WO2008057402A2 - N-aryl-isoxazolopyrimidin-4-amines and related compounds as activators of caspases and inducers of apoptosis and the use thereof - Google Patents

Abstract

Disclosed are N-aryl-isoxazolopyrimidin-4-amines and related compounds thereof, represented by the Formula (I): wherein Ar, R1-R5, A, B, D, E, F and H are defined herein. The present invention relates to the discovery that compounds having Formula I are activators of caspases and inducers of apoptosis. Therefore, the activators of caspases and inducers of apoptosis of this invention may be used to induce cell death in a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.

Description

N- ARYL-IS OXAZOLOP YRIMIDIN-4- AMINES AND RELATED

COMPOUNDS AS ACTIVATORS OF CASPASES AND INDUCERS OF

APOPTOSIS AND THE USE THEREOF

BACKGROUND OF THE INVENTION

Field of the Invention

[0001] This invention is in the field of medicinal chemistry. In particular, the invention relates to /V-aryl-isoxazolopyrimidin-4-amines and related compounds, and the discovery that these compounds are activators of caspases and inducers of apoptosis. The invention also relates to the use of these compounds as therapeutically effective anti-cancer agents.

Related Art

[0002] Organisms eliminate unwanted cells by a process variously known as regulated cell death, programmed cell death or apoptosis. Such cell death occurs as a normal aspect of animal development, as well as in tissue homeostasis and aging (Glucksmann, A., Biol. Rev. Cambridge Philos. Soc. 26:59-86 (1951); Glucksmann, A., Archives de Biologie 7(5:419-437 (1965); Ellis, el al, Dev. 772:591-603 (1991); Vaux, el ai, Cell 76:111-119 (1994)). Apoptosis regulates cell number, facilitates morphogenesis, removes harmful or otherwise abnormal cells and eliminates cells that have already performed their function. Additionally, apoptosis occurs in response to various physiological stresses, such as hypoxia or ischemia (PCT published application WO96/20721).

[0003] There are a number of morphological changes shared by cells experiencing regulated cell death, including plasma and nuclear membrane blebbing, cell shrinkage (condensation of nucleoplasm and cytoplasm), organelle relocalization and compaction, chromatin condensation and production of apoptotic bodies (membrane enclosed particles containing intracellular material) (Orrenius, S., J. Internal Medicine 237:529-536 (1995)). [0004] Apoptosis is achieved through an endogenous mechanism of cellular suicide (Wyllie, A. H., in Cell Death in Biology and Pathology, Bowen and Lockshin, eds., Chapman and Hall (1981), pp. 9-34). A cell activates its internally encoded suicide program as a result of either internal or external signals. The suicide program is executed through the activation of a carefully regulated genetic program (Wyllie, et ai, Int. Rev. Cyt. (55/251 (1980); Ellis, et al, Ann. Rev. Cell Bio. 7:663 (1991)). Apoptotic cells and bodies are usually recognized and cleared by neighboring cells or macrophages before lysis. Because of this clearance mechanism, inflammation is not induced despite the clearance of great numbers of cells (Orrenius, S., J. Internal Medicine 237:529-536 (1995)).

[0005] It has been found that a group of proteases are a key element in apoptosis (see, e.g., Thornberry, Chemistry and Biology 5:R97-R103 (1998); Thornberry, British Med. Bull. 53:478-490 (1996)). Genetic studies in the nematode Caenorhabditis elegans revealed that apoptotic cell death involves at least 14 genes, 2 of which are the pro-apoptotic (death-promoting) ced (for cell death abnormal) genes, ced-3 and ced-4. CED-3 is homologous to interleukin 1 beta-converting enzyme, a cysteine protease, which is now called caspase-1. When these data were ultimately applied to mammals, and upon further extensive investigation, it was found that the mammalian apoptosis system appears to involve a cascade of caspases, or a system that behaves like a cascade of caspases. At present, the caspase family of cysteine proteases comprises 14 different members, and more may be discovered in the future. All known caspases are synthesized as zymogens that require cleavage at an aspartyl residue prior to forming the active enzyme. Thus, caspases are capable of activating other caspases, in the manner of an amplifying cascade.

[0006] Apoptosis and caspases are thought to be crucial in the development of cancer {Apoptosis and Cancer Chemotherapy, Hickman and Dive, eds., Humana Press (1999)). There is mounting evidence that cancer cells, while containing caspases, lack parts of the molecular machinery that activates the caspase cascade. This makes the cancer cells lose their capacity to undergo cellular suicide and the cells become cancerous. In the case of the apoptosis process, control points are known to exist that represent points for intervention leading to activation. These control points include the CED-9-BCL-like and CED-3-ICE-like gene family products, which are intrinsic proteins regulating the decision of a cell to survive or die and executing part of the cell death process itself, respectively (see, Schmitt, et al, Biochem. Cell. Biol. 75:301- 314 (1997)). BCL-like proteins include BCL-xL and BAX-alpha, which appear to function upstream of caspase activation. BCL-xL appears to prevent activation of the apoptotic protease cascade, whereas BAX-alpha accelerates activation of the apoptotic protease cascade. It has been shown that chemotherapeutic (anti-cancer) drugs can trigger cancer cells to undergo suicide by activating the dormant caspase cascade. This may be a crucial aspect of the mode of action of most, if not all, known anticancer drugs (Los, et ai, Blood 90:3118-3129 (1997); Friesen, et ai., Nat. Med. 2:51 '4 (1996)). The mechanism of action of current antineoplastic drugs frequently involves an attack at specific phases of the cell cycle. In brief, the cell cycle refers to the stages through which cells normally progress during their lifetime. Normally, cells exist in a resting phase teπned G₀. During multiplication, cells progress to a stage in which DNA synthesis occurs, termed S. Later, cell division, or mitosis occurs, in a phase called M. Antineoplastic drugs, such as cytosine arabinoside, hydroxyurea, 6-mercaptopurine, and methotrexate are S phase specific, whereas antineoplastic drugs, such as vincristine, vinblastine, and paclitaxel are M phase specific. Many slow growing tumors, e.g. colon cancers, exist primarily in the G₀ phase, whereas rapidly proliferating normal tissues, for example bone marrow, exist primarily in the S or M phase. Thus, a drug like 6-mercaptopurine can cause bone marrow toxicity while remaining ineffective for a slow growing tumor. Further aspects of the chemotherapy of neoplastic diseases are known to those skilled in the art (see, e.g., Hardman, et al., eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, Ninth Edition, McGraw-Hill, New York (1996), pp. 1225-1287). Thus, it is clear that the possibility exists for the activation of the caspase cascade, although the exact mechanisms for doing so are not clear at this point. It is equally - A -

clear that insufficient activity of the caspase cascade and consequent apoptotic events are implicated in various types of cancer. The development of caspase cascade activators and inducers of apoptosis is a highly desirable goal in the development of therapeutically effective antineoplastic agents. Moreover, since autoimmune disease and certain degenerative diseases also involve the proliferation of abnormal cells, therapeutic treatment for these diseases could also involve the enhancement of the apoptotic process through the administration of appropriate caspase cascade activators and inducers of apoptosis.

[0008] Adhikari et al. {Current Science, 21 : 703-7 (1988)) reported the synthesis and antimicrobial activities of some new 4-arylamino isoxazolo[5,4- (/jpyrimidine derivatives. Compounds of formula I (R¹ = tolyl, ClC₆H₄, Ph; R² = H, Br, Cl, OEt, OH, COMe) were reported to show bactericidal and fungicidal activity.

[0009] Tanaka et al. {Acta Chemica Scandinavica, Series B: Organic

Chemistry and Biochemistry, B40: 760-3 (1986)) reported the synthesis of trifluoromethylisoxazoloazine. Compound III was prepared by reacting 5- acetamidoisoxazole I with a mixture Of P₂O₅, PhNH₂ and Et₃NHCl.

[0010] Martin-Kohler et al. {Helvetica Chimica Acta, 87: 956-975 (2004)) reported the synthesis of oxazolo[5,4-d]pyrimidines and furo[2,3- JJpyrimidines as inhibitors of VEGFR2 and EGFR with IC₅₀ values in the low nanomolar range. They reported that generally the furopyrimidines were somewhat more active than the oxazolopyrimidines. [0011] WO2002092603 discloses the preparation of oxazolo- and furopyrimidines for treating benign and malignant tumors and deregulated angiogenesis:

Q- Y I

wherein, R = alkyl, aryl, heterocyclyl, etc., X = N, CRi, Ri = H, CO₂R₂, R₂ = alkyl, H, aryl, etc., Y = NR₃, S, O, R₃ = H, alkyl, Q = aryl, arylalkyl, cycloalkyl, etc.

[0012] WO2005117890 discloses the preparation of thiazolopyrimidines and thienopyrimidines as antagonists of CCR2b receptors for the treatment of chemokine-mediated diseases:

wherein, X₁, X₂ = S, N or CH; X₃, X₄ = N or CH; Ra - H, alkyl; p = 0-4; R₁ = H, (un)substituted cycloalkyl or aryl; Z = (un)substituted NH or -NHC(O)-; Y = bond, O, C(O); R₂ = bond, (un)substituted alkylene; R₃, R₄ = (un)substituted alkyl, alkenyl, alkynyl or heterocycle; R₃ and R₄ may link together to form a cycle, etc., Compound II is one of the specific examples.

[0013] WO2005095419 discloses the preparation of thiazolo[5,4-(f]pyrimidine derivatives as growth factor receptor tyrosine kinase inhibitors:

wherein, A represents optionally substituted aryl or optionally substituted heteroaryl; Ri represents a group bonded through carbon; R₂ represents hydrogen or an aliphalic hydrocarbon group; and X represents -NR₃-, -O-, -S-, -SO-, -SO₂-, or -CHR₃-, wherein R₃ represents hydrogen or an aliphalic hydrocarbon group.

[0014] JP06001793 discloses the preparation of thiazolo[5,4-<i]pyrimidines as agrochemical microbicides:

wherein, R = (halo)alkyl, benzyl, Ph, alkenyl, cycloalkyl, alkoxycarbonylalkyl, alkoxyalkyl, phenylalkyl; X = H, halo, (halo)alkyl, alkoxy, Ph, anilino, (halo-, alkyl-, or alkoxy-substituted) phenoxy; Y = H, halo, alkyl, alkoxy, Ph, phenoxy, anilino; n = 1, 2.

[0015] WO2004005291 discloses the preparation of imidazotriazines as selective phosphodiesterase- 10a inhibitors for the treatment of cancer and neurodegenerative diseases: I I

I II

wherein, R| = (un)substituted heteroaryl; R₂ = alkyl, cycloalkyl; R₃ = Me; A = 0, NH; R₄ = (un)substituted aryl, e.g., halo, CHO, C02H, etc. Compounds II and III are two of the specific examples. WO2003000693 discloses the preparation of imidazotriazines as phosphodiesterase 1OA inhibitors for the treatment of neurodegenerative diseases:

wherein, R₁ = (un)substituted aryl, SO₂NR₅R₆; R₅, R₆ = H, alkyl; R₂ = alkyl; R₃ = Me, Et; A = 0, S, NR₇; R₇ = H, (un)substituted alkoxy, alkyl; E = alkandiyl (sic); R₄ = (un)substituted aryl, heteroaryl. WO2005082908 discloses the preparation of pyrazolotriazines as kinase inhibitors for treating cancer and other diseases associated with a kinase:

wherein, Ri is H, optionally substituted alkyl, aryl, heteroaryl, heteroarylalkyl, arylalkyl, NR₆R₇, cycloalkyl and cycloalkylalkyl; R₂ is alkyl, cycloalkyl, alkenyl, alkynyl, trifluoromethyl, OR₇, SR₇, hydroxyalkyl, haloalkyl, aryl, heteroaryl, halo, CN, formyl, nitro, alkylcarbonyl, aralkylcarbonyl, heteroaralkyicarbonyl, or alkylene-N(R₈Rc)), wherein R₈ and R₉ represent H or alkyl, or R₈ and Rg taken together with the nitrogen in -N(R₈Rg) form a five- to seven-membered heterocycle; R₃ is -NR4R₅, substituted heterocycle, H, alkyl, alkylthio, aralkylthio, alkylsulfinyl, or aralkylsulfinyl; R₄ is optionally substituted alkyl, cycloalkyl or heterocyclyl; R₅ is H, alkyl, aryl, heteroaryl, arylalkyl, cycloalkyl, heterocyclyl, acyl or heteroarylalkyl; R₆ is H, alkyl or aryl; R₇ is H or alkyl.

[0018] WO2004069837 discloses the preparation of pyrazolotriazines as cannabinoid CBl receptor antagonists:

„ 4

wherein, Ri, R₂ = (substituted) aryl, heteroaryl; R₃ = H, alkyl, haloalkyl, alkoxy; R₄ = Qi, Q₂; R41 = H, alkyl; R₄₂, R₄₃ = H, cyano, OH, amino, H₂NCO, (substituted) alkyl, alkoxy, acyloxy, acyl, aryl, heteroaryl, etc.; R₄₄, R₄₅ = H, cyano, OH, amino, H₂NCO, (substituted) alkyl, aryl, heteroaryl, heterocyclyl, etc.; pairs Of R_4I-R₄₅ may form bonds, methylene, ethylene bridges; X = bond, CH₂CH₂, etc.; Y = O, S, CO, etc.; Z = bond, CH₂CH₂, etc.

[0019] WO2004072078 discloses the preparation of pyrazolotriazines I, exemplified by compounds II and III, as cyclic nucleotide phosphodiesterase, in particular PDE4 inhibitors, for treating inflammations.

I II III

10020] WO2004011464 discloses new substituted pyrazolo[l,5-α]-l,3,5- triazines and their analogs, pharmaceutical compositions containing them, their use as drugs (particularly as neurotrophic factor production stimulants), and process for their preparation.

wherein, R₂, R₃ = H, halo, NO₂, alkyl, carboxyalkyl, trifluoroalkyl, cycloalkyl, acyl, alkenyl, alkynyl, aryl, etc. R₄ = H, alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, heterocyclyl, NH₂ or derivatives; Y = halo, alkyl, alkenyl, alkynyl, Ph, OH or derivatives., SH or derivatives., NH₂ or derivatives, exemplified by specific compounds IV.

[0021] WO2002050079 discloses pyrazolo[l,5-α]-l,3,5-triazine derivatives with activity as cyclin-dependent kinase (CDK) and glycogen synthase kinase- 3 (GSK-3) inhibitors, and their preparation, pharmaceutical compositions, and use as, e.g., antiproliferative agents.

