z (%): 281 ([M+H]⁺, 100)

Example 102: Synthesis of 5-amino-2-(3-pyridinyl)-7-methylthiothiazolo[5,4-dlpyrimidine

This compound was synthesized from 5-amino-2-(3-pyridinyl)thiazolo[5,4-d]pyrimidine-7-thiol (261 mg, 1.0 mmol), yielding the pure title compound (150 mg, 54%).

MS m/z (%): 276 ([M+H]⁺, 100)

Example 103: Synthesis of 5-amino-2-(4-chlorobenzyl)-7-methylthiothiazolo[5,4-dlpyrimidine This compound was synthesized from 5-amino-2-(4-chlorobenzyl)thiazolo[5,4-d]pyrimidine-7- thiol (308 mg, 1.0 mmol), yielding the pure title compound (100 mg, 31 %).

MS m/z (%): 323 ([M+H]\ 100)

Example 1 04 : Synthesis of 5-amino-2-(3-methoxyphenyl)-7-methylthiothiazolof5,4- dlpyrimidine

This compound was synthesized from 5-amino-2-(3-methoxyphenyl)thiazolo[5,4- d]pyrimidine-7-thiol (290 mg, 1.0 mmol), yielding the pure title compound (250 mg, 82 %). MS m/z (%): 305 ([M+H]⁺, 100)

Example 105: Synthesis of 5-amino-2-(4-chlorophenyl)-7-(methylthio)thiazolof5,4- dlpyrimidine

This compound was synthesized from 5-amino-2-(4-chlorophenyl)thiazolo[5,4-d]pyrimidine-7- thiol (443 mg, 1.5 mmol), yielding the pure title compound (380 mg, 82%).

MS m/z (%): 309 ([M+H]\ 100)

Example 106: Synthesis of 5-amino-2-cyclopropyl-7-methylsulfonylthio-thiazolo[5,4- d]pyrimidine

To an ice-cooled suspension of 5-amino-2-cyclopropyl-7-methylthiothiazolo[5,4-d]pyrimidine (120 mg, 0.5 mmol) in dichloromethane (5 ml), was added mCPBA (1250 mg, 1.0 mmol). The resulting mixture was stirred at 0°C for 1 hour and then warmed to room temperature. The reaction mixture was evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of acetone and dichloromethane (in a ratio of 1/30), yielding the pure title compound (81 mg, 60%).

MS m/z (%): 271 ([M+H]⁺, 100)

Example 107: Synthesis of 5-amino-2-cyclopropyl-7-methoxythiazolo[5,4-d]pyrimidine

A mixture of 5-amino-2-cyclopropyl-7-(methylsulfonyl)thiazolo[5,4-d]pyrimidine (54 mg, 0.2 mmol) and K₂C0₃ (69 mg, 0.5 mmol) in dioxane (10 ml) and methanol (5 ml) was stirred at room temperature overnight. The reaction mixture was evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/60), yielding the pure title compound (40 mg, 90%).

MS m/z (%): 223 ([M+H]^*, 100)

Example 108: Synthesis o f 5-amino-2-cyclopropyl-7-A/-piperazino-thiazolo[5, 4- djpyrimidine

To a solution of 5-amino-2-cyclopropyl-7-(methylsulfonyl)thiazolo[5,4-d]pyrimidine (54 mg, 0.2 mmol) in dioxane (5 ml) was added piperazine (86 mg, 1.0 mmol). The resulting mixture was stirred at room temperature for 12 h. The solvents were evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/5), yielding the pure title compound (50 mg, 91 %).

MS m/z (%): 277 ([M+H]⁺, 100)

Examples 109 - 111 : Synthesis of 5-amino-2-substituted-7-(A/-piperazino)thiazolo[5,4- d]pyrimidine analogues

General procedure

A mixture of a 5-amino-2-substituted thiazolo[5,4-d]pyrimidine-7-thiol analogue (4.0 mmol) and piperazine (1 .72 g, 20 mmol) in 1 , 1 ,1 ,3,3,3-hexamethyldisilazane (HMDS, 5 ml) and pyridine (20 ml) was heated under reflux for 12 hours. The reaction mixture was evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/5), yielding the pure title compounds.

The following compounds were made according to this procedure:

Example 109 : Synthesis of 5-amino-2-(3,4-dichlorophenyl)-7-(N-piperazino)thiazolo[5,4- dlpyrimidine

This compound was synthesized from 5-amino-2-(3,4-chlorophenyl)thiazolo[5,4-d]pyrimidine- 7-thiol in 51 % yield.

MS m/z (%): 381 ([M+H]\ 100)

Example 110 : Synthesis of 5-amino-2-(1-phenylcvclopropyl)-7-(N-piperazino)thiazolo[5, 4- dlpyrimidine

This compound was synthesized from 5-amino-2-(1-phenylcyclopropyl)thiazolo[5,4- d]pyrimidine-7-thiol (600 mg, 2.0 mmol), yielding the pure title compound (450 mg, 64%).

MS m/z (%): 353 ([M+H]⁺, 100)

Example 1 1 1 : Synthesis of 5-amino-2-(1-(4-chlorophenyl)cyclopropyl)-7-(N- piperazino)thiazolof5,4-dlpyrimidine

This compound was synthesized from 5-amino-2-(1 -phenylcyclopropyl)thiazolo[5, 4- d]pyrimidine-7-thiol (1.34 g, 4.0 mmol), yielding the pure title compound (1.1 g, 71 %).

MS m/z (%): 387 ([M+Hf, 100)

Example 112 : Synthesis of 5-amino-2-methylthio-7-oxo-thiazolo[5,4-d]pyrimidine

A suspension of ethyl 2-amino-4,6-dihydroxypyrimidin-5-ylcarbamate (0.43 g, 2.0 mmol) and P₂S₅ (1 .33 g, 6 mmol) in pyridine (20 ml) was heated under reflux for 6 hours. After concentration under reduced pressure, the residue was suspended in water (20 ml). Sodium carbonate (1 .27 g, 9 mmol) was added and the mixture was stirred at room temperature for 1 h. The reaction mixture was neutralized to pH = 5-6, the precipitate was filtered off and washed with water. The crude product was dissolved in 1 N NaOH (20 ml) and Mel (120 μΙ, 2.0 mmol) was added. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with dichloromethane and washed with water and brine. The organic layer was evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/50), yielding the pure title compound (210 mg, 49%).

MS m/z (%): 215 ([M+H]\ 100) Example 113 : Synthesis of 5-amino-7-A/-piperazino-2-methylthio-thiazolo[5, 4- djpyrimidine

To a suspension of 5-amino-7-oxo-2-thiomethyl-thiazolo[5,4-d]pyrimidine (107 mg, 0.5 mmol) in D F (5 ml) were added piperazine (215 mg, 2.5 mmol), benzotriazol-1 - yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP, 290 mg, 0.66 mmol) and 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 120 μΙ, 0.79 mmol), respectively. The resulting reaction mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with dichloromethane and washed with water and brine. The organic phase was evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/8), yielding the pure title compound (130 mg, 82%).

MS m/z (%): 283([M+H]⁺, 100)

Examples 114 - 117 : Synthesis of 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1 - yl]-2-substituted thiazolo[5,4-d]pyrimidine analogues

General procedure

To a solution of a 5-amino-2-substituted-7-/V-piperazino-thiazolo[5,4-d]pyrimidine analogue (260 mg, 1.0 mmol) in dioxane (10 ml), was added DIPEA (330 μΙ , 2.0 mmol) and 4- chlorophenoxyacetyl chloride (246 mg, 1.2 mmol) respectively. The resulting reaction mixture was stirred at room temperature for 30 minutes. The mixture was evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/40), yielding the pure title compounds.

The following compounds were synthesized according to this procedure :

Exa mple 1 1 4 : Synthesis of 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1 -yl1-2-(1 - phenylcvclopropyl)thiazolo[5,4-dlpyrimidine

This compound was synthesized from 5-amino-2-(1-phenylcyclopropyl)-7-(N- piperazino)thiazolo[5,4-d]pyrimidine (35 mg, 0.1 mmol), yielding the pure title compound (49 mg, 92%).

MS m/z (%): 521 ([M+H]⁺, 100)

Example 1 15 : Synthesis of 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yll-2- methylthio-thiazolof5,4-dlpyrimidine

This compound was synthesized from 5-amino-7-(A/-piperazino)-2-methylthio-thiazolo[5,4- d]pyrimidine (113 mg, 0.36 mmol), yielding the pure title compound (120 mg, 75%).

MS m/z (%): 451 ([M+H]⁺, 100) Example 1 16 : Synthesis of 5-amino-7-i4-(4-chlorophenoxyacetyl)piperazin-1-yll-2-(3,4- dichlorophenyl)thiazolo[5,4-d1pyrimidine

This compound was synthesized from 5-amino-2-(3,4-dichlorophenyl)-7-(N- piperazino)thiazo!o[5,4-d]pyrimidine (190 mg, 0.5 mmol), yielding the pure title compound (150 mg, 55%).

H NMR (300 MHz, DMSO-d6, 25 °C): δ = 8.13 (s, 1 H, ArH), 7.91 (d, J=8.6 Hz, 1 H, ArH), 7.74 (d, J=8.6 Hz, 1 H, ArH), 7.32 (d, J= 9.0 Hz, 2H, ArH), 6.97 (d, J= 9.0 Hz, 2H, ArH), 4.93 (s, 2H, NH₂), 4.90 (s, 2H, CH₂), 4.42 (br s, 2H, NCH₂), 4.22 (br s, 2H, NCH₂), 3.64 (br s, 4H, NCH₂) ppm.

MS m/z (%): 549 ([M+H]⁺, 98)

Example 1 1 7 : Synthesis of 5-amino-7-f4-(4-chlorophenoxyacetyl)piperazin-1 -yl1-2-(1-(4- chlorophenyl)cvclopropyl)thiazolo[5,4-dlpyrimidine

This compound was synthesized from 5-amino-2-(1-(4-chlorophenyl)cyclopropyl)-7-(/V- piperazino)thiazolo[5,4-d]pyrimidine (39 mg, 0.1 mmol), yielding the pure title compound (50 mg, 89%).

MS m/z (%): 555 ([M+H]\ 100)

Examples 118 - 124 : Synthesis of 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1 - yl]-2-substituted-thiazolo[5,4-d]pyrimidine analogues

General procedure

To a solution of a 5-amino-7-methylthio-2-substituted-thiazolo[5,4-d]pyrimidine analogue (76 mg, 0.25 mmol) in dichloromethane (10 ml) was added mCPBA (250 mg, 1.0 mmol). The solution was stirred at room temperature for 2 h. Then, a solution of piperazine (215 mg, 2.5 mmol) in dioxane (10 ml) was added. The resulting mixture was stirred at room temperature for another 2 h. The reaction mixture was diluted with dichloromethane and washed with water and brine. The organic phase was evaporated in vacuo and the residue was dissolved in dioxane (5 ml). Then, a solution of 4-chlorophenoxyacetyl chloride in dioxane (2 ml) was added. The mixture was stirred at room temperature for 1 h. The solvents were evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1 /50), yielding the pure title compound.

The following compounds were made according to this procedure :

Exa mple 1 1 8 : Synth esi s of 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yll-2-(2- phenylethyl)thiazolo[5, 4-dlpyrimidine

This compound was made from 5-amino-7-methylthio-2-(2-phenylethyl)thiazolo[5, 4- d]pyrimidine in 71% yield.

MS m/z (%): 509 ([M+H]⁺, 100) Example 119 : Synthesis of 5-amino-2-cvclopropyl-7-f4-(4-chlorophenoxyacetyl)piperazin-1 - yll-thiazolo[5,4-dlpyrimidine

This compound was made from 5-amino-2-cyclopropyl-7-/V-piperazino-thiazolo[5, 4- d]pyrimidine (15 mg, 0.05 mmol), yielding the pure title compound (20 mg, 83%).

MS m/z (%): 445 ([M+H]⁺, 100)

E xa m p le 1 20 : Synthesis of 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1 -yll-2- cvclohexylthiazolo[5,4-d1pyrimidine

This compound was made from 5-amino-2-cyclohexyl-7-methylthiothiazolo[5,4-d]pyrimidine (56 mg, 0.2 mmol), yielding the pure title compound (60 mg, 62%).

MS m/z (%): 487 ([M+H]⁺, 100)

Example 121 : Synthesis of 5-amino-7-f4-(4-chlorophenoxyacetvnpiperazin-1-yl1-2-(pyridine- 3-yl)thiazolor5,4-d1pyrimidine and 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1 -yll-2-(N- oxopyridine-3-yl)thiazolo[5,4-dlpyrimidine

These compounds were prepared from 5-amino-7-(methylthio)-2-(pyridine-3-yl)thiazolo[5,4- d]pyrimidine (69 mg, 0.25 mmol), yielding examples 121a and 121 b.

E x a m p l e 1 2 1 a : 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1 -yl]-2-(pyridine-3- yl)thiazolo[5,4-d]pyrimidine (50 mg, 41 %)

MS m/z (%): 482 ([M+H]\ 100)

and

Exa mpl e 1 2 1 b : 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1 -yl]-2-(N-oxopyridine-3- yl)thiazolo[5, 4-d]pyrimidine (20 mg, 17%).

MS m/z (%): 498 ([M+H]⁺, 100)

Example 122 : Synthesis of 5-amino-7-f4-(4-chlorophenoxyacetyl)piperazin-1 -yll-2-(4- chlorophenylmethyl)thiazolo[5,4-dlpyrimidine

This compound was made from 5-amino-2-(4-chlorophenylmethyl)-7-methylthiothiazolo[5,4- djpyrimidine (100 mg, 0.31 mmol), yielding the pure title compound (140 mg, 85%).

MS m/z (%): 529 ([M+H]⁺, 100)

Example 123 : Synthesis of 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1 -yl1-2-(4- chlorophenyl)thiazolof5,4-d1pyrimidine

This compound was made from 5-amino-2-(4-chlorophenyl)-7-methylthiothiazolo[5,4- d)pyrimidine (154 mg, 0.5 mmol), yielding the pure title compound (190 mg, 74%).

¹H NMR (300 MHz, DMSO-d6, 25 °C): δ = 7.94(d, J= 9.0 Hz, 2H, ArH), 7.58 (d, J=9.0 Hz, 2H, ArH), 7.34 (d, J= 9.0 Hz, 2H, ArH), 6.99 (d, J= 9.0 Hz, 2H, ArH), 6.55 (s, 2H, NH₂), 4.93 (s, 2H, CH₂), 4.35 (br s, 2H, NCH₂), 4.22 (br s, 2H, NCH₂), 3.64 (br s, 4H, NCH₂) ppm. MS m/z (%): 515 ([M+H]⁺, 100)

Example 124 : Synthesis of 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl1-2-(3- methoxyphenyl)thiazolo[5,4-dlpyrimidine

This compound was made from 5-amino-2-(3-methoxyphenyl)-7-methylthiothiazolo[5,4- d]pyrimidine (152 mg, 0.5 mmol), yielding the pure title compound (120 mg, 47%).

H NMR (300 MHz, DMSO-d6, 25 °C): δ = 7.51-7.41 (m, 3H, ArH), 7.32 (d, J=9.0 Hz, 2H, ArH), 7.09 (m, H, ArH), 6.97 (d, J= 9.0 Hz, 2H, ArH), 6.52 (s, 2H, NH₂), 4.93 (s, 2H, CH₂), 4.36 (br s, 2H, NCH₂), 4.22 (br s, 2H, NCH₂), 3.84 (s, 3H, OCH₃), 3.64 (br s, 4H, NCH₂) ppm. MS m/z (%): 51 1 ([M+H]⁺, 100)

Example 125 : Synthesis of 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1 -yl]-2-(1- (4-chlorophenyl)ethyl)thiazolo[5,4-d]pyrimidine

To a suspension of 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1 -yl]-2-(4- chlorophenylmethyl)thiazolo[5,4-d]pyrimidine (53 mg, 0.1 mmol) in DMF (2 ml) was added 1 N NaOH (150 μΙ, 0.15 mmol) and Mel (7 μΙ, 0.1 1 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane and washed with water and brine. The organic layer was evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/80), yielding the pure title compound (40 mg, 74%).

MS m/z (%): 543 ([M+H]⁺, 100)

Example 1 26 : Synthesis of 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2- methylsulfinyl-thiazolo[5,4-d]pyrimidine

To an ice cooled suspension of 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1 -yl]-2- methylthio-thiazolo[5,4-d]pyrimidine (90 mg, 0.2 mmol) in dichloromethane (5 ml) was added mCPBA (125 mg, 0.5 mmol). The resulting mixture was stirred at 0°C for 2 h. The solvents were evaporated in vacuo and the crude residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/80), yielding the pure title compound (65 mg, 70%).

MS m/z (%): 467 ([M+H]⁺, 100)

Example 127 : Synthesis of 5-amino-7-[4-{4-chlorophenoxyacetyl)piperazin-1-yl]-2-(4- fluorophenylamino)-thiazolo[5,4-d]pyrimidine

A m i x t u r e o f 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1 -yl]-2-methylsulfinyl- thiazolo[5,4-d]pyrimidine (47 mg, 0.1 mmol) and 4-fluoroaniline (95 μΙ, 1 mmol) in dioxane (5 ml) was heated under reflux for 12 hours. The reaction mixture was evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/80), yielding the pure title compound (45 mg, 88%). MS m/z (%): 514 ([M+H]^*, 100)

Examples 128-129 : Synthesis of 5-amino-2-(4-fluorophenyl)-7-(4-(2-aryloxyacetyl)- piperazin-1-yl)-thiazolo[5,4-d]pyrimidine analogues

General procedure

To a solution of 5-amino-2-(4-fluorop enyl)-7-piperazin-1 -yl-thiazolo[5,4-d]pyrimidine (50 mg, 0.15 mmol) and a 2-aryloxyacetic acid derivative (0.23 mmol) in DMF (2 ml) was added TBTU (0.23 mmol) followed by diisopropylethylamine (0.23 mmol, 37 μΙ_). The reaction was stirred at room temperature for 24 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 1 % CH₃OH in CH₂CI₂), yielding the pure title compounds which were characterized by their mass spectra as indicated below.

The following compounds were synthesized according to this procedure :

Example 128 : Synthesis of 5-amino-2-(4-fluorophenyl)-7-(4-[2-(4-bromophenoxy)acetyll- piperazin-1 -yl)-thiazolo[5,4-dlpyrimidine

This compound was obtained from 2-(4-bromophenoxy)acetic acid (43 mg);

MS m/z (%) : 543 ([M+H]⁺, 100).

Example 129 . Synthesis of 5-amino-2-(4-fluorophenyl)-7-(4-f2-(3-nitrophenoxy)acetyll- piperazin-1 -yl)-thiazolo[5,4-d1pyrimidine

This compound was obtained from 2-(3-nitrophenoxy)acetic acid (49 mg).

MS m/z (%) : 510 ([M+H]⁺, 100).

E x a m p le 1 30 : S y nt h e s i s of 5-amino-2-(4-fluorophenyl)-7-(4-(2-phenoxyacetyl)- piperazin-1-yl)-thiazolo[5,4-d]pyrimidine

To a solution of 5-amino-2-(4-fluorophenyl)-7-piperazin-1 -yl-thiazolo[5,4-d]pyrimidine (50 mg, 0.15 mmol) in DMF (2 ml) was added diisopropylethylamine (0.33 mmol, 55 μΙ_) followed by phenoxyacetyl chloride (0.17 mmol). The reaction was stirred at room temperature for 4 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica , the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 0.5% CH₃OH in CH₂CI₂), yielding the pure title compound (30 mg) which was characterized by its mass spectrum: MS m/z (%) : 465 ([Μ+Η , 100).

E x a m p l e 1 3 1 : S y n t h e s i s o f 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-[2-{3- nitrophenoxy)acetyl]piperazin-1-yl)-thiazolo[5,4-d]pyrimidine

To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (50 mg, 0.14 mmol) and 3-nitrophenoxyacetic acid (0.23 mmol) in DMF (2 ml) was added TBTU (0.21 mmol) followed by diisopropylethylamine (0.21 mmol, 35 pL). The reaction was stirred at room temperature for 24 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 0.5% CH₃OH in CH₂CI₂), yielding the pure title compound (41 mg) which was characterized by its mass spectrum: MS m/z (%) : 538 ([M+H]⁺, 100).

E x a m p l e 1 3 2 : S y n t h e s i s o f 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-[2-(4- chlorophenyl)acetyl]piperazin-1-yl)-thiazolo[5,4-d]pyrimidine

To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-thiazolo[5_l4-d]pyrimidine (50 mg, 0.14 mmol) and 4-chlorophenylacetic acid (0.21 mmol) in DMF (2 ml) was added TBTU (0.21 mmol) followed by diisopropylethylamine (0.21 mmol, 35 μΙ_). The reaction was stirred at room temperature for 24 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 1% CH3OH in CH₂CI₂), yielding the pure title compound (44 mg) which was characterized by its mass spectrum: MS m/z (%) : 51 1 ([M+H]⁺, 100).

E x a m p l e 1 3 3 : S y n t h e s i s o f 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-m- tolylcarbamoylpiperazin-1-yl)-thiazolo[5,4-d]pyrimidine

To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (50 mg, 0.14 mmol) in dichloromethane (4 ml) was added 3-methylphenylisocyanate (0.15 mmol). The reaction was stirred at room temperature for 2 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 2% CH₃OH in CH₂CI₂), yielding the pure title compound (28 mg) which was characterized by its mass spectrum: MS m/z (%) : 492 ([M+H]⁺, 100).

E x a m p l e 1 3 4 : S y n t h e s i s o f 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-[2- phenoxyacetyl]piperazin-1-yl)-thiazolo[5,4-d]pyrimidine

To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (50 mg, 0.14 mmol) in dichloromethane (4 ml) was added diisopropylethylamine (0.33 mmol, 55 pl_) followed by phenoxyacetyl chloride (0.17 mmol). The reaction was stirred at room temperature for 4 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica , the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 2% CH₃OH in CH₂CI₂), yielding the pure title compound (34 mg) which was characterized by its mass spectrum: MS m/z (%) : 493 ([ +HJ⁺, 100). Example 135 : Synthesis of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-[4-{4- chlorobenzoyl)piperazin-1-yl]-thiazolo[5,4-d]pyrimidine

To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (50 mg, 0.14 mmol) in dichloromethane (4 ml) was added diisopropylethylamine (0.33 mmol, 55 pL) and 4-chlorobenzoyl chloride (0.15 mmol). The reaction was stirred at room temperature for 16 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 1% CH₃OH in CH₂CI₂), yielding the pure title compound (31 mg) which was characterized by its mass spectrum: MS m/z (%) : 497 ([M+H]⁺, 100).

Example 136 : Synthesis of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-[4-(3- phenylpropionyl)piperazin-1 -yl]-thiazolo[5,4-d]pyrimidine

To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (80 mg, 0.22 mmol) in dichloromethane (4 ml) was added diisopropylethylamine (0.49 mmol, 81 pL) and 3-phenylpropionyl chloride (0.25 mmol). The reaction was stirred at room temperature for 16 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 1% CH₃OH in CH₂CI₂), yielding the pure title compound (43 mg) which was characterized by its mass spectrum: MS m/z (%) : 491 ([M+H]⁺, 100).

Exa mple 137 : Synthes is of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-[4- phenylmethanesulfonylpiperazin-1-yl]-thiazolo[5,4-d]pyrimidine

To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (80 mg, 0.22 mmol) in 1,4-dioxane (4 ml) was added diisopropylethylamine (0.49 mmol, 81 μΐ) and phenylmethanesulfonyl chloride (0.25 mmol). The reaction was stirred at 90°C for 16 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 00% CH₂CI₂ to 1% CH₃OH in CH₂CI₂), yielding the pure title compound (13 mg) which was characterized by its mass spectrum: MS m/z (%) : 513 ([M+H]⁺, 100).

Example 138 : Synthesis of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-[2-(4- chlorophenoxy)acetyl]homopiperazin-1 -yl)-thiazolo[5,4-d]pyrimidine

To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-methanesulfonyl-thiazolo[5,4- djpyrimidine (50 mg, 0.14 mmol) in dichloromethane (4 ml) was added homopiperazine (1.4 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was extracted, the organic phase was dried over MgS0₄ after which the solvent was removed in vacuo. The residue was dissolved in dichloromethane whereupon diisopropylethylamine (0.28 mmol, 47 μ[_) followed by 4-chlorophenoxyacetyl chloride (0.14 mmol) were added. The reaction was stirred at room temperature for 24 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 1 % CH₃OH in CH₂CI₂), yielding the pure title compound (38 mg) which was characterized by its mass spectrum: MS m/z (%) : 541 ([M+H]⁺, 100).

Exa mples 139 - 141 Synthesis of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-{4- [alkyl(aryl)methylphenylcarbamoyl)methyl]piperazin-1-yl)-thia2olo[5,4-d]pyrimidine analogues

General procedure

To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-methanesulfonyl-thiazolo[5,4- djpyrimidine (100 mg, 0.28 mmol) in dichloromethane (5 ml) was added diisopropylethylamine (0.59 mmol, 98 μΙ_) and a piperazine derivative (0.31 mmol). The reaction mixture was stirred at room temperature for 18 hours whereupon the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 1 % CH₃OH in CH₂CI₂), yielding the pure title compounds which were characterized by their mass spectra as indicated below.

The following compounds were made according to this procedure :

E x a m p l e 1 3 9 : S y n t h e s i s o f 5-amino-2-[2-(4-fluorophenyl)ethvH-7-(4- f(methylphenylcarbamoyl)-methyllpiperazin-1-yl)-thiazolo[5,4-dlpyrimidine

This compound was obtained from W-methyl-A/-phenyl-2-piperazin-1 -yl-acetamide (62 mg).

MS m/z (%) : 506 ([M+HJ⁺, 100).

Example 140 : Synthesis of 5-amino-2-[2-(4-fluorophenyl)ethyll-7-(4-thiazol-2-yl-piperazine- 1 -yl)-thiazolo[5,4-d1pyrimidine

This compound was obtained from 4-thiazol-2-yl-piperazine (65 mg).

MS m/z (%) : 442 ([M+H]⁺, 100).

Example 141 : Synthesis of 5-amino-2-f2-(4-fluorophenyl)ethyl|-7- 4-(phenethylcarbamoyl- methyl)piperazin-1 -yl)-thiazolo[5,4-d1pyrimidine

This compound was obtained from 4-(phenethylcarbamoyl-methyl)piperazine (84 mg).

MS m/z (%) : 520 ([M+H]⁺, 100). E x a m p le 1 42 : S yn th e s i s of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-((3-(R)-fert- butoxycarbonylamino)pyrrolidin-1-yl)-thiazolo[5,4-d]pyrimidine

To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-methanesulfonyl-thiazolo[5,4- d]pyrimidine (150 mg, 0.42 mmol) in dichloromethane (10 ml) was added diisopropylethylamine (0.94 mmol, 155 pL) and 3-(f?)-fert-(butoxycarbonylamino)pyrrolidine (0.47 mmol). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was extracted with a saturated sodium bicarbonate solution and the organic phase was collected and dried over magnesium sulfate. The solvent was removed in vacuo and the resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 1 % CH₃OH in CH₂CI₂), yielding the pure title compound (168 mg) which was characterized by its mass spectrum: MS m/z (%) : 459 ([M+H]⁺, 100).

Examples 143 - 1 44 : Synthes i s of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(3-(W)- acylaminopyrrolidin-1 -yl)-thiazolo[5,4-d]pyrimidine analogues

General procedure

To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-((3-(R)-tert- butoxycarbonylamino)pyrrolidin-1 -yl)-thiazolo[5,4-d]pyrimidine (70 mg, 0.15 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (3 ml). The reaction mixture was stirred at room temperature for 2 hours after which the solvents were removed in vacuo. The residue was dissolved in dichloromethane (3 ml) and diisopropylethylamine (1.5 mmol, 252 pL) and an acyl chloride (0.17 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours whereupon the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 1 .5% CH₃OH in CH₂CI₂), yielding the pure title compounds which were characterized by their mass spectra as indicated below.

The following compounds were made according to this procedure :

E x a m p l e 1 4 3 : S y n t h e s i s o f 5-amino-2-f2-(4-fluorophenyl)ethyll-7-(3-( )-f2-(4- chlorophenoxy)-acetylaminolpyrrolidin-1-yl)-thiazolo[5,4-dlpyrimidine

This compound was obtained from 4-chlorophenoxyacetyl chloride (43 mg);

MS m/z (%) : 527 ([M+H]⁺, 100).

Example 144 : Synthesis of 5-amino-2-[2-(4-fluorophenyl)ethyll-7-(3-(f?)-(4- chlorobenzoylamino)-pyrrolidin-1 -ylVthiazolo[5,4-dlpyrimidine

This compound was obtained from 4-chlorobenzoyl chloride (44 mg).

MS m/z (%) : 497 ([Μ+ΗΓ, 100). Exa mple 145 : Sy nthes is of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(1- benzyloxycarbonylpiperidin-3-ylamino)-thiazolo[5,4-d]pyrimidine

To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-methanesulfonyl-thiazolo[5,4- d]pyrimidine (50 mg, 0.14 mmol) in 1,4-dioxane (5 ml) was added potassium carbonate (0.42 mmol) and benzyl 3-aminopiperidine-1-carboxylate hydrogen chloride (0.15 mmol). The reaction mixture was stirred at room temperature for 24 hours whereupon the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 1% CH₃OH in CH₂CI₂), yielding the pure title compound (59 mg) which was characterized by its mass spectrum: MS m/z (%) : 507 ([M+H]⁺, 100).

Example 146 : Synthesis of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(1 -tert- butoxycarbonylpyrrolidin-3-(S)-ylamino)-thiazolo[5,4-d]pyrimidine

To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-methanesulfonyl-thiazolo[5,4- djpyrimidine (150 mg, 0.42 mmol) in dichloromethane (10 ml) was added diisopropylethylamine (3.0 mmol, 492 pL) and ferf-butyl 3-(S)-aminopyrrolidine-1-carboxylate (2.1 mmol). The reaction mixture was refluxed for 40 hours whereupon the mixture was extracted with a saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 1% CH₃OH in CH₂CI₂), yielding the pure title compound (81 mg) which was characterized by its mass spectrum: MS m/z{%) : 459 ([M+H]\ 100).

Exa mple 147 : Synthesis of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(1-(4- chlorophenoxyacetyl)pyrrolidin-3-(S)-ylamino)-thiazolo[5,4-d]pyrimidine

To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(1-fe/-butoxycarbonyl-pyrrolidin-3-(S)- ylamino)-thiazolo[5,4-d]pyrimidine (70 mg, 0.15 mmol) in dichloromethane (1 ml) was added trifluoroacetic acid (1 ml). The reaction mixture was stirred at room temperature for 2 hours after which the solvents were removed in vacuo. The residue was dissolved in dichloromethane (3 ml) and diisopropylethylamine (1.5 mmol, 252 pL) and 4- chlorophenoxyacetyl chloride (0. 7 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours whereupon the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 1.5% CH₃OH in CH₂CI₂), yielding the pure title compound (37 mg) which was characterized by its mass spectrum: MS m/z (%) : 527 ([M+H]⁺, 100). Example 148 : Synthesis of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-benzoylpiperidine- 1 -yl)-thiazolo[5,4-d]pyrimidine

T o a s o l u t i o n o f 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-methanesulfonyl-thiazolo[5,4- d]pyrimidine (50 mg, 0.14 mmol) in acetonitrile (5 ml) was added diisopropylethylamine (0.45 mmol, 74 μΙ_) and 4-benzoylpiperidine hydrogen chloride (0.15 mmol). The reaction mixture was stirred at room temperature for 16 hours whereupon the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 1 % CH₃OH in CH₂CI₂), yielding the pure title compound (59 mg) which was characterized by its mass spectrum: MS m/z (%) : 462 ([M+H]^*, 100).

E x a m p l e 1 4 9 : S y n t h e s i s o f 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-(2- phenoxyethyl)piperazin-1 -yl)-thiazolo[5,4-d]pyrimidine

To a so lution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-6H-thiazolo[5,4-d]pyrimidin-7-one (133 mg, 0.46 mmol) in DMF (5 ml) was added DBU (0.69 mmol), BOP (0.59 mmol) and 1 -(2- phenoxyethyl)piperazine (1 .37 mmol). The reaction mixture was stirred at room temperature for 3 hours whereupon the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2CI2 to 2% CH₃OH in CH₂CI₂), yielding the pure title compound (56 mg) which was characterized by its mass spectrum: MS m/z (%) : 479 ([M+H]\ 100).

E x a m p l e 1 5 0 : S y n t h e s i s o f 5-amino-2-[1- 4-fluorophenyl)propyl]-7-(4-[2-<4- chlorophenoxy)acetyl]piperazin-1 -yl)thiazolo[5,4-d]pyrimidine

To a solution of 5-amino-2-(4-fluorobenzyl)-7-methylsulfanylthiazolo[5,4-d]pyrimidine (100 mg, 0.33 mmol) in DMSO (1 .5 ml) was added sodium hydroxide (2N, 171 μ|_) and ethyl iodide (0.34 mmol). The reaction mixture was stirred at room temperature for 16 hours whereupon the mixture was extracted with ethyl acetate and brine. The organic phase was dried over magnesium sulfate and concentrated by evaporation in vacuo. The resulting residue was dissolved in dichloromethane (3 ml), cooled to 0°C and m-chloroperoxybenzoic acid (0.81 mmol) was added. The reaction mixture was stirred at room temperature for 7 hours. The mixture was first extracted with a saturated sodium bicarbonate solution, then with brine. The combined organic phases were dried over magnesium sulfate. After evaporating the solvents in vacuo, the residue was dissolved again in dichloromethane (3 ml) and piperazine (3.3 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours whereupon the mixture was extracted with brine. The organic phase was dried over magnesium sulfate and evaporated in vacuo. The crude residue was reacted at room temperature for 16 hours with 4-chlorophenoxyacetyl chloride (0.35 mmol) in the presence of diisopropylethylamine (0.72 mmol, 1 19pL). After removing the solvent in vacuo, the crude mixture was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 1 .5% CH3OH in CH2CI2), yielding the pure title compound (30 mg) which was characterized by its mass spectrum: MS m/z (%) : 541 ([M+H]⁺, 100).

Example 151 : Synthesis of 5-amino-2-[cyclopentyl-(4-fluorophenyl)methyl]-7-(4-[2-(4- chlorophenoxy)acetyl]piperazin-1 -yl)thiazolo[5,4-d]pyrimidine

T o a solution of 5-amino-2-(4-fluorobenzyl)-7-methylsulfanylthiazolo[5,4-d]pyrimidine (100 mg, 0.33 mmol) in DMSO (1.5 ml) was added sodium hydroxide (2N, 171 μΙ_) and cyclopentyl iodide (0.34 mmol). The reaction mixture was stirred at room temperature for 16 hours whereupon the mixture was extracted with ethyl acetate and brine. The organic phase was dried over magnesium sulfate and concentrated by evaporation in vacuo. The resulting residue was dissolved in dichloromethane (3 ml), cooled to 0°C and m-chloroperoxybenzoic acid (0.81 mmol) was added. The reaction mixture was stirred at room temperature for 7 hours. The mixture was first extracted with a saturated sodium bicarbonate solution, then with brine. The combined organic phases were dried over magnesium sulfate. After evaporating the solvents in vacuo, the residue was redissolved in dichloromethane (3 ml) and piperazine (3.3 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours whereupon the mixture was extracted with brine. The organic phase was dried over magnesium sulfate and evaporated in vacuo. The crude residue was reacted at room temperature for 16 hours with 4-chlorophenoxyacetyl chloride (0.35 mmol) in the presence of diisopropylethylamine (0.72 mmol, 1 19 μΙ_). After removing the solvent in vacuo, the crude mixture was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 1.5% CH3OH in CH₂CI₂), yielding the pure title compound (47 mg) which was characterized by its mass spectrum: MS m/z (%) : 581 ([M+H]⁺, 100).

Example 152 : Synthesis of N-(2-amino-4,6-dihydroxypyrimidin-5-yl)-3-thiophen-2-yl- propionamide

To a solution of 2,5-diaminopyrimidine-4,6-diol hydrogen chloride (1.04 g, 5.8 mmol) in sodium hydroxide (17.8 mmol) solution (25 ml of H₂0) was added 3-thiophen-2-ylpropionyl chloride (6.4 mmol), The latter was prepared by refluxing 3-thiophen-2-ylpropionic acid (6.4 mmol) in thionyl chloride (500 μί.) for 1 hour whereupon the excess of thionyl chloride was removed by evaporation in vacuo. The reaction mixture was stirred at room temperature for 18 hours. The pH of the suspension was adjusted to approximately 6 and the solids were filtered off. The title compound (1.25 g) was characterized by its mass spectrum: MS m/z (%) : 515 ([M+H]⁺, 100). E x a m p l e 1 53 : S y n t h e s i s of 5-amine-7-piperazin-1-yl-2-{2-thiophen-2-yl-ethyl)- thiazolo[5,4-d]pyrimidine

To a suspension of / /-(2-amino-4,6-dihydroxypyrimidin-5-yl)-3-thiophen-2-yl-propionarr)ide (example 153, 1 g, 3.6 mmol) in o-xy!ene (25 ml) was added phosphorus pentasulfide (5.3 mmol, P4S₁0). The reaction mixture was refluxed until all starting material was consumed (TLC monitoring) whereupon the mixture was cooled down to room temperature. The reaction was quenched by adding potassium carbonate (32 mmol) and the mixture was stirred at room temperature for one additional hour. The precipitate was filtered off and the solids were extensively washed with water and subsequently dried. Next, the solids were dissolved in pyridine (20 ml) and piperazine (17.8 mmol), ammonium sulfate (36 mg), p- toluenesulfonic acid (36 mg) and 1 ,1 ,1 ,3,3,3-hexamethyldisilazane (3.6 ml) were added. The reaction mixture was refluxed for 24 hours after which the solvent was evaporated in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 5% CH₃OH in CH₂CI₂), yielding the pure title compound (656 mg) which was characterized by its mass spectrum: MS m/z (%) : 347 ([Μ+Η , 100).

Examples 154 - 156 : Synthesis of 5-amino-2-(2-thiophen-2-ylethyl)-7-(4-acylpiperazin- 1 -yl)thiazolo[5,4-d]pyrimidine

General procedure

To a solution of 5-amine-7-piperazin-1-yl-2-(2-thiophen-2-yl-ethyl)-thiazolo[5,4-d]pyrimidine (example 154, 50 mg, 0.14 mmol) in dichloromethane (3 ml) was added diisopropylethylamine (35 mmol) and an acyl chloride (0.17 mmol). The reaction mixture was stirred at room temperature for 16 hours whereupon the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 1 % CH₃OH in CH₂CI2), yielding the pure title compounds which were characterized by their mass spectra as indicated below.

The following compounds were synthesized according to this procedure :

Example 154 : Synthesis of 5-amino-2-(2-thiophen-2-ylethyl)-7-(4-[2-(4-chloro- phenoxy)acetyllPiperazin-1-yl)thiazolof5,4-dlpyrimidine

This compound was obtained from 4-chlorophenoxyacetyl chloride (31 mg).

MS m/z (%) : 515 ([M+H]^*, 100).

Example 155 : Synthesis of 5-amino-2-(2-thiophen-2-ylethyl)-7-(4-r2-(4-chloro- phenyl)acetyllpiperazin-1 -yl)thiazolo[5,4-dlpyrimidine

This compound was obtained from 4-chlorophenylacetic chloride (23 mg).

MS m/z (%) : 499 ([M+H]^*, 100). Example 156 : Synthesis of 5-amino-2-(2-thiophen-2-ylethyl)-7-(4-(4-chloro- benzoyl)piperazin-1 -yl)thiazoloi5,4-dlPyrimidine

This compound was obtained from 4-chlorobenzoyl chloride (29 mg).

MS m/z (%) : 485 ([M+H)\ 100).

E x a m p l e 1 5 7 : S y n t h e s i s o f 5-amino-2-(2-thiophen-2-ylethyl)-7-(4-/77- tolylcarbamoylpiperazin-1 -yl)thiazolo[5,4-d]pyrimidine

To a solution of 5-amine-7-piperazin- 1-yl-2-(2-thiophen-2-yl-ethyl)-thiazolo[5,4-d]pyrimidine (50 mg, 0.14 mmol) in dichloromethane (3 ml) was added 3-methylphenylisocyanate (0.17 mmol). The reaction mixture was stirred at room temperature for 16 hours whereupon the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 0.5% CH₃OH in CH₂CI₂), yielding the pure title compound (33 mg) which was characterized by its mass spectrum: MS m/z (%) : 480 ([M+H]⁺, 100).

Example 158 : Synthesis of A/-(4,6-dihydroxypyrimidin-5-yl)-4-fluorobenzamide

Formamidine acetate (0.46 g, 4.46 mmol) and dimethyl 2-(4-fluorobenzamido)malonate (1 .0 g, 3.71 mmol) were added to a solution of sodium (0.17 g, 7.43 mmol) in ethanol (37 ml). The reaction mixture was refluxed for 3 hours. After cooling down, the precipitate was filtered off and washed with ethanol. The product was dissolved in a minimal volume of water and acidified to pH 4-5 with 5M HCI. The precipitate was collected, washed with water and dried to yield the title compound as a white solid (0.60 g, 64 %).

H N MR (300 MHz, DMSO, 25 °C): δ = 12.03 (s, 2H , OH), 9.25 (s, 1 H, CH), 8.01 -8.05 (m, 3H, PhH, NH), 7.32 (t, J= 8.3 Hz, 2H, PhH) ppm.

MS: 247 8 [M-H]

Example 159 Synthesis of W-(4,6-dihydroxypyrimidin-5-yl)-2-(4- fluorophenyl)acetamide

This compound was prepared from example 2 in a yield of 24%, according to the procedure for the synthesis of example 158.

¹H NMR (300 MHz, DMSO, 25 °C): δ = 12.00 (s, 2H, OH), 9.09 (s, 1 H, NH), 7.97 (s, 1 H, CH), 7.33-7.37 (m, 2H, PhH), 7.12 (t, J= 8.6 Hz, 2H, PhH), 3.59 (s, 2H, CH₂) ppm.