I I wherein, A = H, halo, formyl, cyano, NO₂, guanidinoaminomethylenyl, (1,3- dihydro-2-oxoindol)-3-ylidenemethyl, alkylcarbonyl, aralkylcarbonyl, or heteroaralkylcarbonyl radical, or -L-NR]R₂ radical, wherein L = alkylene radical and Ri and R₂ = H and alkyl, or NR)R₂ = (un)substituted 5-7- membered heterocycle; X = H, alkylthio, aralkylthio, alkylthioxo or aralkylthioxo (thioxo = sulfinyl), or NR₄R₅ wherein R₄ = alkyl, hydroxyalkyl, (un)substituted cycloalkyl, aralkyl, heteroaryl, or heteroaryl alkyl, and R₅ = H; or NR₄R₅ = heterocycle; Y = NH or O; Z = bond, alkyl or alkylthioalkyl linker; Ar = (un)substituted carbo- or heterocyclic aryl radical or a pyridinium salt radical, exemplified by specific compounds II.

[0022] WO9967247 discloses the preparation of pyrazolo[l ,5-α]triazine corticotropin releasing factor antagonists.

wherein, X = N, CH, CR₅; R₁ = H, alkyl, alkenyl, etc.; R₂ = H, alkyl, cycloalkyl, etc.; R₃ = (un)substituted Ci_-I0 alkyl, C₂-I₀ alkenyl, C_2-Io alkynyl, etc.; R₄ = H, alkyl, allyl, propargyl; R₅ = alkyl, alkenyl, alkynyl, etc.; r = 0=4; exemplified by specific compounds II.

SUMMARY OF THE INVENTION

[0023] The present invention is related to the discovery that /V-aryl- isoxazolopyrimidin-4-amines and related compounds, as represented in Formulae I-XI, are activators of the caspase cascade and inducers of apoptosis. Thus, an aspect of the present invention is directed to the use of compounds of Formulae I-XI as inducers of apoptosis. _

- 12 -

[0024] A second aspect of the present invention is to provide a method for treating, preventing or ameliorating neoplasia and cancer by administering a compound of one of the Formulae I-XI to a mammal in need of such treatment.

[0025] Many of the compounds within the scope of the present invention are novel compounds. Therefore, a third aspect of the present invention is to provide novel compounds of Formulae I-XI, and to also provide for the use of these novel compounds for treating, preventing or ameliorating neoplasia and cancer.

[0026] A fourth aspect of the present invention is to provide a pharmaceutical composition useful for treating disorders responsive to the induction of apoptosis, containing an effective amount of a compound of one of the Formulae I-XI in admixture with one or more pharmaceutically acceptable carriers or diluents.

[0027] A fifth aspect of the present invention is directed to methods for the preparation of novel compounds of Formulae I-XI.

DETAILED DESCRIPTION OF THE INVENTION

|0028] The present invention arises out of the discovery that Λ/-aryl- isoxazolopyrimidin-4-amines and related compounds, as represented in Formulae I-XI, are potent and highly efficacious activators of the caspase cascade and inducers of apoptosis. Therefore, compounds of Formulae I-XI are useful for treating disorders responsive to induction of apoptosis.

[0029] Specifically, compounds of the present invention are represented by

Formula I:

or pharmaceutically acceptable salts or prodrugs or tautomers thereof, wherein:

Ar is optionally substituted aryl or optionally substituted heteroaryl;

A, B and D are independently carbon, nitrogen, oxygen or sulfur, wherein when A, B or D are nitrogen, oxygen or sulfur, then there is no substituent at the nitrogen, oxygen or sulfur; with the proviso that when one of A or D is sulfur, then the other of A or D is not carbon;

E and F are independently carbon or nitrogen;

H is an aromatic ring, and the line between A and B, B and D, D and E, E and F, E and A can be a single bond or a double bond.

Ri is hydrogen, halo, optionally substituted amino, optionally substituted alkoxy, optionally substituted Ci-io alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano, acylamido, hydroxy, thiol, sulfone, sulfoxide, acyloxy, azido, carboxy, carbonylamido or optionally substituted alkylthiol;

R₂ is hydrogen or optionally substituted alkyl;

R₃-R₅ independently are hydrogen, halo, amino, alkoxy, Ci -1₀ alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano, acylamido, hydroxy, thiol, sulfone, sulfoxide, acyloxy, azido, carboxy, carbonylamido, alkylthiol, or any two adjacent substituents form methylenedioxy. Preferred compounds of Formula I include compounds wherein Ar is phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, isoxazolyl, pyrazolyl, imidazolyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted. More preferably, Ar is phenyl or pyridyl. Another group of preferred compounds of Formula I include compounds wherein Ri is hydrogen, halo, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkylthiol, or optionally substituted CM_O alkyl. Another group of preferred compounds of Formula I include compounds wherein R₂ is hydrogen. Another group of preferred compounds of Formula I include compounds wherein R₂ is methyl or ethyl. Another group of preferred compounds include compounds wherein A, E and F are carbon, B is nitrogen and D is oxygen. Another group of preferred compounds include compounds wherein B, E and F are carbon, A is nitrogen and D is oxygen. Another group of preferred compounds include compounds wherein B, E and F are carbon, A is nitrogen and D is sulfur. Another group of preferred compounds include compounds wherein A, D and F are carbon, B and E are nitrogen. Another group of preferred compounds include compounds wherein B, D and E are carbon, A and F are nitrogen. One group of preferred compounds of the present invention are represented by Formulae H-VI:

R₂^ .. Ar

N

N- N (IV)

or pharmaceutically acceptable salts, prodrugs or tautomers thereof, wherein:

Ri is hydrogen, halo, optionally substituted amino, optionally substituted alkoxy, optionally substituted C_{1 -1 O} alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano, acylamido, hydroxy, thiol, sulfone, sulfoxide, acyloxy, azido, carboxy, carbonylamido or optionally substituted alkylthiol;

R₂ is hydrogen or optionally substituted alkyl;

R₃-R₅ independently are hydrogen, halo, amino, alkoxy, C_{M 0} alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano, acylamido, hydroxy, thiol, sulfone, sulfoxide, acyloxy, azido, carboxy, carbonylamido, alkylthiol, or any two adjacent substituents form methylenedioxy. Preferred compounds of Formulae II-VI include compounds wherein

Ar is phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, isoxazolyl, pyrazolyl, imidazolyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted. More preferably, Ar is optionally substituted phenyl or pyridyl. Another groυp of preferred compounds of Formulae II- VI include compounds wherein Ri is hydrogen, halo, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkylthiol, or optionally substituted Ci_{-I 0} alkyl. Another group of preferred compounds of Formulae II-VI include compounds wherein R₂ is hydrogen. Another group of preferred compounds of Formulae II-VI include compounds wherein R₂ is methyl or ethyl. Another group of preferred compounds of the present invention are represented by Formulae VII-XI:

or pharmaceutically acceptable salts, prodrugs or tautomers thereof, wherein:

Rι is hydrogen, halo, optionally substituted amino, optionally substituted alkoxy, optionally substituted C_{M 0} alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroaryl alkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano, acylamido, hydroxy, thiol, sulfone, sulfoxide, acyloxy, azido, carboxy, carbonylamido or optionally substituted alkylthiol;

R₂ is hydrogen or optionally substituted alkyl;

R₃-R₁₀ independently are hydrogen, halo, amino, alkoxy, Ci.₁₀ alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano, acylamido, hydroxy, thiol, sulfone, sulfoxide, acyloxy, azido, carboxy, carbonylamido, alkylthiol, or any two adjacent substituents form methylenedioxy.

[0034] Preferred compounds of Formulae VII-XI include compounds wherein

Ar is phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, isoxazolyl, pyrazolyl, imidazolyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted. More preferably, Ar is optionally substituted phenyl or pyridyl. Another group of preferred compounds of Formulae VII-XI include compounds wherein Ri is hydrogen, halo, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkylthiol, or optionally substituted Ci-io alkyl. Another group of preferred compounds of Formulae VII-XI include compounds wherein R.₂ is hydrogen. Another group of preferred compounds of Formulae VlI-XI include compounds wherein R₂ is methyl or ethyl.

[0035] Exemplary preferred compounds of Formulae I-XI that may be employed in the method of the invention include, without limitation:

N-(4-Methoxyphenyl)-N,3-dimethylisoxazolo[5,4-<i]pyrimidin-4- amine;

Λf-(4-Methoxyphenyl)-/V,3,6-trimethylisoxazolo[5,4-(f]pyrimidin-4- amine;

N-(2,5-Dimethoxyphenyl)-2,5-dimethyloxazolo[5,4-i/]pyrimidin-7- amine;

N-(3,5-Dimethoxyphenyl)-2,5-dimethyloxazolo[5,4-</]pyrimidin-7- amine;

N-(4-Methoxyphenyl)-N,2,5-trimethyloxazolo[5,4-</]pyrimidin-7- amine;

N-(2,5-Dimethoxyphenyl)-2-methyloxazolo[5,4-ύT]pyrimidin-7-amine; jV-(3,5-Dimethoxyphenyl)-2-methyloxazolo[5,4-cT]ρyrimidin-7-amine; jV-(3,5-Dimethoxyphenyl)thiazolo[5,4-cTlpyrimidin-7-amine;

N-(2,5-Dimethoxyphenyl)thiazolo[5,4-cT|pyrimidin-7-amine;

7V-(4-Methoxyphenyl)-N-methylthiazolo[5,4-uTlpyrimidin-7-amine;

N-(3,5-Dimethoxy-phenyl)-5-methylimidazo[5,l-/][l,2,4]triazin-4- amine; //-(3,5-Dimethoxyphenyl)-2-methylpyrazolo[l,5-fl][l ,3,5]triazin-4- amine;

N-(4-Methoxyphenyl)-N,2-dimethylpyrazolo[l,5-<3][l,3,5]triazin-4- amine; and pharmaceutically acceptable salts or prodrugs thereof. The present invention is also directed to novel compounds within the scope of Formulae I-XI. Exemplary preferred compounds that may be employed in this invention include, without limitation:

N-(4-Methoxyphenyl)-3,6-dimethylisoxazolo[5,4-cT]pyrimidin-4- amine;

7V-(4-Methoxyphenyl)-3-methylisoxazolo[5,4-(f|pyrimidin-4-amine; jV-(3,5-Dimethoxyphenyl)-3-methylisoxazolo[5,4-(i]pyrimidin-4- amine;

3-Methyl-N-(3-methyl-lH-pyrazol-5-yl)isoxazolo[5,4-J]pyrimidin-4- amine; iV-(3-Bromophenyl)-3-methylisoxazolo[5,4-J]pyrimidin-4-amine;

N-(4-Methoxyphenyl)-yV,3-dimethylisoxazolo[5,4-cT]pyrimidin-4- amine;

7V-(4-Methoxyphenyl)-N,3,6-trimethylisoxazolo[5,4-</]pyrimidin-4- amine;

N-(2,5-Dimethoxyphenyl)-2,5-dimethyloxazolo[5,4-J]pyrimidin-7- amine; iV-(3 ,5 -Dimethoxyphenyl)-2 , 5 -dimethyloxazolo [5 ,4-c/]pyrimidin-7- amine;

N-(3-Bromophenyl)-2,5-dimethyloxazolo[5,4-J]pyrimidin-7-amine;

N-(4-Methoxyphenyl)-N,2,5-trimethyloxazolo[5,4-cf]pyrimidin-7- amine;

N-(2,5-Dimethoxyphenyl)-2-methyloxazolo[5,4-</lpyrimidin-7-amine;

N-(3,5-Dimethoxyphenyl)-2-methyloxazolo[5,4-<f|pyrimidin-7-amine;

N-(3-Bromophenyl)-2-methyloxazolo[5,4-(i]pyrimidin-7-amine;

N-(3-Methyl-l//-pyrazol-5-yl)-2-phenyloxazolo[5,4-JJpyrimidin-7- amine; N-(3-Bromophenyl)-2-phenyloxazolo[5,4-(/]pyrimidin-7-amine;

2,5-Dimethyl-N-(3-methyl-l//-pyrazol-5-yl)oxazolo[5,4-<i]pyrimidin- 7-amine;

N-(4-(2,5-Dimethyloxazolo[5,4-(i]pyrimidin-7- ylamino)phenyl)benzamide;

2-Methyl-Λ^-(3-methyl-lH-pyrazol-5-yl)oxazolo[5,4-(fJpyi-imidin-7- amine;

7V-(3,5-Dimethoxyphenyl)thiazolo[5,4-£/]pyrimidin-7-amine;

N-(3-Bromophenyl)thiazolo[5,4-cT)pyrimidin-7-amine;

N-(2,5-Dimethoxyphenyl)thiazolo[5,4-£/]pyrimidin-7-amine;

N-(3-Methyl-lH-pyrazol-5-yl)thiazolo[5,4-</]pyrimidin-7-amine;

N-(4-(Thiazolo[5,4-(fJpyrimidin-7-ylamino)phenyl)benzamide;

//-(4-Methoxyphenyl)-iV-methylthiazolo[5,4-(flpyrimidin-7-amine;

5-Methyl-N-(3-methyl-l//-pyrazol-5-yl)thiazolo[5,4-(fjpyrimidin-7- amine; jV-(3,5-Dimethoxy-phenyl)-5-methylimidazo[5,l-/][l,2,4]triazin-4- amine;

5-Methyl-Λ^f-(3-methyl-lH-pyrazol-5-yl)imidazo[l,5-/l[l,2,4]triazin-4- amine;

N-(4-Methoxyphenyl)-N,5-dimethylimidazo[5,l-/J[l ,2,4]triazin-4- amine;

2,5-Dimethyl-N-(3-methyl-l//-pyrazol-5-yl)imidazo[l,5- /J[1 ,2,4]triazin-4-amine; jV-(3,5-Dimethoxyphenyl)-2-methylpyrazolo[l ,5-fl][l,3,5]triazin-4- amine;

2-Methyl-yV-(3-methyl-li/-pyrazol-5-yl)pyrazolo[l,5-α][l,3,5]triazin- 4-amine;

/V-(4-Methoxyphenyl)-N,2-dimethylpyrazolo[l,5-a][l,3,5]triazin-4- amine; and pharmaceutically acceptable salts or prodrugs thereof. The term "alkyl" as employed herein by itself or as part of another group refers to both straight and branched chain radicals of up to ten carbons. Useful alkyl groups include straight-chained and branched C _{M O} alkyl groups, more preferably Ci_-6 alkyl groups. Typical C_M0 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, terϊ-butyl, 3-pentyl, hexyl and octyl groups, which may be optionally substituted.

(0038] The term "alkenyl" as employed herein by itself or as part of another group means a straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, including at least one double bond between two of the carbon atoms in the chain. Typical alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl and 2-butenyl.

[0039] The term "alkynyl" is used herein to mean a straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, wherein there is at least one triple bond between two of the carbon atoms in the chain. Typical alkynyl groups include ethynyl, 1-propynyl, l-methyl-2- propynyl, 2-propynyl, 1-butynyl and 2-butynyl.

[0040] Useful alkoxy groups include oxygen substituted by one of the C_{M 0} alkyl groups mentioned above, which may be optionally substituted. Alkoxy substituents include, without limitation, halo, morpholino, amino including alkylamino and dialkylamino, and carboxy including esters thereof.

[0041] Useful alkylthio groups include sulfur substituted by one of the C_{M O} alkyl groups mentioned above, which may be optionally substituted. Also included are the sulfoxides and sulfones of such alkylthio groups.

[0042] Useful amino and optionally substituted amino groups include -NH₂, -

NHRi ₅ and -NRi₅Ri₆, wherein Ri₅ and Ri 6 are CM_O alkyl or cycloalkyl groups, or R] ₅ and Ri₆ are combined with the N to form a ring structure, such as a piperidine, or Ri₅ and Ri₆ are combined with the N and other group to form a ring, such as a piperazine. The alkyl group may be optionally substituted.

[0043] Optional substituents on the alkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, carbocyclic and heterocyclic groups include one or more halo, hydroxy, carboxyl, amino, nitro, cyano, Ci-C₆ acylamino, Ci-C₆ acyloxy, Ci-C₆ alkoxy, aryloxy, alkylthio, C₆-Ci_O aryl, C4-C7 cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-Ci₀ aryl(C₂-C₆)alkenyl, C₆-Ci_O aryl(C₂-C₆)alkynyl, saturated and unsaturated heterocyclic or heteroaryl.

|0044] Optional substituents on the aryl, arylalkyl, arylalkenyl, arylalkynyl and heteroaryl and heteroarylalkyl groups include one or more halo, C]-C₆ haloalkyl, C₆-Ci₀ aryl, C₄-C₇ cycloalkyl, CpC₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₆-C₀ aryl(C,-C₆)alkyl, C₆-C₁₀ aryl(C₂-C₆)alkenyl, C₆-C₁₀ aryl(C₂-C₆)alkynyl, Ci-C₆ hydroxyalkyl, nitro, amino, ureido, cyano, C]-C₆ acylamino, hydroxy, thiol, sulfone, sulfoxide, Ci-C₆ acyloxy, azido, Ci-C₆ alkoxy or carboxy.

[0045J The term "aryl" as employed herein by itself or as part of another group refers to monocyclic, bicyclic or tricyclic aromatic groups containing from 6 to 14 carbons in the ring portion.

[0046] Useful aryl groups include C₆-H aryl, preferably C₆-Io aryl. Typical

C<₅-i₄ aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups.

[0047) The term "carbocycle" as employed herein include cycloalkyl and partially saturated carbocyclic groups. Useful cycloalkyl groups are C₃.₈ cycloalkyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0048] Useful saturated or partially saturated carbocyclic groups are cycloalkyl groups as described above, as well as cycloalkenyl groups, such as cyclopentenyl, cycloheptenyl and cyclooctenyl.

[0049] Useful halo or halogen groups include fluorine, chlorine, bromine and iodine.

[0050] The term "arylalkyl" is used herein to mean any of the above- mentioned C]-_I0 alkyl groups substituted by any of the above-mentioned C₆-_M aryl groups. Preferably the arylalkyl group is benzyl, phenethyl or naphthylmethyl.

[0051] The term "arylalkenyl" is used herein to mean any of the above- mentioned C₂-_I0 alkenyl groups substituted by any of the above-mentioned C₆.| ₄ aryl groups. [0052] The term "arylalkynyl" is used herein to mean any of the above- mentioned C₂-₁₀ alkynyl groups substituted by any of the above-mentioned C₆-H aryl groups.

[0053] The term "aryloxy" is used herein to mean oxygen substituted by one

. of the above-mentioned C₆.₁₄ aryl groups, which may be optionally substituted. Useful aryloxy groups include phenoxy and 4-methylphenoxy.

[0054] The term "arylalkoxy" is used herein to mean any of the above mentioned Ci.₁₀ alkoxy groups substituted by any of the above-mentioned aryl groups, which may be optionally substituted. Useful arylalkoxy groups include benzyloxy and phenethyloxy.

[0055] Useful haloalkyl groups include C_{M 0} alkyl groups substituted by one or more fluorine, chlorine, bromine or iodine atoms, e.g., fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1 ,1-difluoroethyl, chloromethyl, chlorofluoromethyl and trichloromethyl groups.

[0056] Useful acylamino (acylamido) groups are any Ci_-6 acyl (alkanoyl) attached to an amino nitrogen, e.g., acetamido, chloroacetamido, propionamido, butanoylamido, pentanoylamido and hexanoylamido, as well as aryl-substituted Cι-₆ acylamino groups, e.g., benzoylamido, and pentafluorobenzoylamido.

[0057] Useful acyloxy groups are any Ci_-6 acyl (alkanoyl) attached to an oxy

(-O-) group, e.g., formyloxy, acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy and hexanoyloxy.

[0058] The term heterocycle is used herein to mean a saturated or partially saturated 3-7 membered monocyclic, or 7-10 membered bicyclic ring system, which consists of carbon atoms and from one to four heteroatoms independently selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, the nitrogen can be optionally quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, and wherein the heterocyclic ring can be substituted on carbon or on a nitrogen atom if the resulting compound is stable. [0059] Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, moφholinyl, isochromanyl, chromanyl, pyrazolidinyl pyrazolinyl, tetronoyl and tetramoyl groups.

(0060] The term "heteroaryl" as employed herein refers to groups having 5 to

14 ring atoms; 6, 10 or 14 π electrons shared in a cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms.

[0061] Useful heteroaryl groups include thienyl (thiophenyl), benzo[6]thienyl, naphtho[2,3-6]thienyl, thianthrenyl, furyl (furanyl), pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, including without limitation 2//-pyrrolyl, imidazolyl, pyrazolyl, pyridyl (pyridinyl), including without limitation 2-pyridyl, 3-pyridyl, and 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4//-qιιinolizinyl, isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acrindinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, 1,4-dihydroquinoxaline- 2,3-dione, 7-aminoisocoumarin, pyrido[l,2-α]pyrimidin-4-one, pyrazolo[l ,5- αjpyrimidinyl, including without limitation pyrazolo[l,5-α]pyrimidin-3-yl, l,2-benzoisoxazol-3-yl, benzimidazolyl, 2-oxindolyl and

2-oxobenzimidazolyl. Where the heteroaryl group contains a nitrogen atom in a ring, such nitrogen atom may be in the form of an iV-oxide, e.g., a pyridyl TV-oxide, pyrazinyl TV-oxide and pyrimidinyl TV-oxide.

[0062] The term "heteroaryloxy" is used herein to mean oxygen substituted by one of the above-mentioned heteroaryl groups, which may be optionally substituted. Useful heteroaryloxy groups include pyridyloxy, pyrazinyloxy, pyrrolyloxy, pyrazolyloxy, imidazolyloxy and thiophenyloxy.

[0063] The term "heteroarylalkoxy" is used herein to mean any of the above- mentioned Ci-io alkoxy groups substituted by any of the above-mentioned heteroaryl groups, which may be optionally substituted. [0064] Some of the compounds of the present invention may exist as stereoisomers including optical isomers. The invention includes all stereoisomers and both the racemic mixtures of such stereoisomers as well as the individual enantiomers that may be separated according to methods that are well known to those of ordinary skill in the art.

[0065] Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, such as hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalate; and inorganic and organic base addition salts with bases, such as sodium hydroxy, Tris(hydroxymethyl)aminomethane (TRIS, tromethane) and N-methyl-glucamine.

[0066] Examples of prodrugs of the compounds of the invention include the simple esters of carboxylic acid containing compounds (e.g., those obtained by condensation with a C_M alcohol according to methods known in the art); esters of hydroxy containing compounds (e.g., those obtained by condensation with a Ci_-4 carboxylic acid, C_3-6 dioic acid or anhydride thereof, such as succinic and fumaric anhydrides according to methods known in the art); imines of amino containing compounds (e.g., those obtained by condensation with a Ci_-4 aldehyde or ketone according to methods known in the art); carbamate of amino containing compounds, such as those described by Leu, et. ai, (J. Med. Chem. 42:3623-3628 (1999)) and Greenwald, et. al, (J. Med. Chem. 42:3657-3661 (1999)); and acetals and ketals of alcohol containing compounds (e.g., those obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art).

[0067] The compounds of this invention may be prepared using methods known to those skilled in the art, or the novel methods of this invention. Specifically, the compounds of this invention with Formulae I-II and VII could be prepared as illustrated by the exemplary reaction in Scheme 1. Reaction of 5-amino-3-methylisoxazole-4-carbonitrile with phosphorous oxychloride and N,N-dimethyl acetamide produced 4-chloro-3,6- dimethylisoxazolo[5,4-(/]pyrimidine. Reaction of 4-chloro-3,6- dimethylisoxazolo[5,4-</]pyrimidine with a substituted aniline, such as 4- methoxyaniline, in a solvent such as /-proponol (/-PrOH), produced N-(A- methoxyphenyl)-3,6-dimethylisoxazolo[5,4-J]pyrimidin-4-amine.

Scheme 1

H₂

[0068] Other compounds of this invention with Formulae I-II and VII could be prepared similarly as illustrated by the exemplary reaction in Scheme 2. Reaction of S-amino-S-methylisoxazole-^carbonitrile with dimethylformamide dimethyl acetal produced (E)-5-(2-

(dimethylamino)ethylideneamino)-3-methylisoxazole-4-carbonitrile. Reaction of (E)-5-(2-(dimethylamino)ethylideneamino)-3-methylisoxazole-4- carbonitrile with a substituted aniline such as 4-methoxyaniline in acetonitrile and glacial acetic acid in a microwave reactor produced yV-(4-methoxyphenyl)- 3-methylisoxazolo[5,4-<f]pyrimidin-4-amine.

Scheme 2

[0069] Alternatively, compounds of this invention with Formulae I-II and VII could be prepared as illustrated by the exemplary reaction in Scheme 3. Reaction of 5-amino-3-methylisoxazole-4-carboxamide with triethylorthoformate in acetic anhydride produced 3-methylisoxazolo[5,4- c/]pyrimidin-4-ol, which was converted into 4-chloro-3-methylisoxazolo[5,4- (fjpyrimidine via reaction with phosphorous oxychloride. Reaction of 4- chloro-3-methylisoxazolo[5,4-<i]pyrimidine with a substituted aniline such as 3,5-dimethoxyaniline in the presence of an amine such as triethylamine and in a solvent such as isopropanol produced N-(3,5-dimethoxyphenyl)-3- methylisoxazolo[5,4-t/]pyrimidin-4-amine.

Scheme 3

Similarly, compounds of this invention with Formulae I-II and VII could be prepared as illustrated by the exemplary reaction in Scheme 4. Reaction of 5-amino-3-methylisoxazole-4-carboxami.de with triethyl orthoacetate in acetic anhydride in a microwave reactor produced 3,6- dimethylisoxazolo[5,4-cTjpyrimidin-4-ol, which was converted into 4-chloro- 3,6-dimethylisoxazolo[5,4-c(]pyrimidine via reaction with phosphorous oxychloride. Reaction of 4-chloro-3,6-dimethylisoxazolo[5,4-<f)pyrimidine with a substituted aniline such as N-methyl-4-methoxyaniline produced N-(A- methoxyphenyl)-Λ^,3,6-trimethylisoxazolo[5,4-rf]pyrimidin-4-amine. Scheme 4

Compounds of this invention with Formulae I, III and VIII could be prepared as illustrated by the exemplary reaction in Scheme 5. Reaction of 5- amino-2-rnethylpyrimidine-4,6-diol with acetic anhydride produced 2,5- dimethyloxazolo[5,4-<i]pyrimidin-7-ol, which was converted into 7-chloro- 2,5-dimethyloxazolo[5,4-<i]pyrimidine via reaction with phosphorous oxychloride in the presence of Λf Λf-dimethylaniline in anhydrous toluene. Reaction of 7-chloro-2,5-dimethyloxazolo[5,4-<f]pyrimidine with a substituted aniline, such as 2,5-dimethoxyaniline, in the presence of a base such as diisopropylethyl amine and a solvent such as THF in a microwave reactor produced N-(2,5-dimethoxyphenyl)-2,5-dimethyloxazolo[5,4-cT]pyrimidin-7- amine.

Scheme 5

120⁰C

(J-Pr

)₂EtN, microwave/THF [0072] Similarly, compounds of this invention with Formulae I, III and VIII could be prepared as illustrated by the exemplary reaction in Scheme 7. Reaction of 5-amino-2-methylpyrimidine-4,6-diol with benzoic anhydride produced 2-phenyloxazolo[5,4-<f]pyrimidin-7-ol, which was converted into 7- chloro-2-phenyloxazolo[5,4-<f]pyrirnidine via reaction with phosphorous oxychloride. Reaction of 7-chloro-2-phenyloxazolo[5,4-cf]pyrimidine with a substituted aniline such as 3-bromoaniline produced N-(3-bromophenyl)-2- phenyloxazolo[5,4-<f]pyrimidin-7-amine.

Scheme 7

THF/H₂O, NaOAc, 75⁰C

[0073] Alternatively, compounds of this invention with Formulae I, III and

VIII could be prepared as illustrated by the exemplary reaction in Scheme 7. Reaction of 7-chloro-2,5-dimethyloxazolo[5,4-d]pyrimidine with a substituted aniline such as iV-methyl-4-methoxyaniline in the presence of a base such as sodium acetate in solvents such as THF and water produced N-(4- Methoxyphenyl)-N,2,5-trimethyloxazolo[5,4-cT]pyrimidin-7-amine.

Scheme 7

o o neat, 14O⁰C POCU, Me,NPh

PfAcAph

MePh

IPA₁ Et₃N, 12O C

[0074] Compounds of this invention with Formulae I, IV and IX could be prepared as illustrated by the exemplary reaction in Scheme 8. Reaction of sodium hydrosulfide with 5-amino-4,6-dichloropyrimidine in solvents such as water and methanol produced 5-amino-6-chloropyrimidine-4-thiol, which was cyclized to produce 7-chlorothiazolo[5,4-<i]pyrimidine via reaction with triethoxymethane. Reaction of 7-chlorothiazolo[5,4-c/]pyrimidine with a 1 substituted aniline, such as 3,5-dimethoxyaniline, produced N-(3,5- dimethoxyphenyl)thiazolo[5,4-</]pyrimidin-7-amine.