HRMS: calcd for C^Hn FNaOs 264.07844, found 264.07769.

Example 160 Synthesis of W-(4,6-dihydroxy-2-methyl-pyrimidin-5-yl)-2-<4- fluorophenyl)acetamide

This compound was prepared from example 2 in a yield of 29%, according to the procedure for the synthesis of example 9. ¹H NMR (300 MHz, DMSO, 25 °C): δ = 1 1 .97 (s, 2H, OH), 8.89 (s, 1 H, NH), 7.32-7.37 (m, 2H, PhH), 7.12 (t, J= 8.6 Hz, 2H, PhH), 3.56 (s, 2H, CH₂), 2.24 (s, 3H, CH₃) ppm.

HRMS: calcd for C₁₃H₁₃FN₃0₃278.09409, found 278.09331 .

Example 161 : Synthesis of 7-chloro-2-(4-fluorophenyl)-oxazolo[5,4-d]pyrimidine

To a solution of A -(4,6-dihydroxypyrimidin-5-yl)-4-fluorobenzamide (0.30 g, 1.20 mmol) in POC (6 ml) was added diisopropylethylamine (0.42 ml, 2.41 mmol). The reaction mixture was stirred under N₂ at 90°C for 3.5 hours. The reaction mixture was allowed to cool down to room temperature and the volatiles were evaporated to dryness. The residue was diluted with water and the aqueous phase was extracted with diethyl ether. The combined organic layers were washed with a saturated NaHC0₃ solution and brine, dried over Na₂S0₄, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH₂CI₂/MeOH 100: 1 ) to yield the title compound as a white solid (0.13 g, 30 %).

H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.64 (s, 1 H, CH), 8.23-8.27 (m, 2H, PhH), 7.25 (t, J= 8.2 Hz, 2H, PhH) ppm.

E x a m p l e 1 62 : S y n t h e s i s o f 7-chloro-2-(4-fluorophenyl)-5-methyloxazolo[5,4- d]pyrimidine

This compound was prepared from example 9 in a yield of 40%, according to the procedure for the synthesis of example 161.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.28-8.33 (m, 2H, PhH), 7.26 (t, J= 8.6 Hz, 2H, PhH), 2.84 (s, 3H, CH₃) ppm.

HRMS: calcd for C₁₂H₈CIFN₃0 264.03399, found 264.03318.

Exa m ple 163 : Synthesi s of 7-chloro-2-(4-fluorophenyl)-oxazolo[5,4-d]pyrimidin-5- amine

This compound was prepared from example 5 in a yield of 28%, according to the procedure for the synthesis of example 161.

¹H NMR (300 MHz, DMSO, 25 °C): δ = 8.13-8.18 (m, 2H, PhH), 7.48 (s, 2H, NH₂), 7.45 (t, J= 8.9 Hz, 2H, PhH) ppm.

HRMS: calcd for CnH_/CIFN^ 265.02924, found 265.02851.

Example 164 : Synthesis of 7-chloro-2-{4-fluorobenzyl)-oxazolo[5,4-d]pyrimidine

This compound was prepared from example 159 in a yield of 73%, according to the procedure for the synthesis of example 160.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.77 (s, 1 H, CH), 7.36-7.41 (m, 2H, PhH), 7.06 (t, J=

8.6 Hz, 2H, PhH), 4.32 (s, 2H, CH₂) ppm.

HRMS: calcd for C₁₂H₈CIFN₃0 264.03399, found 264.03349. E x a m p l e 1 65 : S y n t h e s i s of 7-chloro-2-(4-fluorobenzyl)-5-methyl-oxazolo[5,4- d]pyrimidine

This compound was prepared from example 1 59 in a yield of 40%, according to the procedure for the synthesis of example 161 .

1H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.35-7.40 (m, 2H, PhH), 7.08 (t, J= 8.6 Hz, 2H, PhH), 4.14 (s, 2H, CH₂), 2.68 (s, 3H, CH₃) ppm.

Example 166 : Synthesis of 7-chloro-2-(4-fluorophenethyl)-oxazolo[5,4-d]pyrimidin-5- amine

This compound was prepared from example 7 in a yield of 34%, according to the procedure for the synthesis of example 161.

¹H NMR (300 MHz, DMSO, 25 °C): δ = 7.28-7.33 (m, 2H, PhH), 7.10 (t, J= 8.8 Hz, 2H, PhH), 6.43 (s, 2H, NH₂), 3.16 (br s, 4H, ChfeCHg) ppm.

Example 167 : Synthesis of 2-(4-chlorophenoxy)-1 -(4-(2-(4-fluorophenyl)oxazolo[5,4- d]pyrimidin-7-yl)piperazin-1 -yl)ethanone

This compound was prepared from example 161 in a yield of 60%, according to the procedure for the synthesis of example 47.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.34 (s, 1 H, CH), 7.90-7.94 (m, 2H, PhH), 7.18-7.24 (m, 4H, PhH), 6.83 (d, J= 6.8 Hz, 2H, PhH), 4.66 (s, 2H, CH₂), 3.77 (br s, 2H, NCH₂), 3.68 (br s, 2H, NCH₂), 3.65 (s, 4H, CONfCH^) ppm.

HRMS: calcd for C₂₃H₂₁CIFN₆0₃ 483.13477, found 483.13334.

Exa m ple 1 68 : Synthesis of 2-(4-chlorophenoxy)-1-(4-(2-(4-fluorophenyl)-5-methyl- oxazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)ethanone

This compound was prepared from example 162 in a yield of 93% , according to the procedure for the synthesis of example 47.

1H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.13-8.18 (m, 2H, PhH), 7.27 (d, J= 8.9 Hz, 2H, PhH), 7.20 (t, J= 8.5 Hz, 2H, PhH), 6.93 (d, J= 8.9 Hz, 2H, PhH), 4.76 (s, 2H, CH₂), 4.27 (br s, 4H, N(CH₂)₂), 3.78 (br s, 4H, CON(CH2)₂), 2.59 (s, 3H, CH₃) ppm.

HRMS: calcd for C₂₄H₂₂CIFN₅0₃ 482.13952, found 482.13800.

Example 169 : Synthesis of 1 -(4-(5-amino-2-(4-fluorophenyl)oxazolo[5,4-d]pyrimidin-7- yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone

This compound was prepared from example 163 in a yield of 55%, according to the procedure for the synthesis of example 47.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.03-8.08 (m, 2H, PhH), 7.40 (t, J= 8.8 Hz, 2H, PhH), 7.33 (d, J= 8.8 Hz, 2H, PhH), 6.98 (d, J= 8.8 Hz, 2H, PhH), 6.54 (s, 2H, NH₂), 4.93 (s, 2H, CH₂), 4.19 (br s, 2H, NCH₂), 4.09 (br s, 2H, N(CH₂)₂), 3.62 (br s, 4H, CON(CJi>)₂) ppm. HR S: calcd for C₂₃H₂₁CIFN₆0₃483.13477, found 483.13367.

Example 170 : Synthesis of 2-(4-chlorophenoxy)-1-(4-(2-(4-fluorobenzyl)oxazolo[5_l4- d]pyrimidin-7-yl)piperazin-1-yl)ethanone

This compound was prepared from example 164 in a yield of 58%, according to the procedure for the synthesis of example 47.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.33 (s, 1H, CH), 7.30-7.35 (m, 2H, PhH), 7.26 (d, J= 6.8 Hz, 2H, PhH), 7.03 (t, J= 8.7 Hz, 2H, PhH), 6.91 (d, J= 6.8 Hz, 2H, PhH), 4.74 (s, 2H, OCH₂), 4.17 (s, 2H, CH₂), 4.17 (br s, 4H, N(CH₂)₂), 3.75 (brs, 4H, CON(CJ½)₂) ppm.

HRMS: calcd for C₂₄H₂₂CIFN₅0₃482.13952, found 482.13796.

Example 171 : Synthesis of 2-(4-chlorophenoxy)-1-(4-(2-(4-fluorobenzyl)-5- methyloxazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)ethanone

This compound was prepared from example 165 in a yield of 68%, according to the procedure for the synthesis of example 47..

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.25 (d, J= 8.9 Hz, 2H, PhH), 7.10-7.15 (m, 2H, PhH), 6.99 (t, J= 8.5 Hz, 2H, PhH), 6.86 (d, J= 8.9 Hz, 2H, PhH), 4.67 (s, 2H, OCH₂), 3.66 (br s, 4H, N(CH₂)₂), 3.55 (s, 2H, CH₂), 3.53 (brs, 4H, CON(CH2», 2.61 (s, 3H, CH₃) ppm.

Example 172 : Synthesis of 1-(4-(5-amino-2-(4-fluorophenethyl)oxazolo[5₎4- d]pyrimidin-7-yl)piperazin-1-yl)-2-(4-chlorophenoxy)ethanone

This compound was prepared from example 166 in a yield of 34%, according to the procedure for the synthesis of example 47.

¹H NMR (300 MHz, CDCI_3l 25 °C): δ = 7.26 (d, J= 8.9 Hz, 2H, PhH), 7.14-7.19 (m, 2H, PhH), 6.96 (t, J= 8.7 Hz, 2H, PhH), 6.91 (d, J= 8.9 Hz, 2H, PhH), 4.78 (s, 2H, NH₂), 4.73 (s, 2H, CH₂), 4.11 (br s, 4H, N(CH₂)₂), 3.68 (br s, 4H, CON(CH2», 3.07 (br s, 4H, C^C ^ ppm.

Example 173 : Synthesis of W-(3-chloro-4-fluorophenyl)-2-(4-fluorophenyl)-oxazolo[5,4- d]pyrimidin-7 -amine

To a solution of 7-chloro-2-(4-fluorophenyl)-oxazolo[5,4-d]pyrimidine (85 mg, 0.34 mmol) in 1,2-dichloroethane/t-BuOH (1:1, 2 ml) was added 3-chloro-4-fluoroaniline (50 mg, 0.34 mmol). The mixture was heated at 90°C for 1 day. After cooling down to room temperature, the solvent was removed under reduced pressure. The crude residue was purified by silica gel chromatography (CH₂CI₂/MeOH 50:1) to yield the title compound as a white solid (0.1 g, 82 %).

¹H NMR (300 MHz, DMSO, 25 °C): δ= 10.52 (s, 1H, NH), 8.55 (s, 1H, CH), 8.23-8.27 (m, 2H, PhH), 7,84-7.87 (m, 1H, PhH), 7.50 (t, J= 8.8 Hz, 2H, PhH), 7.43 (t, J= 9,1 Hz, 1H, PhH) ppm.

HRMS: calcd for C₁₇H₁₀CIF₂N4O 359.05112, found 359.05016. Example 174 Synthesis of /V-7-(3-chloro-4-fluorophenyl)-2-(4-fluorophenyl)- oxazolo[5,4-d]pyrimidine-5,7-diamine

This compou nd was prepared from example 1 63 in a yield of 32% , according to the procedure for the synthesis of example 173.

1H NMR (300 MHz, DMSO, 25 °C): δ = 10.00 (s, 1 H, NH), 8.22-8.26 (m, 1 H, PhH), 8.08-8.12 (m, 2H, PhH), 7.95-7.99 (m, 1 H, PhH), 7.44 (t, J= 8.8 Hz, 2H, PhH), 7.35 (t, J= 9.1 Hz, 1 H, PhH), 6.81 (s, 2H, NH₂) ppm.

HRMS: calcd for C HuCIFzNsO 374.06202, found 374.06101 .

Examples 1 75-179 : Synthesis of 5-amino-7-chloro-2-substituted-oxazolo[5, 4- d]pyrimidine analogues

General procedure

To a suspension of a 2-amino-4,6-dihydroxy-5-substituted pyrimidine analogue (3.0 mmol) in toluene (20 ml) were added DIPEA (1 .19 ml, 9 mmol) and POCI₃ (830 pi, 9 mmol) respectively. The resulting mixture was heated at 95°C for 2 h. The solvents were evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of acetone and dichloromethane (in a ratio of 1 /50) , yielding the pu re title compounds.

The following compounds were synthesized according to this procedure .

Example 175 : Synthesis of 5-amino-7-chloro-2-cvclopropyloxazolo[5,4-dlpyrimidine

This compound was obtained from 2-amino-4,6-dihydroxy-5-(cyclopropanamido)pyrimidine (630 mg, 3.0 mmol) yielding the pure title compound (550 mg, 87%).

MS m/z (%): 21 1 ([M+H]⁺, 100)

Example 176 : Synthesis of 5-amino-7-chloro-2-methoxymethyloxazoloi5,4-dlpyrimidine

From 2-amino-4, 6-dihydroxy-5-methoxyacetamidopyrimidine (642 mg, 3.0 mmol), yielding the pure title compound (430 mg, 67%).

MS m/z (%): 215 ([M+Hf, 100)

Example 177 . Synthesis of 5-amino-7-chloro-2-cvclohexyloxazolo[5,4-dlpyrimidine

From 2-amino-4, 6-dihydroxy-5-cyclohexanecarboxamidopyrimidine (760 mg, 3.0 mmol), yielding the pure title compound (390 mg, 51 %).

MS m/z (%): 253 ([M+Hf, 100)

Example 178 : Synthesis of 5-amino-7-chloro-2-pentyloxazolo[5.4-dlpyrimidine

From 2-amino-4, 6-dihydroxy-5-hexanamidopyrimidine (720mg, 3.0 mmol), yielding the pure title compound (480 mg, 67%).

MS m/z (%): 241 ([M+H]⁺, 100) Example 179 : Synthesis of 5-arnino-7-chloro-2-(2-phenylethyl)oxazolo[5,4-d1pyrirnidine

From 2-amino-4,6-dihydroxy-5-phenylpropanamidopyrimidine (686 mg, 2.5 mmol), yielding the pure title compound (320 mg, 46%).

MS m/z (%): 276 ([M+H]⁺, 100)

Examples 180 - 184 : Synthesis of 5-amino-7-N-piperazino-2-substituted oxazolo[5,4- djpyrimidine analogues

General procedure

To a solution of the 5-amino-7-chloro-2-substituted oxazolo[5,4-d]pyrimidine (420 mg, 2.0 mmol) in dioxane (10 ml), was added piperazine (860 mg, 10 mmol). The resulting mixture was stirred at room temperature for 12 h. The mixture was evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/6), yielding the pure title compounds.

The following compounds were synthesized according to this general procedure:

Example 180 : Synthesis of 5-amino-2-cyclopropyl-7-A/-piperazino-oxazolof5,4-dlpyrimidine This compound was obtained in 92 % yield from 5-amino-7-chloro-2-cyclopropyl-oxazolo[5,4- d]pyrimidine.

MS m/z (%): 261 ([Μ+Η , 100)

Example 181 : Synthesis of 5-amino-2-methoxymethyl-7-M-piperazino-oxazolof5,4- dlpyrimidine

This compound was obtained in 57 % yield from 5-amino-7-chloro-2-methoxymethyl- oxazolo[5, 4-d]pyrimidine.

MS m/z (%): 265 ([M+H]⁺, 100)

Example 182 : Synthesis of 5-amino-2-cyclohexyl-7-/\/-piperazino-oxazolo[5,4-d1pyrimidine

This compound was obtained in 97 % yield from 5-amino-7-chloro-2-cyclohexyloxazolo[5, 4- djpyrimidine.

MS m/z (%): 303 ([M+H]⁺, 100)

Example 183 : Synthesis of 5-amino-2-pentyl-7-N-piperazino-oxazolo[5,4-dlPyrimidine

This compound was obtained in 86 % yield from 5-amino-7-chloro-2-pentyloxazolo[5, 4- d]pyrimidine.

MS m/z (%): 291 ([M+H]⁺, 100)

E x a m pl e 1 84 : Synthesis of 5-amino-2-(2-phenylethyl)-7-N-piperazino-oxazolo[5,4- dlpyrimidine

This compound was obtained in 99 % yield from 5-amino-7-chloro-2-(2- phenylethyl)oxazolo[5,4-d]pyrimidine. MS m/z (%): 325 ([M+HV\ 100)

Examples 185 - 1 8 9 : Synthesis of 5-amino-2-substituted-7-[4-<4- chlorophenoxyacetyl)piperazin-1 -yl]-oxazolo[5,4-d]pyrimidine analogues

General procedure

To a solution of a 5-amino-2-substituted-7-A -piperazino-oxazolo[5,4-d]pyrimidine analogue (1 .0 mmol) in dioxane (10 ml), was added DIPEA (330 μΙ, 2.0 mmol) and 4- chlorophenoxyacetyl chloride (246 mg, 1.2 mmol), respectively. The resulting mixture was stirred at room temperature for 30 minutes. The solvents were evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/40), yielding the pure title compounds.

The following compounds were synthesized according to this procedure :

Example 185 : Synthesis of 5-amino-2-cvclopropyl-7-f4-(4-chlorophenoxyacetyl)piperazin-1- yl1-oxazolo[5,4-dlpyrimidine

This compound was synthesized from 5-amino-2-cyclopropyl-7-/\/-piperazino-oxazolo[5, 4- d]pyrimidine in 93 % yield.

MS m/z (%): 429 ([M+Hf, 100)

Example 186 : Synthesis of 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2- methoxylmethyloxazolo[5,4-dlpyrimidine

This compound was synthesized from 5-amino-2-methoxymethyl-7-N-piperazino- oxazolo[5,4-d]pyrimidine in 60 % yield.

MS m/z (%): 433 ([M+Hf, 100)

Example 187 : Synthesis of 5-amino-2-cyclohexyl-7-[4-(4-chlorophenoxyacetyl)piperazin-1- yl]oxazoloi5, 4-dlpyhmidine

This compound was synthesized from 5-amino-2-cyclohexyl-7-N-piperazino-oxazolo[5,4- d]pyrimidine in 73 % yield.

MS m/z (%): 471 ([M+Hf, 100)

Example 188 : Synthesis of 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1 -yll-2- pentyloxazolo[5,4-dlpyrimidine

This compound was synthesized from 5-amino-2-pentyl-7-/V-piperazino-oxazolo[5,4- d]pyrimidine in 71 % yield.

MS m/z (%): 459 ([M+H]⁺, 100)

Example 189. : Synthesis of 5-amino-2-(2-phenylethyl)-7-[4-(4- chlorophenoxyacetyl)piperazin-1 -yl1oxazolof5, 4-dlpyrimidine

This compound was synthesized from 5-amino-2-pentyl-7-/V-piperazino-oxazolo[5,4- d]pyrimidine in 85 % yield. MS m/z (%): 493 ([Μ+ΗΓ, 100)

Examples 190 - 192 : S y n t he s i s of 5-amino-2-(4-fluorophenyl)-7-piperazin-1-yl- oxazolo[5,4-d]pyrimidine analogues

General procedure

To a solution of 5-amino-7-chloro-2-(4-fluorophenyl)-oxazolo[5,4-d]pyrimidine X (50 mg, 0.19 mmol) in dioxane (5 ml) was added diisopropylethylamine (0.28 mmol, 47 μΙ_) and a piperazine derivative (0.28 mmol). The reaction was stirred at 70°C for 6 hours after which the solvent was removed in vacuo. The resulting resid ue wa s pu rified by fla sh chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 2% CH₃OH in CH₂CI₂), yielding the pure title compounds which were characterized by their mass spectra as indicated below:

The following compounds were synthesized according to this procedure :

E x a m p l e 1 90 : S y n t h e s i s o f 5-amino-2-(4-fluorophenyl)-7-(4-isobutylpiperazin-1 -yl)- oxazolo[5,4-dlpyrimidine

This compound was obtained from 1-isobutyl-piperazine (32 mg);

MS m/z (%) : 371 ([M+H]⁺, 100).

Example 191 : Synthesis of 5-amino-2-(4-fluorophenyl)-7-(4-acetylpiperazin-1 -yl)- oxazolo[5,4-dlpyrimidine

This compound was obtained from 1 -acetyl piperazine (27 mg).

MS m/z (%) : 357 ([M+H]⁺, 100).

Example 192 : Synthesis of 5-amino-2-(4-fluorophenyl)-7-i4-(2-methoxyethyl)-piperazin-1 -yll- oxazolof5,4-dlpyrimidine

This compound was obtained from 1-(2-methoxyethyl) piperazine (30 mg).

MS m/z (%) : 373 ([M+H]⁺, 100).

Example 193 : Synthesis of 5-amino-2-(4-fluorophenyl)-7-(4-[2-{3-nitrophenoxy)acetyl]- piperazin-1 -yl)-oxazolo[5,4-d]pyrimidine

To a solution of 5-amino-2-(4-fluorophenyl)-7-piperazin-1 -yl-oxazolo[5,4-d]pyrimidine (50 mg, 0.15 mmol) and 2-(3-nitrophenoxy)acetic acid (0.22 mmol) in DMF (2 ml) was added TBTU (0.22 mmol) followed by diisopropylethylamine (0.22 mmol, 36 μΙ_). The reaction was stirred at room temperature for 24 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 1 % CH₃OH in CH₂CI₂), yielding the pure title compound which was characterized by its mass spectrum: MS m/z (%) : 522 ([M+H]⁺, 100). Examples 194 - 195 : Sy nt h e s i s of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-[2- alkylacetyl]piperazin-1-yl)-oxazolo[5,4-d]pyrimidine

General procedure

To a solution of 5-amino-2-(4-fluorophenyl)-7-piperazin-1-yl-oxazolo[5,4-d]pyrimidine (50 mg, 0.15 mmol) in dichloromethane (4 ml) was added diisopropylethylamine (0.32 mmol, 53 μΐ_) followed by an acyl chloride (0.16 mmol). The reaction was stirred at room temperature for 16 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatogra phy on silica , the mobile phase being a mixtu re of metha nol a n d dichloromethane (in a ratio gradually ranging from 100% CH₂CI_: to 1 % CH₃OH in CH2CI2), yielding the pure title compounds which were characterized by their mass spectra as indicated below.

The following compounds were synthesized according to this procedure :

E x a m p l e 1 9 4 : S y n t h e s i s o f 5-amino-2-f2-(4-fluorophenyl)ethyr|-7-(4-[2-(4- chlorophenyl)acetyll-piperazin-1 -yl)-oxazolo[5,4-dlpyrimidine

This compound was obtained from 4-chlorophenylacetyl chloride (57 mg);

MS m/z (%) : 495 ([M+H]⁺, 100).

Example 195 : Synthesis of 5-amino-2-[2-(4-fluorophenyl)ethyl1-7-(4-f4- chlorobenzoyllpiperazin-1-yl)-oxazolo[5,4-dlPyrimidine

This compound was obtained from 4-chlorobenzoyl chloride (62 mg).

MS m/z (%) : 481 ([M+H]\ 100).

E x a m p l e 1 9 6 : S y n t h e s i s o f 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-m- tolylcarbamoylpiperazin-1-yl)-oxazolo[5,4-d]pyrimidine

To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-oxazolo[5,4-d]pyrimidine (50 mg, 0.15 mmol) in dichloromethane (4 ml) was added 3-methylphenylisocyanate (0.16 mmol). The reaction was stirred at room temperature for 2 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 2% CH₃OH in CH₂CI₂), yielding the pure title compound (30 mg) which was characterized by its mass spectrum: MS m/z (%) : 476 ([M+H]\ 100).

Exa mples 1 97 - 198 Synthesis of 5-amino-2-[2-<4-fluorophenyl)ethyl]-7-(4- alkylpiperazin-1 -yl)-oxazolo[5,4-d]pyrimidine analogues

General procedure

To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-6H-oxazolo[5,4-d]pyrimidin-7-one (50 mg, 0.18 mmol) in DMF (2 ml) was added DBU (0.27 mmol), BOP (0.23 mmol) and a piperazine derivative (0.23 mmol). The reaction mixture was stirred at room temperature for 16 hours whereupon the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica , the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 2% CH₃OH in CH₂CI₂), yielding the pure title compounds which were characterized by their mass spectra as indicated below.

The following compounds were made according to this general procedure :

E x a m p l e 1 9 7 : S y n t h e s i s o f 5-arnino-2-[2-(4-fluorophenyl)ethyl1-7-(4-(2- phenoxyethyl)piperazin-1 -yl)-oxazolo[5,4-d1pyrimidine

This compound was obtained from 1-(2-phenoxyethyl)-piperazine (57 mg).

MS m/z (%) : 463 ([M+H]⁺, 100).

E x a m p le 1 98 : S y n t h e s i s o f 5-amino-2-f2-(4-fluorophenyl)ethyll-7-(4-f(methylphenyl- carbamoyl)methyl|piperazin-1 -yl)-oxazolo[5.4-dlPyrimidine

This compound was obtained from A/-methyl-/V-phenyl-2-piperazin-1-yl-acetamide (27 mg).

MS m/z (%) : 371 ([M+H]⁺, 100).

Examples 199 - 201 : Synthesis of 2-amino-5-acylamino-4,6-dihydroxypyrimidine analogues

General procedure

To a solution of 2,5-diamino-4,6-dihydroxypyrimidine (1 g, 5.6 mmol) in water (15 ml) was added sodium hydroxide (17 mmol, 672 mg) and an appropriate acid chloride (6.72 mmol) at 0 °C. The reaction was then stirred at room temperature for 3 hours. The reaction mixture was acidified till pH = 5. A light pink precipitate was formed, which was filtered off yielding the pure title compounds, in yields varying from 85-95%.

The following compounds were made according to this procedure:

Example 199 : Synthesis of 2-amino-5-benzamido-4,6-dihydroxypyrimidine

This compound was synthesized according to the general procedure using benzoyl chloride.

¹H NMR (300 MHz, DMSO): δ = 10.82 (br s, 2H, 2 x OH), 8.73 (s, 1 H, arom H), 7.9 (m, 2H, arom H), 7.45 (m, 3H, arom H), 6.97 (br s, 2H, NH₂) ppm.

Example 200 : Synthesis of 2-amino-5-(2-furancarboxamido)-4,6-dihydroxypyrimidine

This compound was synthesized according to the general procedure using 2-furoyl chloride H NMR (300 MHz, DMSO): δ = 10.67 (br s, 2H, 2 x OH), 8.56 (s, 1 H, arom H), 7.81 (s, 1 H, arom H), 7.16 (s, 1 H, arom H), 6.65 (br s, 2H, NH₂) ppm.

Example 201 : Synthesis of 2-amino-5-(4-fluorobenzamido)-4.6-dihydroxypyrimidine

This compound was synthesized according to the general procedure using 4-fluorobenzoyl chloride Examples 202 - 204: Synthesis of 5-amino-2-substituted-thiazolo[5,4-d]pyrimidine-7- thiol analogues

General procedure

A suspension of the appropriate 2-amino-4,6-dihydroxy-5-(acylamino)pyrimidine analogue (4.24 mmol) and P₂S₅ (8.47 mmol, 3.77 g) in pyridine (20 ml) was heated under reflux for 12 hours. After concentration under reduced pressure, the residue was resuspended in water (15 ml). Potassium carbonate (1.76 g, 13 mmol) was added and the mixture was stirred at room temperature for 1 h. The precipitate was collected by filtration and washed with water, yielding the crude title compound which was used without further purification.

The following compounds were synthesized according to this procedure :

Example 202 : Synthesis of 5-amino-2-phenyl-thiazolo[5,4-dlpyrimidine-7-thiol

This compound was synthesized from 2-amino-5-benzamido-4,6-dihydroxypyrimidine

Example 203 : Synthesis of 5-amino-2-(2-furyl)-thiazolo[5,4-dlpyrimidine-7-thiol

This compound was synthesized from 2-amino-5-(2-furancarboxamido)-4,6- dihydroxypyrimidine

Example 204 : Synthesis of 5-amino-2-(4-fluoro-phenyl)-thiazolof5,4-dlpyrimidine-7-thiol

This compound was synthesized from 2-amino-5-(4-fluorobenzamido)-4,6- dihydroxypyrimidine

Examples 205 - 207 : Synthesis of 5-amino-7-N-piperazinyl-2-substituted-thiazolo[5,4- djpyrimidine analogues

General procedure

To a solution of a 5-amino-2-substituted-thiazolo[5,4-d]pyrimidine-7-thiol analogue (3.37 mmol) in pyridine (20 ml) was added 1 ,1 ,1 , 3,3, 3-hexamethyldisilazane (HMDS, 6.1 ml) and piperazine (33.7 mmol, 2.9 g). The reaction mixture was refluxed overnight. After cooling down to room temperature, the solvents were evaporated in vacuo. The residue was adsorbed on silica and purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a gradient gradually raising from 8% to 9% methanol in dichloromethane), yielding the title compounds as yellow powders, in yields ranging from 40-50%.

The following compounds were made according to this procedure :

Example 205 : Synthesis of 5-amino-2-phenyl-7-N-piperazinyl-thiazolo[5,4-dlpyrimidine

This compound was synthesized from 5-amino-2-phenyl-thiazolo[5,4-d]pyrimidine-7-thiol.

Example 206 : Synthesis of 5-amino-2-(2-furyl)-7-N-piperazinyl-thiazoloi5.4-dlpyrimidine

This compound was synthesized from 5-amino-2-(2-furyl)-thiazolo[5,4-d]pyrimidine-7-thiol. Example 207 : Synthesis of 5-amino-2-(4-fluoro-phenyl)-7-N-piperazinyl-thiazolof5,4- dlpyrimidine

This compound was synthesized from 5-amino-2-(4-fluoro-phenyl)-thiazolo[5,4-d]pyrimidine- 7-thiol.

Examples 208 - 214: Synthesis of 5-amino-7-N-(acylpiperazinyl)-2-substituted- thiazolo[5,4-d]pyrimidine analogues

General procedure

To a solution of a 5-amino-7-A/-piperazinyl-2-substituted-thiazolo[5,4-d]pyrimidine analogue (0.65 mmol) in DMF (10 ml) was added diisopropylamine (1.3 mmol, 215 μΙ), 0-(benzotriazol- 1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU, 0.78 mmol, 251 mg) and an appropriate carboxylic acid (0.78 mmol). The reaction was stirred at room temperature for 2 hours. An extraction was carried out (water/dichloromethane) and the solvents were evaporated in vacuo. The residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually raising from 1% to 1 .5% methanol in dichloromethane), yielding pure final compounds in yields varying from 70 to 80%.

The following compounds were made according to this procedure :

Example 208 : Synthesis of 1 -(4-(5-amino-2-phenylthiazolo[5,4-dlpyrimidin-7-yl)piperazin-1- yl)-2-(4-methoxyphenoxy)ethanone

This compound was obtained from 5-amino-2-phenyl-7-A/-piperazinyl-thiazolo[5,4- d]pyrimidine and 4-methoxy-phenoxyacetic acid.

¹H N R (300 MHz, DMSO): δ = 7.91 (m, 2H, arom H), 7.49 (m, 3H, arom H), 6.87 (q, 4H, arom H), 6.51 (br s, 2H, NH₂), 4.81 (s, 2H, CH₂), 4.36 (br s, 2H, piperazine H), 4.21 (br s, 2H, piperazine H), 3.68 (s, 3H, OCH₃), 3.62 (br s, 4H, piperazine H) ppm.

Example 209: Synthesis of 1-(4-(5-amino-2-(furan-2-yl)thiazolo[5,4-dlpyrimidin-7- yl)piperazin-1 -yl)-2-(4-fluorophenoxy)ethanone

This compound was obtained f ro m 5-amino-2-(2-furyl)-7-N-piperazinyl-thiazolo[5,4- d]pyrimidine and 4-fluoro- phenoxyacetic acid.

¹H NMR (300 MHz, DMSO): δ = 7.91 (s, 1 H, arom H), 7.10-7.14 (m, 3H, arom H), 6.96-6.98 (m, 2H, arom H), 6.72 (q, 1 H, arom H), 6.52 (br s, 2H, NH₂), 4.89 (s, 2H, CH₂), 4.33 (br s, 2H, piperazine H), 4.19 (br s, 2H, piperazine H), 3.62 (br s, 4H, piperazine H) ppm.

E x a m p l e 2 1 0 : S y n t h e s i s o f 1 -(4-(5-amino-2-(furan-2-yl)thiazolo(5,4-dlpyrimidin-7- yl)piperazin-1 -yl)-2-(m-tolyloxy)ethanone

This compound was obtained from 5-amino-2-(2-furyl)-7-N-piperazinyl-thiazolo[5,4- d]pyrimidine and 3-methyl-phenoxyacetic acid. H NMR (300 MHz, DMSO): δ = 7.89 (s, 1 H, arom H), 7.13-7.16 (m, 2H, arom H), 6.72-6.78 (m, 4H, arom H), 6.49 (br s, 2H, NH₂), 4.85 (s, 2H, CH₂), 4.32 (br s, 2H, piperazine H), 4.18 (br s, 2H, piperazine H), 3.63 (br s, 4H, piperazine H), 2.27 (s, 3H, CH₃) ppm.

Example 21 1 : Synthesis of 1 -(4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-dlpyrimidin-7- yl)piperazin-1-yl)-2-(m-tolyloxy)ethanone

This compound was obtained from 5-amino-2-(4-fluoro-phenyl)-7-N-piperazinyl-thiazolo[5,4- d]pyrimidine and 3-methyl-phenoxyacetic acid.

¹H NMR (300 MHz, DMSO): δ = 7.96-8.00 (m, 2H, arom H), 7.36 (t, 2H, arom H), 7.16 (t, 1 H, arom H), 6.76-6.79 (m, 3H, arom H), 6.51 (br s, 2H, NH₂), 4.86 (s, 2H, CH₂), 4.35 (br s, 2H, piperazine H), 4.22 (br s, 2H, piperazine H), 3.65 (br s, 4H, piperazine H), 2.28 (s, 3H, CH₃) ppm.

Exa mp l e 2 1 2 : Syn t h e s i s of 1-(4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-dlpyrimidin-7- yl)piperazin-1 -yl)-2-(2,4-dichlorophenoxy)ethanone

This compound was obtained from 5-amino-2-(4-fluoro-phenyl)-7-A/-piperazinyl-thiazolo[5,4- djpyrimidine and 2,4-dichloro-phenoxyacetic acid.

¹H NMR (300 MHz, DMSO): δ = 7.95-8.00 (m, 2H, arom H), 7.58 (d, 2H, arom H), 7.36 (m, 3H, arom H), 7.01 (d, 1 H, arom H), 6.52 (br s, 2H, NH₂), 5.09 (s, 2H, CH₂), 4.36 (br s, 2H, piperazine H), 4.22 (br s, 2H, piperazine H), 3.64 (br s, 4H, piperazine H) ppm.

Example 213: Synthesis of 1 -(4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d1pyrimidin-7- yl)piperazin-1 -yl)-2-(4-chloro-2-methylphenoxy)ethanone

This compound was obtained from 5-amino-2-(4-fluoro-phenyl)-7-N-piperazinyl-thiazolo[5,4- djpyrimidine and 4-chloro-o-tolyl-oxyacetic acid.

H NMR (300 MHz, DMSO): δ = 7.95-8.00 (m, 2H, arom H), 7.33-7.39 (t, 2H, arom H), 7.16- 7.23 (m, 2H, arom H), 6.90 (d, 1 H, arom H), 6.51 (br s, 2H, NH₂), 4.94 (s, 2H, CH₂), 4.35 (br s, 2H, piperazine H), 4.22 (br s, 2H, piperazine H), 3.64 (br s, 4H, piperazine H), 2.20 (s, 3H, CH₃) ppm.

Example 214: Synthesis of 1 -(4-(5-amino-2-(4-f1uorophenyl)thiazolo[5,4-d1pyrimidin-7- yl)piperazin-1-yl)-2-(3-chlorophenoxy)ethanone

This compound was obtained from 5-amino-2-(4-fluoro-phenyl)-7-N-piperazinyl-thiazolo[5,4- djpyrimidine and 3-chloro-phenoxyacetic acid.

¹H NMR (300 MHz, DMSO): δ = 7.97 (m, 2H, arom H), 7.36 (m, 3H, arom H), 6.93-6.99 (m, 3H, arom H), 6.51 (br s, 2H, arom H), 4.96 (s, 2H, CH₂), 4.36 (br s, 2H, piperazine H), 4.23 (br s, 2H, piperazine H), 3.64 (br s, 4H, piperazine H) ppm. E xa m p l e 21 5 : Synthesis of 1^4-(5-amino-2-phenylthiazolo[5,4-d]pyrimidin-7- yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone

To a solution of 5-amino-2-phenyl-7-N-piperazinyl-thiazolo[5,4-d]pyrimidine (90 mg, 0.28 mmol) in dioxane (5 ml) was added triethylamine (0.86 mmol, 120 μΙ) and 4- chlorophenoxyacetyl chloride (0.35 mmol, 71 mg). The reaction was stirred at room temperature for 2 hours. The solvents were evaporated and the residue was purified by silica gel flash ch ro matogra phy , th e mo bile ph ase bein g a mixtu re of metha nol a n d dichloromethane (in a ratio gradually raising from 1 % to 2% methanol in dichloromethane), yielding the pure title compound.

1H NMR (300 MHz, DMSO): δ = 7.92 (m, 2H, arom H), 7.51 (m, 3H, arom H), 7.32-7.35 (m, 2H, arom H), 6.97-7.00 (m, 2H, arom H), 6.51 (br s, 2H, arom H), 4.93 (s, 2H, CH₂), 4.38 (br s, 2H, piperazine H), 4.22 (br s, 2H, piperazine H), 3.64 (br s, 4H, piperazine H) ppm.

Examples 216 - 220: Synthesis of 5-amino-7-N-(carbamoylpiperazinyl)-2-substituted- thiazolo[5,4-d]pyrimidine analogues

General procedure

To a solution of a 5-amino-7-N-piperazinyl-2-substituted-thiazolo[5,4-d]pyrimidine analogue (0.61 mmol) in DM F (10 ml) was added diisopropylamine (1 .2 mmol, 200 μΙ) and an appropriate isocyanate (0.91 mmol). The reaction was stirred at room temperature for 2 hours. The solvents were evaporated in vacuo. The residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually raising from 1 % to 1 .5% methanol in dichloromethane), yielding pure final compounds in yields varying from 70 to 80%.

The following compounds were made according to this procedure :

Example 216: Synthesis of 4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-dlpyrimidin-7-yl)-N-(4- cyanophenyl)piperazine-1 -carboxamide

This compound was obtained from 5-amino-2-(4-fluoro-phenyl)-7-N-piperazinyl-thiazolo[5,4- d]pyrimidine and 4-cyanophenylisocyanate.

¹H NMR (300 MHz, DMSO): δ = 9.08 (s, 1 H, NH), 7.95-7.99 (m, 2H, arom H), 7.70 (s, 4H, arom H), 7.37 (t, 2H, arom H), 6.51 (br s, 2H, NH₂), 4.31 (br s, 4H, piperazine H), 3.66 (br s, 4H, piperazine H) ppm.

Example 217: Synthesis of 4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-dlpyrimidin-7-yl)-N-(2,4- difluorophenyl)piperazine-1-carboxamide

This compound was obtained from 5-amino-2-(4-f)uoro-phenyl)-7-N-piperazinyl-thiazolo[5,4- d]pyrimidine and 2,4-difluoro-phenylisocyanate. H NMR (300 MHz, DMSO): δ = 8.40 (s, 1 H, NH), 7.97 (m, 2H, arom H), 7.36 (m, 5H, arom H), 7.04 (m, 1 H, arom H), 6.50 (br s, 2H, NH₂), 4.30 (br s, 4H, piperazine H), 3.62 (br s, 4H, piperazine H) ppm.

Example 218: Synthesis of 4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-dlPyrimidin-7-yl)-N-(4- bromophenyl)piperazine-1-carboxamide

This compound was obtained from 5-amino-2-(4-fluoro-phenyl)-7-N-piperazinyl-thiazolo[5,4- djpyrimidine and 4-bromo-phenylisocyanate.

H NMR (300 MHz, DMSO): δ = 8.72 (s, 1 H, NH), 7.95-7.98 (m, 2H, arom H), 7.43-7.48 (m, 6H, arom H), 6.49 (br s, 2H, NH₂), 4.30 (br s, 4H, piperazine H), 3.63 (br s, 4H, piperazine H) ppm.

Example 219: Synthesis of 4-(5-amino-2-(4-fluorophenyl)thiazolof5,4-dlpyrimidin-7-yl)-N-(2- methoxyphenyl)piperazine-1 -carboxamide

This compound was obtained from 5-amino-2-(4-fluoro-phenyl)-7-N-piperazinyl-thiazolo[5,4- d]pyrimidine and 2-methoxy-phenylisocyanate.

Example 220: Synthesis of 4-(5-amino-2-phenylthiazolof5.4-dlpyrimidin-7-yl)-N-m- tolylpiperazine-1 -carboxamide

This compound was obtained from 5-amino-2-phenyl-7-N-piperazinyl-thiazolo[5,4- d]pyrimidine and 3-methyl-phenylisocyanate.

¹H NMR (300 MHz, DMSO): δ = 8.52 (s, 1 H, NH), 7.91 (dd, 2H, arom H), 7.50 (m, 3H, arom H), 7.32 (m, 2H, arom H), 7.12 (t, 1 H, arom H), 6.76 (d, 1 H, arom H), 6.52 (br s, 2H, NH₂), 4.30 (br s, 4H, piperazine H), 3.62 (br s, 4H, piperazine H), 2.26 (s, 3H, CH₃) ppm.

Example 221 : Synthesis of 5-amino-7-(/V-piperazin-1-yl)-2-(pyridine-3-yl)thiazolo[5, 4- djpyrimidine

A mixture of 5-amino-7-thiol-2-(pyridine-3-yl)thiazolo[5,4-d]pyrimidine (1.31 g, 5 mmol), piperazine (2.15 g, 25 mmol) and 1 ,1 , 1 ,3,3,3-hexamethyldisilazane (HMDS, 5 ml) in pyridine (40 ml) was heated in a microwave oven (CEM discover, 150°C, 150 W) for 30 minutes. The reaction mixture was evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/3), yielding the pure title compound as a yellowish solid (0.95 g, 60%).

MS m/z (%): 314 ([M+H]⁺, 100)

Example 222: Synthesis of 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N-p- tolylpiperazine-1 -carboxamide

To a suspension of 5-amino-7-(piperazin-1-yl)-2-(pyridine-3-yl)thiazolo[5,4-d]pyrimidine (150 mg, 0.48 mmol) in dioxane (10 ml) was added 4-tolyl isocyanate (63 μΙ, 0.5 mmol). The resulting reaction mixture was stirred at room temperature for 30 minutes. The solvents were evaporated in vacuo and the residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1 /25), yielding the pure title compound as a yellowish solid (170 mg, 79 %).

MS m/z (%): 447 ([M+H]⁺, 00)

Example 223: Synthesis of 1 - 4-(5-amino-2-{4-fluorophenethyl)thiazolo[5,4-d]pyrimidin- 7-yl)piperazin-1 -yl)-3-<4-bromophenyl)propan-1 -one

This compound was prepared from example 27 using 3-(4-bromophenyl)propionic acid in a yield of 71 %, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.42 (d, 2H, PhH), 7.10-7.24 (m, 4H, PhH), 6.96 (t, 2H, PhH), 4.69 (s, 2H, NH₂), 4.17 (br s, 4H, N(CH₂)2), 3.71 (br s, 2H, NCH₂), 3.47 (br s, 2H, NCH₂), 3.23 (t, 2H, CH₂), 3.07 (t, 2H, CH₂), 2.97 (t, 2H, CH₂), 2.65 (t, 2H, CH₂) ppm.

Example 224: Synthesis of 1 -(4-(5-amino-2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin- 7-yl)piperazin-1 -yl)-2-(4-hydroxyphenoxy)ethanone

This compound was prepared from example 27 using 4-hydroxyphenoxyacetic acid in a yield of 12%, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.13-7.18 (m, 2H, PhH), 6.96 (t, 2H, PhH), 6.75-6.87 (m, 4H, PhH), 4.71 (s, 2H, NH₂), 4.69 (s, 2H, OCH₂), 4.25 (br s, 2H, NCH₂), 4.21 (br s, 2H, NCH₂), 3.70 (br s, 4H, N(CH₂)₂), 3.23 (t, 2H, CH₂), 3.07 (t, 2H, CH₂) ppm.

Example 225: Synthesis of methyl 4-(2-(4-(5-amino-2-(4-fluorophenethyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1 -yl)-2-oxoethoxy)benzoate

This compound was prepared from example 27 using 4-methoxycarbonylphenoxyacetic acid in a yield of 41%, according to the procedure for the synthesis of example 50.

'H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.01 (d, 2H, PhH), 7.13-7.18 (m, 2H, PhH), 7.01 (d, 2H, PhH), 6.96 (t, 2H, PhH), 4.81 (s, 2H, OCH₂), 4.71 (s, 2H, NH₂), 4.25 (br s, 2H, NCH₂), 4.20 (br s, 2H, NCH₂), 3.88 (s, 3H, CH₃), 3.73 (br s, 2H, NCH₂), 3.65 (br s, 2H, NCH₂), 3.23 (t, 2H, CH₂), 3.07 (t, 2H, CH₂) ppm

Example 226: Synthesis of 1 -(4-(5-amino-2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin- 7-yl)piperazin-1-yl)-2-(4-(trifluoromethoxy)phenoxy)ethanone

This compound was prepared from example 27 using 4-trifluoromethoxyphenoxyacetic acid in a yield of 54%, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.13-7.18 (m, 4H, PhH), 6.93-6.99 (m, 4H, PhH), 4.75 (s, 2H, OCH₂), 4.71 (s, 2H, H₂), 4.26 (br s, 2H, NCH₂), 4.21 (br s, 2H, NCH₂), 3.72 (br s, 2H, NCH₂), 3.65 (br s, 2H, NCH₂), 3.23 (t, 2H, CH₂), 3.07 (t, 2H, CH₂) ppm E x a m p l e 2 2 7 : S y n t h e s i s o f 2-(4-acetylphenoxy)-1 -(4-<5-amino-2-(4- fluorophenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)ethanone

This compound was prepared from example 27 using 4-acetylphenoxyacetic acid in a yield of 67%, according to the procedure for the synthesis of example 50.

1H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.97 (d, 2H PhH), 7.13-7.18 (m, 4H, PhH), 6.93-7.04 (m, 4H, PhH), 4.82 (s, 2H, OCH2), 4.71 (s, 2H, NH2), 4.25 (br s, 2H, NCH2), 4.20 (br s, 2H, NCH2), 3.72 (br s, 2H, NCH2), 3.65 (br s, 2H, NCH2), 3.23 (t, 2H, CH2), 3.07 (t, 2H, CH2), 2.56 (s, 3H, CH3) ppm

Example 228: Synthesis of 1 -(4-{5-amino-2-{4-fluorophenethyl)thiazolo[5,4-d]pyrimidin- 7-yl)piperazin-1-yl)-2-(3-chlorophenoxy)ethanone

This compound was prepared from example 27 using 3-chlorophenoxyacetic acid in a yield of 51 %, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.00-7.23 (m, 3H, PhH), 6.93-6.99 (m, 4H, PhH), 6.87 (d, 1 H, PhH), 4.73 (s, 2H, OCH₂), 4.72 (s, 2H, NH₂), 4.26 (br s, 2H, NCH₂), 4.22 (br s, 2H, NCH₂), 3.71 (t, 2H, NCH₂), 3.64 (t, 2H, NCH₂), 3.23 (t, 2H, CH₂), 3.07 (t, 2H, CH₂) ppm

Example 229: Synthesis of 4-(5-amino-2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin-7- yl)-N-(4-cyanophenyl)piperazine-1 -carboxamide

This compound was prepared from example 27 using 4-cyanophenyl isocyanate in a yield of 64%, according to the procedure for the synthesis of example 42.

H NMR (300 MHz, DMSO, 25 °C): δ = 9.06 (s, 1 H, NH), 7.69 (s, 4H, PhH), 7.28-7.33 (m, 2H, PhH), 7.10 (t, 2H, PhH), 6.30 (s, 2H, NH₂), 4.20 (br s, 4H, N(CH₂)₂), 3.59 (br s, 4H, N(CH₂)₂) 3.26 (t, 2H, CH₂), 3.05 (t, 2H, CH₂) ppm.

Example 230: Synthesis of 1-(4-(5-amino-2-(4-fluorobenzyl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1 -yl)-2-(4-methoxyphenoxy)ethanone

This compound was prepared from example 26 using 4-methoxyphenoxyacetic acid in a yield of 59%, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.23-7.28 (m, 2H, PhH), 7.02 (t, 2H, PhH), 8.82-6.93 (m, 4H, PhH), 4.78 (s, 2H, NH₂), 4.70 (s, 2H, OCH₂), 4.28 (br s, 4H, N(CH₂)₂), 4.21 (s, 2H, CH₂), 3.77 (s, 3H, CH₃), 3.73 (br s, 4H, N(CH₂)₂) ppm

Example 231 : Synthesis of 1 -(4-(5-amino-2-(4-fluorobenzyl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1-yl)-2-(4-bromophenoxy)ethanone

This compound was prepared from example 26 using 4-bromophenoxyacetic acid in a yield of 80%, according to the procedure for the synthesis of example 50. ¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.40 (d, 2H, PhH), 7.23-7.27 (m, 2H, PhH), 7.02 (t, 2H, PhH), 6.87 (d, 2H, PhH), 4.78 (s, 2H, NH₂), 4.73 (s, 2H, OCH₂), 4.28 (br s, 4H, N(CH₂)₂), 4.21 (s, 2H, CH₂), 3.67-3.72 (m, 4H, N(CH₂)₂) ppm

Example 232: Synthesis of 4-(5-amino-2-(4-fluorobenzyl)thiazolo[5,4-d]pyrimidin-7-yl)- N-(4-cyanophenyl)piperazine-1 -carboxamide

This compound was prepared from example 26 using 4-cyanophenyl isocyanate in a yield of 58%, according to the procedure for the synthesis of example 42.

¹H NMR (300 MHz, DMSO, 25 °C): δ = 9.06 (s, 1 H, NH), 7.69 (s, 4H, PhH), 7.37-7.42 (m, 2H, PhH), 7.18 (t, 2H, PhH), 6.33 (s, 2H, NH₂), 4.29 (s, 2H, CH2), 4 22 (br s, 4H, N(CH₂)₂), 3.60 (br s, 4H, N(CH₂)₂) ppm.

Example 233: Synthesis of 1-(4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1 -yl)-2-(4-fluorophenoxy)ethanone

This compound was prepared from example 25 using 4-fluorophenoxyacetic acid in a yield of 58%, according to the procedure for the synthesis of example 50.

1H NMR (500 MHz, DMSO, 25 °C): δ = 7.95-7.98 (m, 2H PhH), 7.35 (t, 2H, PhH), 7.11 (t, 2H, PhH), 6.95-6.98 (m, 2H PhH), 6.51 (s, 2H, NH₂), 4.88 (s, 2H, CH₂), 4,35 (br s, 2H NCH₂), 4.21 (br s, 2H, NCH₂), 3.63 (br s, 4H N(CH₂)₂) ppm

Example 234: Synthesis of 1-(4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1-yl)-2-<4-methoxyphenoxy)ethanone

This compound was prepared from example 25 using 4-methoxyphenoxyacetic acid in a yield of 95%, according to the procedure for the synthesis of example 50.

H NMR (300 MHz, DMSO, 25 °C): δ = 7.95-8.00 (m, 2H, PhH), 7.35 (t, 2H, PhH), 6.84-6.92 (m, 4H, PhH), 6.51 (s, 2H, NH₂), 4.81 (s, 2H, OCH₂), 4.33 (br s, 2H, NCH₂), 4.21 (br s, 2H, NCH₂), 3.69 (s, 3H, CH₃), 3.64 (br s, 4H, N(CH₂)₂) ppm.

Example 235: Synthesis of 1 -(4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1 -yl)-2-(4-bromophenoxy)ethanone

This compound was prepared from example 25 using 4-bromophenoxyacetic acid in a yield of 47%, according to the procedure for the synthesis of example 50.

¹H NMR (500 MHz, DMSO, 25 °C): δ = 7.95-7.98 (m, 2H PhH), 7.47 (d, 2H, PhH), 7.35 (t, 2H, PhH), 6.92 (d, 2H, PhH), 6.50 (s, 2H, NH₂), 4.91 (s, 2H, CH₂), 4,37 (br s, 2H NCH₂), 4.21 (br s, 2H, NCH₂), 3.63 (br s, 4H N(CH₂)₂) ppm.

Example 236: Synthesis of 1 -(4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1 -yl)-3-(4-fluorophenyl)propan-1 -one

This compound was prepared from example 25 using 3-(4-fluoropheny)propionic acid in a yield of 62%, according to the procedure for the synthesis of example 50. H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.85-7.89 (m, 2H, PhH), 7.1 1-7.22 (m, 4H, PhH), 6.98 (t, 2H, PhH), 4.84 (s, 2H, NH₂), 4.29 (br s, 4H, N(CH₂)₂), 3.78 (t, 2H, NCH₂), 3.55 (t, 2H, NCH₂), 3.00 (t, 2H, CH₂), 2.67 (t, 2H, CH₂) ppm.

Example 237: Synthesis of 1-(4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1-yl)-2-(4-chlorophenoxy)-2-methylpropan-1-one

This compound was prepared from example 25 using 2-(4-chlorophenoxy)-2- methylpropanoic acid in a yield of 58%, according to the procedure for the synthesis of example 50.

H NMR (300 MHz, DMSO, 25 °C): δ = 7.94-7.98 (m, 2H, PhH), 7.32-7.38 (m, 4H, PhH), 6.87 (d, 2H, PhH), 6.46 (s, 2H, NH₂), 4.14 (br s, 2H, NCH₂), 3.93 (br s, 4H, N(CH₂)₂), 3.68 (br s, 2H, NCH₂), 1.56 (s, 6H, CH₃, CH₃) ppm.

Examples 238 - 240: Synthesis of 2-amino-4,6-dihydroxy-5-(acylamino)pyrimidine analogues

General procedure

A suspension of a carboxylic acid (6.7 mmol) in SOCI₂ (5 ml) was heated under reflux for 1 h. After concentration under reduced pressure, the residue was redissolved in dioxane (5 ml) and added to a stirring solution of 2,5-diamino-4,6-dihydroxypyrimidine hydrochloride (1 .0 g, 5.6 mmol) in 1 N NaOH (20 ml) at 0°C. The mixture was stirred and warmed to room temperature over 1 hour. After neutralization with 1 N hydrochloric acid to pH = 5, the precipitate was filtered off, washed with water and dried over P₂0₅, yielding the title compound.

The following compounds were synthesized according to this procedure:

E x a m p l e 2 3 8 : S y n t h esis of N-(2-amino-4,6-dihvdroxypyrimidin-5-yl)-3-(3- methoxyphenvQpropanamide

This compound was synthesized using 3-(3-methoxyphenyl)propionic acid, yielding the title compound in 87% yield.

E x a m p l e 2 3 9 : S y n t h e s i s o f N-(2-amino-4,6-dihvdroxypyrimidin-5-yl)-3-(3,4- dimethoxyphenvDpropanamide

This compound was synthesized using 3-(3,4-dimethoxyphenyl)propionic acid, yielding the title compound in 46% yield.

Example 240: Synthesis of N-(2-amino-4,6-dihvdroxypyrimidin-5-yl)-3-p-tolylpropanamide

This compound was synthesized using 3-(4-tolyl)propionic acid, yielding the title compound in 67% yield. Examples 241 - 243 : Synthesis of 5-amino-2-substituted-thiazolo[5,4-d]pyrimidine-7- thiol analogues

General procedure

A suspension of a 2-amino-4,6-dihydroxy-5-N-acylamino-pyrimidine analogue (3.3 mmol) and P₂S₅ (1 68 g, 7.6 mmol) in pyridine (15 ml) was heated under reflux for 6 hours. After concentration under reduced pressure, the residue was purified by flash chromatography on silica (CH₂CI₂/MeOH 30:1 ), yielding the title compounds as a yellow solid.

The following compounds were synthesized according to this procedure :

Example 241 : Synthesis of 5-amino-2-(3-methoxyphenethyl)thiazolo[5,4-dlpyrimidine-7-thiol This compound was synthesized from N-(2-amino-4,6-dihydroxypyrimidin-5-yl)-3-(3- methoxyphenyl)propanamide, yielding the title compound in 82% yield.

Example 242: Synthesis of 5-amino-2-(3,4-dimethoxyphenethyl)thiazolof5,4-dlpyrimidine-7- thiol

This compound was synthesized from N-(2-amino-4,6-dihydroxypyrimidin-5-yl)-3-(3,4- dimethoxyphenyl)propanamide, yielding the title compound in 48% yield.

MS m/z (%):349 ([M+H]⁺, 100)

Example 243: Synthesis of 5-amino-2-(4-methylphenethyl)thiazolo[5,4-dlpyrimidine-7-thiol

This compound was synthesized from N-(2-amino-4,6-dihydroxypyrimidin-5-yl)-3-p- tolylpropanamide, yielding the title compound in 76% yield.

Examples 244 - 246: Synthesis of 5-amino-2-substituted-7-methylthio-thiazolo[5,4- d]pyrimidine analogues

General procedure

To a solution of 5-amino-2-substituted-thiazolo[5,4-d]pyrimidine-7-thiol (2.4 mmol) and triethylamine (0.83 ml, 5.97 mmol) in DMSO (10 ml) was added iodomethane (0.29 ml, 4.77 mmol). The reaction mixture was stirred for 12 h under N₂ at 25°C. The mixture was poured into water and extracted with EtOAc. The organic extracts were dried over Na₂SO<j and the solvents were removed under reduced pressure. The crude residue was purified by flash chromatography on silica (CH₂CI₂/lv1eOH 80:1 ), yielding the title compound as a light yellow solid.

The following compounds were synthesized according to this procedure :

Example 244: Synthesis of 2-(3-methoxyphenethyl)-7-(methylthio)thiazolof5,4-dlpyrimidin-5- amine

This compound was synthesized from 5-amino-2-(3-methoxyphenethyl)thiazolo[5,4- d]pyrimidine-7-thiol, yielding the title compound in 73% yield. Example 245: Synthesis of 2-(3,4-dimethoxyphenethvn-7-(methylthio)thiazolof5,4- dlpyrimidin-5-amine

This compound was synthesized from 5-amino-2-(3,4-dimethoxyphenethyl)thiazolo[5,4- d]pyrimidine-7-thiol, yielding the title compound in 96% yield.

Example 246: Synthesis of 2-(4-methylphenethyl)-7-(methylthio)thiazolo[5,4-dlPyrimidin-5- amine

This compound was synthesized from 5-amino-2-(4-methylphenethyl)thiazolo[5,4- dJpyrimidine-7-thiol, yielding the title compound in 55% yield.

Examples 247 - 249 : Synthesis of 5-amino-2-substituted-7-methylsulfonyl- thiazolo[5,4-d]pyrimidine analogues

General procedure

To a solution of a 2-substituted-7-(methylthio)thiazolo[5,4-d]pyrimidin-5-amine analogue (0.90 mmol) in dichloromethane (5 ml) was added mCPBA (70 %, 0.39 g, 2.26 mmol) at 0°C. The reaction mixture was stiffed for 3 hours, whereby the reaction temperature was gradually increased from 0°C to room temperature. The reaction mixture was diluted with CHC and was washed with a saturated NaHC0₃ solution, brine and dried over Na₂SO„. After removing the solvents under reduced pressure, the residue was purified by flash chromatography on silica (CH₂CI₂/MeOH 50:1 ), affording the title compound.

The following compounds were synthesized according to this procedure :

Example 247 : Synthesis of 2-(3-methoxyphenethvn-7-(methylsulfonyl)thiazolo[5,4- dlpyrimidin-5-amine

This compound was synthesized from 2-(3-methoxyphenethyl)-7-(methylthio)thiazolo[5,4- d]pyrimidin-5-amine, yielding the title compound in 85% yield.

Example 248 : Synthesis of 2-(3,4-dimethoxyphenethyl)-7-(methylsulfonyl)thiazolof5,4- dlpyrimidin-5-amine

This compound was synthesized from 2-(3,4-dimethoxyphenethyl)-7-(methylthio)thiazolo[5,4- d]pyrimidin-5-amine, yielding the title compound in 69% yield.

Example 249 : Synthesis of 2-(4-methylphenethyl)-7-(methylsulfonyl)thiazolo[5,4-dlpyrimidin- 5-amine

This compound was synthesized from 2-(4-methylphenethyl)-7-(methylthio)thiazolo[5,4- d]pyrimidin-5-amine, yielding the title compound in 51 % yield. Examples 250 - 252: Synthesis of 5-amino-2-substituted-7-piperazinyl-thiazolo[5,4- d]pyrimidine analogues

General procedure

To a solution of a 2-substituted-7-(methylsulfonyl)thiazolo[5,4-d]pyrimidin-5-amine analogue (0.55 mmol) and triethylamine (0.12 ml, 0.82 mmol) in dioxane (4 ml) was added piperazine (71 mg, 0.82 mmol). The reaction mixture was heated at 60 °C for 5 hours. After cooling, the volatiles were removed under reduced pressure. The crude residue was purified by flash chromatography on silica (CH₂CI₂/MeOH 15:1 ), furnishing the title compound. The following compounds were synthesized according to this procedure :

Example 250 : Synthesis of 2-(3-methoxyphenethyl)-7-(piperazin-1-yl)thiazolof5,4- dlPyrimidin-5-amine

This compound was synthesized from 2-(3-methoxyphenethyl)-7- (methylsulfony!)thiazolo[5,4-d]pyrimidin-5-amine, yielding the title compound in 98% yield. Example 251 : Synthesis of 2-(3,4-dimethoxyphenethyl)-7-(piperazin-1-yl)thiazolo[5,4- dlpyrimidin-5-amine

This compound was synthesized from 2-(3,4-dimethoxyphenethyl)-7- (methylsulfonyl)thiazolo[5,4-d]pyrimidin-5-amine, yielding the title compound in 89% yield.

Example 252 : Synthesis of 2-(4-methylphenethyl)-7-(piperazin-1 -yl)thiazolo[5,4-dlpyrimidin- 5-amine

This compound was synthesized from 2-(4-methylphenethyl)-7-(methylsulfonyl)thiazolo[5,4- d]pyrimidin-5-amine, yielding the title compound in 79% yield.

Example 253 : Synthesis of 1 -(4-(5-amino-2-(3-methoxyphenethyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1-yl)-2-(4-methoxyphenoxy)ethanone

This compound was prepared from 2-(3-methoxyphenethyl)-7-(piperazin-1-yl)thiazolo[5,4- d]pyrimidin-5-amine using 4-methoxyphenoxyacetic acid in a yield of 66%, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.22 (t, 1 H, PhH), 6.81 -6.93 (m, 4H, PhH), 6.73-6.81 (m, 3H, PhH), 4.76 (s, 2H, NH₂), 4.69 (s, 2H, OCH₂), 4.25 (br s, 2H, NCH₂), 4.19 (br s, 2H, NCH₂), 3.77 (s, 3H, CH₃), 3.76 (s, 3H, CH₃), 3.69 (br s, 4H, N(CH₂)₂), 3.25 (t, 2H, CH₂), 3.07 (t, 2H, CH₂) ppm. Ex a m p l e 254 : S y n t h e s i s of 1 -(4-(5-amino-2-(3-methoxyphenethyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1-yl)-2-(4-bromophenoxy)ethanone

This compound was prepared from 2-(3-methoxyphenethyl)-7-(piperazin-1 -yl)thiazolo[5,4- d]pyrimidin-5-amine using 4-bromophenoxyacetic acid in a yield of 65%, according to the procedure for the synthesis of example 50.

H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.39 (d, 2H PhH), 7.20 (t, 1 H , PhH), 6.86 (d, 2H, PhH), 6.73-6.81 (m, 3H, PhH), 4.77 (s, 2H, NH₂), 4.72 (s, 2H, OCH₂), 4.25 (br s, 2H, NCH₂),

4.19 (br s, 2H, NCH₂), 3.77 (s, 3H, CH₃), 3.70 (br s, 2H, NCH₂), 3.64 (br s, 2H, NCH₂), 3.25 (t, 2H, CH₂), 3.07 (t, 2H, CH₂) ppm.

E x a m p l e 255 : S y n t h e s i s of 1 -(4-(5-amino-2-(3-methoxyphenethyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1-yl)-2-(4-chlorophenoxy)ethanone

This compound was prepared from 2-(3-methoxyphenethyl)-7-(piperazin-1 -yl)thiazolo[5,4- d]pyrimidin-5-amine using 4-chlorophenoxyacetic acid in a yield of 48%, according to the procedure for the synthesis of example 50.

1H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.26 (d, 2H, PhH), 7.20 (t, 1 H, PhH), 6.92 (d, 2H PhH), 6.73-6.82 (m, 3H, PhH), 4.73 (s, 2H, OCH₂), 4.71 (2, 2H, NH₂), 4.26 (br s, 2H, NCH₂),

4.20 (br s, 2H, NCH₂), 3.78 (s, 3H, CH₃), 3.70 (br s, 2H, NCH₂), 3.67 (br s, 2H, NCH₂), 3.26 (t, 2H, CH₂), 3.07 (t, 2H, CH₂) ppm.

Example 256 : Synthesis of 1-(4-(5-amino-2-(3,4-dimethoxyphenethyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1-yl)-2-(4-bromophenoxy)ethanone

This compound was prepared from 2-(3,4-dimethoxyphenethyl)-7-(piperazin-1 - yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-bromophenoxyacetic acid in a yield of 74%, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.39 (d, 2H, PhH), 6.87 (d, 2H, PhH), 6.72-6.78 (m, 3H, PhH), 4.73 (s, 2H, OCH₂), 4.69 (s, 2H, NH₂), 4.24 (br s, 4H, N(CH₂)₂), 3.85 (s, 6H, CH₃, CH₃), 3.71 (br s, 2H, NCH₂), 3.65 (br s, 2H, NCH₂), 3.24 (t, 2H, CH₂), 3.04 (t, 2H, CH₂) ppm. Example 257 : Synthesis of 1 -(4-(5-amino-2-(3,4-dimethoxyphenethyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1-yl)-2-(4-methoxyphenoxy)ethanone

This compound was prepared from 2-(3,4-dimethoxyphenethyl)-7-(piperazin-1 - yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-methoxyphenoxyacetic acid in a yield of 71%, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 6.73-6.93 (m, 7H, PhH), 4.76 (s, 2H, NH₂), 4.70 (s, 2H, OCH₂), 4.26 (br s, 2H, NCH₂), 4.22 (br s, 2H, NCH₂), 3.85 (s, 3H, CH₃), 3.84 (s, 3H, CH₃), 3.76 (s, 3H, CH₃), 3.71 (br s, 4H, N(CH₂)₂), 3.23 (t, 2H, CH₂), 3.04 (t, 2H, CH₂) ppm. E x a m p l e 25 8 : S y n t h e s i s o f 1-{4-<5-amino-2-(4-methylphenethyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1-yl)-2-(4-bromophenoxy)ethanone

This compound was prepared from 2-(4-methylphenethyl)-7-(piperazin-1 -yl)thiazolo[5,4- d]pyrimidin-5-amine using 4-bromophenoxyacetic acid in a yield of 47%, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.39 (d, 2H, PhH), 7.10 (s, 4H, PhH), 6.87 (d, 2H, PhH), 4.73 (s, 2H, OCH₂), 4.70 (s, 2H, NH₂), 4.27 (br s, 2H, NCH₂), 4.20 (br s, 2H, NCH₂), 3.64-3.72 (m, 4H, N(CH₂)₂), 3.24 (t, 2H, CH₂), 3.06 (t, 2H, CH₂), 2.32 (s, 3H, CH₃) ppm.

Example 259 : Synthesis of 1 -(4-(5-amino-2-(4-methylphenethyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4-methoxyphenoxy)ethanone

This compound was prepared from 2-(4-methylphenethyl)-7-(piperazin-1 -yl)thiazolo[5,4- d]pyrimidin-5-amine using 4-methoxyphenoxyacetic acid in a yield of 68%, according to the procedure for the synthesis of example 50.

H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.10 (s, 4H, PhH), 6.82-6.93 (m, 4H, PhH), 4.70 (s, 4H, NH₂, OCH₂), 4.27 (br s, 2H, NCH₂), 4.21 (br s, 2H, NCH₂), 3.76 (s, 3H, OCH₃), 3.70 (br s, 4H, N(CH₂)₂), 3.23 (t, 2H, CH₂), 3.05 (t, 2H, CH₂), 2.31 (s, 3H, CH₃) ppm

Example 260 : Synthesis of 1-<4-(5-amino-2-(4-methylphenethyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone

This compound was prepared from 2-(4-methylphenethyl)-7-(piperazin-1 -yl)thiazolo[5,4- d]pyrimidin-5-amine using 4-chlorophenoxyacetic acid in a yield of 51%, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.26 (d, 2H, PhH), 7.10 (s, 4H, PhH), 6.92 (d, 2H, PhH), 4.73 (s, 2H, OCH₂), 4.71 (s, 2H, NH₂), 4.27 (br s, 2H, NCH₂), 4.20 (br s, 2H, NCH₂), 3.66-3.72 (m, 4H, N(CH₂)₂), 3.23 (t, 2H, CH₂), 3.05 (t, 2H, CH₂), 2.31 (s, 3H, CH₃) ppm.

Example 261 : Synthesis of 4,6-dichloropyrimidine-2,5-diamine

A suspension of 2,5-diamino-4,6-dihydroxypyrimidine hydrochloride (5.0 g, 28 mmol)and tetraethylammonium chloride (27.8 g, 0.167 mmol) in phosphorus oxychloride (80 ml) was heated at 1 05°C for 20 hours. After cooling down to room temperature, the excess phosphorus oxychloride was distilled off under vacuum. The reaction mixture was poured into ice water and the pH was adjusted to 4, and the mixture was stirred for 1 hour at 50°C. The pH was adjusted to 7 and the product was extracted with ethyl acetate, washed with a saturated NaHC0₃ solution, brine and dried over Na₂S0₄. After removing the solvents under reduced pressure, the residue was purified by flash chromatography on silica (CH₂CI₂/MeOH 50:1 ), affording the title compound (3.21 g, 64 %). Examples 262 - 263 Synthesis of ferf-butyl 4-(5-amino-2-substituted-6- chloropyrimidin-4-yl)piperazine-1 -carboxylate analogues

General procedure

To a solution of a 4,6-dichloropyrimidine analogue (11.2 mmol) and DIPEA (2.9 ml, 16.8 mmol) in dioxane (40 ml) was added fert-butyl piperazine-1 -carboxylate (3.12 g, 16.8 mmol). The reaction mixture was heated at 100°C for overnight., After cooling, the volatile was removed under reduced pressure. The crude residue was diluted with CHCI₃ and was washed with a saturated NaHC0₃ solution, brine and dried over Na₂S0₄. After removing the solvents under reduced pressure, the residue was purified by flash chromatography on silica (CH₂CI₂/MeOH 50:1 ), affording the title compound.

The following compounds were synthesized according to this procedure :

Example 262 : Synthesis of tert-butyl 4-(2,5-diamino-6-chloropyrimidin-4-yl)piperazine-1- carboxylate

This compound was synthesized from 2,5-diamino-4,6-dichloropyrimidine, yielding the title compound in 94% yield.

Example 263 : Synthesis of terf-butyl 4-(5-amino-6-chloropyrimidin-4-yl)piperazine-1 - carboxylate

This compound was synthesized from 5-amino-4,6-dichloropyrimidine, yielding the title compound in 91 % yield.

Examples 264 - 265 Synthesis of ferf-butyl 4-(5-amino-2-substituted-6- mercaptopyrimidin-4-yl)piperazine-1 -carboxylate analogues

General procedure

To a solution of a ierf-butyl 4-(2,5-diamino-6-chloropyrimidin-4-yl)piperazine-1 -carboxylate analogue (6.1 mmol) in DMSO (15 ml) was added sodium sulfide nonahydrate (2.9 g, 12.1 mmol). The reaction mixture was heated at 50°C overnight., After cooling down to room temperature, water (15 ml) was added and the solution was evaporated under reduced pressure. The crude residue was diluted with water (20 ml) and neutralized with HCI. The precipitate was collected by filtration, washed with water and dried over P₂0₅, yielding the title compound.

The following compounds were synthesized according to this procedure :

Example 264 : Synthesis of tert-butyl 4-(2,5-diamino-6-mercaptopyrimidin-4-yl)piperazine-1 - carboxylate

This compound was synthesized from tert-butyl 4-(2,5-diamino-6-chloropyrimidin-4- yl)piperazine-1-carboxylate, yielding the title compound in 61 % yield.

Example 265 : Synthesis of terf-butyl 4-(5-amino-6-mercaptopyrimidin-4-yl)piperazine-1 - carboxylate

This compound was synthesized from tert-butyl 4-(5-amino-6-chloropyrimidin-4-yl)piperazine- 1-carboxylate, yielding the title compound in 80% yield.

Examples 266 - 269 : Synthesis of 7-(piperazin-1-yl)-2-substituted-thiazolo[5,4- d]pyrimidin-5-amine analogues

General procedure

To a solution of a tert-butyl 4-(6-mercaptopyrimidin-4-yl)piperazine-1-carboxylate analogue (6.1 mmol) in DMSO (10 ml) was added an appropriate aldehyde ( 2.36 mmol). The reaction mixture was heated at 150°C for 1 hour. After cooling down to room temperature, the mixture was diluted with ethyl acetate and washed with water, brine and dried over Na₂S0₄. After removing the solvents under reduced pressure, the residue was diluted with dichloromethane (5 ml) and treated with TFA (1.6 ml, 21 .4 mmol). The reaction mixture was stirred at room temperature overnight. The volatiles were evaporated under reduced pressure and the residue was diluted with water and neutralized with 1 N NaOH. The precipitate was collected by filtration, washed with water and dried over P₂0₅, yielding the title compound.

The following compounds were synthesized according to this procedure :

Example 266 : Synthesis of 7-(piperazin-1-yl)-2-(PYridin-3-yl)thiazolor5,4-dlpyrimidin-5-amine

This compound was synthesized using nicotinaldehyde, yielding the title compound in 56% yield.

Example 267 : Synthesis of 7-(piperazin-1-yl)-2-(pyridin-2-yl)thiazolo[5,4-dlpyrimidin-5-amine This compound was synthesized using picolinaldehyde, yielding the title compound in 44% yield.

Example 268 : Synthesis of 7-(piperazin-1 -yl)-2-(pyridin-4-yl)thiazolof5,4-dlpyrimidin-5-amine

This compound was synthesized using isonicotinaldehyde, yielding the title compound in 46% yield.

Example 269 : Synthesis of 2-(4-chlorophenyl)-7-(piperazin-1 -yl)thiazolof5,4-d1pyrimidin-5- amine This compound was synthesized using 4-chlorobenzaldehyde, yielding the title compound in 60% yield.

Example 270 : Synthesis of 1 -(4-(5-amino-2-(4-chlorophenyl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1-yl)-2-(4-methoxyphenoxy)ethanone

This compound was prepared from 2-(4-chlorophenyl)-7-(piperazin-1-yl)thiazolo[5,4- d]pyrimidin-5-amine using 4-methoxyphenoxyacetic acid in a yield of 63%, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, CDCI₃, 25 °C): 6 = 7.82 (d, 2H, PhH), 7.43 (d, 2H, PhH), 6.83-6.94 (m, 4H, PhH), 4.80 (s, 2H, NH₂), 4.72 (s, 2H, CH₂), 4.37 (br s, 2H, NCH₂), 4.32 (br s, 2H, NCH₂), 3.77 (s, 7H, CH₃, N(CH₂)₂) ppm.

Exa mple 271 : Synthesis of 1 -(4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1 -yl)-2-(4-methoxyphenoxy)ethanone

This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin- 5-amine using 4-methoxyphenoxyacetic acid in a yield of 52%, according to the procedure for the synthesis of example 50.

H NMR (300 MHz, DMSO, 25 °C): δ = 9.14 (s, 1 H, 2-pyridyl-H), 8.66 (d, J = 4.7 Hz, 1 H, 4- pyridyl-H), 8.30 (d, J = 5.5 Hz, 1 H, 6-pyridyl-H), 7.53-7.57 (m, 1 H, 5-pyridyl-H), 6.84-6.93 (m, 4H, PhH), 6.58 (s, 2H, NH₂), 4.81 (s, 2H, OCH₂), 4.34 (br s, 2H, CH₂), 4.23 (br s, 2H, CH₂), 3.70 (s, 3H, CH₃), 3.66 (br s, 4H, CH₂) ppm.

Example 272 : Synthesis of 1 -(4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1 -yl)-2-(4-fluorophenoxy)ethanone

This compound was prepared from 7-(piperazin-1 -yl)-2-(pyridin-3-yl)thiazolo[5,4-d)pyrimidin- 5-amine using 4-fluorophenoxyacetic acid in a yield of 67%, according to the procedure for the synthesis of example 50

1H NMR (300 MHz, DMSO, 25 °C): δ = 9.14 (d, J = 2.0 Hz, 1 H, 2-pyridyl-H), 8.66 (d, J = 3.6 Hz, 1 H, 4-pyridyl-H), 8.29 (d, J = 8.0 Hz, 1 H, 6-pyridyl-H), 7.53-7.57 (m, 1 H, 5-pyridyl-H), 7.12 (t, J = 8.9 Hz, 2H, PhH), 6.95-6.99 (m, 2H, PhH), 6.58 (s, 2H, NH₂), 4.89 (s, 2H, OCH₂), 4.37 (br s, 2H, CH₂), 4.24 (br s, 2H, CH₂), 3.66 (br s, 4H, CH₂) ppm.

Example 273 : Synthesis of 1 -(4-(5-amino-2-<pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1 -yl)-2-(4-trifluoromethoxyphenoxy)ethanone

This compound was prepared from 7-(piperazin-1 -yl)-2-(pyridin-3-yl)thiazolo[5,4-d)pyrimidin- 5-amine using 4-trifluoromethoxyphenoxyacetic acid in a yield of 45%, according to the procedure for the synthesis of example 50.

H NMR (300 MHz, DMSO, 25 °C): δ = 9.14 (d, J = 1.7 Hz, 1 H, 2-pyridyl-H), 8.66 (dd, J = 4.7 Hz, J = 1.5 Hz, 1 H, 4-pyridyl-H), 8.28 (dd, J = 8.2 Hz, j = 2.0 Hz, 1 H, 6-pyridyl-H), 7.53-7.57 (m, 1 H, 5-pyridyl-H), 7.30 (d, J = 8.6 Hz, 2H, PhH), 7.05 (d, J = 8.6 Hz, 2H, PhH), 6.58 (s, 2H, NHo), 4.96 (s, 2H, OCH₂), 4.38 (br s, 2H, CH₂), 4.25 (br s, 2H, CH₂), 3.65 (br s, 4H, CH₂) ppm.

Exa mple 274 : Synthesis of 1 -<4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7- y|)piperazin-1 -yl)-2-(4-chlorophenoxy)-2-methylpropan-1 -one

This compound was prepared from 7-(pipera2in-1-yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin- 5-amine using 2-(4-chlorophenoxy)-2-methylpropanoic acid in a yield of 45%, according to the procedure for the synthesis of example 50.

¹H N R (300 MHz, DMSO, 25 °C): δ = 9.12 (d, J = 2.3 Hz, 1 H, 2-pyridyl-H), 8.66 (d, J = 4.7 Hz, 1 H, 4-pyridyl-H), 8.27 (d, J = 8.0 Hz, 1 H, 6-pyridyl-H), 7.52-7.56 (m, 1 H, 5-pyridyl-H), 7.34 (d, J = 8.8 Hz, 2H, PhH), 6 86 (d, J = 8.8 Hz, 2H, PhH), 6.53 (s, 2H, NH₂), 3.94 (br s, 4H, CH₂), 3.69 (br s, 4H, CH₂), 1.59 (s, 6H, CH₃) ppm.

Exa mple 275 : Synthesis of 1-(4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1 -yl)-2-(m-tolyloxy)ethanone

This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin- 5-amine using 3-tolyloxyacetic acid in a yield of 45%, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, DMSO, 25 °C): δ = 9.13 (s, 1 H, pyridyl-H), 8.66 (d, 1 H, pyridyl-H), 8.28 (d, 1 H, pyridyl-H), 7.52-7.56 (m, 1 H, pyridyl-H), 7.16 (t, 1 H, PhH), 6.73-6.78 (m, 3H, PhH), 6.56 (s, 2H, NH₂), 4.85 (s, 2H, CH₂), 4.36 (br s, 2H, NCH₂), 4.23 (br s, 2H, NCH₂), 3.65 (br s, 4H, N(CH₂)₂), 2.27 (s, 3H, CH₃) ppm.

Example 276 : Synthesis of 4-(5-amino-2-{pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N- m-tolylpiperazine-1 -carboxamide

This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin- 5-amine using 3-tolyl isocyanate in a yield of 42%, according to the procedure for the synthesis of example 42.

H NMR (300 MHz, DMSO, 25 °C): δ = 9.13 (d, J = 1 .7 Hz, 1 H, 2-pyridyl-H), 8.66-8.68 (m, 1 H, 4-pyridyl-H), 8.52 (s, 1 H, NH), 8.28 (d, J = 5.9 Hz, 1 H, 6-pyridyl-H), 7.53-7.57 (m, 1 H, 5- pyridyl-H), 7.32 (s, 1 H, 2-tolyl-H), 7.29 (d, J = 8.5 Hz, 1 H, 6-tolyl-H), 7.12 (t, J = 7.6 Hz, 1 H, 5-tolyl-H), 6.77 (d, J = 7.0 Hz, 1 H, 4-tolyl-H), 6.57 (s, 2H, NH₂), 4.30 (br s, 4H, CH₂), 3.62 ( br s, 4H, CH₂), 2.26 (s, 3H, CH₃) ppm.

Example 277 : Synthesis of 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N- (4-chlorophenyl)piperazine-1 -carboxamide

This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin- 5-amine using 4-chlorophenyl isocyanate in a yield of 38%, according to the procedure for the synthesis of example 42. ¹H NMR (300 MHz, DMSO, 25 °C): δ = = 9.13 (d, J = 2.3 Hz, 1 H, 2-pyridyl-H), 8.73 (s, 1 H, NH), 8.66 (d, J = 4.7 Hz, 1 H, 4-pyridyl-H), 8.28 (d, J = 8.0 Hz, 1 H, 6-pyridyl-H), 7.54-7.57 (m, 1 H, 5-pyridyl-H), 7.53 (d, J = 8.9 Hz, 2H, PhH), 7.30 (d, J = 8.9 Hz, 2H, PhH), 6.60 (s, 2H, NH₂), 4.32 (br s, 4H, CH₂), 3.64 (br s, 4H, CH₂) ppm.

Example 278 : Synthesis of 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N- (4-methoxybenzyl)piperazine-1-carboxamide

This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin- 5-amine using 4-methoxybenzyl isocyanate in a yield of 40%, according to the procedure for the synthesis of example 42.

1H NMR (300 MHz, DMSO, 25 °C): δ = 9.11 (s, 1 H, 2-pyridyl-H), 8.66 (d, J = 4.6 Hz, 1 H, 4- pyridyl-H), 8.27 (d, J = 8.1 Hz, 1 H, 6-pyridyl-H), 7.53-7.57 (m, 1 H, 5-pyridyl-H), 7.21 (d, J = 8.8 Hz, 2H, PhH), 7.08 (s, 1 H, NH), 6.87 (d, J = 8.8 Hz, 2H, PhH), 6.54 (s, 2H, NH₂), 4.20 (br s, 6H, CH₂, NHCH^), 3.72 (s, 3H, CH₃), 3.50 (br s, 4H, CH₂) ppm

Example 279 : Synthesis of 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N- (4-cyanophenyl)piperazine-1 -carboxamide

This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin- 5-amine using 4-cyanophenyl isocyanate in a yield of 53%, according to the procedure for the synthesis of example 42.