Scheme 8

H

[0075] Compounds of this invention with Formulae I, V and X could be prepared as illustrated by the exemplary reaction in Scheme 9. Reaction of ethyl 4-methyl-5-imidazole carboxylate with Lithium hexamethyldisilane followed by treatment with o-(diphenylphosphinyl)-hydroxylamine produced ethyl l-amino-4-methyl-l//-imidazole-5-carboxylate, which was cyclized to produce 5-methylimidazo[l,5-/j[l,2,4]triazin-4(3H)-one via reaction with formamide. Reaction of 5-methylimidazo[l,5-/|[l,2,4]triazin-4(3H)-one with phosphorous oxychloride in the presence of /V,iV-dimethylaniline produced 4- chloro-5-methylimidazo[5,l-/][l,2,4]tπazine, which was reacted with a substituted aniline, such as 3,5-dimethoxyaniline, produced /V-(3,5- dimethoxyphenyl)-5-methylimidazo[5,l-/][l ,2,4]triazin-4-amine. Scheme 9

[0076] Compounds of this invention with Formulae I, VI and XI could be prepared as illustrated by the exemplary reaction in Scheme 10. Reaction of 3-aminopyrazole with ethyl acetimidate in anhydrous acetonitrile and glacial acetic acid produced /V-(l//-pyrazol-5-yl)acetamidine, which was cyclized to produce 2-methyl-3/7-pyrazolo[l ,5-α][l,3,5]triazin-4-one via reaction with diethyl carbonate in 21% NaOEt in EtOH. Reaction of 2-methyl-3H- pyrazolo[l ,5-fl][l,3,5]triazin-4-one with phosphorous oxychloride in the presence of /V,iV-dimethylaniline produced 4-chloro-2-methyl-pyrazolo[l,5- α][l ,3,5]triazine, which was reacted with a substituted aniline, such as 3,5- dimethoxyanihne, produced N-(3,5-dimethoxy-phenyl)-2-methylpyrazolo[l,5- α][l,3,5]triazin-4-amine.

Scheme 10

NH N- NH NH

Λ N- NH CH₁COOH 21%NaOEt

O HCI

NH,

CH₃CN H Diethyl carbonate

[0077] An important aspect of the present invention is the discovery that compounds having Formulae I-XI are activators of caspases and inducers of apoptosis. Therefore, these compounds are useful in a variety of clinical conditions in which there is uncontrolled cell growth and spread of abnormal cells, such as in the case of cancer.

[0078] Another important aspect of the present invention is the discovery that compounds having Formulae I-XI are potent and highly efficacious activators of caspases and inducers of apoptosis in drug resistant cancer cells, such as breast and prostate cancer cells, which enables these compounds to kill these drug resistant cancer cells. In comparison, most standard anti-cancer drugs are not effective in killing drug resistant cancer cells under the same conditions. Therefore, compounds of this invention are useful for the treatment of drug resistant cancer, such as breast cancer in animals.

[0079] The present invention includes a therapeutic method useful to modulate in vivo apoptosis or in vivo neoplastic disease, comprising administering to a subject in need of such treatment an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of the compound of Formulae I-XI, which functions as a caspase cascade activator and inducer of apoptosis.

[0080] The present invention also includes a therapeutic method comprising administering to an animal an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of said compound of Formulae I- XI, wherein said therapeutic method is useful to treat cancer, which is a group of diseases characterized by the uncontrolled growth and spread of abnormal cells. Such diseases include, but are not limited to, Hodgkin's disease, non- Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, soft-tissue sarcoma, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small-cell lung carcinoma, stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, head or neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, essential thrombocytosis, adrenal cortex carcinoma, skin cancer, and prostatic carcinoma.

[0081] In practicing the therapeutic methods, effective amounts of compositions containing therapeutically effective concentrations of the compounds formulated for oral, intravenous, local and topical application, for the treatment of neoplastic diseases and other diseases in which caspase cascade mediated physiological responses are implicated, are administered to an individual exhibiting the symptoms of one or more of these disorders. The amounts are effective to ameliorate or eliminate one or more symptoms of the disorders. An effective amount of a compound for treating a particular disease is an amount that is sufficient to ameliorate, or in some manner reduce, the symptoms associated with the disease. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective. The amount may cure the disease but, typically, is administered in order to ameliorate the symptoms of the disease. Typically, repeated administration is required to achieve the desired amelioration of symptoms.

[0082] In another embodiment, a pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt of said compound of Formulae I-XI, which functions as a caspase cascade activator and inducer of apoptosis in combination with a pharmaceutically acceptable vehicle is provided.

[0083] Another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of said compound of Formulae I- XI, which functions as a caspase cascade activator and inducer of apoptosis, in combination with at least one known cancer chemotherapeutic agent, or a pharmaceutically acceptable salt of said agent. Examples of known cancer chemotherapeutic agents which may be used for combination therapy include, but not are limited to alkylating agents, such as busulfan, cis-platin, mitomycin C, and carboplatin; antimitotic agents, such as colchicine, vinblastine, paclitaxel, and docetaxel; topo I inhibitors, such as camptothecin and topotecan; topo II inhibitors, such as doxorubicin and etoposide; RNA/DNA antimetabolites, such as 5-azacytidine, 5-fluorouracil and methotrexate; DNA antimetabolites, such as 5-fluoro-2'-deoxy-uridine, ara-C, hydroxyurea and thioguanine; antibodies, such as campath, Herceptin® or Rituxan®. Other known cancer chemotherapeutic agents which may be used for combination therapy include melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen, Gleevec® and alanosine.

[0084] In practicing the methods of the present invention, the compound of the invention may be administered together with at least one known chemotherapeutic agent as part of a unitary pharmaceutical composition. Alternatively, the compound of the invention may be administered apart from at least one known cancer chemotherapeutic agent. In one embodiment, the compound of the invention and at least one known cancer chemotherapeutic agent are administered substantially simultaneously, i.e. the compounds are administered at the same time or one after the other, so long as the compounds reach therapeutic levels in the blood at the same time. On another embodiment, the compound of the invention and at least one known cancer chemotherapeutic agent are administered according to their individual dose schedule, so long as the compounds reach therapeutic levels in the blood.

[0085] It has been reported that alpha- 1 -adrenoceptor antagonists, such as doxazosin, terazosin, and tamsulosin can inhibit the growth of prostate cancer cell via induction of apoptosis (Kyprianou, N., et al., Cancer Res 60:4550- 4555, (2000)). Therefore, another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis, in combination with at least one known alpha- 1 -adrenoceptor antagonists, or a pharmaceutically acceptable salt of said agent. Examples of known alpha- 1 -adrenoceptor antagonists, which can be used for combination therapy include, but are not limited to, doxazosin, terazosin, and tamsulosin.

[0086] It has been reported that sigma-2 receptors are expressed in high densities in a variety of tumor cell types (Vilner, B. J., et al., Cancer Res. 55: 408-413 (1995)) and that sigma-2 receptor agonists, such as CB-64D, CB- 184 and haloperidol activate a novel apoptotic pathway and potentiate antineoplastic drugs in breast tumor cell lines. (Kyprianou, N., et al., Cancer Res. (52:313-322 (2002)). Therefore, another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis, in combination with at least one known sigma-2 receptor agonist, or a pharmaceutically acceptable salt of said agonist. Examples of known sigma-2 receptor agonists that can be used for combination therapy include, but are not limited to, CB-64D, CB- 184 and haloperidol.

[00871 It has been reported that combination therapy with lovastatin, a HMG-

CoA reductase inhibitor, and butyrate, an inducer of apoptosis in the Lewis lung carcinoma model in mice, showed potentiating antitumor effects (Giermasz, A., et al, Int. J. Cancer 97:746-750 (2002)). Therefore, another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis, in combination with at least one known HMG-CoA reductase inhibitor, or a pharmaceutically acceptable salt of said agent. Examples of known HMG-CoA reductase inhibitors, which can be used for combination therapy include, but are not limited to, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin.

[0088] It has been reported that HIV protease inhibitors, such as indinavir or saquinavir, have potent anti-angiogenic activities and promote regression of Kaposi sarcoma (Sgadari, C, et al., Nat. Med. 5:225-232 (2002)). Therefore, another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis, in combination with at least one known HIV protease inhibitor, or a pharmaceutically acceptable salt of said agent. Examples of known HIV protease inhibitors, which can be used for combination therapy include, but are not limited to, amprenavir, abacavir, CGP-73547, CGP-61755, DMP-450, indinavir, nelfmavir, tipranavir, ritonavir, saquinavir, ABT-378, AG 1776, and BMS-232,632.

[0089] It has been reported that synthetic retinoids, such as fenretinide (N-(A- hydroxyphenyl)retinamide, 4HPR), have good activity in combination with other chemotherapeutic agents, such as cisplatin, etoposide or paclitaxel in small-cell lung cancer cell lines (Kalemkerian, G. P., et al., Cancer Chemother. Pharmacol. 43: 145-150 (1999)). 4HPR also was reported to have good activity in combination with gamma-radiation on bladder cancer cell lines (Zou, C, et al, Int. J. Oncol. 73: 1037-1041 (1998)). Therefore, another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis, in combination with at least one known retinoid and synthetic retinoid, or a pharmaceutically acceptable salt of said agent. Examples of known retinoids and synthetic retinoids, which can be used for combination therapy include, but are not limited to, bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, α-difluoromethylomithine, ILX23-7553, fenretinide, and iV-4-carboxyphenyl retinamide.

[0090] It has been reported that proteasome inhibitors, such as lactacystin, exert anti-tumor activity in vivo and in tumor cells in vitro, including those resistant to conventional chemotherapeutic agents. By inhibiting NF-kappaB transcriptional activity, proteasome inhibitors may also prevent angiogenesis and metastasis in vivo and further increase the sensitivity of cancer cells to apoptosis (Almond, J. B., et al., Leukemia 7(5:433-443 (2002)). Therefore, another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis, in combination with at least one known proteasome inhibitor, or a pharmaceutically acceptable salt of said agent. Examples of known proteasome inhibitors, which can be used for combination therapy include, but are not limited to, lactacystin, MG- 132, and PS-341.

[0091] It has been reported that tyrosine kinase inhibitors, such as STI571

(Imatinib mesilate, Gleevec®), have potent synergetic effect in combination with other anti-leukemic agents, such as etoposide (Liu, W.M., et al. Br. J. Cancer 5(5:1472-1478 (2002)). Therefore, another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis, in combination with at least one known tyrosine kinase inhibitor, or a pharmaceutically acceptable salt of said agent. Examples of known tyrosine kinase inhibitors, which can be used for combination therapy include, but are not limited to, Gleevec®, ZD 1839 (Iressa), SH268, genistein, CEP2563, SU6668, SUl 1248, and EMD121974.

[0092] It has been reported that prenyl-protein transferase inhibitors, such as farnesyl protein transferase inhibitor Rl 15777, possess preclinical antitumor activity against human breast cancer (Kelland, L.R., et. al, Clin. Cancer Res. 7:3544-3550 (2001)). Synergy of the protein farnesyltransferase inhibitor SCH66336 and cisplatin in human cancer cell lines also has been reported (Adjei, A. A., et al, Clin. Cancer. Res. 7:1438-1445 (2001)). Therefore, another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis, in combination with at least one known prenyl-protein transferase inhibitor, including farnesyl protein transferase inhibitor, inhibitors of geranylgeranyl-protein transferase type I (GGPTase-I) and geranylgeranyl-protein transferase type- II, or a pharmaceutically acceptable salt of said agent. Examples of known prenyl- protein transferase inhibitors, which can be used for combination therapy include, but are not limited to, Rl 15777, SCH66336, L-778,123, BAL9611 and TAN-1813.

[0093] It has been reported that cyclin-dependent kinase (CDK) inhibitors, such as flavopiridol, have potent synergetic effect in combination with other anticancer agents, such as CPT-1 1, a DNA topoisomerase I inhibitor in human colon cancer cells (Motwani, M., et ai, CHn. Cancer Res. 7:4209-4219, (2001)). Therefore, another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis, in combination with at least one known cyclin-dependent kinase inhibitor, or a pharmaceutically acceptable salt of said agent. Examples of known cyclin- dependent kinase inhibitor, which can be used for combination therapy include, but are not limited to, flavopiridol, UCN-01 , roscovitine and olomoucine.

[0094] It has been reported that in preclinical studies COX-2 inhibitors were found to block angiogenesis, suppress solid tumor metastases, and slow the growth of implanted gastrointestinal cancer cells (Blanke, C. D., Oncology (Huntingt) 16 (No. 4 Suppl. 3):17-21 (2002)). Therefore, another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis, in combination with at least one known COX-2 inhibitor, or a pharmaceutically acceptable salt of said inhibitor. Examples of known COX-2 inhibitors that can be used for combination therapy include, but are not limited to, celecoxib, valecoxib, and rofecoxib.

[0095] Another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a bioconjugate of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis, in biocoηjugation with at least one known therapeutically useful antibody, such as Herceptin^® or Rituxan^®, growth factors, such as DGF, NGF; cytokines, such as IL-2, IL-4, or any molecule that binds to the cell surface. The antibodies and other molecules will deliver a compound described herein to its targets and make it an effective anticancer agent. The bioconjugates could also enhance the anticancer effect of therapeutically useful antibodies, such as Herceptin^® or Rituxan^®.

[0096] Similarly, another embodiment of the present invention is directed to a composition effective to inhibit neoplasia comprising a compound, or a pharmaceutically acceptable salt or prodrug of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis, in combination with radiation therapy. In this embodiment, the compound of the invention may be administered at the same time as the radiation therapy is administered or at a different time.

[0097] Yet another embodiment of the present invention is directed to a composition effective for post-surgical treatment of cancer, comprising a compound, or a pharmaceutically acceptable salt or prodrug of a compound described herein, which functions as a caspase cascade activator and inducer of apoptosis. The invention also relates to a method of treating cancer by surgically removing the cancer and then treating the animal with one of the pharmaceutical compositions described herein.

[0098] A wide range of immune mechanisms operates rapidly following exposure to an infectious agent. Depending on the type of infection, rapid clonal expansion of the T and B lymphocytes occurs to combat the infection. The elimination of the effector cells following an infection is one of the major mechanisms for maintaining immune homeostasis. The elimination of the effector cells is regulated by apoptosis. Autoimmune diseases have lately been determined to occur as a consequence of deregulated cell death. In certain autoimmune diseases, the immune system directs its powerful cytotoxic effector mechanisms against specialized cells, such as oligodendrocytes in multiple sclerosis, the beta cells of the pancreas in diabetes mellitus, and thyrocytes in Hashimoto's thyroiditis (Ohsako, S. & Elkon, K.B., Cell Death Differ. 6: 13-21 (1999)). Mutations of the gene encoding the lymphocyte apoptosis receptor Fas/APO-l/CD95 are reported to be associated with defective lymphocyte apoptosis and autoimmune lymphoproliferative syndrome (ALPS), which is characterized by chronic, histologically benign splenomegaly, generalized lymphadenopathy, hypergammaglobulinemia, and autoantibody formation. (Infante, AJ. , et al, J. Pediatr. 733:629-633 (1998) and Vaishnaw, A.K., et al, J. CHn. Invest. 703:355-363 (1999)). It was reported that overexpression of Bcl-2, which is a member of the bcl-2 gene family of programmed cell death regulators with anti-apoptotic activity, in developing B cells of transgenic mice, in the presence of T cell dependent costimulatory signals, results in the generation of a modified B cell repertoire and in the production of pathogenic autoantibodies (Lopez-Hoyos, M., et al, Int. J. MoI. Med. 7:475-483 (1998)). It is therefore evident that many types of autoimmune disease are caused by defects of the apoptotic process. One treatment strategy for such diseases is to turn on apoptosis in the lymphocytes that are causing the autoimmune disease (O'Reilly, L.A. & Strasser, A., Inflamm. Res. 45:5-21 (1999)).