¹H NMR (300 MHz, DMSO, 25 °C): δ = 9.14 (s, 1 H, NH), 9.09 (s, 1 H, 2-pyridyl-H), 8.67 (d, J = 4.9 Hz, 1 H, 4-pyridyl-H), 8.29 (d, J = 6.3 Hz, 1 H, 6-pyridyl-H), 7.69 (s, 4H, PhH), 7.54-7.57 (m, 1 H, 5-pyridyl-H), 6.57 (s, 2H, NH₂), 4.32 (br s, 4H, CH₂), 3.67 (br s, 4H, CH₂) ppm.

Example 280 : Synthesis of 1-(4-(5-amino-2-(4-chlorophenyl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1 -yl)-2- 4-methoxyphenoxy)ethanone

This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin- 5-amine using phenylmethanesulfonyl chloride in a yield of 40%, according to the procedure for the synthesis of example 41 .

¹H NMR (300 MHz, DMSO, 25 °C): δ = 9.14 (s, 1 H, 2-pyridyl-H), 8.67 (d, J = 4.4 Hz, 1 H, 4- pyridyl-H), 8.29 (d, J = 7.3 Hz, 1 H, 6-pyridyl-H), 7.53-7.57 (m, 1 H, 5-pyridyl-H), 7.36-7.41 (m, 5H, PhH), 6.59 (s, 2H, NH₂), 4.45 (s, 2H, SCH₂), 4.31 (br s, 4H, CH₂), 3.35 (br s, 4H, CH₂) ppm.

Example 281 : Synthesis of 1 -(4-(5-amino-2-(pyridin-4-yl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1-yl)-2-(4-chlorophenoxy)ethanone

This compound was prepared from 7-(piperazin-1 -yl)-2-(pyridin-4-yl)thiazolo[5,4-d]pyrimidin- 5-amine using 4-chlorophenoxyacetic acid in a yield of 43%, according to the procedure for the synthesis of example 50. ¹H NMR (300 MHz, DMSO, 25 °C): δ = 8.71 (d, 2H, pyridyl-H), 7.87 (d, 2H, pyridyl-H), 7.34 (d, 2H, PhH), 6.99 (d, 2H, PhH), 6.66 (s, 2H, NH₂), 4.93 (s, 2H, CH₂),4.37 (br s, 2H, NCH₂), 4.25 (br s, 2H, NCH₂), 3.65 (br s, 4H, N(CH₂)₂) ppm.

Example 282 : Synthesis of 1 -(4-(5-amino-2-(pyridin-2-yl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1-yl)-2-(4-chlorophenoxy)ethanone

This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-2-yl)thiazolo[5,4-d]pyrimidin- 5-amine using 4-chlorophenoxyactic acid in a yield of 57%, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, DMSO, 25 °C): δ = 8.63 (d, 1 H, pyridyl-H), 8.16 (d, 1 H, pyridyl-H), 7.96 (t, 1 H, pyridyl-H), 7.48 (t, 1 H , pyridyl-H), 7.33 (d, 2H, PhH), 6.99 (d, 2H, PhH), 6.54 (s, 2H, NH₂), 4.93 (s, 2H, CH₂),4.36 (br s, 2H, NCH₂), 4.25 (br s, 2H, NCH₂), 3.65 (br s, 4H, N(CH₂)₂) ppm.

Examples 283 - 287 : Synthesis of 7-(piperazin-1-yl)-2-substituted-thiazolo[5,4- d]pyrimidin-5-amine analogues

General procedure

A suspension of an appropriate carboxylic acid (0.42 mmol) in SOCI₂ (1 ml) was heated under reflux for 1 hour. After concentration under reduced pressure, the residue was redissolved in dioxane (1 ml) and added to a stirring solution of terf-butyl 4-(5-amino-6- mercaptopyrimidin-4-yl)piperazine-1-carboxylate (0.1 g, 0.32 mmol) and DIPEA (0.22 ml, 1 .28 mmol) in DMF (3 ml). The reaction mixture was stirred for 2 hours. The mixture was extracted with ethyl acetate, washed with water, brine and dried over sodium sulfate. After removing solvent under reduced pressure, the crude mixture was diluted with dioxane (5 ml) and 3M HCI in dioxane (1 ml) was added and the mixture was heated at 60°C for 5 hours. After cooling, the mixture was concentrated under reduced pressure and the residue was diluted with water and neutralized with 1 NaOH. The precipitate was collected by filtration, washed with water and dried over P₂0₅, yielding the title compound.

The following compounds were synthesized according to this procedure :

Example 283 : Synthesis of 2-(4-fluorophenethyl)-7-(piperazin-1-yl)thiazolo[5,4-dlpyrimidine

This compound was synthesized from terf-butyl 4-(5-amino-6-mercaptopyrimidin-4- yl)piperazine-1-carboxylate using 3-(4-fluorophenyl)propionic acid, yielding the title compound in 80% yield.

Example 284 : Synthesis of 2-(4-fluorophenyl)-7-(piperazin-1-yl)thiazolo[5,4-dlpyrimidine

This compound was synthesized from terf-butyl 4-(5-amino-6-mercaptopyrimidin-4- yl)piperazine-1-carboxylate using 4-fluorobenzoic acid, yielding the title compound in 74% yield. Example 285 : Synthesis of 2-(3-(4-fluorophenyl)propyl)-7-(piperazin-1-yl)thiazolo[5,4- dlpyrimidin-5-amine

This compound was synthesized from fert-butyl 4-(2,5-diamino-6-mercaptopyrimidin-4- yl)piperazine-1-carboxylate using 4-(4-fluorophenyl)butanoic acid, yielding the title compound in 48% yield.

Example 286 : Synthesis of 2-(4-(4-fluorophenyl)butyl)-7-(piperazin-1 -yl)thiazolo[5,4- dlpyrimidin-5-amine

This compound was synthesized from ie/ -butyl 4-(2,5-diamino-6-mercaptopyrimidin-4- yl)piperazine-1 -carboxylate using 4-(4-fluorophenyl)butanoic acid, yielding the title compound in 58% yield.

Example 287 : Synthesis of 2-(4-bromophenethyl)-7-(piperazin-1 -yl)thiazolo[5,4-dlpyrimidin- 5-amine

This compound was synthesized from iert-butyl 4-(2,5-diamino-6-mercaptopyrimidin-4- yl)piperazine-1-carboxylate using 3-(4-bromophenyl)propionic acid, yielding the title compound in 70% yield.

Examples 288 - 289 : Synthesis of 7-(N-piperazin-1 -yl)-2-substituted-thiazolo[5,4- d]pyrimidin-5-amine analogues

General procedure

To a solution of fert-butyl 4-(2,5-diamino-6-mercaptopyrimidin-4-yl)piperazine-1 -carboxylate (0.1 g, 0.31 mmol) and pyridine (37 μΙ, 0.46 mmol) in DMF (3 ml) was added an appropriate acid chloride (0.34 mmol). The reaction mixture was stirred for 2 hours. The mixture was extracted with ethyl acetate, washed with water, brine and dried over sodium sulfate. After removing solvent under reduced pressure, the crude mixture was diluted with dioxane (5 ml) and 3M HCI in dioxane (1 ml) was added and the mixture was heated at 60°C for 5 hours. After cooling, the mixture was concentrated under reduced pressure and the residue was diluted with water and neutralized with 1 N NaOH. The precipitate was collected by filtration, washed with water and dried over P₂0₅, yielding the title compound.

The following compounds were synthesized according to this procedure :

Example 288 : Synthesis of 2-pentyl-7-(piperazin-1-yl)thiazolof5,4-dlpyrimidin-5-amine

This compound was synthesized from tert-butyl 4-(2,5-diamino-6-mercaptopyrimidin-4- yl)piperazine-1 -carboxylate using hexanoyl chloride, yielding the title compound in 67% yield.

Example 289 : Synthesis of 7-(piperazin-1-yl)-2-p-tolylthiazolo[5,4-dlpyrimidin-5-amine

This compound was synthesized from tert-butyl 4-(2,5-diamino-6-mercaptopyrimidin-4- yl)piperazine-1 -carboxylate using p-toluoyl chloride, yielding the title compound in 80% yield. Example 290 : Synthesis of 1-(4-(5-amino-2-(3-(4-fluorophenyl)propyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone

T h i s c o m p o u n d w a s p r e p a r e d f ro m 2-(3-(4-fluorophenyl)propyl)-7-(piperazin-1 - yl)thia20lo[5,4-d]pyrimidin-5-amine using 4-chlorophenoxyacetic acid in a yield of 33%, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.24 (d, 2H, PhH), 7.10-7.15 (m, 2H, PhH), 6.96 (t, 2H, PhH), 6.90 (d, 2H, PhH), 4.71 (s, 4H, NH₂, OCH₂), 4.27 (br s, 2H, NCH₂), 4.23 (br s, 2H, NCH₂), 3.65-3.73 (m, 4H, N(CH₂)₂), 2.92 (t, 2H, CH₂), 2.68 (t, 2H, CH₂), 2.07 (quint, 2H, CH₂) ppm.

Example 291 : Synthesis of 1-(4-(5-amino-2-(3-(4-fluorophenyl)propyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4-methoxyphenoxy)ethanone

T h i s c o m p o u n d w a s p re p a r e d f ro m 2-(3-(4-fluorophenyl)propyl)-7-(piperazin-1 - yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-methoxyphenoxyacetic acid in a yield of 30%, according to the procedure for the synthesis of example 50.

1H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.7.1 1-7.16 (m, 2H, PhH), 6.94 (t, 2H, PhH), 6.82-6.93 (m, 4H, PhH), 4.71 (s, 2H, NH₂), 4.70 (s, 2H, OCH₂), 4.29 (br s, 2H, NCH₂), 4.24 (br s, 2H, NCH₂), 3.76 (s, 3H, CH₃), 3.71 (br s, 4H, N(CH₂)₂), 2.94 (t, 2H, CH₂), 2.70 (t, 2H, CH₂), 2.08 (quint, 2H, CH₂) ppm

Example 292 : Synthesis of 1-(4-(5-amino-2-(4-(4-fluorophenyl)butyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone

This compound was prepared from 2-(4-(4-fluorophenyl)butyl)-7-(piperazin-1-yl)thiazolo[5,4- d]pyrimidin-5-amine using 4-chlorophenoxyacetic acid in a yield of 23%, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.28 (d, 2H, PhH), 7.12-7.16 (m, 2H PhH), 7.00 (t, 2H, PhH), 6.94 (d, 2H PhH), 4.75 (s, 4H, NH₂, OCH₂), 4.30 (br s, 2H, NCH₂), 4.26 (br s, 2H, NCH₂), 3.75 (t, 2H, NCH₂), 3.69 (t, 2H, NCH₂), 2.98 (t, 2H, CH₂), 2.66 (t, 2H, CH₂), 1.78-1.87 (m, 2H, CH₂), 1.70-1 .74 (m, 2H CH₂) ppm

Example 293 : Synthesis of 1-(4-(5-amino-2-(4-(4-fluorophenyl)butyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4-methoxyphenoxy)ethanone

This compound was prepared from 2-(4-(4-fluorophenyl)butyl)-7-(piperazin-1 -yl)thiazolo[5,4- d]pyrimidin-5-amine using 4-methoxyphenoxyacetic acid in a yield of 35%, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.08-7.13 (m, 2H, PhH), 6.95 (t, 2H, PhH), 6.82-6.93 (m, 4H, PhH), 4.69 (s, 4H, NH_2l OCH₂), 4.27 (br s, 2H, NCH₂), 4.23 (br s, 2H, NCH₂), 3.76 (s, 3H, CH₃), 3.71 (br s, 4H, N(CH₂)₂), 2.95 (t, 2H, CH₂), 2.63 (t, 2H, CH₂), 1.75-1.84 (m, 2H, CH₂), 1 .60-1.72 (m, 2H CH₂) ppm Example 294 : Synthesis of 1 -(4-(5-amino-2-p-tolylthiazolo[5,4-d]pyrimidin-7- yl)piperazin-1-yl)-2-(4-methoxyphenoxy)ethanone

This compound was prepa red from 7-(piperazin-1-yl)-2-p-tolylthiazolo[5,4-d]pyrimidin-5- amine using 4-methoxyphenoxyacetic acid in a yield of 41%, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.78 (d, 2H, PhH), 7.25 (d, 2H, PhH), 6.83-6.94 (m, 4H, PhH), 4.76 (s, 2H, NH₂), 4.72 (s, 2H, CH₂), 3.77 (br s, 7H, OCH₃, N(CH₂)₂), 42.41 (s, 3H, CH₃) ppm

Example 295 : Synthesis of 1 -(4-(5-amino-2-p-tolylthiazolo[5,4-d]pyrimidin-7- yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone

Th is compound was prepared from 7-(piperazin-1 -yl)-2-p-tolylthiazolo[5,4-d]pyrimidin-5- amine using 4-chlorophenoxyacetic acid in a yield of 32%, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.78 (d, 2H, PhH), 7.24-7.27 (m, 4H, PhH), 6.93 (d, 2H, PhH), 4.77 (s, 2H, NH₂), 4.75 (s, 2H, CH₂), 4.38 (br s, 2H, NCH₂), 4.32 (br s, 2H, NCH₂), 3.71-3.79 (m, 4H, N(CH₂)₂), 2.41 (s, 3H, CH₃) ppm

Example 296 : Synthesis of 1-{4-(5-amino-2-pentylthiazolo[5,4-d]pyrimidin-7- yl)piperazin-1-yl)-2-(4-methoxyphenoxy)ethanone

Th is compound was prepared from 2-pentyl-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5- amine using 4-methoxyphenoxyacetic acid in a yield of 34%, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, DMSO, 25 °C): δ = 6.89-6.90 (m, 4H, PhH), 6.30 (s, 2H, NH₂), 4.79 (s, 2H, CH₂), 4.26 (br s, 2H, NCH₂), 4.13 (br s, 2H, NCH₂), 3.69 (s, 3H, OCH₃), 3.58 (br s, 4H, N(CH₂)₂), 2.91 (t, 2H, CH₂), 1 .71 (qiuint, 2H, CH₂), 1.31 -1.36 (m, 4H, CH₂, CH₂), 0.87 (t, 3H, CH₃) ppm.

E x a m p l e 2 97 : S y n t h e s i s o f 1-(4-(5-amino-2-pentylthiazolo[5,4-d]pyrimidin-7- yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone

This compound was prepared from 2-pentyl-7-(piperazin-1 -yl)thiazolo[5,4-d]pyrimidin-5- amine using 4-chlorophenoxyacetic acid in a yield of 30%, according to the procedure for the synthesis of example 50.

H NMR (500 MHz, CDCI₃, 25 °C): δ = 7.25 (d, 2H, PhH), 6.91 (d, 2H, PhH), 4.73 (s, 2H, OCH2), 4.69 (s, 2H, NH₂), 4.29 (br s, 2H, NCH₂), 4.24 (br s, 2H, NCH₂), 3.73 (br s, 2H, NCH₂), 3.68 (br s, 2H, NCH₂), 2.92 (t, 2H, CH₂), 1.78 (quint, 2H, CH₂), 1.37 (m, 4H, CH₂, CH₂), 0.91 (t, 3H, CH₃) ppm

E x a m p l e 29 8 : S y n t h e s i s o f 1 -(4-(5-amino-2-(4-bromophenethyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4-methoxyphenoxy)ethanone This compound was prepa red from 2-(4-bromophenethyl)-7-(piperazin-1 -yl)thiazolo[5,4- d]pyrimidin-5-amine using 4-methoxyphenoxyacetic acid in a yield of 40%, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.40 (d, 2H, PhH), 7.07 (d, 2H, PhH), 6.82-6.93 (m, 4H, PhH), 4.71 (s, 2H, NH₂), 4.70 (s, 2H, OCH₂), 4.23 (br s, 2H, NCH₂), 4.19 (br s, 2H, NCH₂), 3.77 (s, 3H, CH₃), 3.67-3.75 (m, 4H, N(CH₂)₂), 3.23 (t, 2H, CH₂), 3.05 (t, 2H, CH₂) ppm

Example 299 : Synthesis of 1 -(4-(5-amino-2-(4-bromophenethyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1-yl)-2-(4-chlorophenoxy)ethanone

This compound was prepa red from 2-(4-bromophenethyl)-7-(piperazin-1-yl)thiazolo[5,4- d]pyrimidin-5-amine using 4-chlorophenoxyacetic acid in a yield of 29%, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.40 (d, 2H, PhH), 7.26 (d, 2H, PhH), 7.07 (d, 2H, PhH), 6.92 (d, 2H, PhH), 4.73 (s, 2H, OCH₂), 4.71 (s, 2H, NH₂), 4.20 (br s, 4H, N(CH₂)₂), 3.71 (t, 2H, NCH₂), 3.65(t, 2H, NCH₂). 3.23 (t, 2H, CH₂), 3.05 (t, 2H, CH₂) ppm

Example 300 : Synthesis of 1 -(4-(2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1 -yl)-2-(4-methoxyphenoxy)ethanone

T h i s co mpo u n d wa s pre pa re d fro m 2-(4-fluorophenyl)-7-(piperazin-1 -yl)thiazolo[5,4- d]pyrimidine using 4-methoxyphenoxyacetic acid in a yield of 51 %, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.44 (s, 1 H, CH), 7.95-8.00 (m, 2H, PhH), 7.19 (t, 2H, PhH), 6.83-6.95 (m, 4H, PhH), 4.73 (s, 2H, CH₂), 4.42 (br s, 4H, N(CH₂)₂), 3.81 (br s, 4H, N(CH₂)₂), 3.77 (s, 3H, CH₃) ppm.

E x a m p l e 30 1 : S y n t h e s i s of 1 -(4-(2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1 -yl)-2-{4-chlorophenoxy)ethanone

This compound was prepared from 2-(4-fluorophenyl)-7-(piperazin-1 -yl)thiazolo[5,4- djpyrimidine using 4-chlorophenoxyacetic acid in a yield of 48%, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.45 (s, 1 H, CH), 7.95-8.00 (m, 2H, PhH), 7.27 (d, 2H, PhH), 7.19 (d, 2H, PhH), 6.93 (d, 2H, PhH), 4.76 (s, 2H, CH₂), 4.43 (br s, 4H, N(CH₂)₂), 3.81 (br s, 4H, N(CH₂)₂) ppm.

Example 302 : Synthesis of 1 -(4-(2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1 -yl)-2-(4-methoxyphenoxy)ethanone

Th is co mpou nd was prepa red from 2-(4-fluorophenethyl)-7-(piperazin-1-yl)thiazolo[5,4- djpyrimidine using 4-methoxyphenoxyacetic acid in a yield of 39%, according to the procedure for the synthesis of example 50. ¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.40 (s, 1 H, CH), 7.14-7.19 (m, 2H, PhH), 6.97 (t, 2H, PhH), 6.82-6.91 (m, 4H, PhH), 4.71 (s, 2H, NH₂), 4.31 (br s, 4H, N(CH₂)₂), 3.76 (s, 3H, CH₃), 3.74(br s, 4H, N(CH₂)₂), 3.34 (t, 2H, CH₂), 3.12 (t, 2H, CH₂) ppm.

Example 303 : Synthesis of 1 -(4-(2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1-yl)-2-(4-chlorophenoxy)ethanone

This compou nd was pre pa red from 2-(4-fluorophenethyl)-7-(piperazin-1 -yl)thiazolo[5,4- d]pyrimidine using 4-chlorophenoxyacetic acid in a yield of 48%, according to the procedure for the synthesis of example 50.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.41 (s, 1 H, CH), 7.26 (d, 2H, PhH), 7.14-7.19 (m, 2H, PhH), 6.97 (t, 2H, PhH), 6.91 (d, 2H, PhH), 4.74 (s, 2H, NH₂), 4.31 (br s, 4H, N(CH₂)₂), 3.75 (br s, 2H, NCH₂), 3.69 (br s, 2H, NCH₂), 3.35 (t, 2H, CH₂), 3.12 (t, 2H, CH₂) ppm.

Example 304 : Synthesis of thieno[2,3-d]pyrimidin-4(3H)-one

A solution of methyl 2-aminothiophene-3-carboxylate (3.0 g, 19.1 mmol) in formamide (95 ml) was heated at 190°C for 4 hours. The cooled mixture was poured into water. The precipitate was filtered off, washed with water and dried. The crude product was purified by silica gel chromatography (CH₂CI₂/MeOH 50:1 ) to yield the title compound as a white solid (1.93 g, 66%).

¹H NMR (300 MHz, DMSO, 25 °C): δ = 12.49 (s, 1 H, NH), 8.13 (s, 1 H, CH), 7.58 (d, J = 5.8 Hz, 1 H, CH), 7.39 (d, J = 5.8 Hz, 1 H, CH) ppm.

HRMS: calcd for C₆H₅N₂OS 153.01226, found 153.01155.

Example 305 : Synthesis of 2-methylthieno[2,3-d]pyrimidin-4(3H)-one

To a solution of ethyl 2-aminothiophene-3-carboxylate (0.1 g, 0.64 mmol) and acetonitrile (50 μΙ, 0.95 mmol) in dioxane (3 ml) was added 4M HCI in dioxane (3 ml). The mixture was stirred at room temperature overnight. The solvents were removed under reduced pressure. The residue was diluted with water and made alcaline with a saturated aqueous sodium bicarbonate solution. The precipitate was filtered off, washed with water and dried. The crude residue was purified by flash chromatography on silica gel (CH₂CI₂/MeOH 50:1 ) to yield the title compound as a white solid (42 mg, 40 %).

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 12.92 (s, 1 H, NH), 7.46 (d, J = 5.8 Hz, 1 H, CH), 7.21 (d, J = 5.8 Hz, 1 H, CH), 2.61 (s, 3H, CH₃) ppm.

Example 306 : Synthesis of 2-aminothieno[2,3-d]pyrimidin-4(3H)-one

A mixture of ethyl 2-aminothiophene-3-carboxylate (0.5 g, 3.18 mmol), chloroformamidine hydrochloride (0.91 g, 7.95 mmol) and dimethylsulfone (1.50 g, 15.9 mmol) was heated at 120-130°C for 30 minutes. After cooling down to room temperature, water (10 ml) was added and ammonium hydroxide was used to neutralize the suspension. The solid was filtered off, washed with water and dried. The crude residue was purified by flash chromatography on silica gel (CH₂CI₂/MeOH 10:1 ) to yield the title compound as a white solid (0.24 g, 45 %). H NMR (300 MHz, D SO, 25 °C): δ = 10.89 (s, 1 H, NH), 7.09 (d, J = 5.8 Hz, 1 H, CH), 6.97 (d, J = 5.8 Hz, 1 H, CH), 6.52 (s, 2H, NH₂) ppm.

HRMS: calcd for C₆H₆N₃OS 168.02316, found 168.02239.

Example 307 : Synthesis of 4-chlorothieno[2,3-d]pyrimidine

DMF (1.53 ml, 19 7 mmol) in dichloromethane (50 ml) was cooled to 0°C and oxalyl chloride (2.5 ml, 29.6 mmol) was added slowly forming a white gel. Thieno[2,3-d]pyrimidin-4(3H)-one (1.5 g, 9.86 mmol) was added and the reaction mixture was refluxed for 3 hours. The mixture was cooled down to room temperature and poured into water. The mixture was extracted with dichloromethane, dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by silica gel chromatography (EtOAc/hexane 15:1 ) to yield the title compound as a white solid (1.61 g, 96%).

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.88 (s, 1 H, CH), 7.64 (d, J = 6.0 Hz, 1 H, CH), 7.47 (d, J = 5.8 Hz, 1 H, CH) ppm.

HRMS: calcd for C₆H₄CIN₂S 170.97837, found 170.97804.

Examples 308 and 309 : Synthesis of 6-bromo-4-chlorothieno[2,3-d]pyrimidine and 6- bromo-2-butyl-4-chlorothtenol2,3-d]pyrimidine

n-BuLi (1 .6 M in hexane, 1 .9 ml, 2.5 mmol) in THF (8 ml) was cooled to -78°C. 4- Chlorothieno[2,3-d]pyrimidine (0.34 g, 2.0 mmol) was dissolved in THF (2 ml) and slowly added to the reaction mixture over 5 minutes. After 20 min, CBr₄ (0.73 g, 2.2 mmol) in THF (3 ml) was slowly added to the reaction mixture. The temperature was maintained at -78°C for 20 minutes and then warmed to room temperature for 2 hours. The mixture was poured into water and extracted with chloroform, dried over sodium sulfate, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (EtOAc/hexane 40:1 ) to yield two pure compounds a white solid (example 203: 0.13 g, 25% and example 204: 0.16 g, 26 %)·

Example 308

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.82 (s, 1 H, H-2), 7.49 (s, 1 H, H-5) ppm.

Example 309

Ή NMR (300 MHz, CDCI₃, 25 °C ) : δ = 7.4 (s , 1 H , H-5), 2.99 (t, J= 7.5 Hz, 2H, CH2CH₂CH₂CH₃), 1.83 (quint, J= 7.6 Hz, 2H, CH₂CH2CH₂CH₃), 1.42 (sixtet, J= 7.4 Hz, 2H, CH₂CH₂CH2CH₃), 0.96 (t, J= 7.4 Hz, 2H, CH₂CH₂CH₂CH₃) ppm.

Example 310 : Synthesis of 4-Chloro-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine A s o l u t i o n o f 6-bromo-4-chlorothieno[2,3-d]pyrimidine (0.12 g, 0.48 mmol), 4- fluorophenylboronic acid (67 mg, 0.48 mmol), K₂C0₃ (0.266 g, 1.92 mmol) and Pd(PPh₃)₄ in dioxane/H₂0 (3:1 , 3 ml) was refluxed under N₂ for 2 hours. After cooling to room temperature, 1 HCI was added slowly to neutralize the mixture to pH=7-8. The mixture was extracted with CH₂CI₂, washed with water and brine and dried over Na₂S0₄. After removing the solvents under reduced pressure, the crude residue was purified by silica gel chromatography (hexane/EtOAc 30:1 ) to yield the title compound as a pale yellow solid (60 mg, 47 %).

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.82 (s, 1 H, CH-2), 7.70-7.74 (m, 2H, PhH), 7.52 (s, 1 H, CH-5), 7.19 (t, J= 8.4 Hz, 2H, PhH) ppm.

HRMS: calcd for C₁₂H₇CIFN₂S 265.00025, found 264.99949.

Example 311 : Synthesis of 2-butyl-4-chloro-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine

This compound was prepared from example 309 in a yield of 57%, according to the procedure for the synthesis of example 310.

1H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.57-7.62 (m, 2H, PhH), 7.36 (s, 1 H, H-5), 7.08 (t, J= 8.4 Hz, 2H , PhH), 2.94 (t, J= 7.6 Hz, 2H , CH_₂CH₂CH₂CH₃), 1 .78 (quint, J= 7.6 Hz, 2H, CH₂CH₂CH₂CH₃) , 1 .36 (sixtet, J= 7.5 Hz, 2H, CH₂CH₂CH₂CH₃) , 0.89 (t, J= 7.4 Hz, 2H, CH₂CH₂CH₂CH₃) ppm.

HRMS: calcd for C₁₆H₁₅CIFN₂S 321.06285, found 321.06206.

Example 312 : Synthesis of 2-(4-chlorophenoxy)-1-(4-(6-(4-fluorophenyl)thieno[2,3- d]pyrimidin-4-yl)piperazin-1 -yl)ethanone

To a solution of 4-chloro-6-(4-fluoropheny!)thieno[2,3-d]pyrimidine (20 mg, 0.08 mmol) and triethylamine (42 μΙ, 0.3 mmol) in dioxane (1 ml) was added 2-(4-chlorophenoxy)-1 - (piperazin-l -yl)ethanone (25 mg, 0.1 mmol). The mixture was heated at 60°C for 2 hours. After cooling down to room temperature, the solvents were removed under reduced pressure. The crude residue was purified by silica gel chromatography (CH₂CI₂/MeOH 50:1 ) to yield the title compound as a white solid (27 mg, 75 %).

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.51 (s, 1 H, CH-2), 7.60-7.65 (m, 2H, PhH), 7.36 (s, 1 H, CH-5), 7.26 (d, J= 8.8 Hz, PhH), 7.14 (t, J= 8.5 Hz, 2H, PhH), 6.91 (d, J= 8.8 Hz, 2H, PhH), 4.75 (s, 2H, CH₂), 3.95 (br s, 4H, NCH₂), 3.82 (br s, 4H, NCH₂) ppm.

HRMS: calcd for C₂₄H₂₁CIFN₄0₂S 483.10578, found 483.10438.

Exa mple 313 : Synthesis of 1 -(4-(2-butyl-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4- yl)piperazin-1 -yl)-2-<4-chlorophenoxy)ethanone

This compound was prepared from example 31 1 in a yield of 57%, according to the procedure for the synthesis of example 312. ¹H NMR (300 MHz, CDCI₃, 25 °C): 6 = 7.58-7.63 (m, 2H, PhH), 7.32 (s, 1 H, CH-5), 7.26 (d, J= 9.0 Hz, PhH), 7.13 (t, J= 8.6 Hz, 2H, PhH), 6.91 (d, J= 9.0 Hz, 2H, PhH), 4.74 (s, 2H, CH₂), 3.95 (br s, 4H, N(CH₂)₂), 3.81 (br s, 4H, CON(CH₂)₂), 2.84 (t, J= 7.6 Hz, 2H , CH2CH₂CH₂CH₃), 1.80 (quint, J= 7.6 Hz, 2H, CH₂CH2CH₂CH₃) , 1 42 (sixtet, J= 7.6 Hz, 2H, CH₂CH₂CH2CH₃) , 0.96 (t, J= 7.6 Hz, 2H, CH₂CH₂CH₂CH₃) ppm.

HRMS: calcd for C₂₈H₂₉CIFN₄0₂S 539.16838, found 539.16680.

Example 314 : Synthesis of A/-(3-chloro-4-fluorophenyl)-6-{4-fluorophenyl)thieno[2,3- d]pyrimidin- -amine

To a solution of 4-chloro-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine (40 mg, 0.15 mmol) in 1 ,2- dichloroethane/r-BuOH (1 :1 , 1 ml) was added 3-chloro-4-fluoroaniline (22 mg, 0.15 mmol). The mixture was heated at 90°C for 2 days. After cooling down to room temperature, the solvents were removed under reduced pressure. The crude residue was purified by silica gel chromatography (CH₂CI₂/MeOH 100:1 ) to yield the title compound as a white solid (28 mg, 50 %).

1H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.61 (s, 1 H, H-2), 7.89 (dd, J= 6.5 Hz, J= 2.6 Hz, 1 H, PhH), 7.62-7.67 (m, 2H, PhH), 7.48-7.53 (m, 1 H, PhH), 7.28 (s, 1 H, H-5), 7.13-7.26 (m, 3H, PhH), 6.87 (s, 1 H, NH) ppm.

HRMS: calcd for deHnCIF^aS 374.03303, found 374.03216.

Example 315 Synthesis of 2-butyl-A/-(3-chloro-4-fluorophenyl)-6-(4- fluorophenyl)thieno[2,3-d]pyrimidin- -amine

This compound was prepared from example 31 1 in a yield of 47%, according to the procedure for the synthesis of example 314.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.03 (dd, J= 6.30 Hz, J= 2.3 Hz, 1 H, PhH), 7.59-7.64 (m, 2H, PhH), 7.48-7.53 (m, 1 H, PhH), 7.23 (s, 1 H, H-5), 7.10-7.19 (m, 3H, PhH, PhH), 6.89 (s, 1 H, NH), 2.93 (t, J= 7.5 Hz, 2H, CH2CH₂CH₂CH₃), 1.87 (quint, J= 7.6 Hz, 2H, CH₂CH2CH₂CH₃), 1 .45 (sixtet, J= 7.5 Hz, 2H, CH₂CH₂CH2CH₃) , 0.98 (t, J= 7.3 Hz, 2H, CH₂CH₂CH₂CH₃) ppm.

Example 316 : Synthesis of 2-(4-fluorophenyl)acetaldehyde

To a stirred suspension of pyridinium chlorochromate (6.9 g, 21.4 mmol) in CH₂CI₂ (100 ml) was added a solution of 2-(4-fluorophenyl)ethanol (3.0 g, 21.4 mmol) in CH₂CI₂ (10 ml). The resulting suspension was stirred for 2 hours at room temperature and was then diluted with ether. The resulting suspension was filtered through a pad of Celite and washed with ether. The solvents were removed under reduced pressure to yield the crude title compound as a green oil (2.6 g, 86 %), which was used as such for further reaction.

1H NMR (300 MHz, CDCI₃, 25 °C): δ = 9.75 (s, 1 H, CH), 7.19-7.22 (m, 2H, PhH), 7.06 (t, J= 8.5 Hz, PhH), 3.68 (s, 2H, CH₂) ppm. Example 317 : Synthesis of ethyl 2-amino-5-(4-fluorophenyl)thiophene-3-carboxylate

Triethylamine (0.98 ml, 7.01 mmol) was added to a stirred suspension of ethyl cyanoacetate (2.79 ml, 13.7 mmol) and sulfur (0.44 g, 13.7 mmol) in DMF (70 ml). A solution of 2-(4- fluorophenyl)acetaldehyde (example 316, 1.9 g, 13.7 mmol) in DMF (5 ml) was added dropwise over a period of 50 minutes, while the temperature was maintained at 50°C. The solution was cooled down to room temperature and stirred overnight. The reaction was poured into water and the aqueous phase was extracted with diethylether. The organic layer was separated and washed with water, brine and dried over Na₂S0 . The solvents were evaporated and the crude residue was purified by flash chromatography on silica gel (EtOAc/Hexane 1 :15) to yield the title compound as a white solid (1 .3 g, 38 %).

¹H NMR (300 MHz, CDCI_3l 25 °C): δ = 7.33-7.39 (m, 2H, PhH), 7.14 (s, 1 H, CH), 6.99 (t, J= 8.6 Hz, PhH), 6.06 (s, 2H, NH₂), 4.29 (q, J= 7.1 , 2H, CH₂), 1.36 (t, J= 7.1 , 3H, CH₃) ppm.

HRMS: calcd for C₁₃H₁₃FN0₂S 266.06510, found 266.06425.

Example 318 : Synthesis of ethyl 2-amino-5-phenyl-thiophene-3-carboxylate

This compound was synthesized using the procedure as described for example 317, using phenylacetaldehyde.

Example 319 : Synthesis of 6-(4-fluorophenyl)-2-methylthieno[2,3-d]pyrimidin-4(3H)- one

To a solution of ethyl 2-amino-5-(4-fluorophenyl)thiophene-3-carboxylate (0.3 g, 1.13 mmol) and acetonitrile (0.56 ml, 1 1.3 mmol) in dioxane (4 ml) was added 4M HCI in dioxane (4 ml). The mixture was stirred at room temperature overnight. The solvents were removed under reduced pressure. The residue was diluted with water and made alcaline with a saturated aqueous sodium bicarbonate solution. The precipitate was filtered off, washed with water and dried. The crude residue was purified by flash chromatography on silica gel (CH₂CI₂/MeOH 60:1 ) to yield the title compound as a white solid (0.29 g, 81 %).

¹H NMR (300 MHz, DMSO, 25 °C): δ = 12.47 (s, 1 H, NH), 7.76-7.81 (m, 2H, PhH), 7.71 (s, 1 H, CH), 7.28 (t, J= 8.7 Hz, PhH), 2.38 (s, 3H, CH₃) ppm.

HRMS: calcd for C₁₃H₁₀FN₂OS 261.04979, found 261.04889.

Exa mple 320 : Synthesis of 2-amino-6-(4-fluorophenyl)thieno[2,3-d]pyrimiclin-4(3H)- one

A mixture of ethyl 2-amino-5-(4-fluorophenyl)thiophene-3-carboxylate (0.3 g, 1 .13 mmol), chloroformamidine hydrochloride (0.33 g, 2.83 mmol) and dimethylsulfone (0.53 g, 5.65 mmol) was heated at 120-1 30°C for 30 minutes. After cooling down to room temperature, water (10 ml) was added and ammonium hydroxide was used to neutralize the suspension. The solid was filtered off, washed with water and dried. The crude residue was purified by flash chromatography on silica gel (CH₂CI₂/MeOH 10: 1) to yield the title compound as a white solid (0.28 g, 95 %).

¹H NMR (300 MHz, DMSO, 25 °C): δ = 1 1 .05 (s, 1 H, NH), 7.66-7.71 (m, 2H, PhH), 7.51 (s, 1 H, CH), 7.23 (t, J= 8.8 Hz, PhH), 6.73 (s, 2H, NH₂) ppm.

HRMS: calcd for C₁₂H₉FN₃OS 262.04504, found 262.04413.

Example 321 : Synthesis of 2-amino-6-phenyl-thieno[2,3-d]pyrimidin-4(3H)-one

This compound was synthesized from example 318 according to the procedure mentioned for the synthesis of example 320.

MS m/z (%) : 244 ([M+H]⁺, 100)

Example 322 : Synthesis of 6-(4-fluorophenyl)-2-phenylthieno[2,3-d]pyrimidin (3H)- one

To a solution of ethyl 2-amino-5-(4-fluorophenyl)thiophene-3-carboxylate (0.2 g, 0.75 mmol) and benzonitrile (0.23 g, 2.26 mmol) in dioxane (4 ml) was added 4M HCI in dioxane (4 ml). The mixture was stirred at room temperature overnight. The precipitate was filtered off, washed with diethyl ether and dried. The solid was redissolved in DMF and the mixture was heated at 100°C for 3 hours. The solvents were removed under reduced pressure. The residue was diluted with water and the solid was filtered off, washed with water and dried. The crude residue was purified by flash chromatography on silica gel (CH₂CI₂/MeOH 60:1) to yield the title compound as a white solid (0.20 g, 82 %).

1H NMR (300 MHz, DMSO, 25 °C): δ = 12.78 (s, 1 H, NH), 8.16 (d, J= 7.4 Hz, 2H, PhH), 7.81 - 7.85 (m, 3H, PhH), 7.57 (s, 1 H, CH), 7.55 (t, J= 7.4 Hz, 2H, PhH), 7.30 (t, J= 8.5 Hz, PhH) ppm.

HRMS: calcd for C₁₈Hi₂FN₂OS 323.06544, found 323.06461.

Exa mple 323 : Synthes is of ethyl 6-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno[2,3- d]pyrimidine-2-carboxylate

This compound was prepared from example 317 in a yield of 96%, according to the procedure for the synthesis of example 322, using ethyl cyanoformate.

¹H NMR (300 MHz, DMSO, 25 °C): δ = 12.97 (s, 1 H, NH), 7.91 (s, 1 H, CH), 7.86-7.89 (m, 2H, PhH), 7.32 (t, J= 8.8 Hz, PhH), 4.38 (q, J= 7.1 Hz, 2H, CH₂), 1.36 (t, J= 7.1 Hz, 3H, CH₃) ppm.

HRMS: calcd for C₁₅H_l2FN₂0₃S 319.05527, found 319.05433.

Example 324 : Synthesis of ethyl 2-(6-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno[2,3- d]pyrimidin-2-yl)acetate

This compound was prepared from example 317 in a yield of 93%, according to the procedure for the synthesis of example 322, using ethyl cyanoacetate. ¹H NMR (300 MHz, DMSO, 25 °C): δ = 12.63 (s, 1 H, NH), 7.79-7.84 (m, 2H, PhH), 7.77 (s, 1 H, H-5), 7.30 (t, J= 8.7 Hz, PhH), 4.15 (q, J= 7.1 Hz, 2H, OCH₂), 3.79 (s, 2H, CH₂), 1 .21 (t, J= 7.1 Hz, 3H, CH₃) ppm.

HRMS: calcd for C₁₆H₁₄FN₂0₃S 333.07092, found 333.07010.

E x a m p l e 3 2 5 : S y n t h e s i s o f 2-<4-chlorophenoxy)-1-(4-(6-(4-fluorophenyl)-2- methylthieno[2,3-d]pyrimidin-4-yl)piperazin-1 -yl)ethanone

To a solution of 6-(4-fluorophenyl)-2-methylthieno[2,3-d]pyrimidin-4(3H)-one (40 mg, 0.15 mmol) and BOP (88 mg, 0.20 mmol) in CH₃CN (1 ml) was added DBU (34 μΙ, 0.23 mmol). After stirring for 1 0 minutes at room temperature, 2-(4-chlorophenoxy)-1 -(piperazin-1- yl)ethanone (59 mg, 0.23 mmol) was added. The reaction was stirred at room temperature overnight and then heated at 60°C for 4 hours. The solvents were removed under reduced pressure, and the crude residue was purified by flash chromatography on silica gel (CH₂CI₂/MeOH 100: 1 ) to yield the title compound as a white solid (66 mg, 86%).

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.56-7.61 (m, 2H, PhH), 7.31 (s, 1 H, CH), 7.25 (d, J= 8.9 Hz, 2H, PhH), 7.11 (t, J= 8.5 Hz, PhH), 6.90 (d, J= 8.9 Hz, 2H, PhH), 4.74 (s, 2H, CH₂), 3.92 (br s, 4H, NCH₂), 3.80 (br s, 4H, NCH₂), 2.60 (s, 3H, CH₃) ppm.

HRMS: calcd for C₂₅H₂₃CIFN„0₂S 497.12143, found 497.1 1983.

Example 326 : Synthesis of 1-(4-(2-amino-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4- yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone

This compound was prepared from example 320 in a yield of 55%, according to the procedure for the synthesis of example 325.

¹H NMR (300 MHz, DMSO, 25 °C): δ = 7.52-7.57 (m, 2H, PhH), 7.27 (s, 1 H, CH), 7.22 (d, J= 8.9 Hz, 2H, PhH) 7.10 (t, J= 8.7 Hz, PhH), 6.91 (d, J= 8.9 Hz, 2H, PhH), 4.78 (s, 2H, NH₂), 4.74 (s, 2H, CH₂), 3.86 (br s, 4H, NCH₂), 3.78 (br s, 4H, NCH₂) ppm.

HRMS: calcd for C₂₄H₂₂CIFN₅0₂S 498.1 1668, found 498.1 151 1.

Example 327 : Synthesis of 2-amino-4-A/-benzylamino-6-(4-fluorophenyl)-thieno[2,3- djpyrimidine

To a solution of 2-amino-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-(3H)-one (100 mg, 0.39 mmol) in acetonitrile (20 ml) was added 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.58 mmol, 86 μΙ), benzotriazol-1 -yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP, 0.77 mmol, 84 μΙ) and benzylamine (0.77 mmol, 84 μΙ). The reaction was stirred at room tempe ratu re overn ig ht . The reaction mixtu re wa s dil uted with water and dichloromethane. The organic layer was washed with water. The combined organic layers were evaporated in vacuo and the residue was redissolved in ethylacetate. This solution was extracted with brine (3 x). The combined organic layers were again evaporated and the crude residue was purified by flash chromatography on silica using a mixture of methanol and dichloromethane (in a ratio gradually ranging from 1 :99 to 3:97) as mobile phase, yielding the title compound (86 mg, 63 %).

MS m/z (%) : 351 ([M+H]⁺, 100)

Example 328 : Synthesis of 2-amino-4-/V-piperazinyl-6-phenyl-thieno[2,3-d]pyrimidine This compound was synthesized from example 321 according to the procedure of example 327 in 71 % yield, using piperazine.

MS m/z (%) : 312 ([Μ+ΗΓ, 100)

E x a m p l e 3 2 9 : S y n t h e s i s o f 1 -(4-(2-amino-6-phenylthieno[2,3-d]pyrimidin-4- yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone

To a solution of 2-amino-4-/\/-piperazino-6-phenyl-thieno[2,3-d]pyrimidine (90 mg, 0.29 mmol) in dioxane (10 ml) was added diisopropylethylamine (0.58 mmol, 96 μΙ) and 4- chlorophenoxyacetyl chloride (0.35 mmol, 71 mg). The reaction was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane and extracted with water and brine. The organic phase was evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 2% CH₃OH in CH₂CI₂), yielding the pure title compound (115 mg, 83 %).

MS m/z (%) : 480 ([M+H]\ 100)

Exa m p le 330 : Sy nthes i s of 4-{2-amino-6-phenylthieno[2,3-d]pyrimidin-4-yl)-N-m- tolylpiperazine-1 -carboxamide

To a solution of 2-amino-4-/\/-piperazino-6-phenyl-thieno[2,3-d]pyrimidine (70 mg, 0.23 mmol) in dioxane (10 ml) was added m-tolylisocyanate (0.27 mmol, 35 μΙ). The reaction was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane and extracted with water and brine. The organic phase was evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH₂CI₂ to 2% CH₃OH in CH₂CI₂), yielding the pure title compound (59 mg, 58 %).

MS m/z (%) : 445 ([M+H]⁺, 100)

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.56-7.61 (m, 2H, arom H), 7.15-7.45 (m, 6H, arom H), 6.88 (s, 1 H, arom H), 6.33 (s, 1 H, arom H), 4.79 (2 H, br s, NH₂), 4.01 (t, 4H, piperazine CH₂ ), 3.74 (br s, 4H, piperazine CH₂), 2.34 (br s, 3H, CH₃) ppm.

Exa mp le 331 : Sy nthes is of 4-(2-amino-6-phenylthieno[2,3-d]pyrimidin-4-yl)-N-(4- chlorophenyl)piperazine-1 -carboxamide

This compound was synthesized in 76 % yield from example 328 according to the procedure for the synthesis of example 330, using 4-chloro-phenylisocyanate. MSm/z(%) :465 ([M+H]⁺, 100)

Example 332 : Synthesis of 1-(4-(2-amino-6-phenylthieno[2,3-d]pyrimidin-4- yl)piperazin-1-yl)-2-phenoxyethanone

To a solution of 2-amino-4-(/V-piperazin-1-yl)-6-phenyl-thieno[2,3-d]pyrimidine (48 mg, 0.15 mmol) and pyridine (15 μΙ, 0.18 mmol) in DMF (1 ml) was added phenoxyacetyl chloride (0.17 mmol). The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was quenched with water, extracted with EtOAc, brine and was dried over Na₂S0₄. After removing the solvents, the crude residue was purified by flash chromatography on silica (CH₂CI₂/ eOH 100:1) to yield the title compound as a white solid (39 mg, 58 %).

MS m/z (%) : 446 ([M+H]^*, 100)

Example 333 Synthesis of 2-amino-4-/V-homopiperazinyl-6-phenyl-thieno[2,3- d]pyrimidine

This compound was synthesized from example 321 according to the procedure of example 328, using homopiperazine, in 53 % yield.

MS m/z (%) : 326 ([M+H]\ 100)

Example 334 : Synthesis of 1-(4-(2-amino-6-phenylthieno[2,3-d]pyrimidin-4-yl)-1,4- diazepan-1-yl)-2-(4-chlorophenoxy)ethanone

This compound was synthesized in 69 % yield from example 333, according to the procedure described for the synthesis of example 332, using 4-chloro-phenoxyacetyl chloride.

MS m/z (%) : 495 ([M+H]⁺, 100)

Example 335 : Synthesis of (4-(2-amino-6-phenylthieno[2,3-dJpyrimidin-4-yl)-1,4- diazepan-1 -yl)(4-chlorophenyl)methanone

This compound was synthesized from example 333 according to the procedure for the synthesis of example 332, using 4-chlorobenzoylchloride.

MS m/z (%) : 464 ([M+H]*, 100)

Example 336 : Synthesis of 2-(4-(2-amino-6-phenylthieno[2,3-d]pyrimidin-4- yl)piperazin-1-yl)-N-methyl-N-phenylacetamide

This compound was synthesized according to the procedure of example 327, using 2- (piperazin-l-yl)-acetic acid /V-methyl-ZV-phenyl-amide in 52 % yield.

MS m/z (%) : 459 ([M+H]⁺, 100)

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.56 (d, 2H, arom H), 7.20-7.50 (m, 9H, arom H), 4.75 (br s, 2H, NH₂), 6.33 (s, 1 H, arom H), 4.79 (2 H, br s, NH₂), 4.01 (t, 4H, piperazine CH₂ ), 3.74 (br s, 4H, piperazine CH₂), 2.99 (2 H, s, CH2), 2.34 (br s, 3H, CH₃) ppm

Example 337 : Synthesis of 4-(4-(2-phenoxyethyl)piperazin-1-yl)-6-phenylthieno[2,3- d]pyrimidin-2-amine This compound was synthesized according to the procedure of example 327, using 1 -(2- phenoxyethy -piperazine in 49 % yield.

MS m/z (%) : 432 ([M+H]⁺, 100)

'H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.57 (d, 2H, arom H), 7.25-7.35 (m, 5H, arom H), 6.94 (m, 4H, arom H), 4.79 (br s, 2H, NH₂), 4.17 (2 H, t, CH₂), 3.90 (t, 4H, piperazine CH₂ ), 2.89 (t, 2H, CH₂), 2.74 (4H, t, piperazine CH₂) ppm.

Exa mple 338 : Synthesis of (R)-tert-butyl 1-(2-amino-6-<4-fluorophenyl)tnieno[2,3- d]pyrimidin-4-yl)pyrrolidin-3-ylcarbamate

This compound was synthesized according to the procedure of example 327, in 61 % yield, using (R)-3-/V-Boc-aminopyrrolidine.

MS m/z (%) : 430 ([Μ+Η , 100)

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.51 (m, 2H, arom H), 7.35 (s, 1 H, arom H), 7.07 (t, 2H, arom H), 4.78 (br s, 2H, NH₂), 4.38 (br s, 1 H, NH), 4.06-3.70 (m, 5H), 2.27 (m, 1 H, CH₂), 2.04 (m, 1 H, CH₂) ppm.

Example 339 : Synthesis of (R)-4-(3-aminopyrrolidin-1 -yl)-6-(4-fluorophenyl)thieno[2,3- d]pyrimidin-2 -amine

To a solution of the compound of example 338 (66 mg, 0.15 mmol) in dichloromethane (6 ml) was added trifluoroacetic acid (3 ml). The solution was stirred at room temperature for 30 minutes. The solvents were evaporated in vacuo and co-evaporated with toluene. The residue was directly used for further reaction without any purification.

MS m/z (%) : 330 ([M+H]\ 100)

Example 340 : Synthesis of (R)-N-(1-(2-amino-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin- 4-yl)pyrrolidin-3-yl)-2-(4-chlorophenoxy)acetamide

This compound was synthesized in 78 % yield from example 339 according to the procedure of example 332, using 4-chlorophenoxyacetyl chloride.

MS m/z (%) : 498 ([M+H]⁺, 100)

¹H NMR (300 MHz, DMSO, 25 °C): δ = 8.42 (d, 1 H, NH), 7.67 (d, 2H, arom H), 7.31 (t, 2H, arom H), 6.98(d, 2H, arom H), 6.21 (br s, 2H, NH₂), 4.51 (s, 1 H, CH2), 3.87-3.67 (m, 5H), 2.17 (m, 1 H, CH₂), 1.99 (m, 1 H, CH₂) ppm.

Example 341 : Synthesis of (R)-N-(1-(2-amino-6-(4-fluorophenyl)thieno[2₎3-d]pyrimidin- 4-yl)pyrrolidin-3-yl)-4-chlorobenzamide

This compound was synthesized from example 339 according to the procedure of example 332, using 4-chlorobenzoylchloride in 65% yield.

MS m/z (%) : 468 ([M+H]⁺, 00) Example 342 : Synthesis of 2-amino-4-W-piperazinyl-6-(4-fluorophenyl)-thieno[2,3- djpyrimidine

This compound was synthesized according to the procedure of example 327, using piperazine in 54 % yield.

MS m/z (%) : 330 ([M+H]⁺, 100)

Example 343 : Synthesis of 1 -(4-(2-amino-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4- yl)piperazin-1 -yl)-3-phenylpropan-1 -one

This compound was synthesized in 55 % yield from 2-amino-4-/V-piperazino-6-(4- fluorophenyl)-thieno[2,3-d]pyrimidine according to the procedure for the synthesis of example 329, using hydrocinnamoylchloride.

MS m/z (%) : 462 ([M+H]\ 100)

E x a m p l e 3 4 4 : S y n t h e s i s o f 4-(4-(benzylsulfonyl)piperazin-1-yl)-6-(4- fluorophenyl)thieno[2,3-d]pyrimidin-2 -amine

This compound was synthesized in 51 % yield from 2-amino-4-/V-piperazino-6-(4- fluorophenyl)-thieno[2,3-d]pyrimidine according to the procedure for the synthesis of example 329, using a-toluenesulfonyl chloride.

MS m/z (%) : 484 ([M+H]⁺, 100)

Example 345 : Synthesis of (4-(2-amino-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4- yl)piperazin-1 -yl)(cyclohexyl)methanone

This compound was synthesized in 66 % yield from 2-amino-4-/V-piperazino-6-(4- fluorophenyl)-thieno[2,3-d]pyrimidine according to the procedure for the synthesis of example 329, using cyclohexanecarboxylic acid chloride.

MS m/z (%) : 440 ([M+H]⁺, 100)

Example 346 : Synthesis of (4-(2-amino-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4- yl)piperazin-1-yl)(pyridin-3-yl)methanone

This compound was synthesized in 49 % yield from 2-amino-4-/V-piperazino-6-(4- fluorophenyl)-thieno[2,3-d]pyrimidine using nicotinoyi chloride according to the procedure for the synthesis of example 329.

MS m/z (%) : 435 ([M+H]⁺, 100)

Example 347 : Synthesis of 4-^2-amino-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)- N,f\l-diisopropylpiperazine-1 -carboxamide

This compound was synthesized in 61 % yield from 2-amino-4-/V-piperazino-6-(4- fluorophenyl)-thieno[2,3-d]pyrimidine using diisopropylcarbamoyl chloride according to the procedure for the synthesis of example 329, using diisopropylcarbamoyl chloride.

MS m/z (%) : 457 ([M+H]⁺, 100) Exa mple 348 : Synthesis of (1^2-amjno-6-(4-fluorophenyl)thieno[2,3-d]pyrimiclin-4- yl)piperidin-4-yl)(phenyl)methanone

This compound was synthesized in 44 % yield from 2-amino-4-/V-piperazino-6-(4- fluorophenyl)-thieno[2,3-d]pyrimidine using 4-benzoylpiperidine hydrochloride according to the procedure for the synthesis of example 327, using 4-benzoylpiperidine hydrochloride. MS m/z (%) : 433 ([M+H]⁺, 100)

¹H NMR (300 MHz, CHCI₃, 25 °C): δ = 7.98 (d, 2H, arom H), 7.53 (m, 5H, arom H), 7.08 (t, 2H, arom H), 4.79 (br s, 2H, NH₂), 4.55 (d, 2H, NCH2), 3.61 (m, 1 H, CH), 3.37 (t, 2H, NCH₂), 2.01 (m, 4H, CH₂) ppm.

Example 349 : Synthesis of 2-amino-thieno[2,3-d]pyrimidin-4-(3H)-one

A s u s pe n s i o n o f e t h y l 2-amino-thiophene-3-carboxylate (0.4 g, 2.34 mmol), chloroformamidine hydrochloride (0.67 g, 5.84 mmol) and dimethylsulfone (0.53 g, 1 1.7 mmol) was heated at 130°C for 30 minutes. After cooling down to room temperature, water (10 ml) was added and ammonium hydroxide was used to neutralize the suspension till pH = 8. The solid was filtered off, washed with water and dried, yielding the crude title compound (71 %, 277 mg). The crude residue was used as such for further reaction.

MS m/z (%) : 168 ([M+H]⁺, 100)

Example 350 : Synthesis of 2-amino-4-A -piperazino-thieno[2,3-d]pyrimidine

To a solution of 2-amino-thieno[2,3-d]pyrimidin-4-(3H)-one (250 mg, 1 .5 mmol) in acetonitrile (20 ml) was added 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2.24 mmol, 335 μΙ), benzotriazol-1 -yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP, 862 mg) and piperazine (3 mmol, 258 mg). The reaction was stirred at room temperature overnight and then for 4 hours at 70°C. The solvents were evaporated in vacuo and the crude residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol, dichloromethane and a 33% aq. NH₃ solution (in a ratio gradually ranging from 3: 96.5:0.5 to 5:94.5:0.5) yielding the title compound (48 %, 169 mg).

MS m/z (%) : 236 ([M+H]^*, 100)

Example 351 : Synthesis of 1-(4-(2-aminothieno[2₎3-d]pyrimidin-4-yl)piperazin-1-yl)-2- (4-chlorophenoxy)ethanone

To a solution of 2-amino-4-A/-piperazino-thieno[2,3-d]pyrimidine (100 mg, 0.43 mmol) in dioxane (15 ml) was added diisopropylethylamine (DIPEA, 0.85 mmol, 141 μΙ) and 4- chlorophenoxyacetylchloride (0.43 mmol, 88 mg). The reaction was stirred overnight at room temperature. The solvents were evaporated in vacuo. The residue was redissolved in ethylacetate and extracted with brine (3 x). The combined organic layers were evaporated in vacuo and the crude residue was purified by silica gel flash chromatography, the mobile phase consisting of a mixture of methanol and dichloromethane (in a ratio gradually ranging from 1 :99 to 2:98), yielding the pure title compound (121 mg, 70 %).

MS m/z (%) : 404 ([M+H]⁺, 100)

H NMR (300 MHz, CHCI₃, 25 °C): δ = 7.25 (d, 2H, arom H), 7.13 (d, 1 H, arom H), 6.91 (d, 1 H, arom H), 6.89 (d, 1 H, arom H), 4.74 (br s, 2H, NH₂), 4.73 (s, 2H, CH₂), 3.83 (br s, 4H, CH₂), 3.77 (br s, 1 H, CH₂) ppm.

E x a m p l e 3 5 2 : S y n t h e s i s o f 2-(4-chlorophenoxy)-1 -(4-(6-(4-fluorophenyl)-2- phenylthieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)ethanone

This compound was prepared from example 322 in a yield of 77%, according to the procedure for the synthesis of example 325.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.41 -8.45 (m, 2H, PhH), 7.58-7.63 (m, 2H, PhH), 7.45- 7.47 (m, 3H, PhH), 7.33 (s, 1 H, CH), 7.26 (d, J= 8.9 Hz, 2H, PhH), 7.13 (t, J= 8.5 Hz, PhH), 6.92 (d, J= 8.9 Hz, 2H, PhH), 4.74 (s, 2H, CH₂), 4.01 (br s, 4H, NCH₂), 3.85 (br s, 4H, NCH₂) ppm.

HRMS: calcd for C₃₀H₂₅CIFN₄O₂S 559.13708, found 559.13554.

Example 353 : Synthesis of ethyl 4-(4-(2-(4-chlorophenoxy)acetyl)piperazin-1 -yl)-6-<4- fluorophenyl)thieno[2,3-d]pyrimidine-2-carboxylate

This compound was prepared from example 323 in a yield of 89%, according to the procedure for the synthesis of example 325.

H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.62-7.67 (m, 2H, PhH), 7.42 (s, 1 H, CH), 7.26 (d, J= 8.9 Hz, 2H, PhH), 7.16 (t, J= 8.5 Hz, PhH), 6.91 (d, J= 8.9 Hz, 2H, PhH), 4.75 (s, 2H, CH₂), 4.51 (q, J= 7.1 Hz, 2H, CH₂), 4.09 (br s, 2H, NCH₂), 4.03 (br s, 2H, NCH₂), 3.84 (br s, 4H, NCH₂), 1 .47 (t, J= 7.1 Hz, 3H, CH₃) ppm.

HRMS: calcd for C₂₇H₂₅CIFN₄0₄S 555.12691 , found 555.12507.

Example 354 : Synthesis of ethyl 2-<4-{4-(2-(4-chlorophenoxy)acetyl)piperazin-1 -yl)-6- (4-fluorophenyl)thieno[2,3-d]pyrimidin-2-yl)acetate

This compound was prepared from example 324 in a yield of 58%, according to the procedure for the synthesis of example 325.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.56-7.60 (m, 2H, PhH), 7.32 (s, 1 H, CH), 7.24 (d, J= 8.8 Hz, 2H, PhH), 7.10 (t, J= 8.5 Hz, PhH), 6.89 (d, J= 8.8 Hz, 2H, PhH), 4.72 (s, 2H, OCH₂), 4.21 (q, J= 7.1 Hz, 2H, CH₂), 3.92 (br s, 4H, NCH₂), 3.88 (s, 2H, CH₂), 3.78 (br s, 4H, NCH₂), 1 .28 (t, J= 7.1 Hz, 3H, CH₃) ppm.

HRMS: calcd for C₂₈H₂7CIFN₄0₄S 569.1426, found 569.1426.

E x a m p l e 355 : S y nthesis of 4-(4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)-6- 4- fluorophenyl)thieno[2,3-d]pyrimidine-2-carboxamide A s u s p e n s i o n o f e t h y l 4-(4-(2-(4-chlorophenoxy)acetyl)piperazin-1 -yl)-6-(4- fluorophenyl)thieno[2,3-d]pyrimidine-2-carboxylate (40 mg, 0.07 mmol) in 7N NH₃ in MeOH (1 ml) was stirred at room temperature for 3 hours. The solvents were removed under reduced pressure, and the crude residue was purified by flash chromatography on silica gel (CH₂CI₂/MeOH 40:1 ) to yield the title compound as a white solid (25 mg, 66%).

H NMR (300 MHz, DMSO, 25 °C): δ = 8.14 (s, 1 H, NH), 8.00 (s, 1 H, CH), 7.90-7.95 (m, 2H, PhH), 7.35 (t, J= 8.8 Hz, 2H, PhH), 7.33 (d, J= 9.0 Hz, 2H, PhH), 6.99 (d, J= 9.0 Hz, 2H, PhH), 4.94 (s, 2H, CH₂), 4.15 (br s, 2H, NCH₂), 4.08 (br s, 2H, NCH₂), 3.73 (br s, 4H, NCH₂) ppm.

HRMS: calcd for CssH^CIFNsOaS 526.1 1 159 found 526.1 1031 .

E xa m ple 356 : S yn thes is of 4-(4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)-6-(4- fluorophenyl)-/V-(2-methoxyethyl)thieno[2,3-d]pyrimidine-2-carboxamide

To a suspension of ethyl 4-(4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)-6-(4- fluorophenyl)thieno[2,3-d]pyrimidine-2-carboxylate (30 mg, 0.05 mmol) in MeOH (7 ml) was added 2-methoxyethylamine (0.7 ml). The mixture was stirred at room temperature for 3 hours. The solvents were removed under reduced pressure and the crude residue was purified by flash chromatography on silica gel (CH₂CI₂/MeOH 50: 1 ) to yield the title compound as a white solid (29 mg, 92%).

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.20 (s, 1 H, NH), 7.59-7.64 (m, 2H, PhH), 7.40 (s, 1 H, CH), 7.25 (d, J= 8.8 Hz, 2H, PhH), 7.14 (t, J= 7.15 Hz, 2H, PhH), 6.91 (d, J= 8.8 Hz, 2H, PhH), 4.75 (s, 2H, CH₂), 4.05 (br s, 2H, NCH₂), 3.99 (br s, 2H, NCH₂), 3.69 (br s, 4H, NCH₂),3.69 (t, J= 5.1 Hz, 2H, CH₂), 3.60 (t, J= 5.1 Hz, 2H, CH₂), 3.41 (s, 3H, CH₃) ppm. HRMS: calcd for C₂₈H₂₈CIFN₅0_S 584.15346, found 584.15178.

E xa m pl e 357 : Sy n th es i s of 4-{4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)-6-(4- fluorophenyl)thieno[2,3-d]pyrimidine-2-carboxylic acid

A solution of ethyl 4-(4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)-6-(4- fluorophenyl)thieno[2,3-d]pyrimidine-2-carboxylate (0.12 g, 0.22 mmol) in methanol/2M NaOH/CH₂CI₂ (5:5: 1 , 5 ml) was stirred at room temperature for 3 hours after which it was neutralized with a 2N HCI solution in dioxane. The solvents were removed under reduced pressure, and the crude residue was purified by flash chromatography on silica gel (CH₂CI₂/MeOH 8:1 ) to yield the title compound as a pale yellow solid (50 mg, 44%).

H NMR (300 MHz, DMSO, 25 °C): δ = 8.02 (s, 1 H, CH), 7.92-7.97 (m, 2H, PhH), 7.32-7.39 (m, 4H, PhH), 6.98 (d, J= 8.7 Hz, 2H, PhH), 4.93 (s, 2H, CH₂), 4.11 (br s, 2H, NCH₂), 4.04 (br s, 2H, NCH₂), 3.68 (br s, 4H, NCH₂) ppm.

HRMS: calcd for C^H^CIFN^S 527.09561 , found 527.09421 . Exa mple 358 : Synthesis of 2-(4-(4-(2-(4-chlorophenoxy)acetyl)piperazin-1 -yl)-6-(4- fluorophenyl)thieno[2,3-d]pyrimidin-2-yl)acetamide

This compound was prepared from example 354 in a yield of 34%, according to the procedure for the synthesis of example 355.

1H NMR (300 MHz, DMSO, 25 °C): δ = 7.92 (s, 1 H, H-5), 7.86-7.91 (m, 2H, PhH), 7.44 (s, 1 H, NH), 7.30-7.36 (m, 4H, PhH, PhH), 6.99 (s, 1 H, NH), 6.98 (d, J= 9.1 Hz, 2H, PhH), 4.92 (s, 2H, OCH₂), 4.03 (br s, 2H, NCH₂), 3.98 (br s, 2H, NCH₂), 3.70 (br s, 4H, CON(CH₂)₂), 3.57 (s, 2H, CH₂) ppm.

HRMS: calcd for C₂₆H₂₄CIFN₅0₃S 540.12724 found 540.12544.

Example 359 : Synthesis of 4-(2-amino-6-(4-fluorophenyl)thienot2_>3-d]pynmidin-4-yl)- N-m-tolylpiperazine-1 -carboxamide

This compound was prepared from example 320 in a yield of 46%, according to the procedure for the synthesis of example 325, using A/-m-tolylpiperazine-1 -carboxamide.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 8.50 (s, 1 H, NH), 7.73-7.78 (m, 2H, PhH), 7.71 (s, 1 H, PhH), 7.23-7.32 (m, 4H, PhH), 7.12 (t, J= 7.3Hz, PhH), 6.77 (d, J= 7.3 Hz, 1 H, PhH), 6.36 (s, 2H, NH₂), 3.88 (br s, 4H, NCH₂), 3.64 (br s, 4H, NCH₂), 2.26 (s, 3H, CH₃) ppm.

HRMS: calcd for C₂₄H₂₄FN₆OS 463.1716, found 463.1702.

Example 360 : Synthesis of 4-(6-(4-fluorophenyl)-2-phenylthieno[2,3-d]pyrimidin-4-yl)- N-m-tolylpiperazine-1 -carboxamide

This compound was prepared from example 322 in a yield of 69%, according to the procedure for the synthesis of example 325, using /V-m-tolylpiperazine-1 -carboxamide.

¹H NMR (300 MHz, DMSO, 25 °C): δ = 8.54 (s, 1 H, NH), 8.41-8.44 (m, 2H, 5-PhH), 7.99 (s, 1 H, CH), 7.89-7.94 (m, 2H, 2-PhH), 7.50-7.52 (m, 3H, PhH), 7.28-7.38 (m, 4H, PhH), 7.13 (t, J= 7.7 Hz, 1 H, tolyl-H), 6.78 (d, J= 7.4 Hz, 1 H, tolyl-H), 4.13 (br s, 4H, NCH₂), 3.75 (br s, 4H, NCH₂), 2.27 (s, 3H, CH₃) ppm.

HRMS: calcd for C₃₀H₂₇FN₅OS 524.1920, found 524.1921.

Example 361 : Synthesis of ethyl 6-(4-fluorophenyl)-4-(4-(m-tolylcarbamoyl)piperazin- 1-yl)thieno[2,3-dJpyrimidine-2-carboxylate

This compound was prepared from example 323 in a yield of 61 %, according to the procedure for the synthesis of example 325, using A/-m-tolylpiperazine-1 -carboxamide.

H NMR (300 MHz, CDCI₃₎ 25 °C): δ = 7.60-7.65 (m, 2H, PhH), 7.46 (s, 1 H, CH), 7.1 1 -7.17 (m, 4H, PhH), 6.87 (br s, 1 H, PhH), 6.66 (s, 1 H, PhH), 4.50 (q, J= 7.1 Hz, 2H, CH₂), 4.15 (br s, 4H, NCH₂), 3.79 (br s, 4H, NCH₂), 1.46 (t, J= 7.1 Hz, 3H, CH₃) ppm.

HRMS: calcd for C₂₇H₂₇FN₅0₃S 520.18186, found 520.17993. Example 362 : Synthes is of 6-(4-fluorophenylH-(4-(/n-tolylcarbamoyl)piperazin-1- yl)thieno[2,3-d]pyrimidine-2-carboxamide

This compound was prepared from example 361 in a yield of 66%, according to the procedure for the synthesis of example 355.

1H NMR (300 MHz, DMSO, 25 °C): δ = 8.55 (s, 1 H, NH), 8.15 (s, 1 H, CONH), 8.02 (s, 1 H, CH), 7.91 -7.95 (m, 2H, PhH), 7.68 (s, 1 H, CONH), 7.27-7.38 (m, 4H, PhH), 7.13 (t, J= 7.7 Hz, 1 H, PhH), 6.77 (d, J= 7.7 Hz, 1 H, PhH), 4.1 1 (br s, 4H, NCH₂), 3.71 (br s, 4H, NCH_?), 2.26 (s, 3H, CH₃) ppm.

HRMS: calcd for C₂₅H₂₄FN₆0₂S 491 .16655, found 491 .16526.

Example 363 : Synthesis of 4-ethoxy-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-2 -amine

To a solution of 2-amino-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4(3H)-one (50 mg, 0.19 mmol) and BOP (1 10 mg, 0.25 mmol) in EtOH (1 ml) was added DBU (43 μΙ, 0.29 mmol). The resulting mixture was heated at 60°C for 4 hours. After cooling down to room temperature, sodium ethoxide (26 mg, 0.38 mmol) was added. The mixture was again heated at 60°C overnight. The solvents were removed under reduced pressure and the crude residue was purified by flash chromatography on silica gel (CH₂CI₂/MeOH 60:1 ) yielding the title compound as a white solid (30 mg, 54 %).

mp 142°C

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.54-7.59 (m, 2H, PhH), 7.29 (s, 1 H, PhH), 7.07 (t, J= 8.6 Hz, PhH), 5.03 (s, 2H, NH₂), 4.49 (q, J= 7.1 Hz, 2H, CH₂), 1.44 (t, J= 7.1 Hz, 3H, CH₃) ppm.

HRMS: calcd for Ci₄H₁₃FN₃OS 290.0763, found 290.0740.

Example 364 : Synthesis of 6-(4-fluorophenyl)-4-morpholinothieno[2,3-d]pyrimidin-2- amine

This compound was prepared from example 320 using morpholine in a yield of 58%, according to the procedure for the synthesis of example 327.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.52-7.75 (m, 2H, PhH), 7.24 (s, 1 H, CH), 7.09 (t, J= 8.6 Hz, PhH), 4.82 (s, 2H, NH₂), 3.84 (br s, 8H, NCH₂, OCH₂) ppm.

HRMS: calcd for C₁₆Hi₆FN₄OS 331.1029, found 331.1003.

E x a m p l e 3 6 5 : S y n t h e s i s o f 4-chloro-6-(4-fluorophenyl)-2-methylthieno[2,3- d]pyrimidine

A solution of 6-(4-fluorophenyl)-2-methylthieno[2,3-d]pyrimidin-4(3H)-one (0.2 g, 0.77 mmol) and diisopropylethylamine (0.26 ml, 1.54 mmol) in POCI₃ (4 ml) was stirred under N₂ at 90°C for 3.5 hours. The reaction mixture was allowed to cool down to room temperature and poured into an ice-bath. The aqueous phase was extracted with diethyl ether. The combined organic layers were washed with a half-saturated NaHC0₃ solution and brine, dried over Na₂S0₄, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (CH₂CI₂/MeOH 50: 1 ) to yield the title compound as a white solid (14 mg,

6%).

1H N R (300 MHz, CDCI₃, 25 °C): δ = 7.66-7.71 (m, 2H, PhH), 7.45 (s, 1 H, CH), 7.16 (t, J= 8.5 Hz, PhH), 2.81 (s, 3H, CH₃) ppm.

HRMS: calcd for Ci₃H₉CIFN₂S 279.01590, found 279.01510.

Example 366 : Synthesis of ethyl 4-chloro-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine-2- carboxylate

This compound was prepared from example 323 in a yield of 99%, according to the procedure for the synthesis of example 365.

¹H NMR (300 MHz, CDCI₃, 25 °C): δ = 7.71 -7.76 (m, 2H, PhH), 7.57 (s, 1 H, CH), 7.19 (t, J= 8.5 Hz, 2H, PhH), 4.58 (q, J= 7.1 Hz, 2H, CH₂), 1.49 (t, J= 7.1 Hz, 3H, CH₃) ppm.

HRMS. calcd for C₁₅HnCIFN₂0₂S 337.02138, found 337.02038.

Example 367 Synthesis of /V-(3-chloro-4-fluorophenyl)-6-(4-fluorophenyl)-2- methylthieno[2,3-d]pyrimidin-4-amine

To a solution of 4-chloro-6-(4-fluorophenyl)-2-methylthieno[2,3-d]pyrimidine (15 mg, 0.05 mmol) in 1 ,2-dich)oroethane/t-BuOH (1 :1 , 2 ml) was added 3-chloro-4-fluoroaniline (16 mg, 0.1 1 mmol). The mixture was heated at 90°C for 2 days. After cooling down to room temperature, the solvents were removed under reduced pressure. The crude residue was purified by silica gel chromatography (C^C /MeOH 100:1 ) to yield the title compound as a white solid (1 1 mg, 53 %).

HRMS: calcd for Ci₉H₁₃CIF₂N₃S 388.0487, found 388.0471 .

E x a m p l e 36 8 : S y n t h e s i s o f e t h y l 4-(3-chloro-4-fluorophenylamino)-6-(4- fluorophenyl)thieno[2,3-d]pyrimidine-2-carboxylate

This compound was prepared from example 366 in a yield of 38%, according to the procedure for the synthesis of example 367.

¹H NMR (300 MHz, DMSO, 25 °C): δ = 10.04 (s, 1 H, NH), 8.65-8.67 (m, 1 H, PhH), 8.27 (s, 1 H, PhH), 7.79-7.84 (m, 3H, PhH), 7.39-7.51 (m, 3H, PhH), 4.37 (q, J= 7.0 Hz, 2H, CH₂), 1 .39 (t, J= 7.0 Hz, 3H, CH₃) ppm.

HRMS: calcd for C₂₁H₁₅CIF₂N₃0₂S 446.05416, found 446.05311 .

Examples 369 - 373 : Synthesis of 2-amino-4-(/V-acylpiperazinyl)-6-phenyl-thieno[2,3- djpyrimidine analogues

General procedure To a solution of 2-amino-4-(/\/-piperazinyl)-6-phenyl-thieno[2,3-d]pyrimidine (0.65 mmol) in DMF (10 ml) was added diisopropylethylamine (1 .3 mmol, 215 μΙ), O-(benzotriazol-l -yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (TBTU , 0.78 mmol, 250 mg) and an appropriate carboxylic acid (0.78 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with dichloromethane and extracted with water. The combined organic layers were evaporated in vacuo and the resulting residue was purified by silica gel flash ch romatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually raising from 1 % to 2% methanol), yielding the pure title compounds in yields varying from 62% to 75%.

The following compounds were made according to this procedure

Example 369 : Synthesis of 1-(4-(2-amino-6-phenylthienof2,3-d1pyrimidin-4-yl)piperazin-1 -yl)- 2-(4-methoxyphenoxy)ethanone

This compound was obtained from 2-amino-4-(/V-piperazinyl)-6-phenyl-thieno[2,3- d]pyrimidine and 4-methoxy-phenoxyacetic acid.

1H NMR (300 MHz, CDCI₃): δ = 7.59 (d, 2H, arom H), 7.26-7.40 (m, 4H, arom H), 6.86-6.90 (m, 4H, arom H), 4.81 (br s, 2H, NH₂), 4.71 (s, 2H, CH₂), 3.79 (br s, 4H, piperazine H), 3.77 (br s, 7H, piperazine H and OCH₃) ppm.

Example 370 : Synthesis of 1 -(4-(2-amino-6-phenylthieno[2,3-dlpyrimidin-4-yl)piperazin-1 -yl)- 2-(4-fluorophenoxy)ethanone

This compound was obtained from 2-amino-4-(/V-piperazinyl)-6-phenyl-thieno[2,3- d]pyrimidine and 4-fluoro-phenoxyacetic acid.

¹H NMR (300 MHz, DMSO): δ = 7.57 (m, 2H, arom H), 7.26-7.43 (m, 4H, arom H), 6.93-6.99 (m, 4H, arom H), 5.13 (br s, 2H, NH₂), 4.72 (s, 2H, CH₂), 3.91 (br s, 4H, piperazine H), 3.81 (br s, 4H, piperazine H) ppm.

Example 371 : Synthesis of 1-(4-(2-amino-6-phenylthienor2,3-dlpyrimidin-4-yl)piperazin-1 -yl)- 2-(m-tolyloxy)ethanone

This compound was obtained from 2-amino-4-(/V-piperazinyl)-6-phenyl-thieno[2,3- d]pyrimidine and 3-methyl-phenoxyacetic acid.

Example 372 : Synthesis of 1 -(4-(2-amino-6-phenylthienof2,3-dlpyrimidin-4-yl)piperazin-1 -yl)- 2-(4-bromophenoxy)ethanone

This compound was obtained from 2-amino-4-(/V-piperazinyl)-6-phenyl-thieno[2,3- djpyrimidine and 4-bromo-phenoxyacetic acid.

Ή NMR (300 MHz, CDCI₃): δ = 7.57 (m, 2H, arom H), 7.26-7.41 (m, 4H, arom H), 6.86 (m, 4H, arom H), 4.73 (br s, 2H, NH₂), 4.64 (s, 2H, CH₂), 3.92 (br s, 4H, piperazine H), 3.80 (br s, 4H, piperazine H) ppm. Example 373 : Synthesis of 1-(4-(2-amino^-phenylthienoi2,3-dlpyrimidin-4-yl)piperazin-1 -yl)- 2-(4-chlorophenoxy)-2-methylpropan-1 -one

This compound was obtained from 2-amino-4-(/V-piperazinyl)-6-phenyl-thieno[2,3- d]pyrimidine and 2-(4-chlorophenoxy)-2-methylpropionic acid.

1H NMR (300 MHz, CDCI₃): δ = 7.57 (d, 2H, arom H), 7.39 (t, 2H, arom H), 7.19-7.32 (m, 4H, arom H), 6.79 (d, 2H, arom H), 4.78 (br s, 2H, NH₂), 4.01 (br s, 2H, piperazine H), 3.80 (br s, 4H, piperazine H), 3.56 (br s, 2H, piperazine H), 1.67 (s, 6 H, 2 x CH₃) ppm.

Example 374 : Synthesis of 2,6-diamino-4- V-piperazin-1-yl)pyrimidine

A mixture of 4-chloro-2,6-diaminopyrimidine (4.34 g, 30 mmol), piperazine (2.58 g, 30 mmol) and NaOH (1 .2 g, 30 mmol) in water (50 ml) was heated under reflux for 3 hours. After cooling to room temperature, the precipitate was filtered off. The filtrate was concentrated under reduced pressure to yield the crude title product which was used in the following step without further purification.

MS m/z (%): 195 ([M+H]⁺, 100)

Examples 375 - 381 : Synthesis of 2,6-diamino-4-(A/-acyl-piperazin-1 -yl)-pyrimidine analogues

General procedure

To a solution of 2,6-diamino-4-(/V-piperazin-1-yl)pyrimidine (crude residue, +/- 30 mmol) and potassium carbonate (8.28 g, 60 mmol) in dioxane/methanol (1 :1 ; 100 ml), was added a solution of the appropriate acid chloride (36 mmol) in dioxane (20 ml). The resulting reaction mixture was stirred al room temperature for 1 hour. After concentration under reduced pressure, the residue was resuspended in water (50 ml). The solid was filtered off and washed with water. The precipitate was dried over P₂0₅, yielding the title compound in yields between 70 - 90 % over 2 steps.

The following compounds were synthesized according to this procedure :

Example 375 : 2,6-diamino-4-f4-(4-chlorophenoxyacetyl)piperazin-1 -yllpyrimidine

This compound was synthesized using 4-chlorophenoxyacetyl chloride.

MS m/z (%): 363 ([M+H]⁺, 100)

Example 376 : 2,6-diamino-4-[(4-phenoxyacetyl)piperazin-1-yllpyrimidine

This compound was synthesized using phenoxyacetyl chloride.

MS m/z (%): 329 ([M+H]⁺, 100)

Example 377 : 2,6-diamino-4-([3-methoxy-benzoyl)piperazin-1 -yllpyrimidine

This compound was synthesized using 3-methoxybenzoyl chloride.

MS m/z (%): 329 ([M+H]⁺, 100) Example 378 : 2,6-diarnino-4-f(2-thiophene-acetyl)piperazin-1-yllpyrirnidine

This compound was synthesized using 2-thiophene-acetyl chloride.

MS m/z (%): 319 ([M+H]⁺, 100)

Example 379 : 2,6-diamino-4 (4-chloro-benzoyl)piperazin-1-yllpyrimidine

This compound was synthesized using 4-chloro-benzoyl chloride.

MS m/z (%):333 ([M+H]⁺, 100)

Example 380 : 2,6-diamino-4-[(4-a-toluenesulfonyl)piperazin-1-yllpyrimidine

This compound was synthesized using a-toluenesulfonylchloride.

MS m/z (%):349 ([M+H]⁺, 100)

Example 381 . 2,6-diamino-4-f(1-naphthoyl)piperazin-1-yllpyrimidine

This compound was synthesized using 1 -naphthoylchloride.

MS m/z (%):349 ([M+H]⁺, 100)

Examples 382 - 388 : Synthesis of 2,5,6-triamino-4-[(4-N-acyl-)piperazin-1 -yl]pyrimidine analogues

General procedure

To a suspension of 2,6-diamino-4-[4-acyl-piperazin-1-yl]pyrimidine (10 mmol) and sodium nitrite (0.86 g, 12.5 mmol) in a mixture of water/dioxane/methanol (4/2/1 ; 70 ml), was added acetic acid (1 .5 g, 25 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. A pink precipitate was formed indicating the formation of the nitroso intermediate. To this violet suspension was added a 30% ammonia solution in water (75 mmol) and sodium dithionite (25 mmol). The reaction mixture was stirred at 50°C till the violet color completely disappeared (about 2 hours). After concentration under reduced pressure, the residue was suspended in water (50 ml). The solid was filtered off, washed with water and dried over P₂0₅, yielding the title compound as white solids in yields varying from 60 to 90 %. The following compounds were made according to this procedure :

Example 382 : 2,5,6-triamino-4-[4-(4-chlorophenoxyacetyl)piperazin-1-yllpyrimidine

MS m/z (%): 378 ([M+H]⁺, 100)

Example 383 : 2,5,6-triamino-4-f(4-phenoxyacetyl)piperazin-1-yl1pyrimidine

MS m/z (%): 344 ([M+H]⁺, 100)

Example 384 : 2,5,6-triamino-4-f(3-methoxy-benzoyl)piperazin-1 -ynpyrimidine

MS m/z (%): 344 ([M+Hf, 100)

Example 385 : 2,5,6-triamino-4-f(2-thiophene-acetyl)piperazin-1 -yllpyrimidine

MS m/z (%): 334 ([M+H]⁺, 100)

Example 386 : 2,5,6-triamino-4-f(4-chloro-benzoyl)piperazin-1-yllpyrimidine MS m/z (%): 348 ([M+H]⁺, 100)

Example 387 : 2,5,6-triamino-4-[(4-a-toluenesulfonyl)piperazin-1 -yllpy midine

MS m/z (%): 364 ([M+H]⁺, 100)

Example 388 : 2,5,6-triamino-4-f(1 -naphthoyl)piperazin-1 -yllpyrimidine

MS m/z (%): 378 ([M+H]\ 100)

Examples 389 - 407 : Synthesis of 2-amino-6-[4-(4-chlorophenoxyacetyl)piperazin-1 - yl]-8-substituted-9H-purine analogues

General procedure

A suspension of a 2,5,6-triamino-4-[4-acyl-piperazin-1-yl]pyrimidine analogue (0.5 mmol), an appropriate aldehyde (0.5 mmol) and a drop of acetic acid in methanol (10 ml) was stirred at room temperature for 1 hour, after which the Schiff base intermediate was formed. Then, FeC (0.75 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was evaporated in vacuo and purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1 :25), yielding the pure title compound.