[0099] Fas-Fas ligand (FasL) interaction is known to be required for the maintenance of immune homeostasis. Experimental autoimmune thyroiditis (EAT), characterized by autoreactive T and B cell responses and a marked lymphocytic infiltration of the thyroid, is a good model to study the therapeutic effects of FasL. Batteux, F., et al, (J. Immunol 7(52:603-608 (1999)) reported that by direct injection of DNA expression vectors encoding FasL into the inflamed thyroid, the development of lymphocytic infiltration of the thyroid was inhibited and induction of infiltrating T cells death was observed. These results show that FasL expression on thyrocytes may have a curative effect on ongoing EAT by inducing death of pathogenic autoreactive infiltrating T lymphocytes.

[00100] Bisindolylmaleimide VIlI is known to potentiate Fas-mediated apoptosis in human astrocytoma 1321N1 cells and in Molt-4T cells; both of which were resistant to apoptosis induced by anti-Fas antibody in the absence of bisindolylmaleimide VIII. Potentiation of Fas-mediated apoptosis by bisindolylmaleimide VIII was reported to be selective for activated, rather than non-activated, T cells, and was Fas-dependent. Zhou T., et al, (Nat. Med. 5:42-48 (1999)) reported that administration of bisindolylmaleimide VIII to rats during autoantigen stimulation prevented the development of symptoms of T cell-mediated autoimmune diseases in two models, the Lewis rat model of experimental allergic encephalitis and the Lewis adjuvant arthritis model. Therefore, the application of a Fas-dependent apoptosis enhancer, such as bisindolylmaleimide VIII, may be therapeutically useful for the more effective elimination of detrimental cells and inhibition of T cell-mediated autoimmune diseases. Therefore, an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of the compound of Formulae I- XI, which functions as a caspase cascade activator and inducer of apoptosis, is an effective treatment for autoimmune diseases.

[00101] Psoriasis is a chronic skin disease that is characterized by scaly red patches. Psoralen plus ultraviolet A (PUVA) is a widely used and effective treatment for psoriasis vulgaris. Coven, et al., Photodermatol. Photoimmunol. Photomed. 75:22-27 (1999), reported that lymphocytes treated with psoralen 8-MOP or TMP and UVA, displayed DNA degradation patterns typical of apoptotic cell death. Ozawa, et al., J. Exp. Med. 189:11 1-718 (1999) reported that induction of T cell apoptosis could be the main mechanism by which 312- nm UVB resolves psoriasis skin lesions. Low doses of methotrexate may be used to treat psoriasis to restore a clinically noπnal skin. Heenen, et al., Arch. Dermatol. Res. 290:240-245 (1998), reported that low doses of methotrexate may induce apoptosis and that this mode of action could explain the reduction in epidermal hyperplasia during treatment of psoriasis with methotrexate. Therefore, an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of the compound of Formulae I-XI, which functions as a caspase cascade activator and inducer of apoptosis, is an effective treatment for hyperproliferative skin diseases, such as psoriasis.

[00102] Synovial cell hyperplasia is a characteristic of patients with rheumatoid arthritis (RA). It is believed that excessive proliferation of RA synovial cells, as well as defects in synovial cell death, may be responsible for synovial cell hyperplasia. Wakisaka, et al., CHn. Exp. Immunol. 114: \ 19-128 (1998), found that although RA synovial cells could die via apoptosis through a Fas/FasL pathway, apoptosis of synovial cells was inhibited by proinflammatory cytokines present within the synovium. Wakisaka, et al. also suggested that inhibition of apoptosis by the proinflammatory cytokines may contribute to the outgrowth of synovial cells, and lead to pannus formation and the destruction of joints in patients with RA. Therefore, an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of the compound of Formulae I-Xl, which functions as a caspase cascade activator and inducer of apoptosis, is an effective treatment for rheumatoid arthritis.

[00103] There has been an accumulation of convincing evidence that apoptosis plays a major role in promoting resolution of the acute inflammatory response. Neutrophils are constitutively programmed to undergo apoptosis, thus limiting their pro-inflammatory potential and leading to rapid, specific, and non- phlogistic recognition by macrophages and semi-professional phagocytes (Savill, J., J. Leukoc. Biol. 67:375-380 (1997)). Boirivant, et al, Gastroenterology 116:551-565 (1999), reported that lamina propria T cells, isolated from areas of inflammation in Crohn's disease, ulcerative colitis, and other inflammatory states, manifest decreased CD2 pathway-induced apoptosis. In addition, studies of cells from inflamed Crohn's disease tissue indicate that this defect is accompanied by elevated Bcl-2 levels. Therefore, an effective amount of a compound, or a pharmaceutically acceptable salt or prodrug of the compound of Formulae I-XI, which functions as a caspase cascade activator and inducer of apoptosis, is an effective treatment for inflammation.

100104] Caspase cascade activators and inducers of apoptosis may also be a desirable therapy in the elimination of pathogens, such as HIV, Hepatitis C and other viral pathogens. The long lasting quiecence, followed by disease progression, may be explained by an anti-apoptotic mechanism of these pathogens leading to persistent cellular reservoirs of the virions. It has been reported that HIV- 1 infected T leukemia cells or peripheral blood mononuclear cells (PBMCs) underwent enhanced viral replication in the presence of the caspase inhibitor Z-VAD-fmk. Furthermore, Z-VAD-fmk also stimulated endogenous virus production in activated PBMCs derived from HIV-I- infected asymptomatic individuals (Chinnaiyan, A., et al., Nat. Med. 3:333 (1997)). Therefore, apoptosis serves as a beneficial host mechanism to limit the spread of HIV and new therapeutics using caspase/apoptosis activators are useful to clear viral reservoirs from the infected individuals. Similarly, HCV infection also triggers anti-apoptotic mechanisms to evade the host's immune surveillance leading to viral persistence and hepatocarcinogenesis (Tai, D. I., et al. Hepatology 3:656-64 (2000)). Therefore, apoptosis inducers are useful as therapeutics for HIV and other infectious disease.

(00105] Stent implantation has become the new standard angioplasty procedure. However, in-stent restenosis remains the major limitation of coronary stenting. New approaches have been developed to target pharmacological modulation of local vascular biology by local administration of drugs. This allows for drug applications at the precise site and time of vessel injury. Numerous pharmacological agents with antiproliferative properties are currently under clinical investigation, including actinomycin D, rapamycin or paclitaxel coated stents (Regar E., et al., Br. Med. Bull. 59:227- 248 (2001)). Therefore, apoptosis inducers, which are antiproliferative, are useful as therapeutics for the prevention or reduction of in-stent restenosis.

[00106] Pharmaceutical compositions within the scope of this invention include all compositions wherein the compounds of the present invention are contained in an amount that is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art. Typically, the compounds may be administered to animals, e.g., mammals, orally at a dose of 0.0025 to 50 mg/kg of body weight, per day, or an equivalent amount of the pharmaceutically acceptable salt thereof, to a mammal being treated. Preferably, approximately 0.01 to approximately 10 mg/kg of body weight is orally administered. For intramuscular injection, the dose is generally approximately one-half of the oral dose. For example, a suitable intramuscular dose would be approximately 0.0025 to approximately 25 mg/kg of body weight, and most preferably, from approximately 0.01 to approximately 5 mg/kg of body weight. If a known cancer chemotherapeutic agent is also administered, it is administered in an amount that is effective to achieve its intended purpose. The amounts of such known cancer chemotherapeutic agents effective for cancer are well known to those skilled in the art.

[00107] The unit oral dose may comprise from approximately 0.01 to approximately 50 mg, preferably approximately 0.1 to approximately 10 mg of the compound of the invention. The unit dose may be administered one or more times daily, as one or more tablets, each containing from approximately 0.1 to approximately 10 mg, conveniently approximately 0.25 to 50 mg of the compound or its solvates.

[00108] In a topical formulation, the compound may be present at a concentration of approximately 0.01 to 100 mg per gram of carrier.

|00109] In addition to administering the compound as a raw chemical, the compounds of the invention may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the compounds into preparations that may be used pharmaceutically. Preferably, the preparations, particularly those preparations which may be administered orally and that may be used for the preferred type of administration, such as tablets, dragees, and capsules, and also preparations that may be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, contain from approximately 0.01 to 99 percent, preferably from approximately 0.25 to 75 percent of active compound(s), together with the excipient.

[00110] Also included within the scope of the present invention are the nontoxic pharmaceutically acceptable salts of the compounds of the present invention. Acid addition salts are formed by mixing a solution of the compounds of the present invention with a solution of a pharmaceutically acceptable non-toxic acid, such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, and the like. Basic salts are formed by mixing a solution of the compounds of the present invention with a solution of a pharmaceutically acceptable non-toxic base, such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, Tris, /V-methyl- glucamine and the like.

[00111] The pharmaceutical compositions of the invention may be administered to any animal, which may experience the beneficial effects of the compounds of the invention. Foremost . among such animals are mammals, e.g., humans and veterinary animals, although the invention is not intended to be so limited.

[00112] The pharmaceutical compositions of the present invention may be administered by any means that achieve their intended purpose. For example, administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdeπnal, buccal, intrathecal, intracranial, intranasal or topical routes. Alternatively, or concurrently, administration may be by the oral route. The dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.

[00113] The pharmaceutical preparations of the present invention are manufactured in a manner, which is itself known, e.g., by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Thus, pharmaceutical preparations for oral use may be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.

[00114] Suitable excipients are, in particular: fillers, such as saccharides, e.g. lactose or sucrose, mannitol or sorbitol; cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate; as well as binders, such as starch paste, using, e.g., maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, disintegrating agents may be added, such as the above-mentioned starches and also carboxymethyl -starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, above all, flow-regulating agents and lubricants, e.g., silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxy- propylmethyl-cellulose phthalate, are used. Dye stuffs or pigments may be added to the tablets or dragee coatings, e.g., for identification or in order to characterize combinations of active compound doses.

[00115] Other pharmaceutical preparations, which may be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the active compounds in the form of: granules, which may be mixed with fillers, such as lactose; binders, such as starches; and/or lubricants, such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers may be added.

[00116] Possible pharmaceutical preparations, which may be used rectally include, e.g., suppositories, which consist of a combination of one or more of the active compounds with a suppository base. Suitable suppository bases are, e.g., natural or synthetic triglycerides, or paraffin hydrocarbons. In addition, it is also possible to use gelatin rectal capsules, which consist of a combination of the active compounds with a base. Possible base materials include, e.g., liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

[00117] Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, e.g., water-soluble salts and alkaline solutions. In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or vehicles include fatty oils, e.g., sesame oil, or synthetic fatty acid esters, e.g., ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400), or cremophor, or cyclodextrins. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension include, e.g., sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers.

[00118] In accordance with one aspect of the present invention, compounds of the invention are employed in topical and parenteral formulations and are used for the treatment of skin cancer.

[00119] The topical compositions of this invention are formulated preferably as oils, creams, lotions, ointments and the like by choice of appropriate carriers. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than Cn). The preferred carriers are those in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included, as well as agents imparting color or fragrance, if desired. Additionally, transdermal penetration enhancers may be employed in these topical formulations. Examples of such enhancers are found in U.S. Patent Nos. 3,989,816 and 4,444,762.

[00120] Creams are preferably formulated from a mixture of mineral oil, self- emulsifying beeswax and water in which mixture of the active ingredient, dissolved in a small amount of an oil, such as almond oil, is admixed. A typical example of such a cream is one which includes approximately 40 parts water, approximately 20 parts beeswax, approximately 40 parts mineral oil and approximately 1 part almond oil.

[00121] Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm soft paraffin and allowing the mixture to cool. A typical example of such an ointment is one which includes approximately 30 % almond oil and approximately 70 % white soft paraffin by weight.

[00122] The following examples are illustrative, but not limiting, of the method and compositions of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in clinical therapy and which are obvious to those skilled in the art are within the spirit and scope of the invention.

EXAMPLE 1

N-(4-Methoxyphenyl)-3,6-dimethylisoxazolo[5,4-(f]pyrimidin-4-amine

(00123] a) 4-Chloro-3,6-dimethylisoxazolo[5,4-<f]pyrimidine. To an oven- dried 100 mL one-neck round bottomed flask charged with a magnetic stir bar at room temperature (rt) under argon was added distilled phosphorous oxychloride (40 mL) and N,N-dimethyl acetamide (1 mL) and the solution was stirred at rt for 1 h. To the solution was added 5-amino-3-methylisoxazole-4- carbonitrile (451 mg, 3.66 mmol) and the mixture was heated at 160°C for 36 h. The reaction mixture was cooled to rt and evaporated under reduced pressure to give a brown solid.

[00124] b) N-(4-Methoxyphenyl)-3,6-dimethylisoxazolo[5,4-cT]pyrimidin-4- amine. To the above crude product was added isopropanol (15 mL) and p- anisidine (800 mg, 6.5 mmol) and the mixture was heated at 90°C for 4 h. The resulting solution was cooled to rt, diluted with ethyl acetate (100 mL) and washed with saturated NaHCO₃ (80 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by chromatography (60-65% ethyl acetate/hexane) to give the title compound (140 mg, 14% two steps) as a solid. ¹H NMR (CDCl₃) 11.85 (s, IH), 6.97 (m, 2H), 6.82 (m, 2H), 3.78 (s, 3H), 2.73 (s, 3H), 2.07 (s, 3H). EXAMPLE 2

yV-(4-Methoxyphenyl)-3-methylisoxazolo[5,4-c/]pyrimidin-4-amine

[00125| a) (E)-5-(2-(Dimethylamino)ethylideneamino)-3-methylisoxazole-4- carbonitrile. A mixture of 5-amino-3-methylisoxazole-4-carbonitrile (1.0 g, 8.1 mmol), dimethylformamide dimethyl acetal (5 mL) was heated in a sealed tube for 2 h at 13O⁰C. Upon cooling to rt the reaction mixture was left overnight. The off-white precipitate was collected by filtration, washed with cold diethyl ether and dried under vacuum to obtain the title compound (1.3 g, 90%). ¹H NMR (CDCl₃) 8.23 (s, IH), 3.20 (s, 3H)₃ 3.17 (s, 3H), 2.30 (s, 3H).

[00126] b) //-(4-Methoxyphenyl)-3-methylisoxazolo[5,4-(i]pyrimidin-4-amine.

A mixture of (E)-5-(2-(dimethylamino)ethylideneamino)-3-methylisoxazole- 4-carbonitrile (93 mg, 0.52 mmol), /λ-anisidine (77 mg, 0.62 mmol), acetonitrile (2 mL) and glacial acetic acid (0.6 mL) was microwaved (160°C, 100 Watts, 40 min) in a Discover reactor. The resulting solution was cooled to rt, diluted with ethyl acetate (50 mL) and washed with saturated NaHCO₃ (50 mL x 3). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by chromatography (45% ethyl acetate/hexane) to give the title compound (28 mg, 21%). ¹H NMR (CDCl₃) 7.38 (m, 2H), 7.06 (s, IH), 6.86 (m, 2H), 3.79 (s, 3H), 2.16 (s, 3H). EXAMPLE 3

N-(3,5-Dimethoxyphenyl)-3-methylisoxazolo[5,4-c/]pyrimidin-4-amine

[00127] a) 3-Methylisoxazolo[5,4-<f]pyrimidin-4-ol. To an oven-dried one- neck round bottomed flask charged with a magnetic stir bar at rt under argon was added 5-amino-3-methylisoxazole-4-carboxamide (1.0 g, 7.1 mmol), acetic anhydride (7 mL) and triethylorthoformate (7 niL) and the mixture was refluxed for 3 h (oil bath at 160°C). The resulting light orange solution was cooled to rt, evaporated to dryness and the residue was dissolved in minimum amount of concentrated ammonium hydroxide. The solution was acidified with glacial acetic acid and the mixture was cooled overnight in the refrigerator to obtain the title compound as an off-white solid (0.39 g, 34%). 1H NMR (DMSOd₆) 8.36 (s, IH), 3.18 (s, IH), 2.48 (s, 3H).

[00128] b) 4-Chloro-3-methylisoxazolo[5,4-c/]pyrimidine. To an oven-dried one-neck round bottomed flask charged with a magnetic stir bar at rt under argon was added 3-methylisoxazolo[5,4-c/]pyrimidin-4-ol (470 mg, 3.1 1 mmol) and phosphorous oxychloride (40 mL) and the mixture was heated at 100°C for 4 h. The excess phosphorous oxychloride was evaporated under vacuum and the residue was dissolved in ethyl acetate (80 mL). The solution was washed with saturated NaHCO₃, the organic layer was dried over Na₂SO₄, filtered and concentrated to obtain title compound as a light brown solid (450 mg, 85%). ¹H NMR (CDCl₃) 8.84 (s, IH), 2.78 (s, 3H).

[00129] c) Λ^-(3,5-Dimethoxyphenyl)-3-methylisoxazolo[5,4-<i]pyrimidin-4- amine. A mixture of 4-chloro-3-methylisoxazolo[5,4-</]pyrimidine (65 mg, 0.38 mmol), 3,5-dimethoxybenzenamine (125 mg, 0.82 mmol), triethylamine (0.3 mL, 2.2 mmol) and isopropanol (3 mL) was heated at 75°C for 3 h. The reaction mixture was cooled to rt and evaporated to dryness. The residue was purified by chromatography (25-30% ethyl acetate/hex ane) to give the title compound (28 mg, 26%). ¹H NMR (CDCl₃) 8.62 (s, IH), 6.88 (s, IH), 6.83 (d, 2H, J= 1.8), 6.34 (t, IH, J- 1.8), 3.82 (s, 6H), 2.66 (s, 3H).

EXAMPLE 4

3-Methyl-N-(3-methyl-lH-pyrazol-5-yl)isoxazolo[5,4-<fJpyrimidin-4-amine

[00130| The title compound was prepared in a manner similar to example 3c.

From 4-chloro-3-methylisoxazolo[5,4-c/]pyrimidine (70 mg, 0.42 mmol) and 3-methyl-lH-pyrazol-5-amine (72 mg, 0.74 mmol) was obtained the title compound as a solid (28 mg, 25%). ¹H NMR (DMSOd₆) 9.78 (s, IH), 8.55 (s, IH), 6.44 (s, IH), 2.64 (s, 3H), 2.29 (s, 3H).

EXAMPLE 5

N-(3-Bromophenyl)-3-methylisoxazolo[5,4-c/]pyrimidin-4-amine

[00131] The title compound was prepared in a manner similar to example 3c.

From 4-chloro-3-methylisoxazolo[5,4-d]pyrimidine (107 mg, 0.60 mmol) and 3-bromoaniline (93 mg, 0.54 mmol) was obtained the title compound as a solid (28 mg, 17%). ¹H NMR (CDCl₃): 7.79 (s, IH), 7.40 (d, IH, J = 7.8), 7.14 - 7.25 (m, 3H), 2.18 (s, 3H).

EXAMPLE 6

yV-(4-Methoxyphenyl)-N,3-dimethylisoxazolo[5,4-(f]pyrimidin-4-amine

|00132) A mixture of 4-chloro-3-methylisoxazolo[5,4-J]pyrimidine (105 mg,

0.619 mmol), N-methyl-p-anisidine (102 mg, 0.74 mmol), diisopropylethylamine (300 uL) and THF (2.5 mL) was heated in a sealed tube for 2 days at 140°C. Upon cooling white precipitates formed which was removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by chromatography (20-30% ethyl acetate/hex an e) to give the title compound as an off-white solid (142 mg, 85 %). ¹ H NMR (CDCl₃) 8.59 (s, IH), 7.22 (d, 2H, J = 9.0), 6.98 (d, 2H, J= 8.7), 3.85 (s, 3H), 3.56 (s, 3H), 1.37 (s, 3H).

EXAMPLE 7

W-(4-Methoxyphenyl)-iV,3,6-trimethylisoxazolo[5,4-cf]pyrimidin-4-amine

[00133] a) 3,6-Dirnethylisoxazolo[5,4-c/]pyrimidin-4-ol. A mixture of 5- amino-3-methylisoxazole-4-carboxamide (200 mg, 1.42 mmol), triethyl orthoacetate (3 mL) and acetic anhydride (3 mL) was microwaved (170°C, 80 Watts, 40 min) in a Discover reactor. Upon cooling to rt, precipitated product was collected by filtration, washed with cold ether and dried under vacuum

(98 mg, 42%). ¹H NMR (DMSO-d₆) 3.28 (s, IH), 2.44 (s, 3H), 2.41 (s, 3H). [00134) b) 4-Chloro-3,6-dimethylisoxazolo[5,4-<f]pyrimidine. The title compound was prepared in a manner similar to example 3b. ¹H NMR

(CDCl₃): 2.85 (s, 3H), 2.72 (s, 3H). [00135] c) N-(4-Methoxyphenyl)-//,3,6-trimethylisoxazolo[5,4-t/]pyrimidin-4- amine. The title compound was prepared in a manner similar to example 6.

¹H NMR (CDCl₃) 7.20 (d, 2H, J = 9.0), 6.96 (d, 2H, J = 9.0), 3.85 (s, 3H),

3.53 (s, 3H), 2.66 (s, 3H), 1.33 (s, 3H).

EXAMPLE 8

/V-(2,5-Dimethoxyphenyl)-2,5-dimethyloxazolo[5,4-(f]pyrimidin-7-amine

[00136] a) 2,5-Dimethyloxazolo[5,4-<f]pyrimidin-7-ol. A mixture of 5-amino-2- methylpyrimidine-4,6-diol (0.5 g, 3.54 mmol) and acetic anhydride (8 mL, 39.8 mmol) in a 15 mL sealed tube was heated overnight at 12O⁰C. Upon cooling to room temperature the product solidified. The reaction mixture was diluted with diethylether and the product was collected by filtration (0.308 g, 53%). ¹H NMR (DMSO-(Z₆) 3.34 (s, IH), 2.51 (s, 3H), 2.39 (s, 3H).

[00137] b) 7-Chloro-2,5-dimethyloxazolo[5,4-c/]pyrimidine. To an oven-dried one-neck round bottomed flask charged with a magnetic stir bar at rt under argon was added 2,5-dimethyloxazolo[5,4-cf]pyrimidin-7-ol (0.300 g, 1.82 mmol), anhydrous toluene (15 mL), Λ^N-dimethylaniline (1.0 mL) and distilled phosphorous oxychloride (1.9 mL, 20.7 mmol), and the suspension was heated at 120°C for 45 min and then at 8O⁰C for 3 h. The reaction mixture was cooled to rt, concentrated under vacuum and the residue was dissolved in ethyl acetate (80 mL). The solution was washed with saturated NaHCO₃, IN citric acid (50 mL x 3), water and saturated NaHCO₃ and the organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by chromatography (10-20% ethyl acetate/hexane) to give the title compound as a yellow solid (0.264 g, 79%). ¹H NMR (CDCl₃) 2.81 (s, 3H), 2.73 (s, 3H).

|00138| c) /V-(2,5-Dimethoxyphenyl)-2,5-dimethyloxazolo[5,4-<f]pyrimidin-7- amine. A mixture of 7-chloro-2,5-dimethyloxazolo[5,4-J]pyrimidine (102 mg, 0.56 mmol), 2,5-dimethoxybenzenamine (178 mg, 1.2 mmol), diisopropylethyl amine (0.3 mL) and THF (2.5 mL) was microwaved (140°C, 40 Watts, 30 min) in a Discover reactor. The reaction mixture was cooled to rt and evaporated to dryness. The residue was purified by chromatography (30- 35% ethyl acetate/hexane) to give the title compound (43 mg, 26%). ¹H NMR (CDCl₃) 8.57 (d, I H, J= 3.0), 7.99 (s, IH), 6.83 (d, I H, J= 9.0), 6.57 (dd, I H, J= 8.7, 3.0), 3.91 (s, 3H), 3.85 (s, 3H), 2.71 (s, 3H), 2.65 (s, 3H).

EXAMPLE 9

/V-(3,5-Dimethoxyphenyl)-2,5-dimethyloxazolo[5,4-c/]pyrimidin-7-amine

[00139] The title compound was prepared in a manner similar to example 8c.

From 7-chloro-2,5-dimethyloxazolo[5,4-(/]pyrimidine (100 mg, 0.54 mmol) and 3,5-dimethoxy aniline (180 mg, 1.2 mmol) was obtained the title compound as a solid (124 mg, 76%). ¹H NMR (CDCl₃) 7.29 (s, IH), 7.07 (d, 2H, J = 2.1 ), 6.25 (t, IH, J= 2.7), 3.83 (s, 6H), 2.69 (s, 3H), 2.64 (s, 3H). EXAMPLE 10

N-(3-Bromophenyl)-2,5-dimethyloxazolo[5,4-<f]pyrimidin-7-amine

[00140] The title compound was prepared in a manner similar to example 8.

From 7-chloro-2,5-dimethyloxazolo[5,4-{f|pyrirnidine (102 mg, 0.56 mmol) and 3-bromoaniline (200 mg, 1 .2 mmol) was obtained the title compound as a solid (53 mg, 30%). ¹H NMR (CDCl₃) 8.12 (m, I H), 7.61 - 7.68 (m, I H), 7.31 (s, IH), 7.23 - 7.26 (m, 2H), 2.70 (s, 3H), 2.64 (s, 3H).

EXAMPLT 1 1

/Y-(4-Methoxyphenyl)-N,2,5-trimethyloxazolo[5,4-c/]pyrimidin-7-amine

[00141] A mixture of 7-chloro-2,5-dimethyloxazolo[5,4-</]pyrimidine (40 mg,

0.217 mmol), /Y-methyl-p-anisidine (43 mg, 0.31 mmol), sodium acetate (40 mg, 0.48 mmol) THF (1.5 mL) and water (1.5 mL) in a 15 mL sealed tube was heated at 80°C for 4 h. The reaction mixture was cooled to rt and diluted with ethyl acetate (70 mL). The organic layer was washed with saturated NaHCO₃ and dried over anhydrous Na₂SO₄, filtered and concentrated. The crude product was purified by flash column chromatography (25% ethyl acetate /hexanes) to give the title compound (38 mg, 61 %). ¹H NMR (CDCl₃) 7.18 — 7.22 (m, 2H), 6.91 - 6.97 (m, 2H), 3.86 (s, 3H), 3.70 (s, 3H), 2.55 (s, 3H), 2.44 (s, 3H).

EXAMPLE 12

Λ/-(2,5-Dimethoxyphenyl)-2-methyloxazolo[5,4-rf]pyi'imidin-7-amine

[00142] a) 2-Methyloxazolo[5,4-tf]pyrimidin-7-ol. The title compound was prepared in a manner similar to example 8a. From 5-aminopyrimidine-4,6-diol (2.0 g, 15.7 mmol) and acetic anhydride (18 niL) was obtained the title compound as a solid (1.2 g, 50%). ¹H NMR (DMSCW₆) 8.13 (s, IH), 2.54 (s, 3H).

[00143] b) 7-Chloro-2-methyloxazolo[5,4-ύT]pyrirnidine. The title compound was prepared in a manner similar to example 8b. ¹H NMR (CDCl₃) 8.78 (s, IH), 2.77 (s, 3H).

[00144] c) /V-(2,5-Dimethoxyphenyl)-2-methyloxazolo[5,4-cTlpyrimidin-7- amine. The title compound was prepared in a manner similar to example 8c. From 7-chloro-2-methyloxazolo[5,4-G?]ρyrimidine (81 mg, 0.48 mmol) and 2,5-dimethoxybenzenamine (160 mg, 1.0 mmol) was obtained the title compound as a yellow solid (44 mg, 32%). ¹H NMR (CDCl₃) 8.55 (s, IH), 8.48 (d, IH, J= 3.0), 8.04 (s, IH), 6.85 (d, IH, J= 9.0), 6.58 (dd, IH, J= 8.7, 3.0), 3.92 (s, 3H), 3.84 (s, 3H), 2.68 (s, 3H). EXAMPLE 13

yV-(3,5-Dimethoxyphenyl)-2-methyloxazolo[5,4-rf]pyrimidin-7-amine

(00145] The title compound was prepared in a manner similar to example 8c.

¹H NMR (CDCl₃) 8.53 (s, I H), 7.33 (s, IH), 7.01 (d, 2H, J = 2.1), 6.27 (t, IH, J= 2.4), 3.83 (s, 6H), 2.67 (s, 3H).

EXAMPLE 14

N-(3-Bromophenyl)-2-methyloxazolo[5,4-</jpyrimidin-7-amine

(001461 The title compound was prepared in a manner similar to example 8c.

¹H NMR (CDCl₃) 8.56 (s, IH), 8.10 (m, IH), 7.61 (dt, 2H, J = 6.3, 2.7), 7.43 (s, IH), 7.25 (m, 2H), 2.68 (s, 3H). EXAMPLE 15

Λ^(Benzo[<:/][l,3]dioxol-5-yl)methyl)-2φhenyloxazolo[5,4</]pyrimidin-7- amine

[00147] a) 2-Phenyloxazolo[5,4-<i]pyrimidin-7-ol. A solution of 5- aminopyrimidine-4,6-diol (1.0 g, 7.87 mmol) and benzoic anhydride (9.0 g, 39.8 mmol) in a 75 mL sealed tube was heated at 18O⁰C for 1 h. Upon cooling to room temperature the product solidified. The reaction mixture was diluted with diethylether and the product was collected by filtration (0.802 g, 67%). 1H NMR (DMSO-J₆) 8.29 (s, I H), 8.11 (m, 2H), 7.61 (m, 3H).

|00148] b) 7-Chloro-2-phenyloxazolo[5,4-<f)pyrimidine. The title compound was prepared in a manner similar to example 8b. From 2-phenyloxazolo[5,4- J]pyrimidin-7-ol (0.602 g, 3.98 mmol) was obtained the title compound as a light yellow solid (258 mg, 28%). ¹H NMR (CDCl₃) 8.81 (s, IH), 8.32 (m, 2H), 7.61 (m, 3H).