The following compounds were synthesized according to this procedure :

E x a m p l e 3 8 9 : 1 -(4-(2-amino-8-(4-fluoiOPhenyl)-9H-purin-6-yl)piperazin-1-yl)-2-(4- chlorophenoxy)ethanone

This compound was synthesized from 2,5,6-triamino-4-[4-(4-ch!orophenoxyacetyl)piperazin- 1 -yl]pyrimidine and 4-fluorobenzaldehyde, yielding the pure title compound in 83% yield.

MS m/z (%): 482 ([M+H]⁺, 100)

Example 390 : Synthesis of 1-(4-(2-amino-8-(3,4-dimethoxyphenyl)-9H-purin-6-yl)piperazin- 1 -yl)-2-(4-chlorophenoxy)ethanone

This compound was synthesized from 2,5,6-triamino-4-[4-(4-chlorophenoxyacetyl)piperazin- 1 -yljpyrimidine and 3,4-dimethoxybenzaldehyde yielding the pure title compound in 57 % yield.

MS m/z (%): 524 ([M+H]⁺, 100)

Example 391 : 1 -(4-(2-amino-8-(4-bromophenyl)-9H-purin-6-yl)piperazin-1-yl)-2-(4- chlorophenoxy)ethanone

This compound was synthesized from 2,5,6-triamino-4-[4-(4-chlorophenoxyacetyl)piperazin- 1 -yljpyrimidine and 4-bromobenzaldehyde in 74 % yield.

MS m/z (%): 543 ([M+H]⁺, 100)

Example 392 : 1 -(4-(2-amino-8-(4-chlorophenyl)-9H-purin-6-ynpiperazin-1-yl)-2-(4- chlorophenoxy)ethanone This compound was obtained from 2,5,6-triamino-4-[4-(4-chlorophenoxyacetyl)piperazin-1 - yljpyrimidine and 4-chlorobenzaldehyde in 60 % yield.

S m/z (%): 498 ([M+H]⁺, 100)

Example 393 : 1 -(4-(2-amino-8-(3-chlorophenyl)-9H-purin-6-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone

This compound was obtained from 2,5,6-triamino-4-[4-(4-chlorophenoxyacetyl)piperazin-1- yljpyrimidine and 3-chlorobenzaldehyde in 67 % yield.

MS m/z (%): 498 ([M+H]⁺, 100)

Example 394 : 1 -(4-(2-amino-8-(4-(trifluoromethyl)phenyl)-9H-purin-6-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone

This compound was obtained from 2,5,6-triamino-4-[4-(4-chlorophenoxyacetyl)piperazin-1 - yljpyrimidine and p-trifluoromethylbenzaldehyde in 63 % yield.

MS m/z (%): 532 ((M+H]⁺, 100)

Example 395 : Synthesis of 1 -(4-(2-amino-8-(4-(trifluoromethoxy)phenyl)-9H-purin-6- yl)piperazin-1-y0-2-(4-chlorophenoxy)ethanone

This compound was obtained from 2,5,6-triamino-4-[4-(4-chlorophenoxyacetyl)piperazin-1 - yl]pyrimidine and p-trifluoromethoxybenzaldehyde in 61 % yield.

MS m/z (%): 548 ([Μ+Η , 100)

Example 396 : Synthesis of 1 -(4-(2-amino-8-p-tolyl-9H-purin-6-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone

This compound was obtained from 2,5,6-triamino-4-[4-(4-chlorophenoxyacetyl)piperazin-1 - yljpyrimidine and >-methylbenzaldehyde in 56 % yield.

MS m/z (%): 478 ([M+H]⁺, 100)

Example 397 : Synthesis of 1 -(4-(2-amino-8-propyl-9H-purin-6-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone

This compound was obtained from 2,5,6-triamino-4-[4-(4-chlorophenoxyacetyl)piperazin-1 - yljpyrimidine and butyraldehyde in 47 % yield.

MS m/z (%): 430 ([M+H]⁺, 100)

Example 398 : Synthesis of 1-(4-(2-amino-8-cvclopropyl-9H-purin-6-yl)piperazin-1-yl)-2-(4- chlorophenoxy)ethanone

This compound was obtained from 2,5,6-triamino-4-[4-(4-chlorophenoxyacetyl)piperazin-1 - yl]pyrimidine and cyclopropanecarboxaldehyde, in 78 % yield.

MS m/z (%): 428 ([M+H]⁺, 100) Example 399 : Synthesis of 1-(4-(2-amino-8-tert-butyl-9H-puhn-6-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone

This compound was obtained from 2,5,6-triamino-4-[4-(4-chlorophenoxyacetyl)piperazin-1- yljpyrimidine and trimethylacetaldehyde in 45 % yield.

MS m/z (%): 444 ([M+H]⁺, 100)

Exa mple 400 : Synthesis of 1 -(4-(2-amino-8-methyl-9H-purin-6-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone

This compound was obtained from 2,5, 6-triamino-4-[4-(4-chlorophenoxyacetyl)piperazin-1- yl]pyrimidine and acetaldehyde in 30 % yield.

MS m/z (%): 402 ([M+Hf, 100)

Example 401 : Synthesis of 1-(4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1 -yl)-2- phenoxyethanone

This compound was obtained from 2,5,6-triamino-4-[(4-phenoxyacetyl)piperazin-1- yljpyrimidine and 4-fluorobenzaldehyde in 37 % yield.

MS m/z (%): 448 ([M+H]\ 100)

Example 402 : Synthesis of (4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1-yl)(3- methoxyphenvDmethanone

This compound was obtained from 2,5,6-triamino-4-[(3-methoxy-benzoyl)piperazin-1- yl]pyrimidine and 4-fluorobenzaldehyde in 41 % yield.

MS m/z (%): 448 ([M+H]⁺, 100)

Example 403 : Synthesis of 1-(4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1-yl)-2- (thiophen-2-yl)ethanone

This compound was obtained from 2,5,6-triamino-4-[(2-thiophene-acetyl)piperazin-1- yljpyrimidine and 4-fluorobenzaldehyde in 28 % yield.

MS m/z (%): 438 ([M+H]⁺, 100)

Example 404 : Synthesis of (4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1-yl)(4- chlorophenvQmethanone

This compound was obtained from 2,5,6-triamino-4-[(4-chloro-benzoyl)piperazin-1- yl]pyrimidine and 4-fluorobenzaldehyde in 31 % yield.

MS m/z (%): 452 ([M+H]\ 100)

Example 405 : Synthesis of 6-(4-(benzylsulfonyl)piperazin-1 -yl)-8-(4-fluorophenyl)-9H-purin- 2-amine

This compound was obtained from 2,5,6-triamino-4-(4-a-toluenesulfonyl)piperazin-1- yl]pyrimidine and 4-fluorobenzaldehyde in 21 % yield MS m/z (%): 468 ([M+H]⁺, 100)

Example 406 : Synthesis of (4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1 - yl)(naphthalen-1-yl)methanone

This compound was obtained from 2,5,6-triamino-4-[(1 -naphthoyl)piperazin-1 -yl]pyrimidine and 4-fluorobenzaldehyde in 41 % yield.

MS m/z (%): 468 ([M+H]⁺, 100)

Example 407 : 2-amino-6-hydroxy-8-(4-fluorophenyl)-9H-purine

This compound was synthesized from commercially available 2,5,6-triamino-4- hydroxypyrimidine (40 mmol) and 4-fluorobenzaldehyde (40 mmol), yielding the title compound in 60 % yield.

MS m/z (%): 246 ([M+H]⁺, 100)

Examples 408 - 420 : Synthesis of 2-amino-6-substituted-8-(4-fluorophenyl)-9H-purine analogues

General procedure

To a solutio n of 2-amino-6-hydroxy-8-(4-fluorophenyl)-9H-purine (0.4 mmol), a nitrogen nucleophile (0.6 mmol) and benzotriazol-1 -yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP, 0.65 mmol) in DMF (5 ml), was added 1 ,8- diazabicyclo[5.4.0]undec-7-ene (DBU, 0.5 mmol). The resulting reaction mixture was stirred at room temperature until all starling material disappeared on TLC (4 - 8 hours). The solvents were evaporated in vacuo. The crude residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1 :30), yielding the pure title compounds.

The following compounds were synthesized according to this procedure :

Example 408 : 1 -(4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-vnpiperazin-1-yl)ethanone

This compound was obtained from 1 -acetylpiperazine in 63 % yield.

MS m/z (%): 356 ([M+H]⁺, 100)

Example 409 : 8-(4-fluorOphenyl)-6-(4-(thiazol-2-yl)piperazin-1 -yl)-9H-purin-2-amine

This compound was obtained from 1 -(thiazol-2-yl)piperazine in 63 % yield.

MS m/z (%): 396 ([M+H]⁺, 100)

Example 410 : 2-(4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1 -yl)-1-(pyrrolidin-1- vPethanone

This compound was synthesized from 1 -(piperazin-1-yl)-2-(pyrrolidin-1-yl)ethanone in 45 % yield.

MS m/z (%): 425 ([M+H]', 100) Example 41 1 : 2-(4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1 -yl)-1 - morpholinoethanone

This compound was synthesized from 1 -morpholino-2-(piperazin-1 -yl)ethanone in 45 % yield.

MS m/z (%): 441 ([M+H]⁺, 100)

Example 412 : 2-(4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1 -yl)-N-(pyridin-3- vOacetamide

This compound was obtained from 2-(piperazin-1 -yl)-N-(pyridin-3-yl)acetamide in 16 % yield. MS m/z (%): 448 ([M+H]⁺, 100)

Example 413 : 2-(4-(2-amino-8-(4-fluorophenyl)-9H-puhn-6-yl)piperazin-1 -yl)-N-methyl-N- phenylacetamide

This compound was obtained from 2-(piperazin-1 -yl)-N-methyl-N-phenylacetamide in 43 % yield.

MS m/z (%): 461 ([M+H]\ 100)

Example 414 : 6-(4-(4-chlorophenyl)piperazin-1 -yl)-8-(4-fluorophenyl)-9H-purin-2-amine

This compound was obtained from 1 -(4-chlorophenyl)piperazine in 58 % yield.

MS m/z (%): 424 ([M+H]⁺, 100)

Example 415 : 8-(4-fluorophenyl)-6-(4-(4-fluorophenyl)piperazin-1 -yl)-9H-purin-2-amine

This compound was obtained from 4-fluorophenylpiperazine in 55 % yield.

MS m/z (%): 408 ([M+H]⁺, 100)

Example 416 : 2-(4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1 -yl)-N-(pyridin-2- yl)acetamide

This compound was obtained from 2-(piperazin-1 -yl)-/\/-(pyridin-2-yl)acetamide in 37 % yield. MS m/z (%): 448 (IM+H]\ 100)

Example 417 : 2-(4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1 -yl)-N-(thiazol-2- yQacetamide

This compound was obtained from 2-(piperazin-1 -yl)-A/-(thiazol-2-yl)acetamide in 37 % yield. MS m/z (%): 454 ([M+H]⁺, 100)

Example 418 : 6-(4-(4-fluorobenzyl)piperazin-1 -yl)-8-(4-fluorophenyl)-9H-purin-2 -amine

This compound was obtained from 4-fluorobenzylpiperazine yielding the pure title compound in 36 % yield.

MS m/z (%): 421 ([M+H]⁺, 100)

Example 419 : 8-(4-fluorophenyl)-6-(4-(pyridin-4-yl)piperazin-1 -yl)-9H-purin-2-amine

This compound was obtained from 1 -(pyridin-4-yl)piperazine yielding the title compound in 70 % yield. MS m/z (%): 391 ([M+H]⁺, 100)

Example 420 : 6-(1 ,4-diazepan-1 -yl)-8-(4-fluorophenyl)-9H-purin-2-amine

This compound was obtained from homopiperazine, yielding the title compound in 92 % yield.

MS m/z (%): 328 ([M+H]⁺, 100)

Exa m p le 421 : Synthesis of 1 -(4-{2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)-1 ,4- diazepan-1 -yl)-2-(4-chlorophenoxy)ethanone

To a solution of 2-amino-6-(homopiperazin-1 -yl)-8-(4-fluorophenyl)-9H-purine (0.2 mmol) in dioxane/methanol (1 :1 ; 5 ml) was added potassium carbonate (55 mg, 0.4 mmol) and a solution of 4-chlorophenoxyacetyl chloride (60 mg, 0.24 mmol) in dioxane (1 ml). The resulting mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was purified by flash chromatography on silica (methanol/dichloromethane 1 :40), yielding the pure title compound (60 mg, 60 %).

MS m/z (%): 496 ([M+Hf, 100)

Example 422 : Synthesis of 4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)-N-m-tolyl-1 , 4- diazepane-1 -carboxamide

To a solution of 2-amino-6-(N-homopiperazin-1 -yl)-8-(4-fluorophenyl)-9H-purine (0.2 mmol) in dioxane/methanol (1 : 1 ; 5 ml) was added m-tolyl isocyanate (0.3 mmol). The resulting mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, the residue was purified by flash chromatography on silica (methanol/dichloromethane 1 :40), yielding the pure title compound (60 mg, 65%).

MS m/z (%): 461 ([M+H]⁺, 100)

Example 423 : Synthesis of 1 -(4-(2-amino-8-thioxo-8,9-dihydro-7H-purin-6-yl)piperazin- 1 -yl)-2-(4-chlorophenoxy)ethanone

A mixture of 2,5,6-triamino-6-[4-(4-chlorophenoxyacetyl)piperazin-1 -yl]-pyrimidine (1.3 g, 3.4 mmol), sodium bicarbonate (1 .68 g, 20 mmol) and carbon disulfide (2.5 ml, 40 mmol) in ethanol/water (1 :2 ; 30 ml) was heated under reflux for 8 hours. After cooling down to room temperature, the pH of the mixture was adjusted to 5-6. The precipitate was filtered off, washed with water, and dried over P₂0₅, yielding the title compound (1.0 g, 70 %).

MS m/z (%): 420 ([M+H]⁺, 100)

Examples 424 - 429 : Synthesis of 2-amino-6-[4-(4-chlorophenoxyacetyl)piperazin-1 - yl]- -alkylthio-9H-purine analogues

General procedure

To a solution of 2-amino-6-[4-(4-chlorophenoxyacetyl)piperazin-1 -yl]-8-thiol-purine (0.24 mmol) and potassium carbonate (0.5 mmol) in DMF (5 ml), was added an appropriate alkyl halide (0.24 mmol). The resulting mixture was stirred at room temperature for 30 minutes. After concentration under reduced pressure, the residue was purified by flash chromatography on silica (methanol/dichloromethane 1 :40), yielding the pure title compounds as a white solid.

The following compounds were synthesized according to this procedure :

Example 424 : Synthesis of 1 -(4-(2-amino-8-(methylthio)-9H-purin-6-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone

This compound was synthesized using methyl iodide in 67 % yield.

MS m/z (%): 434 ([M+H]\ 100)

Example 425 : Synthesis of 1-(4-(2-amino-8-(propylthio)-9H-purin-6-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone

This compound was synthesized using propyl iodide yielding the title compound in 65 % yield.

MS m/z (%): 462 ([M+H]⁺, 100)

Example 426 : Synthesis of 1-(4-(2-amino-8-(benzylthio)-9H-purin-6-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone

This compound was synthesized using benzyl bromide yielding the title compound in 63 % yield.

MS m/z (%): 510 ([M+Hf, 100)

Example 427 : Synthesis of 1-(4-(2-amino-8-(phenethylthio)-9H-purin-6-yl)piperazin-1 -yl)-2- (4-chlorophenoxy)ethanone

This compound was synthesized using phenethylbromide yielding the title compound in 67 % yield.

MS m/z (%): 524 ([M+H]⁺, 100)

Example 428 : Synthesis of 1 -(4-(2-amino-9-methyl-8-(methylthio)-9H-purin-6-yl)piperazin-1- yl)-2-(4-chlorophenoxy)ethanone

This compound was synthesized from 2-amino-6-[4-(4-chlorophenoxyacetyl)piperazin-1 -yl]-8- methylthio-9H-purine using methyl iodide, yielding the title compound in 97 % yield.

MS m/z (%): 448 ([M+H]\ 100)

Example 429 : Synthesis of 1-(4-(2-amino-8-(cvclopentylthio)-9H-purin-6-yl)piperazin-1-yl)-2- (4-chlorophenoxy)ethanone

This compound was prepared from 2-amino-6-[4-(4-chlorophenoxyacetyl)piperazin-1 -yl]-8- thiol-9H-purine and cyclopentyl iodide yielding the title compound in 72 % yield.

MS m/z (%): 488 ([M+H]\ 100) Example 430 : Synthesis of 1 -(4-(2-amino-8-(4-fluorophenyl)-9-methyl-9H-purin-6- yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone

To a solution of 2-amino-6-[4-(4-chlorophenoxyacetyl)piperazin-1 -yl]-8-(4-fluorophenyl)-9H- purine (48 mg, 0.1 mmol) in DMF (2 ml) was added potassium carbonate (28 mg, 0.2 mmol) and methyl iodide (6 μΙ, 0.1 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was evaporated in vacuo and the crude residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1 :50), yielding the pure title compound (40 mg, 80%).

MS m/z (%): 496 ([M+H]⁺, 100)

Example 431 : Synthesis of 1 -(4^2-amino-9-benzyl-8-(4-fluorophenyl)-9H-purin-6- yl)piperazin-1-yl)-2-(4-chlorophenoxy)ethanone

This compound was synthesized according to the procedure mentioned for example 430, using benzylbromide instead of iodomethane, yielding the pure title compound in 68 % yield.

MS m/z (%): 591 ([M+H]⁺, 100)

Example 432 : Synthesis of 2,6-diamino-4-thiomethyl-pyrimidine

To a solution of 2,6-diamino-4-mercaptopyrimidine sulfate salt (2 g, 10 mmol) in water (20 ml) was added potassium hydroxide (21 mmol, 1 .17 g) and iodomethane (16 mmol, 977 μΐ_). The reaction mixture was stirred for 1 ,5 hours at room temperature, after which a yellow precipitate was formed. The precipitate was filtered off, washed with water and dried. The product was used for further reactions without any further purification.

MS m/z (%): 157 ([M+Hf, 100)

Example 433 : Synthesis of 2,6-diamino-5-nitroso-4-thiomethyl-pyrimidine

To a suspension of 2,6-diamino-4-thiomethyl-pyrimidine (1 .21 g, 7.75 mmol) in water (17 ml) was added acetic acid (15 mmol, 888 μΙ) and sodium nitrite (9.3 mmol, 641 mg). The reaction was stirred at room temperature for 1 hour, after which a pink precipitate was formed. The reaction mixture was put in the fridge for several hours and the precipitate was filtered off, yielding the title compound.

Example 434 : Synthesis of 2-amino-6-(4-fluorobenzoylamino)-5-nitroso-4-thiomethyl- pyrimidine

To a solution of 2,6-diamino-5-nitroso-4-thiomethyl-pyrimidine (140 mg, 0.75 mmol) in THF (10 ml) was added triethylamine (0.98 mmol, 136 μΙ) and 4-fluorobenzoylchloride (0.83 mmol, 98 μΙ). The reaction was stirred at room temperature for 3 hours. The solvents were evaporated and the crude residue was used for further reaction, without any purification. Example 435: Synthesis of 2-amino-6-thiomethyl-8-(4-fluorophenyl)-9H-purine

The crude residue, as obtained in Example 61 , was redissolved in o-xylene (10 ml) and triphenylphosphine (1.5 mmol, 393 mg) was added. The reaction mixture was heated at 140 °C overnight. The solvents were evaporated in vacuo and the crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually raising from 0.5 % to 2 % methanol), yielding the pure title compound (60 mg)

MS m/z (%): 276 ([M+H]⁺, 100)

Example 436: Synthesis of a mixture of 2-amino-6-methylsulfoxide-8-(4-fluorophenyl)- 9H-purine and 2-amino-6-methylsulfon-8-(4-fluorophenyl)-9H-purine

To a solution of 2-amino-6-thiomethyl-8-(4-fluorophenyl)-9H-purine (60 mg, 0.22 mmol) in dichloromethane (10 ml) was added m-chloroperoxybenzoic acid (mCPBA, 0.66 mmol, 1 13 mg) at 0°C. The reaction temperature was gradually increased to room temperature over 3 hours. The solvents were evaporated in vacuo yielding a mixture of the corresponding sulfoxide and sulfon derivative, which were used as such in the following reaction.

Example 437: Synthesis of 2-amino-6-(piperazin-1-yl)-8-(4-fluorophenyl)-9H-purine

To a solution of the crude residue (as obtained in Example 63) in dioxane ("10 ml) was added piperazine (1.1 mmol, 94 mg). The reaction was heated at 100 °C overnight. The solvents were evaporated in vacuo and the crude residue was further purified by flash chromatography on silica, with methanol and dichloromethane as the mobile phase (in a ratio gradually ranging from 5 % to 6 % methanol always with 0.5 % aqueous ammonia solution), yielding the pure title compound (30 mg).

MS m/z (%): 314 ([M+H]\ 100)

Example 438: Synthesis of 1- 4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1 - yl)-3-phenylpropan-1 -one

To a solution of 2-amino-6-(A/-piperazin-1-yl)-8-(4-fluorophenyl)-9H-purine (30 mg, 0.0958 mmol) in dioxane (10 ml) was added diisopropylethylamine (0.24 mmol, 40 μΙ) and hydrocinnamoyl chloride (0.12 mmol, 17 μΙ). The reaction was stirred overnight at room temperature. The solvents were evaporated in vacuo and the crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually raising from 1 % to 3 % methanol) yielding the pure title compound (70% , 28 mg).

MS m/z (%): 446 ([M+H]⁺, 100) ³ Example 439 : Synthesis of 4.(5-arnino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N- (4-(trifluoromethyl)phenyl)piperazine-1-carboxamide

To a suspension of 7-(pipera2in-1 -yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-5-amine (50 mg, 0.16 mmol) in dioxane ( 10 ml) was added 4-trifluorotolyl isocyanate (0.18 mmol). The resulting reaction mixture was stirred at room temperature for 30 minutes. The solvents were evaporated in vacuo and the crude residue was purified by flash chromatography, the mobile phase being a mixture of methanol and dich!oromethane (in a ratio of 1 :25), yielding the pure title compound as yellowish solid (50 mg, 63 %).

MS /z (%): 501 ([M+H]⁺, 100)

1H NMR (500 MHz, DMSO-d6, 25 °C): δ = 9.13 (d, J = 2.2 Hz, 1 H, Ar-H), 8.98 (s, 1 H, ArNH-),

8.66 (dd, J = 4.7, 1.5 Hz, 1 H, Ar-H), 8.27 (dt, J = 8.0, 1.5 Hz, 1 H, Ar-H), 7.72 (d, J = 8.6 Hz, 2H, Ar-H), 7.61 (d, J = 8.6 Hz, 2H, Ar-H), 7.55 (dd, J = 8.0, 4.7 Hz, 1 H, Ar-H), 6.56 (s, 2H, NH₂), 4.32 (br s, 4H, NCH₂), 3.67(br s, 4H, NCH₂) ppm.

Example 440 : Synthesis of 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N- phenylpiperazine-1 -carboxamide

This compound was synthesized according to the procedure of example 439, using phenyl isocyanate, yielding the title compound in 67% yield.

MS m/z (%): 433 ([M+H]⁺, 100)

¹H NMR (500 MHz, DMSO-d6, 25 °C): δ = 9.12 (d, J = 1 .8 Hz, 1 H, Ar-H), 8.66 (dd, J = 4.8, 1.6 Hz, 1 H, Ar-H), 8.58 (s, 1 H, ArNH-), 8.27 (dt, J = 7.9, 1 .5 Hz, 1 H, Ar-H), 7.54 (dd, J = 7.9Hz, 4.0 Hz, 1 H, Ar-H), 7.49 (d, J = 8.0 Hz, 2H, Ar-H), 7.25 (t, J = 7.7 Hz, 2H, Ar-H), 6.95 (t, J = 7.2 Hz, 1 H, Ar-H), 6.55 (s, 2H, NH₂), 4.31 (br s, 4H, NCH₂), 3.64 (br s, 4H, NCH₂) ppm.

Example 441 : Synthesis of 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N- cyclohexylpiperazine-1 -carboxamide

This compound was synthesized according to the procedure of example 439, using cyclohexyl isocyanate, yielding the title compound in 63 % yield.

MS m/z (%): 439 ([M+H]⁺, 100)

H NMR (500 MHz, DMSO-d6, 25 °C): δ = 9.09 (d, J = 1 .2 Hz, 1 H, Ar-H), 8.65 (d, J = 4.7 Hz, 1 H, Ar-H), 8.25 (d, J = 8.0 Hz, 1 H, Ar-H), 7.53 (dd, J = 8.0 Hz, 4.7 Hz, 1 H, Ar-H), 6.52 (s, 2H, NH₂), 6.21 (d, J = 7.6 Hz, -CONH), 4.21 (br s, 4H, NCH₂), 3.46 (br s, 5H, NCH- & NCH₂),

1.67 (m, 4H, CH₂), 1.20 (m, 6H, CH₂) ppm.

Example 442: Synthesis of 5-amino-7-[4-<N-4-fluorophenylcarboxamide)piperazin-1-yl]- 2-<pyridine-3-yl)thiazolo[5, 4-d]pyrimidine

This compound was synthesized according to the procedure of example 439, using 4- fluorophenyl isocyanate, yielding the title compound in 72 % yield. MS m/z (%): 451 ([M+Hf, 100)

¹H NMR (300 MHz, DMSO-d6, 25 °C): δ = 9.12(d, J=2.2 Hz, 1 H, Ar-H), 8.66(d, J=4.8 Hz, 1 H, Ar-H), 8.63(s, 1 H, ArNH-), 8.27(d, J=8.0 Hz, 1 H, Ar-H), 7.54(dd, J=8.0 Hz, 4.8 Hz, 1 H, Ar-H), 7.51 (dd, J=8.9, 5.4 Hz, 2H, Ar-H), 7.09(t, J=8.8 Hz, 2H, Ar-H), 6.56(s, 2H, NH₂), 4.31 (br. s, 4H, NCH₂), 3.64(br.s, 4H, NCH₂)ppm.

Example 443 : Synthesis of 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N- hexylpiperazine-1-carboxamide

This compound was synthesized according to the procedure of example 439, using hexyl isocyanate, yielding the title compound in 72 % yield.

MS m/z (%): 441 ([M+H]⁺, 100)

'H NMR (500 MHz, DMSO-d6, 25 °C): δ = 9.09 (dd, J = 2.2, 0.6 Hz, 1 H, Ar-H), 8.65 (dd, J = 4.8, 1 .6 Hz, 1 H, Ar-H), 8.24 (dt, J = 8.0, 2.2 Hz, 1 H, Ar-H), 7.54 (ddd, J=8.0, 4.8, 0.6 Hz, 1 H, Ar-H), 6.51 (s, 3H, NH₂ & -CONH-), 4.22 (br s, 4H, NCH₂), 3.46 (br t, J = 5.0 Hz, 4H, NCH₂), 3.03 (q, J = 6.9 Hz, 2H, -NHCH₂-), 1.41 (m, 2H, CH₂), 1 .25 (m, 6H, CH₂), 0.86 (t, J = 7.0 Hz, CH₃) ppm.

Example 444: Synthesis of 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N-p- tolylpiperazine-1 -carbothioamide

This compound was synthesized according to the procedure of example 439, using 4-tolyl isothiocyanate, yielding the title compound in 71 % yield.

MS m/z (%): 463 ([M+H]⁺, 100)

¹H NMR (500 MHz, DMSO-d6, 25 °C): δ = 9.29 (s, 1 H, CONH-), 9.12 (dd, J = 2.2, 0.6 Hz, 1 H, Ar-H), 8.65 (dd, J = 4.8, 1.6 Hz, 1 H, Ar-H), 8.27 (dt, J = 8.0, 1.6 Hz, 1 H, Ar-H), 7.53 (ddd, J = 8.0 Hz, 4.8, 0.6 Hz, 1 H, Ar-H), 7.20 (d, J = 8.2 Hz, 2H, Ar-H), 7.1 1 (d, J = 8.2 Hz, 2H, Ar- H), 6.56 (s, 2H, NH₂), 4.35 (br s, 4H, NCH₂), 4.10 (br s, 4H, NCH₂), 2.28 (s, 3H, ArCH₃) ppm. Example 445 : Synthesis of 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N- methyl-N-p-tolylpiperazine-1- arboxamide

T o a s u s p e n s i o n o f 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N-p- tolylpiperazine-1 -carboxamide (90 mg, 0.2 mmol) in DMF (5 ml) was added NaH (60%, 12 mg, 0.31 mmol). The resulting mixture was stirred at room temperature for 10 minutes. Then, methyl iodide (0.3 mmol) was added to the mixture. After stirring at room temperature for 30 minutes, the solvents were evaporated in vacuo and the crude residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/30), yielding the pure title compound as yellowish solid (40 mg, 43%).

MS m/z (%): 461 ([M+H]⁺, 100) ¹H NMR (500 MHz, DMSO-d6, 25 °C): δ = 9.07 (dd, J = 2.2, 0.6 Hz, 1 H, Ar-H), 8.65 (dd, J = 4.8, 1.6 Hz, 1 H, Ar-H), 8.23 (ddd, J = 8.0, 2.2, 1.6 Hz, 1 H, Ar-H), 7.53 (ddd, J = 8.0, 4.8, 0.6 Hz, 1 H, Ar-H), 7.17 (d, J=8.2 Hz, 2H, Ar-H), 7.06 (d, J = 8.2 Hz, 2H, Ar-H), 6.49 (s, 2H, NH₂), 4.08 (br s, 4H, NCH₂), 3.28 (br.s, 4H, NCH₂), 3.10 (s, 3H, CONCH₃), 2.26 (s, 3H, ArCH₃) ppm.

Example 446 : Synthesis of p-tolyl 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin- 7-yl)piperazine-1 -carboxylate

To a suspension of 7-(piperazin-1 -yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-5-amine (63 mg, 0.2 mmol) in dioxane (10 ml) was added diisopropylethylamine (33 μΙ, 0.2 mmol) and p-tolyl chloroformate (0.2 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The mixture was evaporated in vacuo and the crude residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/30), yielding the pure title compound as yellowish solid (60 mg, 67%).

MS m/z (%): 448 ([M+H]\ 100)

¹H NMR (500 MHz, DMSO-d6, 25 °C): δ = 9.14 (dd, J = 2.2, 0.6 Hz, 1 H, Ar-H), 8.65 (dd, J = 4.8, 1.6 Hz, 1 H, Ar-H), 8.30 (ddd, J = 8.0, 2.2, 1.6 Hz, 1 H, Ar-H), 7.53 (ddd, J = 8.0, 4.8, 0.6 Hz, 1 H, Ar-H), 7.19 (d, J = 8.2 Hz, 2H, Ar-H), 7.04 (d, J = 8.2 Hz, 2H, Ar-H), 6.57 (s, 2H, NH₂), 4.35 (br s, 4H, NCH₂), 3.77-3.62 (br s, 4H, NCH₂), 2.30 (s, 3H, ArCH₃) ppm.

Thiazolo[5,4-d]pyrimidines and oxazolo[5,4-d]pyrimidines

I

Thieno[2,3-d]pyrimidines

Example R⁵ R⁴ R⁶

312 4-fluorophenyl H

— ⁷ 0

Example R^¾ R⁴ R

/— \ p

373 phenyl NH₂ ^•}-N - /=\

H₃C CH₃

Purines

Example R^y R¹¹ R^s R^1a

Example 447 : Inhibition of HSB-2 leukemic cell line proliferation

HSB2 cell line, a human acute lymphoblastic leukemia (ATCC; CCL-120.1 ) cell line, was grown in RPMI-1640 medium (Lonza, Belgium) supplemented with 10% fetal calf serum (Hyclone, US) and antibiotics. Exponential growing phase cells were seed in flat bottom 96- well microp!ates (TTP, Switzerland) at 50000 cells per well in 220 μΙ of medium with compounds (in different concentrations) and incubated for two days at 37°C, 5% C0₂. After incubation, 100 μΙ of supernatant were removed and 10 μΙ of WST-1 (Roche, Switzerland) were added. After 2 hour incubation at 37°C, 5% C0₂, optical densities were measured at 450 nm. Proliferation is calculated with respect of control points (no compound and treatment with Triton X100 to have maximum and minimum proliferation data). The ICsowas determined from a graph with at least four points, each derived from the mean of at least 2 experiments. The IC₅₀ va lue represents the lowest concentration of the thiazolo[5,4-d]pyrimidine, oxazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine or purine derivative (expressed in μΜ) that resulted in a 50% inhibition of the HSB-2 proliferation. The results are shown in Table 1 for a number of compounds.

Table 1 : IC5₀ data of cytotoxicity on HSB-2 cells of selected examples

2 IC₅₀ HSB-2

Example # IC50 HSB- IC50 HSB-2

Example # Example #

(μΜ) (μ ) (MM)

1 16 6,01 220 0,77 295 0,23

1 17 6,28 222 0,05 298 >10

1 18 4,53 224 3,94 299 3,72

1 19 3,03 225 >10 301 2,06

120 4,87 226 >10 326 8,97 121 a 0,20 227 >10 329 13,7

121 b 6, 19 228 >10 330 7,61

123 3,73 230 2,21 331 >10

124 2,29 231 2,63 332 5,50

126 5,47 232 6,89 341 >10

128 5,62 233 >10 343 >10

129 4,76 234 0,20 351 1 ,70

130 0,57 235 0,55 369 5,87

131 >10 236 5,57 370 6,38

133 12,34 253 4,99 372 9,87

134 >10 254 >10 390 0,45

150 >10 255 2,10 391 2,14

154 4,04 256 >10 392 2,23

172 >10 257 >10 393 1 ,38

185 >10 258 >10 394 7,37

186 >10 259 3,00 396 0,49

188 >10 260 4,49 397 4,51

189 >10 270 0,18 398 4,78

193 >10 271 0,06 400 2,06

196 >10 273 0,81 401 >10

198 >10 275 0,07 412 >10

208 0,06 276 0,05 414 >10

209 0,51 277 0,74 421 >10

210 0,48 278 0,75 422 >10

21 1 0,47 279 0,68 424 4,60

213 5,25 282 0,56 425 4,57

214 0,73 290 >10 426 >10

215 0,24 291 >10 428 0,75

216 4,90 292 9,79 429 7,87

218 7,05 293 0,83 430 3,50

219 5,83 294 4,16 440 0,058

Example 448: Inhibition of HL-60 leukemic cell line proliferation

HL-60 cell line, a human promyelocytic leukemia (ATCC; CCL-240) cell line, was grown in RP I-1640 medium (Lonza, Belgium) supplemented with 10% fetal calf serum (Hyclone, US) and antibiotics. Exponential growing phase cells were seed in flat bottom 96-well microplates (TTP, Switzerland) at 50000 cells per well in 220 μΙ of medium with compounds (in different concentrations) and incubated for two days at 37°C, 5% C0₂. After incubation, 100 μΙ of supernatant were removed and 10μΙ of WST-1 (Roche, Switzerland) were added. After 2 hour incubation at 37°C, 5% C0₂, optical densities were measured at 450 nm. Proliferation is calculated with respect of control points (no compound and treatment with Triton X100 to have maximum and minimum proliferation data). The ICso was determined from a graph with at least four points, each derived from the mean of at least 2 experiments. The IC₅₀ value re presents the lowe st concentration of the thiazolo[5,4-d]pyrimidine, oxazolo[5,4- d]pyrimidine, thieno[2,3-d]pyrimidine or purine derivative (expressed in μΜ) that resulted in a 50% inhibition of the HL-60 proliferation. The results are shown in Table 2 for a number of compounds.

Table 2 : IC₅o data of cytotoxicity on HL-60 cells of selected examples

IC₅₀ HL-60 IC₅₀ HL-60 IC₅₀ HL-60

Example # Example # Example #

(μΜ) (μ ) (μ )

1 16 8,59 209 0,57 341 >10

1 17 >10 210 0,39 343 >10

1 18 9,97 21 1 0,69 351 5,08

1 19 3,81 213 6,72 369 6,05

120 > 10 214 6,02 389 >10

121a 0,23 216 6,41 390 >10

121 b 4,89 218 7,35 391 3,65

123 1 ,20 219 6,19 392 3, 14

124 0,96 220 0,92 393 9, 18

126 3,82 222 0,05 394 8,78

128 6,47 232 9,89 396 4,97

129 9,74 236 8,20 397 1 ,26

130 0,82 270 0,45 398 6,08

131 >10 271 0, 10 400 2,98

133 >10 273 4,84 401 >10

134 >10 275 0,05 412 >10

150 >10 276 0,06 414 >10

154 6,45 277 0,83 421 >10

172 >10 278 0,68 422 >10

185 >10 279 0,88 424 0,01

186 >10 282 0,92 425 8,83

188 >10 326 >10 426 >10 189 >10 329 >10 428 1 ,59

193 >10 330 >10 429 >10

196 >10 331 >10 430 0,99

198 >10 332 >10 440 0,064

208 0,07

Example 449 : Inhibition of LNCaP prostate carcinoma cell line proliferation

LNCaP cell line, a prostate carcinoma cell line, was grown in RPMI-1640 medium (Lonza, Belgium) supplemented with 10% fetal calf serum (Hyclone, US) and antibiotics. Exponential growing phase cells were seed in flat bottom 96-well microplates (TTP, Switzerland) at 10000 cells per well in 200 μΙ of medium. The day after, 20 μΙ of compounds (in different concentrations) were added and incubated for two days at 37°C, 5% C0₂. After incubation, 100 μΙ of supernatant were removed and 10 μΙ of ST-1 (Roche, Switzerland) were added. After 2 hour incubation at 37°C, 5% C0₂, optical densities were measured at 450 nm. Proliferation is calculated with respect of control points (no compound and treatment with Triton X100 to have maximum and minimum proliferation data). The IC₅₀ was determined from a graph with at least four points, each derived from the mean of at least 2 experiments. The IC₅o value represents the lowest concentration of the thiazolo[5,4-d]pyrimidine, oxazolo[5,4-d]pyrimidine, thieno[2,3-d]pyrimidine or purine derivative (expressed in μΜ) that resulted in a 50% inhibition of the LNCaP proliferation. The results are shown in Table 3 for a number of compounds.

Table 3 : IC50 data of cytotoxicity on LNCaP cells of selected examples

Example # IC₅₀ LNCaP (μΜ)

121 a 48

220 1 1 ,22

222 2,87

271 >100

274 18,18

275 1 ,09

276 3,05

440 17,12 Example 450 : In vivo cancer model

Methodology

The test compound (Example 222) was dissolved in DMSO (5% final concentration) and further solubilised in 0.5% Tween 80 in 1 % methylcellulose. The resulting suspension was warmed for 10 minutes to 37°C in an ultrasound water bath to obtain a homogeneous formulation for oral administration. At day 0, 24 male NSG mice received a s c. inoculum of 10⁷ EOL-1 cells taken from in vitro culture and mixed with 50% matrigel. At day 10 tumours were palpable, mice were randomized into three treatment groups and therapy initiated. The test compound (Example 222) and the vehicle were administered orally (p.o.) once daily until the end of the experiment. Cyclophosphamide was administered only once intraperitoneally (i.p.). The experiment was finished at day 21 for ethical reasons.

Summary of results and discussion

Figure 1 is a graph showing the efficacy of the test compound (Example 222) against hu EOL-1 leukemia, plotting (mean) tumour volume (cm³) versus days after tumour transplantation. After a latency period of 10 days tumours of the control group grew fast and progressively. Cyclophosphamide (A ) led to highly significant (p<0.05) inhibition of tumour growth relative to vehicle (♦); it was well tolerated with only a 6% body weight loss. The test compound (Example 222) (■) induced a moderate but significant (p<0.05) delay of tumour growth, with an 1 1 % body weight loss. It was well tolerated; the 1 1 % body weight loss was transient and did not lead to any behavioural changes or deaths.

Conclusion

The test compound (Example 222) revealed a significant antileukemic activity in the EOL-1 xenograft model.