[00149] c) N-((Benzo[<f][l,3]dioxol-5-yl)methyl)-2-phenyloxazolo[5,4-

<:/]pyrimidin-7-amine. The title compound was prepared in a manner similar to example 3c. From 7-chloro-2-phenyloxazolo[5,4-c/]pyrimidine (170 mg, 0.73 mmol) and (benzo[cf|[l,3]dioxol-5-yl)methanamine (100 mg, 0.66 mmol) was obtained the title compound (200 mg, 88%). ¹H NMR (CDCl₃) 8.46 (s, IH), 8.16 (m, 2H), 7.52 (m, 3H), 6.78 - 6.91 (m, 3H), 5.96 (s, 2H), 4.78 (s, IH). EXAMPLE 16

yV-(3-Methyl-l//-pyrazol-5-yl)-2-phenyloxazolo[5,4-c/]pyrimidin-7-amine

[0015OJ The title compound was prepared in a manner similar to example 3c.

From 7-chloro-2-phenyloxazolo[5,4-f/]pyrimidine (45 mg, 0.19 mmol) and 3- methyl-lH-pyrazol-5-amine (35 mg, 0.36 mmol) was obtained the title compound as a solid (29 mg, 45%). ¹H NMR (DMSCM₆): 10.31 (s, IH), 8.17 (m, 2H), 7.65 (m, 3H), 6.86 (s, IH), 2.25 (s, 3H).

EXAMPLE 17

jV-(3-Bromophenyl)-2-phenyloxazolo[5,4-c/]pyrimidin-7-amine

[00151] The title compound was prepared in a manner similar to example 3c.

From 7-chloro-2-phenyloxazolo[5,4-<f]pyrimidine (25 mg, 0.108 mmol) and 3- bromo aniline (75 mg, 0.44 mmol) was obtained the title compound (25 mg, 58%). ¹H NMR (DMSO-J₆) 10.53 (s, IH), 8.57 (s, IH), 8.3 (t, IH, J = 2.1), 8.21 (m, 2H), 7.91 (dt, I H, J - 8.1 , 1.5), 7.62 - 7.69 (m, 3H), 7.26 - 7.34 (m, 2H). EXAMPLE 18

2,5-Dimelhyl-N-(3-methyl-l//-pyrazol-5-yl)oxazolo[5,4-(/jpyrimidin-7-amine

[00152] The title compound was prepared in a manner similar to example 3c.

From 7-chloro-2,5-dimethyloxazolo[5,4-<fJpyrimidine (97 mg, 0.108 mmol) and 3-methyl-lH-pyrazol-5-amine (125 mg, 1.29 mmol) was obtained the title compound (45 mg, 28%). ¹H NMR (DMSCM₆) 12.20 (s, I H), 6.28 (s, IH), 2.35 (s, 3H), 2.32 (s, 3H), 2.30 (s, 3H).

EXAMPLE 19

N-(4-(2,5-Dimethyloxazolo[5,4-(/jpyrimidin-7-ylamino)phenyl)benzamide

[00153] The title compound was prepared in a manner similar to example 2b.

From 7-chloro-2,5-dimethyloxazolo[5,4-rf]pyrimidine (30 mg, 0.17 mmol) and N-(4-aminophenyl)benzamide (1 10 mg, 0.52 mmol) was obtained the title compound as a white solid (30 mg, 48%). ¹H NMR (DMSO-^₆) 12.10 (s, IH), 10.52 (s, IH), 7.98 (m, 4H), 7.57 (m, 3H), 7.45 (m, 2H), 2.32 (s, 3H), 2.29 (s, 3H). EXAMPLE 20

2-Methyl-N-(3-methyl-lH-pyrazol-5-yl)oxazolo[5,4-c/]pyrimidin-7-amine

(001541 The title compound was prepared in a manner similar to example 3c.

From 7-chloro-2-methyloxazolo[5,4-<f]pyrimidine (40 mg, 0.235 mmol) and 3- methyl-lH-pyrazol-5-amine was obtained the title compound (70 mg). ¹H NMR (DMSCW₆) 7.95 (s, IH), 6.31 (s, IH), 2.41 (s, 3H), 2.32 (s, 3H).

EXAMPLE 21

N-(3,5-Dimethoxyphenyl)thiazolo[5,4-f/]pyrimidin-7-amine

[00155] a) S-Amino-ό-chloropyrimidine^-thiol. To a clear solution of sodium hydrosulfide (2.1 g, 23 mmol) in water (3 mL) was added 5-amino-4,6- dichloropyrimidine (3.5 g, 21 mmol) and methanol (30 mL), and the mixture was re fluxed for 4 h. It was evaporated and to the residue was added EtOAc (30 mL) and saturated aqueous ammonium chloride (50 mL). The organic layer was separated and dried, concentrated and purified by column chromatography (Hexane/EtOAc 3:1) to give 3.2 g (92%) of the title compound.

[00156] b) 7-Chlorothiazolo[5,4-</]pyrimidine. A mixture of 5-amino-6- chloropyrimidine-4-thiol (1.6 g, 10 mmol) in triethoxymethane (30 mL) was refluxed for 1 h. It was cooled to rt and the brown crystal was collected by filtration and to give 0.90 g of the title compound (53%). ¹H NMR (CDCl₃) 9.22 (s, I H), 8.88 (s, IH).

[00157] c) yV-(3,5-Dimethoxyphenyl)thiazolo[5,4-f/]pyrimidin-7-amine. The title compound was prepared in a manner similar to example Ib. From 7-chlorothiazolo[5,4-c/]pyrimidine (150 mg, 0.87 mmol) and 3,5- dimethoxyaniline (133 mg, 0.87 mmol) was obtained 120 mg (48%) of the title compound as a solid. ¹H NMR (CDCl₃) 8.89 (s, IH), 8.68 (s, IH), 8.02 (bs, I H), 7.09 (s, 2H), 6.28 (bs, IH), 3.84 (s, 6H).

EXAMPLE 22

N-(3-Bromophenyl)thiazolo[5,4-(i]pyrimidin-7-amine

[00158] The title compound was prepared in a manner similar to example Ib.

From 7-chlorothiazolo[5,4-flT)pyrimidine (120 mg, 0.70 mmol) and 3- bromoaniline (120 mg, 0.70 mmol) was obtained 127 mg (59%) of the title compound as a solid. ¹H NMR (CDCl₃) 8.91 (s, IH), 8.71 (s, IH), 8.19 (s, IH), 8.03 (bs, IH), 7.70 (m, IH), 7.29-7.26 (m, 2H).

EXAMPLE 23

Λ^-(2,5-Dimethoxyphenyl)thiazolo[5,4-JJpyrimidin-7-amine

[00159] The title compound was prepared in a manner similar to example Ib.

From 7-chlorothiazolo[5,4-c/]pyrimidine (140 mg, 0.82 mmol) and 2,5- dimethoxyaniline (125 mg, 0.82 mmol) was obtained 68 mg (29%) of the title compound as a solid. ¹H NMR (CDCl₃) 8.90 (s, IH), 8.88 (bs, IH), 8.69 (s, IH), 8.57 (bs, IH), 6.88 (d, J = 9.0 Hz, IH), 6.60 (d, J = 9.0 Hz, IH), 3.94 (s, 3H), 3.85 (s, 3H).

EXAMPLE 24

N-(3-M ethyl- lH-pyrazol-5-yl)thiazolo[5,4-</]pyrimidin-7-amine

[00160] The title compound was prepared in a manner similar to example Ib.

From 7-chlorothiazolo[5,4-c/]pyrimidine (62 mg, 0.36 mmol) and 5-methyl- lH-pyrazol-3 -amine (70 mg, 0.72 mmol) was obtained 80 mg (96%) of the title compound as a solid. ¹H NMR (DMSOd₆) 12.30 (bs, IH), 10.05 (bs, IH), 9.50 (bs, IH), 8.70 (bs, IH), 6.65 (bs, IH), 2.38 (s, 3H). EXAMPLE 25

/V-(4-(Thiazolo[5,4-(/Jpyrimidin-7-ylamino)phenyl)benzamide

[00161] A mixture of 7-chlorothiazolo[5,4-JJpyrimidine (69 mg, 0.40 mmol),

/V-(4-aminophenyl)benzamide (85 mg, 0.40 mmol) in DMF (2 mL) was heated at 16O⁰C for 4 h. It was cooled to rt and to the solution was added ethyl acetate (30 mL) and water (30 mL). The precipitate was collected by filtration to give 75 mg (54%) of the title compound as a solid. ¹H NMR (DMSO-^₆) 10.55 (s, I H), 10.27 (s, 2H), 10.21 (s, 2H), 9.40 (s, I H), 8.80 (s, IH), 8.25 (bs, IH), 8.05-7.50 (m, 5H). 7.89-7.85 (m, 3H), 7.61 (bs, 4H), 7.49-7.40 (m, 2H).

EXAMPLE 26

N-(4-Methoxyphenyl)-N-methylthiazolo[5,4-rf]pyrimidin-7-amine

(00162] The title compound was prepared in a manner similar to example Ib.

From 7-chlorothiazolo[5,4-<fJpyrimidine (0.15 g, 0.87 mmol) and TV-methyl-4- methoxyaniline (0.14 g, 1.0 mmol) was obtained 0.15 g (63%) of the title compound as a solid. ¹H NMR (CDCl₃) 8.58 (s, IH), 8.53 (s, IH), 7.20 (d, J = 9.0 Hz, 2H), 6.96 (d, J= 9.0 Hz, IH), 3.85 (s, 3H), 3.79 (s, 3H). EXAMPLE 27

5-Methyl-/V-(3-methyl-lH-pyrazol-5-yl)thiazolo[5,4-(flpyrimidin-7-amine

100163] a) 5-Amino-6-chloro-2-methyl-pyrimidine-4-thiol. The title compound was prepared in a manner similar to example 17a. From sodium hydrosulfide (2.64 g, 30 mmol) and 5-amino-4,6-dichloro-2-methylpyrimidine (4.45 g, 25 mmol) was obtained 0.51 g (12%) of the title compound.

[00164] b) 7-Chloro-5-methylthiazolo[5,4-<fJpyrimidine. The title compound was prepared in a manner similar to example 21b. From 5-amino-6- chloropyrimidine-4-thiol (0.18 g, 1.0 mmol) in triethoxymethane (10 mL) was obtained 66 mg of the title compound (35%). ¹ H NMR (CDCl₃) 9.09 (s, I H), 2.86 (s, 3H).

(00165] c) 5-Methyl-yV-(3-methyl-lH-pyrazol-5-yl)thiazolo[5,4-rf]pyrimidin-7- amine. The title compound was prepared in a manner similar to example 8c. From 7-chloro-5-methylthiazolo[5,4-tf]pyrimidine (40 mg, 0.22 mmol) and 3- methyl-lH-pyrazol-5-amine (42 mg, 0.43 mmol) was obtained 15 mg (28%) of the title compound as a solid. ¹H NMR (DMSO-J₆) 13.65 (bs, IH), 12.95 (bs, IH), 8.49 (s, IH), 6.54 (s, IH), 2.51 (s, 3H), 2.33 (s, 3H).

EXAMPLE 28

N-(3,5-Dimethoxyphenyl)-5-methylimidazo[5,l-/J[l ,2,4]triazin-4-amine

[001661 a) Ethyl l-amino^-methyl-l/Z-imidazole-S-carboxylate. To an oven- dried three-neck reaction flask charged with a magnetic stir bar, an internal thermometer at rt under argon was added ethyl 4-methyl-lH-imidazole-5- carboxylate (2.20 g, 14.3 mmol) and anhydrous DMF (71 mL). The yellow solution was cooled to -20°C using a dry ice and EtOAc bath. Lithium hexamethyldisilane (1.0M in TΗF, 15.7 mL, 15.7 mmol) was then added dropwise via an addition funnel while maintaining the internal temperature below -12°C. To the solution was then added o-(diphenylphosphinyl)- hydroxylamine (4.00 g, 17.1 mmol) in two portions while maintaining the internal temperature at O⁰C. The resulting white suspension was diluted by the addition of DMF (15 mL) and stirred at rt overnight. The white suspension was quenched with water (5 mL) and the solvent was removed under vacuum. The resulting yellow solid was extracted with CH₂Cl₂ (50 mL), EtOAc (100 mL) and then the organic extracts were combined and concentrated by rotary evaporation to a brown solid. It was purified by flash column chromatography (80 g pre-packed silica gel column, gradient elution with CH₂Cl₂, to CH₂Cl₂:Me0H, 4:96) to give 1.00 g (41%) of the title compound as a white solid. ¹H NMR (CDCl₃) 7.59 (s, I H), 5.32 (br s, 2H), 4.36 (q, J= 7.1 Hz, 2H), 2.45 (s, 3H), 1.40 (t, J= 7.0 Hz, 3H).

[001671 b) 5-Methyl-3H-imidazo[ l ,5-y][l,2,4]triazin-4-one. To an oven-dried sealed reaction flask with a magnetic stir bar at rt was added ethyl 1 -amino-4- methyl-l f/-imidazole-5-carboxylate (0.500 g, 2.96 mmol) and formamide (5.87 niL, 148 mmol). The yellow solution was heated at 18O⁰C for 4 h and then cooled to rt. The resulting precipitate was filtered, washed with EtOAc and collected on a buchner funnel to give 0.145 g (32%) of the title compound as a white solid. ¹H NMR (DMSO-J₆) H .63 (br s, IH), 8.30 (s, IH), 7.81 (s, IH), 2.47 (s, 3H).