Claims

Claims:

1. The use of a compound having the general formula I, II, III or IV :

I II III IV

wherein

- X is S or O;

- R¹ is selected from the group consisting of amino, halogen, cyano, carboxylic acid, acyl, thioacyl, alkoxycarbonyl, acyloxy, carbonate, carbamate, aryl, acetamido, /V-protected amino, (mono- or di) C ₇ alkylamino, (mono- or di) arylamino, (mono- or di) C3-10 cycloalkylamino, (mono- or di) hydroxy C ₇ alkylamino, (mono- or di) C,.₄ alkyl-arylamino, mercapto alkyl, Ci.7 alkyloxy;

- R² is selected from the group consisting of heteroaryl and aryl groups; halogen; d.₇ alkyl; C₂.7 alkenyl; C₂-₇ alkynyl; halo Ci.₇ alkyl; C₃.io cycloalkyl; carboxy Ο _ι alkyl; carboxyaryl; CL₇ alkoxy; C₃.i₀ cycloalkoxy; aryloxy; arylalkyloxy; oxyheterocyclic; heterocyclic-substituted alkyloxy; thio Ci.₇ alkyl; thio C₃.|₀ cycloalkyl; thioaryl; thioheterocyclic; arylalkylthio; heterocyclic-substituted alkylthio; hydroxylamino; thio-acylamino; alkoxyamino; thioalkylamino; acetal; thio-acetal; carboxylic acid; carboxylic acid esters, thiocarboxylic acid; thiocarboxylic acid esters, thioesters, halides, anhydrides, amides and thioamides; hydroxyl; sulfhydryl; nitro; cyano; carbamoyl; thiocarbamoyl; ureido; thioureido; amino; alkylamino; cycloalkylamino; alkenylamino; cyclo-alkenylamino; alkynylamino; arylamino; arylalkylamino; hydroxyalkylamino; mercaptoalkyl-amino; heterocyclic amino; heterocyclic substituted arylamino; heterocyclic-substituted alkyl-amino; oximino; alkyloximino; hydrazino; alkylhydrazino; phenylhydrazino; esters, thioesters, halides, anhydrides, amides and thioamides thereof; aromatic or heterocyclic substituents substituted with an aliphatic spacer between the thiazolo(5,4-d)pyrimidine or oxazolo(5,4-d)pyrimidine ring and the aromatic or heterocyclic substituent, wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, C,.₇ alkyl, C₂.7 alkenyl, C₂.₇ alkynyl, halo alkyl, nitro, hydroxyl, sulfhydryl, amino, C,.₇ alkoxy, C₃.₁₀ cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C,.₇ alkyl, thio C₃.₁₀ cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, a lken yl a m i no , cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino; wherein said aliphatic spacer is a branched or straight, saturated or unsaturated aliphatic chains of 1 to 7 carbon atoms optionally containing one or more functions, atoms or radicals independently selected from the group consisting of halogen, carbonyl, thiocarbonyl, hydroxyl, thiol, ether, thio-ether, acetal, thio-acetal, amino, imino, oximino, a!kyloximino, aminoacid, cyano, acylamino, thioacylamino, carbamoyl, thiocarbamoyl, ureido, thio-ureido, carboxylic acid ester or halide or anhydride or amide, thiocarboxylic acid or ester or thioester or halide or anhydride or amide, nitro, thio Ci_-7 alkyi, thio C3.10 cycloalkyl, hydroxylamino, mercaptoamino, alkyl-amino, cycloalkylamino, alkenylamino, cycloalkenylamino, alkynylamino, arylamino, arylalkyl-amino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic-substituted alkylamino, hetero-cyclic amino, heterocyclic-substituted arylamino, hydrazine alkylhydrazino, phenylhydrazino, sulfonyl, sulfinyl and sulfonamido;

- R³ is selected from the group consisting of piperazinyl, homopiperazinyl, (mono- or di-) d.₁₂ alkylamino; monoarylamino; diarylamino; (mono- or di-) C₃.i₀ cycloalkylamino; (mono- or di-) hydroxy d-7 alkylamino; (mono- or di-) d-4 alkylarylamino; (mono- or di-) aryld-4 alkylamino; morpholinyl; mercapto C1.7 alkyi; -7 alkoxy, aralkylthio, piperidinyl, pyrrolidinyl, and, wherein said piperidinyl, pyrrolidinyl, homopiperazinyl or piperazinyl is optionally N-substituted with a substituent R²⁰ selected from the group consisting of formyl, acyl, thioacyl, amide, thioamide, sulfonyl, sulfinyl, carboxylate, thiocarboxylate, amino-substituted acyl, alkoxyalkyl, C_{3 10} cycloalkyl-alkyl, C3-10 cycloalkyl, dialkylaminoalkyl, heterocyclic-substituted alkyi, acyl- substituted alkyi, thioacyl-substituted alkyi, amido-substituted alkyi, thioamido-substituted alkyi, carboxylato-substituted alkyi, thiocarboxylato-substituted alkyi, (amino-substituted acyl)alkyl, heterocyclic, carboxylic acid ester, ω-cyanoalkyl, ω-carboxylic ester-alkyl, halo d-7 alkyi, C₂.₇ alkenyl, C₂.₇ alkynyl, arylalkenyl, aryloxyalkyl, arylalkyl and aryl, wherein the aryl moiety of each of said arylalkenyl, aryloxyalkyl, arylalkyl and aryl radicals is optionally substituted with one or more substituents independently selected from the group consisting of halogen, .7 alkyi, C₂.₇ alkenyl, C₂.₇ alkynyl, halo - alkyi, nitro, hydroxyl, sulfhydryl, amino, C_{1 7} alkoxy, C3.10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic- substituted alkyloxy, thio -7 alkyi, thio C₃.i₀ cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino , cyclo- a lkenyl a mi n o , a l ky nyla mi no , a ry la mi n o , a ryla l kyla m i n o, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydrazino, alkylhydrazino and phenylhydrazino;

- R⁴ is selected from the group consisting of halogen, cyano, carboxylic acid, acyl, thioacyl, alkoxycarbonyl, acyloxy, carbonate, carbamate, aryl, amino, acetamido, /V-protected amino, (mono- or di) -7 alkylamino, (mono- or di) arylamino, (mono- or di) C₃-₁₀ cycloalkylamino, (mono- or di) hydroxy d-7 alkylamino, (mono- or di) d- alkyl-arylamino, mercapto d-7 alkyl, d-7 alkyloxy;

- R⁵ is selected from the group consisting of heteroaryl and aryl groups, wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, d.₇ alkyl, C₂.₇ alkenyl, C₂.₇ alkynyl, halo d-7 alkyl, nitro, hydroxyl, sulfhydryl, amino, d-7 alkoxy, C₃.i₀ cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio Ci.₇ alkyl, thio C₃.₁₀ cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyi, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino;

- R⁶ is selected from the group consisting of (mono- or di-) d-12 alkylamino, monoarylamino, diarylamino, (mono- or di-) C₃.io cycloalkylamino, (mono- or di-) hydroxy d-7 alkylamino, (mono- or di-) d-4 alkylarylamino, (mono- or di-) aryld ₄ alkylamino, morpholinyl, mercapto d-7 alkyl, .7 alkoxy, homopiperazinyl and piperazinyl, wherein said homopiperazinyl or piperazinyl is optionally N-substituted with a substituent R²¹ selected from the group consisting of formyl, acyl, thioacyl, amide, thioamide, sulfonyl, sulfinyl, carboxylate, thiocarboxylate, amino-substituted acyl, alkoxyalkyl, C₃.₁₀ cycloalkyl-alkyl, C₃.i₀ cycloalkyl, dialkylaminoalkyl, heterocyclic-substituted alkyl, acyl-substituted alkyl, thioacyl-substituted alkyl, amido-substituted alkyl, thioamido-substituted alkyl, carboxylato-substituted alkyl, thiocarboxylato-substituted alkyl, (amino-substituted acyl)alkyl, heterocyclic, carboxylic acid ester, ω-cyanoalkyl, ω-carboxylic ester-alkyl, halo d-7 alkyl, C₂-7 alkenyl, C₂.₇ alkynyl, arylalkenyl, aryloxyalkyl, arylalkyl and aryl; wherein the aryl moiety of each of said arylalkenyl, aryloxyalkyl, arylalkyl and aryl radicals is optionally substituted with one or more substituents independently selected from the group consisting of halogen, d-7 alkyl, C₂.₇ alkenyl, C₂.₇ alkynyl, halo C1.7 alkyl, nitro, hydroxyl, sulfhydryl, amino, Ci.₇ alkoxy, C₃.₁₀ cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio d-7 alkyl, thio C₃.io cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyi, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alke nyla mino, cyclo- alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydrazino, alkylhydrazino and phenylhydrazino;

R¹² is represented by the general formula V:

10

V

and wherein

- each substituent R¹³ of the heterocyclic ring is a group independently selected from the group consisting of halogen, nitro, C_{1 7} alkyl (optionally containing one or more functions or radicals selected from the group consisting of halogen, carbonyl, thiocarbonyl, hydroxyl, sulfhydryl, C,.₇ alkoxy, thio d.₇ alkyl, thio C₃.₁₀ cycloalkyl, acetal, thioacetal, imino, oximino, alkyloximino, amino-acid, cyano, (thio)carboxylic acid, (thio)carboxylic acid ester or amide, nitro, amino, C_{1 7} alkylamino, cycloalkylamino, alkenylamino, cycloalkenyl-amino, alkynyla mino, arylamino, arylalkyla mino, hydroxyalkylamino , mercapto-alkylamino, heterocyclic-substituted alkylamino, heterocyclic amino, heterocyclic-substituted arylamino, hydrazino, alkylhydrazino, phenylhydrazino, sulfonyl and sulfonamido), C₃. alkenyl, C₂.₇ alkynyl, halo C^y alkyl, C3-10 cycloalkyl, aryl, arylalkyl, alkylaryl, alkylacyl, arylacyl, hydroxyl, sulfhydryl, amino, C1.7 alkylamino, cycloalkylamino, alkenylamino, cycloalkenylamino, alkynylamino, arylamino, arylalkyl-amino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic-substituted alkylamino, heterocyclic amino, heterocyclic-substituted arylamino, hydrazino, alkylhydrazino, phenylhydrazino, d.₇ alkoxy, C₃. ₀ cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C1.7 alkyl, thio C₃.io cycloalkyl, thioaryl, thioheterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, hydroxylamino, cyano, (thio)carboxylic acid or esters or thioesters or amides or thioamides thereof;

- n is an integer from 0 to 6;

- R¹⁰ is selected from the group consisting of formyl, acyl, thioacyl, amide, thioamide, sulfonyl, sulfinyl, carboxylate, thiocarboxylate, amino-substituted acyl, alkoxyalkyl, C₃.₁₀ cycloalkyl- alkyl, C3-10 cycloalkyl, dialkylaminoalkyl, heterocyclic-substituted alkyl, acyl-substituted alkyl, thioacyl-substituted alkyl, amido-substituted alkyl, thioamido-substituted alkyl, carboxylato- substituted alkyl, thiocarboxylato-substituted alkyl, (amino-substituted acyl)alkyl, heterocyclic, carboxylic acid ester, ω-cyanoalkyl, ω-carboxylic ester-alkyl, halo C1.7 alkyl, C₂-_? alkenyl, C₂.7 alkynyl, arylalkenyl, aryloxyalkyl, arylalkyl and aryl; wherein the aryl moiety of each of said arylalkenyl, aryloxyalkyl, arylalkyl and aryl radicals is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1.7 alkyl, C₂.7 alkenyl, C2.7 alkynyl, halo C1.7 alkyl, nitro, hydroxyl, sulfhydryl, amino, C-,.₇ alkoxy, C3.10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C_{1 7} alkyl, thio C₃.₁₀ cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenyla mino, cyclo- alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydrazino, alkylhydrazino and phenylhydrazino; and

- R^{1 1} is selected from the group consisting of halogen, cyano, carboxylic acid, acyl, thioacyl, alkoxycarbonyl, acyloxy, carbonate, carbamate, C1-7 alkyl, aryl, amino, acetamido, N- protected amino, (mono- or di) C1-7 alkylamino, (mono- or di) arylamino, (mono- or di) C₃-₁₀ cycloalkylamino, (mono- or di) hydroxy d-₇ alkylamino, (mono- or di) C alkyl-arylamino, mercapto d.₇ alkyl, C1.7 alkyloxy;

- R⁸ is selected from the group consisting of heteroaryl and aryl groups; halogen; d.7 alkyl; C₂-7 alkenyl; C₂.₇ alkynyl; halo C1.7 alkyl; carboxy C,.? alkyl; carboxyaryl; d-7 alkoxy; C₃.₁₀ cycloalkoxy; aryloxy; arylalkyloxy; oxyheterocyclic; heterocyclic-substituted alkyloxy; thio C1.7 alkyl; thio C₃ -i₀ cycloalkyl; thioaryl; thioheterocyclic; arylalkylthio; heterocyclic-substituted alkylthio; hydroxylamino; acylamino; thio-acylamino; alkoxyamino; thioalkyl-amino; acetal; thio-acetal; carboxylic acid; carboxylic acid esters, thioesters, halides, anhydrides, amides and thioamides; thiocarboxylic acid; thiocarboxylic acid este rs , thioesters, halides, anhydrides, amides and thioamides; hydroxyl ; sulfhydryl; n itro; cyano ; carbamoyl ; thiocarbamoyi; ureido; thioureido; amino; alkylamino; cycloalkylamino; alkenylamino; cyclo- alkenylamino; alkynylamino; arylamino; arylalkylamino; hydroxyalkylamino; mercaptoalkylamino; heterocyclic amino; heterocyclic substituted arylamino, heterocydic-substituted alkyl- amino; oximino; alkyloximino; hydrazino; alkylhydrazino; phenylhydrazino; esters, thioesters, halides, anhydrides, amides and thioamides thereof; aromatic or heterocyclic substituents substituted with an aliphatic spacer between the purine ring and the aromatic or heterocyclic substituent; wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, Ci.₇ alkyl, C2-7 alkenyl, C2.7 alkynyl, halo d.₇ alkyl, nitro, hydroxyl, sulfhydryl, amino, C1.7 alkoxy, C3.10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocydic-substituted alkyloxy, thio C1.7 alkyl, thio C₃. 10 cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocydic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyi, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino , cycloalkylamino , alkenylamino, cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino; and wherein said aliphatic spacer is a branched or straight, saturated or unsaturated aliphatic chain of 1 to 7 carbon atoms optionally containing one or more functions, atoms or radicals independently selected from the group consisting of halogen, carbonyl, thiocarbonyl, hydroxyl, thiol, ether, thio-ether, acetal, thio-acetal, amino, imino, oximino, alkyloximino, aminoacid, cyano, acylamino, thioacylamino, carbamoyl, thiocarbamoyi, ureido, thio-ureido, carboxylic acid ester or halide or anhydride or amide, thiocarboxylic acid or ester or thioester or halide or anhydride or amide, nitro, thio C_1-7 alkyl, thio C₃. ₀ cycloalkyl, hydroxylamino, mercaptoamino, alkyl-amino, cycloalkylamino, alkenylamino, cycloalkenylamino, alkynylamino, arylamino, arylalkyl-amino, hydroxyalkylamino, mercaptoalkylamino, heterocydic-substituted alkylamino, hetero-cyclic amino, heterocydic-substituted arylamino, hydrazino, alkylhydrazino, phenylhydrazino, sulfonyl, sulfinyl and sulfonamido;

- R⁷ and R⁹ are selected from the group consisting of hydrogen, C3-7 alkenyl, C₂-i alkynyl, halo C1.7 alkyl, C₃.₁₀ cycloalkyl, aryl, arylalkyl, alkylaryl, acyl sulfonyl and C alkyl , wherein said C1.7 alkyl is optionally containing one or more functions or radicals selected from the group consisting of halogen, carbonyl, thiocarbonyl, hydroxyl, sulfhydryl, C1.7 alkoxy, thio C₁.7 alkyl, thio C3.10 cycloalkyl, acetal, thioacetal, imino, oximino, alkyloximino, amino-acid, cyano, (thio)carboxylic acid, (thio)carboxylic acid ester or amide, nitro, amino, d.7 alkylamino, cycloalkylamino, alkenylamino, cycloalkenyl-amino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercapto-a!kylamino, heterocydic-substituted alkylamino, heterocyclic amino, heterocyclic-substituted arylamino, hydrazino, alkylhydrazino, phenylhydrazino, sulfonyl and sulfonamido),

wherein acyl group refers to a carbonyl group adjacent to a C1.7 alkyl, a C₃.₁₀ cycloalkyl, an aryl, an arylalkyl or a heterocyclic group, or is selected from the group comprising alkanoyl, cycloalkanoyl, cycloalkyl-alkanoyl, alkenoyl, alkylthioalkanoyl, alkanesulfonyl, alkoxycarbonyl, alkylcarbamoyl, alkylcarbamidoyl, alkoxalyl, aroyl, aralkanoyl, aralkenoyl, aryloxyalkanoyl, arylthioalkanoyl, arylaminoalkanoyl, aryloxycarbonyl, aralkoxycarbonyl, arylcarbamoyl, arylglyoxyloyl, arylthiocarbamoyl, arylcarbamidoyl, heterocyclic-carbonyl, heterocyclic- alkanoyl, wherein said heterocyclic group is an aromatic or non-aromatic 5- to 7-membered heterocyclic ring with one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur in said ring;

and/or a pharmaceutical acceptable addition salt thereof and/or a stereoisomer thereof and/or a solvate thereof;

as a medicine for the prevention or treatment of cancer in an animal, mammal or human.

2. The use according to claim 1 , wherein the cancer is selected from the group of hematological malignancies comprising acute leukemia, chronic leukemia, lymphoma, multiple myeloma, myelodysplastic syndrome, or non-hematological cancer.

3. The use according to claim 2, wherein the chronic leukemia is myeloid or lymphoid.

4. The use according to claim 2, wherein the lymphoma is Hodgkin's or non-Hodgkin's lymphoma.

5. The use according to claim 2, wherein the non-hematological cancer is prostate cancer.

6. The use according to any of claims 1 to 5, wherein R , R⁴, and R¹¹ are each independently selected from the group consisting of amino, acetamido, /V-protected amino, (mono- or di) C₁-7 alkylamino, (mono- or di) arylamino, (mono- or di) C₃-₁₀ cycloalkylamino, (mono- or di) hydroxy d-₇ alkylamino, (mono- or di) Ci.₄ alkyl-arylamino.

7. The use according to any of claims 1 to 6, wherein X is S.

8. The use according to any of claims 1 to 6, wherein X is O.

9. The use according to claims any of claims 1 to 8, wherein R³ is selected from the group consisting of monoarylamino; diarylamino; (mono- or di-) arylC- alkylamino; morpholinyl; C₁.7 alkoxy, aralkylthio, piperidinyl, pyrrolidinyl, homopiperazinyl and piperazinyl, wherein said piperidinyl, pyrrolidinyl, homopiperazinyl or piperazinyl is optionally N-substituted with a substituent R²⁰ , wherein R²⁰ has the same meaning as defined in claim 1 .

10. The use according to claims 1 to 6, wherein R⁶ is selected from the group consisting of (mono- or di-) CM₂ alkylamino, monoarylamino, diarylamino, (mono- or di-) C₃.i₀ cycloalkylamino, (mono- or di-) arylCi.₄ alkylamino, morpholinyl, C_y alkoxy, homopiperazinyl and piperazinyl, wherein said homopiperazinyl or piperazinyl is optionally N-substituted with a substituent R , wherein R²¹ has the same meaning as that defined in claim 1.

1 1 . The use according to any of claims 1 to 6, wherein n is 0 and R¹⁰ is selected from the group consisting of formyl, acyl, thioacyl, amide, thioamide, sulfonyl, sulfinyl, carboxylate, thiocarboxylate, amino-substituted acyl, alkoxyalkyl, C₃.₁₀ cycloalkyl-alkyl, C_{3 0} cycloalkyl, dialkylaminoalkyl, heterocyclic-substituted alkyl, acyl-substituted alkyl, thioacyl- substituted alkyl, amido-substituted alkyl, thioamido-substituted alkyl, carboxylato- substituted alkyl, thiocarboxylato-substituted alkyl, (amino-substituted acyl)alkyl, heterocyclic, carboxylic acid ester, ω-carboxylic ester-alkyl, aryloxyalkyl, arylalkyl and aryl; wherein the aryl moiety of each of said aryloxyalkyl, arylalkyl and aryl radicals is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1.7 alkyl, halo C1-7 alkyl, nitro, hydroxyl, sulfhydryl, amino, C_{1 7} alkoxy, C3.10 cycloalkoxy, aryloxy, arylalkyloxy, formyl, carbamoyl, thiocarbamoyl, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, cyano, alkylamino, cycloalkylamino.

12. The use according to any of claims 1 to 8, wherein R² is selected from the group consisting of heteroaryl and aryl groups; d.₇ alkyl; C₃.i₀ cycloalkyl; halo C_1-7 alkyl; carboxy C, 7 alkyl; carboxyaryl; C,.₇ alkoxy; C3.10 cycloalkoxy; aryloxy; arylalkyloxy; heterocyclic- substituted alkyloxy; thio C1.7 alkyl; thio C3.10 cycloalkyl; thioaryl; thioheterocyclic; arylalkylthio; heterocyclic-substituted alkylthio; hydroxylamino; acylamino; thio-acylamino; alkoxyamino; carbamoyl; thiocarbamoyl; aromatic or heterocyclic substituents substituted with an aliphatic spacer between the thiazolo(5,4-d)pyrimidine or oxazolo(5,4- d)pyrimidine ring and the aromatic or heterocyclic substituent, wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, C1.7 alkyl, halo C1.7 alkyl, nitro, hydroxyl, sulfhydryl, amino, C,.₇ alkoxy, C₃.i₀ cycloalkoxy, aryloxy, arylalkyloxy, thio C1.7 alkyl, thio C_{3 10} cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, carbamoyl, thiocarbamoyl, sulfonamido, hydroxylamino, alkoxy-amino, acylamino, thioacylamino, cyano, wherein said aliphatic spacer is a branched or straight, saturated or unsaturated aliphatic chains of 1 to 7 carbon atoms optionally containing one or more functions, atoms or radicals independently selected from the group consisting of halogen, thiol, ether, thio-ether, amino, cyano, acylamino, nitro, thio C,.₇ alkyl.

13. The use according to any of claims 1 to 6 or 10, wherein R⁵ is an aryl group, wherein said aryl group is optionally substituted with one or more substituents selected from the group consisting of halogen, C1.7 alkyl, halo C1.7 alkyl, nitro, hydroxyl, sulfhydryl, C_{1 7} alkoxy, thio CL? alkyl, cyano.

14. The use according to any of claims 1 to 6 or 1 1 , wherein R⁸ is selected from the group consisting of heteroaryl and aryl groups; d-7 alkyl; halo d-7 alkyl; d-7 alkoxy; C₃.₁₀ cycloalkoxy; aryloxy; arylalkyloxy; thio C1.7 alkyl; thio C3.10 cycloalkyl; thioaryl; thioheterocyclic; arylalkylthio; heterocyclic-substituted alkylthio; aromatic or heterocyclic substituents substituted with an aliphatic spacer between the purine ring and the aromatic or heterocyclic substituent; wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, C1.7 alkyl, halo d.7 alkyl, nitro, hydroxyl, sulfhydryl, amino, d-7 alkoxy, C₃.₁₀ cycloalkoxy, thio d.7 alkyl, and wherein said aliphatic spacer is a branched or straight, saturated or unsaturated aliphatic chain of 1 to 7 carbon atoms optionally containing one or more functions, atoms or radicals independently selected from the group consisting of halogen, carbonyl, hydroxyl, thiol, cyano, nitro, thio d-7 alkyl, thio C3.10 cycloalkyl.

15. The use according to any of claims 1 to 6, wherein R³, R⁶ are each independently homopiperazinyl or piperazinyl, wherein said homopiperazinyl or piperazinyl is each respectively optionally N-substituted with a substituent R²⁰, R²¹, wherein R²⁰ and R²¹ have the same meaning as that defined in claim 1.

16. The use according to any of claims 1 to 6, wherein R¹, R⁴ and R¹¹ are each independently amino.

17. The use according to any of claims 1 to 8, wherein R² is selected from the group consisting of phenyl; pyridin-3-yl; pyridin-2-yl; pyridin-4-yl; 4-fluorophenethyl; 4- fluorophenyl; 4-bromophenethyl; pentyl; tolyl; (4-fluorophenyl)butyl; (4- fluorophenyl)propyl; 4-chlorophenyl; 4-methylphenethyl; 3,4-dimethoxyphenethyl; 3- methoxyphenethyl; furan-2-yl; 2-phenylethyl; cyclohexyl; methoxylmethyl; cyclopropyl; 2- thiophen-2-ylethyl; cyclopentyl-(4-fluorophenyl)methyl; 1-(4-fluorophenyl)propyl; 4- fluorophenylamino; methylsulfinyl; 1 -(4-chlorophenyl)ethyl; 3-methoxyphenyl; 4- chlorophenyl; 4-chlorophenylmethyl; N-oxopyridine-3-yl; 1-(4-chlorophenyl)cyclopropyl; 3,4-dichlorophenyl; methylthio; 1 -phenylcyclopropyl; 1 -(4-fluorophenyl)ethyl; 1-(4- fluorophenyl)-2-phenylethyl; 2-(4-fluorophenoxy)ethyl; moφholino.

18. The use according to any of claims 1 to 8, wherein R³ is selected from the group consisting of p-tolyl piperazinyl-1 -carboxylate; N-methy!-N-p-tolylpiperazinyl-1 - carboxamide; N-p-tolylpiperazinyl-1 -carbothioamide; -N-hexylpiperazinyl-1 -carboxamide; 4-(N-4-fluorophenylcarboxamide)piperazin-1 -yl; N-cyclohexylpiperazinyl-1 -carboxamide; N-phenylpiperazinyl-1-carboxamide; N-(4-(trifluoromethyl)phenyl)piperazinyl-1- carboxamide, piperazin-1 -yl-2-(4-chlorophenoxy)ethanone; piperazin-1-yl-2-(4- methoxyphenoxy)ethanone; benzylsulfonylpiperazin-1 -yl; N-(4-cyanophenyl)piperazinyl- 1 -carboxamide; N-(4-methoxybenzyl)piperazinyl-1 -carboxamide; N-(4- chlorophenyl)piperazinyl-1 -carboxamide; N-m-tolylpiperazinyl-1 -carboxamide; piperazin- 1-yl-2-(m-toly!oxy)ethanone; piperazin-1 -yl-2-(4-chlorophenoxy)-2-methylpropan-1 -one; piperazin-1-yl-2-(4-trifluoromethoxyphenoxy)ethanone;piperazin-1-yl-2-(4- fluorophenoxy)ethanone; piperazin-1-yl-2-(4-bromophenoxy)ethanone; piperazin-1 -yl-3- (4-f1uorophenyl)propan-1-o n e ; p i p e ra z i n-1-yl-2-(3-chlorophenoxy)etha n o n e ; 4- acetylphenoxy-piperazin-1 -yl-ethanone; piperazin-1 -yl-2-oxoethoxy)benzoate; piperazin- 1-yl-2-(4-hydroxyphenoxy)ethanone; piperazin-1 -yl-3-(4-bromophenyl)propan-1 -one; N- (2-methoxyphenyl)piperazinyl-carboxamide; N-(4-bromophenyl)piperazinyl-carboxamide; N-(2,4-difluorophenyl)piperazinyl-carboxamide; piperazin-1 -yl-2-(4-chloro-2- methylphenoxy)ethanone; piperazin-1 -yl-2-(2,4-dichlorophenoxy)ethanone; (methylphenyl-carbamoyl)methyl]piperazin-1-yl; phenoxyethyl)piperazin-1-yl; (4- chlorophenyl)acetyl]-piperazin-1 -yl; (4-chlorophenyl)acetyl]-piperazin-1-yl; [2-(3- nitrophenoxy)acetyl]-piperazin-1 -yl; 4-(2-methoxyethyl)-piperazin-1 -yl; 4-acetylpiperazin-

1 - yl; 4-isobutylpiperazin-1 -yl; 3-chloro-4-fluorophenyl-amino; 4-(2- phenoxyethyl)piperazin-1 -yl; 4-benzoylpiperidine-1-yl; 4-chlorophenoxyacetyl)pyrrolidin-3- (S)-ylamino; 1 -tert-butoxycarbonylpyrrolidin-3-(S)-ylannino; 1-benzyloxycarbonylpiperidin-

3- ylamino; 3-(R)-(4-chlorobenzoylamino)-pyrrolidin-1-yl; 3-(R)-[2-(4-chlorophenoxy)- acetylamino]pyrrolidin-1-yl; 3-(R)-tert-butoxycarbonylamino; 4-(phenethylcarbamoyl- methyl)piperazin-1-yl; 4-thiazol-2-yl-piperazine-1-yl; 4-[(methylphenylcarbamoyl)- methyl]piperazin-1 -yl; 4-chlorophenoxy)acetyl]homopiperazin-1 -yl; 4- phenylmethanesulfonylpiperazin-1 -yl; 4-(3-phenylpropionyl)piperazin-1 -yl; 4-[2- phenoxyacetyl]piperazin-1 -yl; 4-[2-(4-chlorophenyl)acetyl]piperazin-1-yl; 4-[2-(3- nitrophenoxy)acetyl]piperazin-1 -yl; 4-(phenylsulfonyl)piperazin-1 -yl; pyrimidin-7-yl- piperazinyl-1 -carboxylate; 4-benzylpiperazin-1-yl; piperazin-1 -yl-1 -morpholinoethanone;

4- pentylpiperazin-1 -yl; 4-(thiazol-2-yl)piperazin-1 -yl; 4-m-tolylpiperazin-1 -yl; 3- methoxypropylamino; ethoxy; 2-methoxyethoxy; benzylthio; benzyl amino.

19. The use according to any of claims 1 to 5, wherein the compound is selected from the group consisting of: 2-(4-fluorophenyl)-7-(piperazin-1-yl)-thiazolo[5,4-d]pyrimidin-5-amine;

2- (4-fluorobenzyl)-7-(piperazin-1 -yl)-thiazolo[5,4-d]pyrimidin-5-amine; 2-(4- fluorophenethyl)-7-(piperazin-1 -yl)thiazolo[5,4-d]pyrimidin-5-amine; 2-(4-fluorophenyl)-7- (2-methoxyethoxy)-thiazolo[5,4-d]pyrimidin-5-amine; 7-ethoxy-2-(4- fluorophenyl)thiazolo[5,4-d]pyrimidin-5-amine; 7-ethoxy-2-(4-fluorobenzyl)thiazolo[5,4- d]pyrimidin-5-amine; 2-(4-fluorophenyl)-N-7-(3-methoxypropyl)thiazolo[5,4-d]pyrimidine- 5,7-diamine; 2-(4-fluorophenyl)-7-morpholino-thiazolo[5,4-d]pyrimidin-5-amine; 2-(4- fluorobenzyl)-7-morpholino-thiazolo[5,4-d]pyrimidin-5-amine; 2-(4-fluorophenyl)-7-(4-m- tolylpiperazin-1 -yl)-thiazolo[5,4-d]pyrimidin-5-amine; 2-(4-fluorophenyl)-7-(4-(thiazol-2- yl)piperazin-1 -yl)thiazolo[5,4-d]pyrimidin-5-amine; 2-(4-fluorophenyl)-7-(4-pentylpiperazin- 1-yl)thiazolo[5,4-d]pyrimidin-5-amine; 2-(4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1 -yl)-1 -morpholinoethanone; 7-(4-benzylpiperazin-1 -y!)-2-(4- fluorophenyl)thiazolo[5,4-d]pyrimidin-5-amine; benzyl-4-(5-amino-2-(4- fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazine-1 -carboxylate; 2-(4-fluorophenyl)-7- (4-(phenylsulfonyl)piperazin-1 -yl)lhiazolo(5,4-d]pyrimidin-5-amine; 4-(5-amino-2-(4- fluorop enyl)-thiazolo[5,4-d]pyrimidin-7-yl)-N-p-tolylpiperazine-1 -carboxamide; 4-(5- amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)-N-m-tolylpiperazine-1 - carboxamide; 4-(5-amino-2-(4-fluorobenzyl)thiazolo[5,4-d]pyrimidin-7-yl)-N-m- tolylpiperazine-1 -carboxamide; 1 -(4-(5-amino-2-(4-fluorop enyl)thiazolo[5,4-d]pyrimidin- 7-yl)piperazin-1-yl)-2-(4-chlorophenoxy)ethanone; 1-(4-(5-amino-2-(4- fluorobenzyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanon 2- (4-chlorophenoxy)-1 -(4-(2-(4-fluorophenyl)-5-methylthiazolo[5,4-d]pyrirnidin-7- yl)piperazin-1 -yl)ethanone; 1 -(4-(5-amino-2-(2-(4-fluorophenoxy)ethyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone; 1 -(4-(5-amino-2-(4- fluorophene1hyl)-thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(4- chlorophenoxy)ethanone; 1 -(4-(5-amino-2-(4-fluorophenethyl)thiazolo(5,4-d]pyrimidin-7- yl)piperazin-1 -yl)-2-(4-methoxyphenoxy)ethanone; 1 -(4-(5-amino-2-(4- fluorophenet yl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(4 luorophenoxy)ethanon 1 -(4-(5-amino-2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- bromophenoxy)ethanone; 1-(4-(5-amino-2-(4-fluorophenet yl)thiazolo(5,4-d]pyrimidin-7- yl)piperazin-1 -yl)-2-(m-tolyloxy)ethanone; 1 -(4-(5-amino-2-(4- fluorophenethy!)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(2,4- dichlorophenoxy)ethanone; 1 -(4-(5-amino-2-(4-fluorophenethyl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1 -yl)-3-(4-fluorophenoxy)propan-1 -one; 1 -(4-(5-amino-2-(1 -(4- fluorophenyl)ethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(4- chlorophenoxy)ethanone; 1-(4-(5-amino-2-(1-(4-fluorophenyl)-2-phenylethyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone; 4-(5-amino-2-(1 -(4- fIuorophenyl)ethyl)lhiazolo[5,4-d]pyrimidin-7-yl)-N-m-tolylpiperazine-1 -carboxamide; 5- amino-2-cyclopropyl-7-methoxythiazolo[5,4-d]pyrimidine; 5-amino-2-cyclopropyl-7-N- piperazino-t h i a z o I o [ 5 , 4-d]pyrimidine; 5-amino-2-(3,4-dichlorophenyl)-7-(N- piperazino)thiazolo[5,4-d]pyrimidine; 5-amino-2-(1-phenylcyclopropyl)-7-(N- piperazino)thiazolo[5, 4-d]pyrimidine; 5-amino-2-(1 -(4-chlorophenyl)cyclopropyl)-7-(N- piperazino)thiazolo[5,4-d]pyrimidine; 5-amino-7-N-piperazino-2-methylthio-t iazolo[5, 4- d]pyrimidine; 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1 -y!]-2-(1 - phenylcyclopropyl)thiazolo[5,4-d]pyrimidine; 5-amino-7-[4-(4- chlorophenoxyacetyl)piperazin-1-yl]-2-methylthio-thiazolo[5,4-d]pyrimidine; 5-amino-7-[4- (4-chlorophenoxyacetyl)piperazin-1 -yl]-2-(3,4-dichlorophenyl)thiazolo[5,4-d]pyrimidine; 5- amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1 -yl]-2-(1 -(4- chlorophenyl)cyclopropyl)thiazolo[5,4-d]pyrimidine; 5-amino-7-[4-(4- chlorophenoxyacetyl)piperazin-1 -yl]-2-(2-phenylethyl)thiazolo[5,4-d]pyrimidine; 5-amino- 2-cyclopropyl-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-thiazolo[5,4-d]pyrimidine; 5- amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2-cyclohexylthiazolo[5,4-d]pyrimidine; 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2-(pyridine-3-yl)thiazolo[5,4- d]pyrimidine; 5-amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1 -yl]-2-(N-oxopyridine-3- yl)thiazolo[5,4-d]pyrimidine; 5-amino-7-[4-(4-chlorop enoxyacetyl)piperazin-1 -yl]-2-(4- chlorophenylmethyl)thiazolo[5,4-d]pyrimidine; 5-amino-7-[4-(4- chlorophenoxyacetyl)piperazin-1 -yl]-2-(4-chlorophenyl)thiazolo[5,4-d]pyrimidine; 5-amino- 7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-2-(3-methoxyphenyl)thiazolo[5,4- d]pyrimidine; 5-amino-7-[4-(4-chlorophenoxyacety!)piperazin-1 -yl]-2-(1 -(4- chlorophenyl)ethyl)thiazolo[5,4-d]pyrimidine; 5-amino-7-[4-(4- chlorophenoxyacetyl)piperazin-1 -y!]-2-(4 luorophenylamino)-thiazolo[5,4-d]pyrinriidine; 5- amino-2-(4-fluorophenyl)-7-(4-[2-(4-brorriophenoxy)acetyl]-piperazin-1 -yl)-thiazolo[5,4- djpyrimidine; 5-amino-2-(4-fluorophenyl)-7-(4-[2-(3-nitrophenoxy)acetyl]-piperazin-1 -yl)- thiazolo[5,4-d]pyrimidine; 5-amino-2-(4-fluorophenyl)-7-(4-(2-phenoxyacetyl)-piperazin-1 - yl)-thiazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4-fluoropheny!)ethyl]-7-(4-[2-(3- nitrophenoxy)acetyl]piperazin-1 -yl)-thiazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4- fluorophenyl)ethyl]-7-(4-[2-(4-chlorophenyl)acetylJpiperazin-1 -yl)-thiazolo[5,4- d]pyrimidine; 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-m-tolylcarbamoylpiperazin-1 -yl)- thiazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-[2- phenoxyacetyl]piperazin-1 -y!)-thiazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4- fluorophenyl)ethyl]-7-[4-(4-chlorobenzoyl)piperazin-1 -yl]-thiazolo[5,4-d]pyrinnidine; 5- amino-2-[2-(4-fluorophenyl)ethyl]-7-[4-(3-phenylpropionyl)piperazin-1 -yl]-thiazolo[5,4- d]pyrimidine; 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-[4-phenylmethanesulfonylpiperazin-1 - yl]-thiazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-[2-(4- chlorophenoxy)acetyl]homopiperazin-1 -yl)-thiazolo[5,4-d]pyrirriidine; 5-amino-2-[2-(4- fluorophenyl)ethyl]-7-(4-[(methylphenylcarbamoyl)-methyl]piperazin-1-yl)-thiazolo[5,4- d]pyrimidine; 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-thiazol-2-yl-piperazine-1 -yl)- thiazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4-fluorophenyl)elhyl]-7-(4-(phenethylcarbamoyl- methyl)piperazin-1-yl)-thiazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-((3- (R)-tert-butoxycarbonylamino)pyrrolidin-1-yl)-thiazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4- fluorophenyl)ethyl]-7-(3-(R)-[2-(4-chlorophenoxy)-acetylamino]pyrrolidin-1 -yl)- thiazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(3-(R)-(4- chlorobenzoylamino)-pyrrolidin-1 -yl)-thiazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4- fluorophenyl)ethyl]-7-(1 ^enzyloxycarbonylpiperidin-3-ylamino) hiazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(1-tert-butoxycarbonylpyrrolidin-3-(S)-ylamino)- thiazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(1 -(4- chlorophenoxyacetyl)pyrrolidin-3-(S)-ylamino)-thiazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4- fluorophenyl)ethyl]-7-(4-benzoylpiperidine-1 -yl)-thiazolo[5,4-d]pyrimidine; 5-amino-2-[2- (4-fluorophenyl)ethyl]-7-(4-(2-phenoxyethyl)piperazin-1 -yl)-thiazolo[5,4-d]pyrimidine; 5- amino-2-[1 -(4-fluorophenyl)propyl]-7-(4-[2-(4-chlorophenoxy)acetyl]piperazin-1- yl)thiazolo[5,4-d]pyrimidine; 5-amino-2-[cyclopentyl-(4-fluorophenyl)met yl]-7-(4-[2-(4- chlorophenoxy)acetyl]piperazin-1 -yl)thiazolo[5,4-d]pyrimidine; 5-amino-7-piperazin-1 -yl-2- (2-thiophen-2-yl-ethyl)-thiazolo[5,4-d]pyrimidine; 5-amino-2-(2-thiophen-2-ylethyl)-7-(4-[2- (4-chloro-phenoxy)acetyl]piperazin-1 -yl)thiazolo[5,4-d]pyrimidine; 5-amino-2-(2-thiophen- 2-ylethyl)-7-(4-[2-(4-chloro-phenyl)acetyl]piperazin-1 -yl)thiazolo[5,4-d]pyrimidine; 5- amino-2-(2-thiophen-2-ylethyl)-7-(4-(4-chloro-benzoyl)piperazin-1 -yl)thiazolo[5,4- d]pyrimidine; 5-amino-2-(2-thiophen-2-ylethyl)-7-(4-m- tolylcarbamoylpiperazin-1 - yl)thiazolo[5,4-d]pyrimidine; 2-(4-chlorophenoxy)-1 -(4-(2-(4-fluorophenyl)oxazolo[5,4- d]pyrimidin-7-yl)piperazin-1 -yl)ethanone; 2-(4-chlorophenoxy)-1-(4-(2-(4-fluorophenyl)-5- methyl-oxazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)ethanone; 1 -(4-(5-amino-2-(4- fluorophenyl)oxazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(4-chlorophenoxy)ethanone; 2- (4-chlorophenoxy)-1 -(4-(2-(4-fluorobenzyl)oxazolo[5,4-d]pyrimidin-7-yl)piperazin-1- yl)ethanone; 2-(4-chlorophenoxy)-1-(4-(2-(4-fluorobenzyl)-5-methyloxazolo[5,4- d]pyrimidin-7-yl)piperazin-1 -yl)ethanone; 1 -(4-(5-amino-2-(4-fluorop enethyl)oxazolo[5,4- d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4-chlorop enoxy)et anone; N-(3-chloro-4- fluorophenyl)-2-(4-fluorophenyl)-oxazolo[5,4-d]pyrimidin-7-amine; N-7-(3-chloro-4- fIuorophenyl)-2-(4-fluorophenyl)-oxazolo[5,4-d]pyrimidine-5,7-diamine; 5-amino-2- cyclopropyl-7-N-piperazino-oxazolo[5,4-d]pyrimidine; 5-amino-2-methoxymethyl-7-N- piperazino-oxazo!o[5,4-d]pyrimidine; 5-amino-2-cyclohexyl-7-N-piperazino-oxazolo[5,4- d]pyrimidine; 5-amino-2-pentyl-7-N-piperazino-oxazolo[5,4-d]pyrimidine; 5-amino-2-(2- phenylethyl)-7-N-piperazino-oxazolo[5,4-d]pyrimidine; 5-amino-2-cyclopropyl-7-[4-(4- chlorophenoxyacetyl)piperazin-1 -yl]-oxazolo[5,4-d]pyrimidine; 5-amino-7-[4-(4- chlorophenoxyacetyl)piperazin-1-yl]-2-methoxymethyloxazolo[5, 4-d]pyrimidine; 5-amino- 2-cyclohexyl-7-[4-(4-chlorophenoxyacetyl)piperazin-1 -yl]oxazolo[5,4-d]pyrimidine; 5- amino-7-[4-(4-chlorophenoxyacetyl)piperazin-1 -yl]- 2-pentyloxazolo[5,4-d]pyrimidine; 5- amino-2-(2-phenylethyl)-7-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]oxazolo[5,4- djpyrimidine; 5-amino-2-(4-fluorophenyl)-7-(4-isobutylpiperazin-1 -yl)-oxazolo[5,4- djpyrimidine; 5-amino-2-(4-fIuorophenyl)-7-(4-acetylpiperazin-1 -yl)-oxazolo[5,4- d]pyrimidine; 5-amino-2-(4-fluorophenyl)-7-[4-(2-methoxyethyl)-piperazin-1 -yl]- oxazolo[5,4-d]pyrimidine; 5-amino-2-(4-fluorophenyl)-7-(4-[2-(3-nitrophenoxy)acetyl]- piperazin-1 -yl)-oxazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4-fIuorophenyl)et yl]-7-(4-[2-(4- chlorophenyl)acetyl]-piperazin-1-yl)-oxazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4- fluorophenyl)ethyl]-7-(4-[4-chlorobenzoyl]piperazin-1 -yl)-oxazolo[5,4-d]pyrimidine; 5- amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-m-tolylcarbamoylpiperazin-1 -yl)-oxazolo[5,4- d]pyrimidine; 5-amino-2-[2-(4-fluoropheny!)ethyl]-7-(4-(2-phenoxyethyl)piperazin-1 -yl)- oxazolo[5,4-d]pyrimidine; 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-(4-[(methylphenyl- carbamoyl)methyl]piperazin-1 -yl)-oxazolo[5,4-d]pyrimidine; 5-amino-2-phenyl-7-N- piperazinyl-thiazolo[5,4-d]pyrimidine; 5-amino-2-(2-furyl)-7-N-piperazinyl-thiazolo[5,4- d]pyrimidine; 5-amino-2-(4-fluoro-phenyl)-7-N-piperazinyl-thiazolo[5,4-d]pyrimidine; 1 -(4- (5-amino-2-phenylthiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- methoxyphenoxy)ethanone; 1 -(4-(5-amino-2-(furan-2-yl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1-yl)-2-(4-fluorophenoxy)ethanone; 1 -(4-(5-amino-2-(furan-2-yl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1 -yl)-2-(m-tolyloxy)ethanone; 1 -(4-(5-amino-2-(4- fIuorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(m-tolyloxy)ethanone; 1 -(4-(5- amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(2,4- dichlorophenoxy)elhanone; 1 -(4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1-yl)-2-(4-chloro-2-methylphenoxy)ethanone; 1 -(4-(5-amino-2-(4- fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(3-chlorophenoxy)ethanone; 1 - (4-(5-amino-2-phenylthiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(4- chlorop enoxy)ethanone; 4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)-N- (4-cyanophenyl)piperazine-1 -carboxamide, 4-(5-amino-2-(4-f)uorophenyl)thiazolo[5,4- d]pyrimidin-7-yl)-N-(2,4-difluorophenyl)piperazine-1 -carboxamide; 4-(5-amino-2-(4- fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)-N-(4-bromophenyl)piperazine-1 -carboxamide; 4-(5-amino-2-(4-fluorop enyl)thiazolo[5,4-d]pyrimidin-7-yl)-N-(2- methoxyphenyl)piperazine-1 -carboxamide; 4-(5-amino-2-p enylthiazolo[5,4-d]pyrimidin- 7-yl)-N-m-tolylpiperazine-1 -carboxamide; 5-amino-7-(N-piperazin-1 -yl)-2-(pyridin-3- yl)thiazolo[5, 4-d]pyrimidine; 4-(5-amino-2-(pyridin-3-yl)ihiazolo[5,4-d]pyrimidin-7-yl)-N-p- tolylpiperazine-1 -carboxamide; 1 -(4-(5-amino-2-(4-fluorophenethyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1 -yl)-3-(4-bromophenyl)propan-1 -one; 1 -(4-(5-amino-2-(4- fluorophenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- hydroxyphenoxy)ethanone; m et h y l 4-(2-(4-(5-amino-2-(4-fluorophenethyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1 -yl)-2-oxoethoxy)benzoate; 1 -(4-(5-amino-2-(4- fluorophenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- (trifluoromethoxy)phenoxy)ethanone; 2-(4-acetylphenoxy)-1 -(4-(5-amino-2-(4- fluorophenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)ethanone; 1 -(4-(5-amino-2-(4- fluorophenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(3- chlorophenoxy)ethanone; 4-(5-amino-2-(4-fIuorophenethyl)thiazolo[5,4-d]pyrimidin-7-yl)- N-(4-cyanophenyl)piperazine-1 -carboxamide; 1 -(4-(5-amino-2-(4- fluorobenzyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4-methoxyphenoxy)ethanone; 1 -(4-(5-amino-2-(4-fluorobenzyl)thiazolo[5,4-d]pyrirnidin-7-yl)piperazin-1-yl)-2-(4- bromophenoxy)ethanone; 4-(5-amino-2-(4-fluorobenzyl)thiazolo[5,4-d]pyrimidin-7-yl)-N- (4-cyanophenyl)piperazine-1 -carboxamide; 1 -(4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4-fIuorophenoxy)ethanone; 1-(4-(5-amino-2-(4- fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4-methoxyphenoxy)ethanone; 1 -(4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrinriidin-7-yl)piperazin-1 -yl)-2-(4- bromophenoxy)ethanone; 1 -(4-(5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1-yl)-3-(4-fluorophenyl)propan-1 -one; 1-(4-(5-amino-2-(4- fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(4-chlorophenoxy)-2- methylpropan-1-one; 2-(3-methoxyphenethyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5- amine; 2-(3,4-dimethoxyphenethyl)-7-(piperazin-1-yl)thiazolo[5^-d]pyrimidin-5-amine; 2- (4-methylphenet yl)-7-(piperazin-1 -yl)thiazolo[5,4-d]pyrimidin-5-amine; 1-(4-(5-amino-2- (3-methoxyphenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- methoxyphenoxy)ethanone; 1 -(4-(5-amino-2-(3-methoxyphenethyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1-yl)-2-(4-bromophenoxy)ethanone; 1 -(4-(5-amino-2-(3- methoxyphenethyl)thiazolo[5,4-d]pyrinnidin-7-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone; 1-(4-(5-amino-2-(3,4-dimethoxyphenethyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4-bromophenoxy)ethanone; 1 -(4-(5-amino-2-(3,4- dirnethoxyphenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(4- methoxyphenoxy)ethanone; 1 -(4-(5-amino-2-(4-methylphenet yl)thiazolo[5,4-d]pyrimidin- 7-yl)piperazin-1 -yl)-2-(4-bromophenoxy)ethanone; 1 -(4-(5-amino-2-(4- methylphenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- methoxyphenoxy)ethanone; 1-(4-(5-amino-2-(4-methylphenethyl)thiazolo[5,4-d)pyrimidin- 7-yl)piperazin-1 -yl)-2-(4-chlorophenoxy)et anone; 7-(piperazin-1 -yl)-2-(pyridin-3- yl)thiazolo[5,4-d]pyrimidin-5-amine; 7-(piperazin-1 -yl)-2-(pyridin-2-yl)thiazolo[5,4- d]pyrimidin-5-amine; 7-(piperazin-1 -yl)-2-(pyridin-4-yl)thiazolo[5,4-d]pyrimidin-5-amine; 2- (4-chlorophenyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine; 1-(4-(5-amino-2-(4- chlorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- methoxyphenoxy)ethanone; 1-(4-(5-amino-2-(pyridin-3-yl)lhiazolo[5,4-d]pyrimidin-7- yl)piperazin-1 -yl)-2-(4-methoxyphenoxy)ethanone; 1 -(4-(5-amino-2-(pyridin-3- yl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4-fluorophenoxy)ethanone; 1-(4-(5- amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrirriidin-7-yl)piperazin-1-yl)-2-(4- trifluoromethoxyphenoxy)et anone; 1-(4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin- 7-yl)piperazin-1 -yl)-2-(4-chlorophenoxy)-2-methylpropan-1 -one; 1 -(4-(5-amino-2-(pyridin- 3-yl)t iazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(m-tolyloxy)ethanone; 4-(5-amino-2- (pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N-m-tolylpiperazine-1-carboxamide; 4-(5- amino-2-(pyridin-3-y!)thiazolo[5^-d]pyrimidin-7-yl)-N-(4-chlorophenyl)piperazine-1 - carboxamide; 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d)pyrimidin-7-yl)-N-(4- methoxybenzyl)piperazine-1 -carboxamide; 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4- d]pyrimidin-7-yl)-N-(4-cyanophenyl)piperazine-1 -carboxamide; 1 -(4-(5-amino-2-(4- chlorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- methoxyphenoxy)ethanone; 1 -(4-(5-amino-2-(pyridin-4-yl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone; 1 -(4-(5-amino-2-(pyridin-2- yl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone; 2-(4- fluorophenethyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidine; 2-(4-fluorophenyl)-7- (piperazin-1 -yl)thiazolo[5,4-d]pyrimidine; 2-(3-(4-fluorophenyl)propyl)-7-(piperazin-1- yl)thiazolo[5,4-d]pyrimidin-5-amine; 2-(4-(4-fluorophenyl)butyl)-7-(piperazin-1 - yl)thiazolo[5,4-d]pyrimidin-5-amine; 2-(4-bromophenethyl)-7-(piperazin-1 -yl)thiazolo[5,4- d]pyrimidin-5-amine; 2-pentyl-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine; 7- (piperazin-1-yl)-2-p-tolylt iazolo[5,4-d]pyrimidin-5-arriine; 1 -(4-(5-amino-2-(3-(4- fluorophenyl)propyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone; 1 -(4-(5-amino-2-(3-(4-fluorophenyl)propyl)thiazolo[5,4- dlpyrimidin-7-yl)piperazin-1 -yl)-2-(4-methoxyphenoxy)ethanone; 1 -(4-(5-amino-2-(4-(4- fluorophenyl)butyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(4- chlorophenoxy)ethanone; 1-(4-(5-amino-2-(4-(4-fluorophenyl)butyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4-methoxyphenoxy)ethanone; 1 -(4-(5-amino-2-p- tolylthiazolo[5,4-d]pyrimidin-7-yl)piperazin-1-yl)-2-(4-methoxyphenoxy)et anone; 1 -(4-(5- amino-2-p-tolylthiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4-chlorophenoxy)eth 1 -(4-(5-amino-2-pentylthiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- methoxyphenoxy)ethanone; 1-(4-(5-arnino-2-pentylthiazolo[5,4-d]pyrimidin-7-yl)piperazin- 1 -yl)-2-(4-chlorophenoxy)ethanone; 1 -(4-(5-amino-2-(4-bromophenethyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1-yl)-2-(4-methoxyphenoxy)ethanone; 1-(4-(5-amino-2-(4- bromophenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone; 1-(4-(2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin- 1 -yl)-2-(4-methoxyp enoxy)ethanone; 1-(4-(2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidin-7- yl)piperazin-1-yl)-2-(4-chlorophenoxy)ethanone; 1-(4-(2-(4-fluorophenethyl)thiazolo[5,4- d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4-methoxyphenoxy)ethanone; 1 -(4-(2-(4- fluorophenethyl)thiazolo[5,4-d]pyrimidin-7-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone; 2-(4-chlorophenoxy)-1-(4-(6-(4-fluorophenyl)thieno[2,3- d]pyrimidin-4-yl)piperazin-1 -yl)ethanone; 1 -(4-(2-butyl-6-(4-fluorophenyl)thieno[2,3- d]pyrimidin-4-yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone; N-(3-chloro-4- fluorophenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-amine; 2-butyl-N-(3-chloro-4- fluorophenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-amine; 2-(4-chlorophenoxy)-1 -(4- (6-(4-fluorophenyl)-2-methylthieno[2,3-d]pyrimidin-4-yl)piperazin-1 -yl)ethanone; 1 -(4-(2- amino-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4- chlorophenoxy)et anone; 2-amino-4-N-benzylamino-6-(4-fluorophenyl)-thieno[2,3- d]pyrimidine; 2-amino-4-N-piperazinyl-6-phenyl-thieno[2,3-d]pyrimidine; 1 -(4-(2-amino-6- phenylthieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenoxy)ethanone; 4-(2- amino-6-phenylthieno[2,3-d]pyrimidin-4-yl)-N-m-tolylpiperazine-1 -carboxamide; 4-(2- amino-6-phenylt ieno[2,3-d]pyrimidin-4-yl)-N-(4-chlorophenyl)piperazine-1-carboxamide; 1-(4-(2-amino-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-phenoxyethanone; 2- amino-4-N-homopiperazinyl-6-phenyl-thieno[2,3-d]pyrimidine; 1 -(4-(2-amino-6- phenylthieno[2,3-d]pyrimidin-4-yl)-1 ,4-diazepan-1-yl)-2-(4-chlorophenoxy)ethanone; 1-(4- (2-amino-6-phenylthieno[2,3-d]pyrimidin-4-yl)-1 ,4-diazepan-1-yl)(4- chlorophenyl)methanone; 2-(4-(2-amino-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperazin-1 - yl)-N-methyl-N-phenylacetamide; 4-(4-(2-phenoxyethyl)piperazin-1-yl)-6- phenylthieno[2,3-d]pyrimidin-2-amine; (R)-tert-b u t y I 1 -(2-amino-6-(4- fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)pyrrolidin-3-ylcarbamate; (R)-4-(3- aminopyrrolidin-1-yl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-2 -amine; (R)-N-(1 -(2- amino^-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)pyn'olidin-3-yl)-2-(4- chlorophenoxy)acetamide (R)-N-(1 -(2-amino-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4- yl)pyrrolidin-3-yl)-4-chlorobenzamide; 2-amino-4-N-piperazinyl-6-(4-fluorophenyl)- t ieno[2,3-d]pyrimidirie; 1-(4-(2-amino-6-(4-fluorop enyl)thieno[2,3-d]pyrimidin-4- yl)piperazin-1-yl)-3-phenylpropan-1 -one; 4-(4-(benzylsulfonyl)piperazin-1-yl)-6-(4- fluorophenyl)thieno[2,3-d]pyrimidin-2 -amine; (4-(2-amino-6-(4-fluorophenyl)thieno[2,3- d]pyrimidin-4-yl)piperazin-1-yl)(cyclohexyl)methanone; 4-(2-amino-6-(4- fIuorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperazin-1 -yl)(pyridin-3-yl)methanone; 4-(2- amino-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)-N,N-diisopropylpiperazine-1 - carboxamide; (1-(2-amino-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4- yl)(phenyl)methanone; 2-amino-4-N-piperazino-thieno[2,3-d]pyrimidine; 1-(4-(2- aminothieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-(4-chlorophenoxy)ethanone; 2-(4- c lorophenoxy)-1-(4-(6-(4-fluorophenyl)-2-phenylthieno[2,3-d]pyrimidin-4-yl)piperazin-1- yl)ethanone; e t h y l 4-(4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)-6-(4- fluorophenyl)thieno[2,3-d]pyrimidine-2-carboxylate; ethyl 2-(4-(4-(2-(4- chlorophenoxy)acetyl)piperazin-1 -yl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-2- yl)acetate; 4-(4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)-6-(4-fluorophenyl)thieno[2,3- d]pyrimidine-2-carboxamide; 4-(4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)-6-(4- fluorophenyl)-N-(2-methoxyethyl)thieno[2,3-d]pyrimidine-2-carboxamide; 4-(4-(2-(4- chlorophenoxy)acetyl)piperazin-1 -yl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine-2- carboxylic acid; 2-(4-(4-(2-(4-chlorophenoxy)acetyl)piperazin-1-yl)-6-(4- fluorophenyl)thieno[2,3-d]pyrimidin-2-yl)acetamide; 4-(2-amino-6-(4- fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)-N-nn-tolylpiperazine-1 -carboxarnide; 4-(6-(4- fluorophenyl)-2-phenylthieno[2,3-d]pyrimidin-4-yl)-N-m-tolylpiperazine-1 -cail30xamide; e t h y l 6-(4-fluorophenyl)-4-(4-(m-tolylcarbamoyl)piperazin-1 -yl)thieno[2,3-d]pyrimidine-2- carboxylate; 6-(4-fluorophenyl)-4-(4-(m-tolylcarbamoyl)piperazin-1 -yl)thieno[2,3- d]pyrimidine-2-carboxamide; 4-ethoxy-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-2-amine; 6-(4-fluoiOphenyl)-4-morpholinothieno[2 ,3-d]pyrimidin-2-amine; N-(3-chloro-4- fluorophenyl)-6-(4-fluorophenyl)-2-methylthieno[2,3-d]pyrirriidin-4-anriine; e t h y l 4-(3- chloro-4-fluorophenylamino)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine-2-carboxylate; 1 - (4-(2-amino-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperazin-1 -yl)-2-(4- methoxyphenoxy)ethanone; 1-(4-(2-amino-6-phenylthieno[2,3-d]pyrimidin-4-yl)piperazin-

1 - yl)-2-(4-fluorophenoxy)ethanone; 1 -(4-(2-amino-6-phenylthieno[2,3-d]pyrimidin-4- yl)piperazin-1 -yl)-2-(m-tolyloxy)ethanone; 1 -(4-(2-amino-6-phenylthieno[2,3-d]pyrimidin-4- yl)piperazin-1 -yl)-2-(4-bromophenoxy)ethanone; 1 -(4-(2-amino-6-phenylthieno[2,3- d]pyrimidin-4-yl)piperazin-1 -yl)-2-(4-chlorophenoxy)-2-methylpropan-1 -one; 1-(4-(2- amino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone; 1 - (4-(2-amino-8-(3,4-dimethoxyphenyl)-9H-purin-6-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone; 1 -(4-(2-amino-8-(4-bromophenyl)-9H-purin-6-yl)piperazin-1 -yl)-

2- (4-chlorophenoxy)ethanone; 1 -(4-(2-amino-8-(4-chlorophenyl)-9H-purin-6-yl)piperazin- 1 -yl)-2-(4-chlorophenoxy)ethanone; 1 -(4-(2-amino-8-(3-chlorophenyl)-9H-purin-6- yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone; 1-(4-(2-amino-8-(4- (trifluoromethyl)phenyl)-9H-purin-6-yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone; 1 -(4- (2-amino-8-(4-(trifluoromethoxy)phenyl)-9H-purin-6-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone; 1 -(4-(2-amino-8-p-tolyl-9H-purin-6-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone; 1 -(4-(2-amino-8-propyl-9H-purin-6-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone; 1 -(4-(2-amino-8-cyclopropyl-9H-purin-6-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone; 1-(4-(2-amino-8-tert-butyl-9H-purin-6-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone; 1 -(4-(2-amino-8-methyl-9H-purin-6-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone; 1 -(4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1 -yl)- 2-phenoxyethanone; 1 -(4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1 -yl)(3- methoxyphenyl)methanone; 1 -(4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1 - yl)-2-(thiophen-2-yl)ethanone; (4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1 - yl)(4-chlorophenyl)methanone; 6-(4-(benzylsulfonyl)piperazin-1 -yl)-8-(4-fluorophenyl)-9H- purin-2 -amine; (4-(2-ainino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1 -yl)(naphthalen-1 - yl)methanone; 1 -(4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)piperazin-1 -yl)ethanone; 8- (4-fluorophenyl)-6-(4-(thiazol-2-yl)piperazin-1 -yl)-9H-purin-2-amine; 2-(4-(2-amino-8-(4- fluorophenyl)-9H-purin-6-yl)piperazin-1 -yl)-1 -(pyrrolidin-1 -yl)ethanone; 2-(4-(2-amino-8- (4-fluorophenyl)-9H-purin-6-yl)piperazin-1 -yl)-1 -morpholinoethanone; 2-(4-(2-amino-8-(4- fluorophenyl)-9H^urin-6-yl)piperazin-1 -yl)-N-(pyridin-3-yl)acetamide; 2-(4-(2-amino-8-(4- fluorophenyl)-9H-purin-6-yl)piperazin-1 -yl)-N-methy!-N-phenylacetamide; 6-(4-(4- chlorophenyl)piperazin-1-yl)-8-(4-fluorophenyl)-9H-purin-2-amine; 8-(4-fluorophenyl)-6-(4- (4-fluorophenyl)piperazin-1 -yl)-9H-purin-2-amine; 2-(4-(2-amino-8-(4-fluorophenyl)-9H- purin-6-yl)piperazin-1-yl)-N-(pyridin-2-yl)acetamide; 2-(4-(2-amino-8-(4-fluorophenyl)-9H- purin-6-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide; 6-(4-(4-fluorobenzyl)piperazin-1 -yl)-8- (4-fluorophenyl)-9H-purin-2-amine; 8-(4-fluorophenyl)-6-(4-(pyridin-4-yl)piperazin-1-yl)- 9H-purin-2-amine; 6-(1 ,4-diazepan-1-y!)-8-(4-fluorophenyl)-9H-purin-2-amine; 1-(4-(2- amino-8-(4-fluorophenyl)-9H-purin-6-yl)-1 ,4-diazepan-1 -y!)-2-(4-chlorophenoxy)ethan 4-(2-amino-8-(4-fluorophenyl)-9H-purin-6-yl)-N-m-tolyl-1 ,4-diazepane-1-carboxamide; 1- (4-(2-amino-8-thioxo-8,9-dihydro-7H-purin-6-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone; 1 -(4-(2-amino-8-(methy lthio)-9H-purin-6-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone; 1 -(4-(2-amino-8-(propylthio)-9H-purin-6-yl)piperazin-1 -yl)-2-(4- chlorophenoxy)ethanone; 1-(4-(2-amino-8-(benzylthio)-9H-purin-6-yl)piperazin-1-yl)-2-(4- chlorophenoxy)ethanone; 1 -(4-(2-amino-8-(phenethylthio)-9H-purin-6-yl)piperazin-1 -yl)-2- (4-chlorophenoxy)ethano n e ; 1 -(4-(2-amino-9-methyl-8-(methylthio)-9H-purin-6- yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone; 1-(4-(2-amino-8-(cyclopentylthio)-9H- purin-6-yl)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone; 1 -(4-(2-amino-8-(4-fluorophenyl)- 9-methyl-9H-purin-6-yl)piperazin-1-yl)-2-(4-chloroprienoxy)ethanone, 1-(4-(2-amino-9- benzy!-8-(4-fluorophenyl)-9H-purin-6-y!)piperazin-1 -yl)-2-(4-chlorophenoxy)ethanone; 2- amino-6-(piperazin-1 -yl)-8-(4-fluorophenyl)-9H-purine; 1-(4-(2-amino-8-(4-fluorophenyl)- 9H-purin-6-yl)piperazin-1-yl)-3-phenylpropan-1 -one; 4-(5-amino-2-(pyridin-3- yl)thiazolo[5,4-d]pyrimidin-7-yl)-N-(4-(trifluoromethyl)phenyl)piperazine-1 -c^ 4- (5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N-phenylpiperazine

4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimi

carboxamide; 5-arnino-7-[4-(N-4-fluorophenylcarboxamide)piperazin-1 -yl]-2-(pyridine-3- yl)thiazolo[5, 4-d]pyrimidine; 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N- hexylpiperazine-1 -carboxamide; 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)- N-p-tolylpiperazine-1-carbothioamide; 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin- 7-yl)-N-methyl-N-p-tolylpiperazine-1 -carboxamide; or p-tolyl 4-(5-amino-2-(pyridin-3- yl)thiazolo[5,4-d]pyrimidin-7-yl)piperazine-1 -carboxylate.

20. A Method of treating or preventing cancer in an animal, mammal or human by using the compounds according to formula I, II, III or IV, pharmaceutically acceptable salts, solvates, tautomers, isomers thereof,

IV

wherein

- X is S or O;

- R¹ is selected from the group consisting of amino, halogen, cyano, carboxylic acid, acyl, thioacyl, alkoxycarbonyl, acyloxy, carbonate, carbamate, aryl, acetamido, /V-protected amino, (mono- or di) Ci-₇ alkylamino, (mono- or di) arylamino, (mono- or di) C₃-₁₀ cycloalkylamino, (mono- or di) hydroxy Ci-₇ alkylamino, (mono- or di) C₁-4 alkyl-arylamino, mercapto C1.7 alkyl, C₁.7 alkyloxy;

- R² is selected from the group consisting of heteroaryl and aryl groups; halogen; C1.7 alkyl; C₂-7 alkenyl; C₂.₇ alkynyl; halo d.₇ alkyl; C₃.₁₀ cycloalkyl; carboxy C1.7 alkyl; carboxyaryl; C^₇ alkoxy; C3-10 cycloalkoxy; aryloxy; arylalkyloxy; oxyheterocyclic; heterocyclic-substituted alkyloxy; thio Ci_-7 alkyl; thio C₃.₁₀ cycloalkyl; thioaryl; thioheterocyclic; arylalkylthio; heterocyclic-substituted alkylthio; hydroxylamino; thio-acylamino; alkoxyamino; thioalkyl- amino; acetal; thio-acetal; carboxylic acid; carboxylic acid esters, thiocarboxylic acid; thiocarboxylic acid esters, thioesters, halides, anhydrides, amides and thioamides; hydroxyl; sulfhydryl; nitro; cyano; carbamoyl; thiocarbamoyl; ureido; thioureido; amino; alkylamino; cycloalkylamino; alkenylamino; cyclo-alkenylamino; alkynylamino; arylamino; arylalkylamino; hydroxyalkylamino; mercaptoalkyl-amino; heterocyclic amino; heterocyclic substituted arylamino; heterocyclic-substituted alkyl-amino; oximino; alkyloximino; hydrazino; alkylhydrazino; phenylhydrazino; esters, thioesters, halides, anhydrides, amides and thioamides thereof; aromatic or heterocyclic substituents substituted with an aliphatic spacer between the thiazolo(5,4-d)pyrimidine or oxazolo(5,4-d)pyrimidine ring and the aromatic or heterocyclic substituent, wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, C1.7 alkyl, C2-7 alkenyl, C2-7 alkynyl, halo Ci_-7 alkyl, nitro, hydroxyl, sulfhydryl, amino, Ci_-7 alkoxy, C3-10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio Ο ._Ί alkyl, thio C3.10 cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino; wherein said aliphatic spacer is a branched or straight, saturated or unsaturated aliphatic chains of 1 to 7 carbon atoms optionally containing one or more functions, atoms or radicals independently selected from the group consisting of halogen, carbonyl, thiocarbonyl, hydroxyl, thiol, ether, thio-ether, acetal, thio-acetal, amino, imino, oximino, alkyloximino, aminoacid, cyano, acylamino, thioacylamino, carbamoyl, thiocarbamoyl, ureido, thio-ureido, carboxylic acid ester or halide or anhydride or amide, thiocarboxylic acid or ester or thioester or halide or anhydride or amide, nitro, thio C_h alky!, thio C3.10 cycloalkyl, hydroxylamino, mercaptoamino, alkyl-amino, cycloalkylamino, alkenylamino, cycloalkenylamino, alkynylamino, arylamino, arylalkyl-amino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic-substituted alkylamino, hetero-cyclic amino, heterocyclic-substituted arylamino, hydrazino, alkylhydrazino, phenylhydrazino, sulfonyl, sulfinyl and sulfonamido;

- R³ is selected from the group consisting of piperazinyl, homopiperazinyl, (mono- or di-) d-12 alkylamino; monoary!amino; diarylamino; (mono- or di-) C₃.₁₀ cycloalkylamino; (mono- or di-) hydroxy d-7 alkylamino; (mono- or di-) C_{1 4} alkylarylamino, (mono- or di-) aryld-₄ alkylamino; morpholinyl; mercapto C_{1 7} alkyl; d.7 alkoxy, aralkylthio, piperidinyl, pyrrolidinyl, and, wherein said piperidinyl, pyrrolidinyl, homopiperazinyl or piperazinyl is optionally N-substituted with a substituent R²⁰ selected from the group consisting of formyl, acyl, thioacyl, amide, thioamide, sulfonyl, sulfinyl, carboxylate, thiocarboxylate, amino-substituted acyl, alkoxyalkyl, C3.10 cycloalkyl-alkyl, C₃.₁₀ cycloalkyl, dialkylaminoalkyl, heterocyclic-substituted alkyl, acyl- substituted alkyl, thioacyl-substituted alkyl, amido-substituted alkyl, thioamido-substituted alkyl, carboxylato-substituted alkyl, thiocarboxylato-substituted alkyl, (amino-substituted acyl)alkyl, heterocyclic, carboxylic acid ester, ω-cyanoalkyl, ω-carboxylic ester-alkyl, halo d-7 alkyl, C₂.₇ alkenyl, C2.₇ alkynyl, arylalkenyl, aryloxyalkyl, arylalkyl and aryl, wherein the aryl moiety of each of said arylalkenyl, aryloxyalkyl, arylalkyl and aryl radicals is optionally substituted with one or more substituents independently selected from the group consisting of halogen, d.₇ alkyl, C₂.₇ alkenyl, C₂.₇ alkynyl, halo d-7 alkyl, nitro, hydroxyl, sulfhydryl, amino, d-₇ alkoxy, C₃.₁₀ cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic- substituted alkyloxy, thio d-7 alkyl, thio C_{3 10} cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or a mides thereof, alkylamino, cycloalkylamino , a lkenyla mino , cyclo- alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydrazino, alkylhydrazino and phenylhydrazino; - R⁴ is selected from the group consisting of halogen, cyano, carboxylic acid, acyl, thioacyl, alkoxycarbonyl, acyloxy, carbonate, carbamate, aryl, amino, acetamido, AAprotected amino, (mono- or di) C1-7 alkylamino, (mono- or di) arylamino, (mono- or di) C3-10 cycloalkylamino, (mono- or di) hydroxy C1.7 alkylamino, (mono- or di) C1.4 alkyl-arylamino, mercapto C1.7 alkyl, C1.7 alkyloxy;

- R⁵ is selected from the group consisting of heteroaryl and aryl groups, wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, C ₇ alkyl, C2.7 alkenyl, C₂.₇ alkynyl, halo C1.7 alkyl, nitro, hydroxyl, sulfhydryl, amino, C1.7 alkoxy, C3.10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C_{1 7} alkyl, thio C₃.₁₀ cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio , formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, a l ke ny l a mi no , cyclo-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino;

- R⁶ is selected from the group consisting of (mono- or di-) C_{1 12} alkylamino, monoarylamino, diarylamino, (mono- or di-) C₃.₁₀ cycloalkylamino, (mono- or di-) hydroxy alkylamino, (mono- or di-) C_{1 4} alkylarylamino, (mono- or di-) arylC_{1 4} alkylamino, morpholinyl, mercapto C1.7 alkyl, C1.7 alkoxy, homopiperazinyl and piperazinyl, wherein said homopiperazinyl or piperazinyl is optionally N-substituted with a substituent R²¹ selected from the group consisting of formyl, acyl, thioacyl, amide, thioamide, sulfonyl, sulfinyl, carboxylate, thiocarboxylate, amino-substituted acyl, alkoxyalkyl, C₃.₁₀ cycloalkyl-alkyl, C₃.₁₀ cycloalkyl, dialkylaminoalkyl, heterocyclic-substituted alkyl, acyl-substituted alkyl, thioacyl-substituted alkyl, amido-substituted alkyl, thioamido-substituted alkyl, carboxylato-substituted alkyl, thiocarboxylato-substituted alkyl, (amino-substituted acyl)alkyl, heterocyclic, carboxylic acid ester, ω-cyanoalkyl, ω-carboxylic ester-alkyl, halo d.7 alkyl, C2.7 alkenyl, C₂-₇ alkynyl, arylalkenyl, aryloxyalkyi, arylalkyi and aryl; wherein the aryl moiety of each of said arylalkenyl, aryloxyalkyi, arylalkyi and aryl radicals is optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci.₇ alkyl, C2.7 alkenyl, C₂.₇ alkynyl, halo d.7 alkyl, nitro, hydroxyl, sulfhydryl, amino, C1.7 alkoxy, C₃.i₀ cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C1.7 alkyl, thio C3.10 cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, Ihioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, a lkenyla mino , cyclo- alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydrazine alkylhydrazino and phenylhydrazino;

R¹² is represented by the general formula V:

R¹⁰

V

and wherein

schematically represents a saturated oro partly unsaturated heterocyclic ring with at least two nitrogen atoms in the said heterocyclic ring and with a total of 5 to 7 atoms in the said heterocyclic ring, and optionally with one or more other heteroatoms in the said heterocyclic ring or attached to one or more carbon atoms of said heterocyclic ring, wherein one of said at least two nitrogen atoms in the heterocyclic ring is attached to a carbon atom 6 of the purine ring;

- each substituent R¹³ of the heterocyclic ring is a group independently selected from the group consisting of halogen, nitro, C1.7 alkyl (optionally containing one or more functions or radicals selected from the group consisting of halogen, carbonyl, thiocarbonyl, hydroxyl, sulfhydryl, C_:.₇ alkoxy, thio C_1-7 alkyl, thio C₃.i₀ cycloalkyl, acetal, thioacetal, imino, oximino, alkyloximino, amino-acid, cyano, (thio)carboxylic acid, (thio)carboxylic acid ester or amide, nitro, amino, C,._? alkylamino, cycloalkylamino, alkenylamino, cycloalkenyl-amino, alkynylamino, arylamino, arylalkyla mino , hydroxyalkyla mino , mercapto-alkylamino, heterocyclic-substituted alkylamino, heterocyclic amino, heterocyclic-substituted arylamino, hydrazino, alkylhydrazino, phenylhydrazino, sulfonyl and sulfonamido), C₃.₇ alkenyl, C₂.₇ alkynyl, halo C,._? alkyl, C₃.₁₀ cycloalkyl, aryl, arylalkyl, alkylaryl, alkylacyl, arylacyl, hydroxyl, sulfhydryl, amino, d.₇ alkylamino, cycloalkylamino, alkenylamino, cycloalkenylamino, alkynylamino, arylamino, arylalkyl-amino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic-substituted alkylamino, heterocyclic amino, heterocyclic-substituted arylamino, hydrazino, alkylhydrazino, phenylhydrazino, C1.7 alkoxy, C3-10 cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio C1.7 alkyl, thio C3.10 cycloalkyl, thioaryl, thioheterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, hydroxylamino, cyano, (thio)carboxylic acid or esters or thioesters or amides or thioamides thereof;

- n is an integer from 0 to 6;

- R¹⁰ is selected from the group consisting of formyl, acyl, thioacyl, amide, thioamide, sulfonyl, sulfinyl, carboxylate, thiocarboxylate, amino-substituted acyl, alkoxyalkyl, C3.10 cycloalkyl- alkyl, C₃.₁₀ cycloalkyl, dialkylaminoalkyl, heterocyclic-substituted alkyl, acyl-substituted alkyl, thioacyl-substituted alkyl, amido-substituted alkyl, thioamido-substituted alkyl, carboxylato- substituted alkyl, thiocarboxylato-substituted alkyl, (amino-substituted acyl)alkyl, heterocyclic, carboxylic acid ester, ω-cyanoalkyl, ω-carboxylic ester-alkyl, halo C ₇ alkyl, C₂.₇ alkenyl, C₂. alkynyl, arylalkenyl, aryloxyalkyl, arylalkyl and aryl; wherein the aryl moiety of each of said arylalkenyl, aryloxyalkyl, arylalkyl and aryl radicals is optionally substituted with one or more substituents independently selected from the group consisting of halogen, d.₇ alkyl, C₂.₇ alkenyl, C₂.₇ alkynyl, halo C₁.7 alkyl, nitro, hydroxyl, sulfhydryl, amino, d.₇ alkoxy, C_{3 1}o cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio d-? alkyl, thio C3.10 cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acyiamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, a l ke nyla min o , cyclo- alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino, hydrazino, alkylhydrazino and phenylhydrazino; and

- R¹¹ is selected from the group consisting of halogen, cyano, carboxylic acid, acyl, thioacyl, alkoxycarbonyl, acyloxy, carbonate, carbamate, Ci-₇ alkyl, aryl, amino, acetamido, N- protected amino, (mono- or di) Ci- alkylamino, (mono- or di) arylamino, (mono- or di) C3-10 cycloalkylamino, (mono- or di) hydroxy Ci-₇ alkylamino, (mono- or di) C₁.4 alkyl-arylamino, mercapto C_1-7 alkyl, C₁.7 alkyloxy;

- R⁸ is selected from the group consisting of heteroaryl and aryl groups; halogen; C,.₇ alkyl; C₂.₇ alkenyl; C₂.₇ alkynyl; halo d-₇ alkyl; carboxy d-7 alkyl; carboxyaryl; d-7 alkoxy; C₃.₁₀ cycloalkoxy; aryloxy; arylalkyloxy; oxyheterocyclic; heterocyclic-substituted alkyloxy; thio d-7 alkyl; thio C3.10 cycloalkyl; thioaryl; thioheterocyclic; arylalkylthio; heterocyclic-substituted alkylthio; hydroxylamino; acyiamino; thio-acylamino; alkoxyamino; thioalkyl-amino; acetal; thio-acetal; carboxylic acid; carboxylic acid esters, thioesters, halides, anhydrides, amides and thioamides; thiocarboxylic acid; thiocarboxylic acid esters, thioesters, halides, anhydrides, amides and thioamides; hydroxyl; sulfhydryl; n itro; cya no ; ca rba moyl ; thiocarbamoyl; ureido; thioureido; amino; alkylamino; cycloalkylamino; alkenylamino; cyclo- alkenylamino; alkynylamino; arylamino; arylalkylamino; hydroxyalkylamino; mercaptoalkylamino; heterocyclic amino; heterocyclic substituted arylamino; heterocyclic-substituted alkylamino; oximino; alkyloximino; hydrazino; alkylhydrazino; phenylhydrazino; esters, thioesters, halides, anhydrides, amides and thioamides thereof; aromatic or heterocyclic substituents substituted with an aliphatic spacer between the purine ring and the aromatic or heterocyclic substituent; wherein said heteroaryl or aryl groups are optionally substituted with one or more substituents selected from the grou p consisting of halogen, d.7 alkyl, C₂.7 alkenyl, C₂.₇ alkynyl, halo d-7 alkyl, nitro, hydroxyl, sulfhydryl, amino, d-7 alkoxy, C₃.i₀ cycloalkoxy, aryloxy, arylalkyloxy, oxyheterocyclic, heterocyclic-substituted alkyloxy, thio d.7 alkyl, thio C3- 10 cycloalkyl, thioaryl, thio-heterocyclic, arylalkylthio, heterocyclic-substituted alkylthio, formyl, carbamoyl, thiocarbamoyl, ureido, thioureido, sulfonamido, hydroxylamino, alkoxy-amino, mercaptoamino, thioalkylamino, acylamino, thioacylamino, cyano, carboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, thiocarboxylic acid or esters or thioesters or halides or anhydrides or amides thereof, alkylamino, cycloalkylamino, alkenylamino, cyc!o-alkenylamino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic amino; and wherein said aliphatic spacer is a branched or straight, saturated or unsaturated aliphatic chain of 1 to 7 carbon atoms optionally containing one or more functions, atoms or radicals independently selected from the group consisting of halogen, carbonyl, thiocarbonyl, hydroxyl, thiol, ether, thio-ether, acetal, thio-acetal, amino, imino, oximino, alkyloximino, aminoacid, cyano, acylamino, thioacylamino, carbamoyl, thiocarbamoyl, ureido, thio-ureido, carboxylic acid ester or halide or anhydride or amide, thiocarboxylic acid or ester or thioester or halide or anhydride or amide, nitro, thio Ci_-7 alkyl, thio C3-10 cycloalkyl, hydroxylamino, mercaptoamino, alkyl-amino, cycloalkylamino, alkenylamino, cycloalkenylamino, alkynylamino, arylamino, arylalkyl-amino, hydroxyalkylamino, mercaptoalkylamino, heterocyclic-substituted alkylamino, hetero-cyclic amino, heterocyclic-substituted arylamino, hydrazino, alkylhydrazino, phenylhydrazino, sulfonyl, sulfinyl and sulfonamido;

- R⁷ and R⁹ are selected from the group consisting of hydrogen, C3.7 alkenyl, C₂.₇ alkynyl, halo .7 alkyl, C₃-io cycloalkyl, aryl, arylalkyl, alkylaryl, acyl sulfonyl and d 7 alkyl , wherein said d.₇ alky' is optionally containing one or more functions or radicals selected from the group consisting of halogen, carbonyl, thiocarbonyl, hydroxyl, sulfhydryl, d.₇ alkoxy, thio C_{1 7} alkyl, thio C3-10 cycloalkyl, acetal, thioacetal, imino, oximino, alkyloximino, amino-acid, cyano, (thio)carboxylic acid, (thio)carboxylic acid ester or amide, nitro, amino, d-7 alkylamino, cycloalkylamino, alkenylamino, cycloalkenyl-amino, alkynylamino, arylamino, arylalkylamino, hydroxyalkylamino, mercapto-alkylamino, heterocyclic-substituted alkylamino, heterocyclic amino, heterocyclic-substituted arylamino, hydrazino, alkylhydrazino, phenylhydrazino, sulfonyl and sulfonamido), wherein acy! group refers to a carbonyl group adjacent to a C1.7 alkyl, a C3.10 cycloalkyl, an aryl, an arylalkyl or a heterocyclic group, or is selected from the group comprising alkanoyi, cycloalkanoyi, cycloalkyl-alkanoyi, alkenoyi, alkylthioalkanoyi, alkanesulfonyl, alkoxycarbonyl, alkylcarbamoyl, alkylcarbamidoyl, alkoxalyl, aroyl, aralkanoyl, aralkenoyl, aryloxyalkanoyl, arylthioalkanoyl, arylaminoalkanoyl, aryloxycarbonyl, aralkoxycarbonyl, arylcarbamoyl, arylglyoxyloyl, arylthiocarbamoyl, arylcarbamidoyl, heterocyclic-carbonyl, heterocyclic- alkanoyl, wherein said heterocyclic group is an aromatic or non-aromatic 5- to 7-membered heterocyclic ring with one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur in said ring.