[00168] c) 4-Chloro-5-methylimidazo[5, l -/J[l ,2,4]triazine. To an oven-dried one-neck reaction flask charged with a magnetic stir bar at rt under argon with a reflux condenser was added 5-methyl-3//-imidazo[5,l-/][l,2,4]triazin-4-one (0.170 g, 1.13 mmol), distilled phosphorous oxychloride (2.34 mL, 25.2 mmol) and NJV-dimethylaniline (0.505 mL, 3.95 mmol). The yellow suspension was refluxed for 1 h at 14O⁰C. The resulting black solution was cooled to rt and concentrated to a black residue. The residue was quenched over ice (5 mL) and then extracted with EtOAc (3 x 40 mL). The organic extracts were combined and dried over Na₂SO₄, filtered and concentrated to yield the crude product as a brown solid. It was purified by flash column chromatography (silica gel 12 g pre-packed column, elution with EtOAc:Hexanes, 1 :1) to give 0.1 16 g (61 %) of the title compound as a yellow solid. ¹ H NMR (CDCl₃) 8.42 (s, IH), 8.10 (s, IH), 2.79 (s, 3H).

|00169] d) jV-(3,5-Dimethoxyphenyl)-5-methylimidazo[5,l -_/][l ,2,4]triazin-4- amine. To an oven-dried sealed reaction flask charged with a magnetic stir bar at rt was added 4-chloro-5-methylimidazo[5,l-/J[l,2,4]triazine (0.030 g, 0.18 mmol), isopropanol (0.9 mL), 3,5-dimethoxyaniline (0.055 g, 0.35 mmol) and p-toulenesulfonic acid (catalytic). The yellow suspension was heated at 90°C for 30 min, and then cooled to rt. The resulting precipitate was filtered and collected to give the crude product as a white solid. It was purified by flash column chromatography (silica gel 12 g pre-packed column, gradient elution with EtOAc:Hexanes, 1 :1) to give 0.010 g (20%) of the title compound as a white solid. ¹H NMR (CDCl₃) 8.20 (s, IH), 7.92 (s,lH), 7.11 (br s, IH), 6.91 (d, J= 2.2 Hz, 2H), 6.34 (t, J= 2.2 Hz, IH), 3.83 (s, 6H), 2.79 (s, 3H). EXAMPLE 29

5-Methyl-N-(3-methyl-l/-/-pyi-azol-5-yl)imidazo[l ,5-/J[l,2,4]triazin-4-amine

[00170] The title compound was prepared in a manner similar to example 28d.

From 4-chloro-5-methylimidazo[l,5-/J[l,2,4]triazine (57 mg, 0.34 mmol) and 3-methyl-lH-pyrazol-5-amine (65 mg, 0.67 mmol) was obtained the title compound (26 mg, 29%) as a solid. ¹H NMR (DMSO-J₆) 9.31 (s, IH), 8.05 (s, IH), 6.06 (s, I H), 2.67 (s, 3H), 2.27 (s, 3H).

EXAMPLE 30

N-(4-Methoxyphenyl)-./V,5-dimethylimidazo[5,l -_/][ 1 ,2,4]triazin-4-amine

[00171] To an oven-dried sealed reaction flask charged with a magnetic stir bar at rt was added 4-chloro-5-methylirnidazo[5,l-/][l ,2,4]triazine (0.030 g, 0.18 mmol), isopropanol (0.90 mL), TV-methyl-p-anisidine (0.049 g, 0.36 mmol) and /5-toluenesulfonic acid (catalytic). The brown solution was heated at 9O⁰C for 2 h and then cooled rt. The resulting precipitate was filtered and collected to give 0.015 g (31%) of the title compound as a white solid. ¹H NMR (DMSO-4) 8.41 (s, IH), 8.02 (s, IH), 7.29 (d, J = 9.1 Hz, 2H), 6.99 (d, J 8.8 Hz, 2H), 3.78 (s, 3H), 3.47 (s, 3H), 1.36 (s, 3H).

EXAMPLE 31

2,5-Dimethyl-/V-(3-methyl-lH-pyrazol-5-yl)imidazo[l ,5-/J[l,2,4]triazin-4- amine

[001721 a) 2,5-Dimethyl-3Η-imidazo[l ,5-/J[l ,2,4]triazin-4-one. To an oven- dried one-neck reaction flask charged with a magnetic stir bar at rt under argon was added 3-amino-5-methyl-3//-imidazole-4-carboxylic acid ethyl ester (0.500 g, 2.96 mmol) and anhydrous acetonitrile (25 mL). To the resulting clear solution was bubbled HCl(_g) for approximately 5 minutes and then the yellow solution was stirred at rt overnight. The solvent was removed by rotary evaporation to give a yellow solid. The solid was dissolved in ethanol (30 mL) and 5% NaOH (7.5 mL) and became a clear solution upon heating at 1 10°C for 5 h. The solution was cooled to rt and then the solvent was removed by rotary evaporation to give white solid. The solid was diluted in H₂O and filtered through a buchner funnel. The filtrate was basified (pH > 10) using 5% NaOH(aq) and then filtered to remove any particles. Neutralization of the filtrate using 6M HCl (pH = 7) resulted in the formation of a precipitate. The precipitate was filtered and collected to give 0.320 g (66%) of the title compound as a white solid. ¹H NMR (DMSO-J₆) 11.60 (s, IH), 8.21 (s, IH), 2.45 (s, 3H), 2.18 (s, 3H).

[00173] b) 4-Chloro-2,5-dimethylimidazo[5,l-/][l,2,4]triazine. The title compound was prepared in a manner similar to example 28c. From 2,5- dimethyl-3H-imidazo[5,l-/][l ,2,4]triazin-4-one (0.293 g, 1.78 mmol), distilled phosphorous oxychloride (3.70 mL, 39.8 mmol) and /V,/V-dimethylaniline (0.795 mL, 6.23 mmol) was obtained 0.060 g (18%) of the title compound as a yellow solid. ¹H NMR (CDCl₃) 8.30 (s, IH), 2.75 (s, 3H), 2.54 (s, 3H). [00174] c) 2,5-Dimethyl-Λφ-methyl-lH-pyrazol-5-yl)imidazo[l ,5-

/][l,2,4]triazin-4-amine. The title compound was prepared in a manner similar to example 28d. From 4-chloro-2,5-dimethylimidazo[l,5-/][l,2,4]triazine (30 mg, 0.16 mmol) and 3-methyl-lH-pyrazol-5-amine (32 mg, 0.35 mmol) was obtained the title compound (33 mg, 72%) as a solid. ¹H NMR (DMSCM₆) 8.21 (s, IH, broad), 6.12 (s, IH, broad), 2.57 (s, 3H), 2.28 (s, 3H), 2.25 (s, 3H).

EXAMPLE 32

/V-(3,5-Diinethoxyphenyl)-2-methylpyτazolo[l ,5-α][l ,3,5]triazin-4-amine

[00175] a) TV-(I H-pyrazol-5-yl)acetamidine. To an oven-dried one-neck reaction flask charged with a magnetic stir bar at rt under argon was added 3- aminopyrazole (2.38 g, 28.6 mmol), ethyl acetimidate (3.72 g, 30.1 mmol), anhydrous acetonitrile (41 mL) and glacial acetic acid (1.65 mL, 28.6 mmol). The white suspension was stirred at rt for 24 h. The resulting precipitate was filtered, washed with acetonitrile and collected on a buchner funnel to give 2.92 g (55%) of the title compound as a white solid. MS (ES) C₅H₈N₄ m/z 125 (M +H)⁺.

[00176] b) 2-methyl-3H-pyrazolo[l,5-α][l,3,5]triazin-4-one. To an oven-dried one-neck reaction flask charged with a magnetic stir bar at rt under argon was added /V-(lH-pyrazol-5-yl)acetamidine (2.92 g, 15.8 mmol), 21% NaOEt in EtOH (60.0 mL, 158 mmol) and diethyl carbonate (15.9 mL, 131 mmol). The brown suspension was re fluxed at 1 10°C for 5.5 h and then stirred overnight at rt. The solvent was removed by rotary evaporation, and the residue was diluted with H₂O (35 mL), then acidified to pH = 5 by the addition of acetic acid. The aqueous solution was concentrated by rotary evaporation, leaving a brown residue. The residue was diluted with cold H₂O (35 mL) and the resulting suspension was filtered to remove precipitate. The aqueous solution was then extracted with CHCl₃ (3 x 200 mL), dried over MgSO₄, filtered and concentrated to yield the crude product as a yellow solid. The yellow solid was washed with CH₂Cl₂, filtered and collected to give 0.777 g (33%) of the title compound as a white solid. ¹H NMR (DMSO-J₆) 12.44 (br s, IH), 8.00 (d, J = 1.8 Hz, IH), 6.37 (d, J = 1.8 Hz, IH), 2.31 (s, 3H).

[00177] c) 4-Chloro-2-methylpyrazolo[l ,5-α][l ,3,5]triazine. The title compound was prepared in a manner similar to example 28c. From 2-methyl- 3H-pyrazolo[ l ,5-Λ][l,3,5]triazin-4-one (0.300 g, 1.99 mmol), distilled phosphorous oxychloride (4.15 mL, 44.5 mmol) and /V,/V-dimethylaniline (0.890 mL, 6.99 mmol) was obtained 0.052 g (15%) of the title compound as a yellow solid. ¹H NMR (CDCl₃) 8.23 (d, J = 1.9 Hz, IH), 6.64 (d, J = 2.2 Hz, IH), 2.71 (s, 3H).

[001781 d) N-(3,5-Dimethoxy-phenyl)-2-methylpyrazolo[l ,5-α][l,3,5]triazin-4- amine. To a 10 mL microwave reaction flask charged with a magnetic stir bar, was added 4-chloro-2-methylpyrazolo[l ,5-α][l,3,5]triazine (0.020 g, 0.12 mmol), isopropanol (0.60 mL), 3,5-dimethoxyaniline (0.036 g, 0.24 mmol) and p-toulenesulfonic acid (catalytic). The suspension was reacted at 130°C for 20 min in a microwave set at 80 watts. The resulting precipitate was filtered and collected to give the crude product as a white solid. It was purified by flash column chromatography (silica gel 4 g pre-packed column, gradient elution with EtOAc:Hexanes, 1 : 1) to give 0.018 g (53%) of the title compound as a yellow solid. ¹H NMR (CD₃OD) 8.05 (d, J= 2.2 Hz, IH), 7.10 (d, J = 2.5 Hz, 2H), 6.33 (d, J= 2.2 Hz, IH), 6.30 (t, J = 2.2 Hz, IH), 3.79 (s, 6H), 2.51 (s, 3H). EXAMPLE 33

2-Methyl-yV-(3-methyl-l//-pyrazol-5-yl)pyrazolo[l ,5-fl][l ,3,5]triazin-4-amine

[00179] The title compound was prepared in a manner similar to example 32d.

From 4-chloro-2-methylpyrazolo[l,5-α][l ,3,5]triazine (0.030 g, 0.18 mmol) and 3-methyl-lH-pyrazol-5-amine (0.035 g, 0.36 mmol) was obtained 0.013 g (32%) of the title compound as a yellow solid. ¹H NMR (DMSO-^₆) 12.33 (br s, I H), 10.27 (br s, IH), 8.16 (d, J = 1.8 Hz, I H), 6.39 (m, 2H), 2.42 (s, 3H), 2.26 (s, 3H).

EXAMPLE 34

/V-(4-Methoxyphenyl)-N,2-dimethylpyrazolo[l ,5-α][l ,3,5]triazin-4-amine

(00180] The title compound was prepared in a manner similar to example 28d.

From 4-chloro-2-methylpyrazolo[l ,5-<2][l,3,5]triazine (0.030 g, 0.18 mmol) and 7V-methyl-/?-anisidine (0.049 g, 0.36 mmol) was obtained 0.005 g (10%) of the title compound as a white solid. ¹H NMR (CDCl₃) 7.70 (d, J = 1.9 Hz, IH), 7.12-7.09 (m, 2H), 6.91-6.88 (m, 2H), 6.22 (d, J = 1.9 Hz, IH), 3.85 (s, 3H), 3.70 (s, 3H), 2.54 (s, 3H). EXAMPLE 35

Identification Of Λ^L(4-Methoxyphenyl)-/V,3,6-trimethylisoxazolo[5,4- <i]pyrimidin-4-amine And Related Compounds As Caspase Cascade

Activators And Inducers Of Apoptosis In Solid Tumor Cells Human breast cancer cell lines T-47D, human hepatocellular carcinoma cell line SNU398, human colon carcinoma cell line HCTl 16, and human lung cancer cell line H 1299 were grown according to media component mixtures designated by American Type Culture Collection + 10% FCS (Invitrogen Corporation), in a 5 % CO₂ -95 % humidity incubator at 37 ⁰C. T- 47D and H 1299 cells were maintained at a cell density between 50 and 80 % confluency at a cell density of 0.1 to 0.6 x 10⁶ cells/mL. Cells were harvested at 600xg and resuspended at 0.65 x 10⁶ cells/mL into appropriate media + 10 % FCS. An aliquot of 22.5 μL of cells was added to a well of a 384-well microtiter plate containing 2.5 μL of a 10 % DMSO in RPMI-1640 media solution containing 0.16 to 100 μM of /V-(4-methoxyphenyl)-7V,3,6- trimethylisoxazolo[5,4-<i]pyrirnidin-4-amine or other test compound (0.016 to 10 μM final). An aliquot of 22.5 μL of cells was added to a well of a 384-well microtiter plate containing 2.5 μL of a 10 % DMSO in RPMI-1640 media solution without test compound as the control sample. The samples were mixed by agitation and then incubated at 37 ⁰C for 24 h or 48 h in a 5 % CO₂- 95 % humidity incubator. After incubation, the samples were removed from the incubator and 25 μL of a solution containing 14 μM of TV-(Ac-DE VO)-N '- ethoxycarbonyl-Rl lO (SEQ ID No.:l) fluorogenic substrate (Cytovia, Inc.; WO99/18856), 20 % sucrose (Sigma), 20 mM DTT (Sigma), 200 mM NaCl (Sigma), 40 mM Na PIPES buffer pH 7.2 (Sigma), and 500 μg/mL lysolecithin (Calbiochem) was added. The samples were mixed by agitation and incubated at room temperature. Using a fluorescent plate reader (Model SPECTRAfluor Plus, Tecan), an initial reading (T = 0) was made approximately 1-2 min after addition of the substrate solution, employing excitation at 485 nm and emission at 530 nm, to determine the background fluorescence of the control sample. After the 3 h incubation, the samples were read for fluorescence as above (T = 3 h). [00182] Calculation:

[00183] The Relative Fluorescence Unit values (RFU) were used to calculate the sample readings as follows:

RFU ₍τ=3h) - Control RFU _(T=₀) = Net RFU_(T=3h) [00184] The activity of caspase cascade activation was determined by the ratio of the net RFU value for Λ^r-(4-methoxyphenyl)-N,3,6-trimethylisoxazolo[5,4- rf]pyrimidin-4-amine (Example 7) or other test compound to that of control samples. The EC₅₀ (nJVI) was determined by a sigmoidal dose-response calculation (Prism 3.0, GraphPad Software Inc.).

[00185] The caspase activation potency (EC₅₀) are summarized in Table I:

Table I. Caspase Activation Potency

Thus, N-(4-methoxyphenyl)-N,3,6-trimethylisoxazolo[5,4-t/]pyrimidin-

4-amine (Example 7) and related compounds are identified as potent caspase cascade activators and inducers of apoptosis in solid tumor cells. EXAMPLE 36

Identification Of Λ^4-Methoxyphenyl)-./V,3,6-trirnethylisoxazolo[5,4- f/]pyrimidin-4-amine And Related Compounds As Antineoplastic Compound

That Inhibits Cell Proliferation (GI₅₀)

|00187] Human breast cancer cell lines T-47D, MX-I and MDAMB435, human sarcoma cell line MES-SA and multi-drug resistant (MDR) human sarcoma cell line MES-SA/ ADR, murine leukemia cell line P388 and multidrug resistant (MDR) murine leukemia cell line P388ADR were grown and harvested as in Example 35. An aliquot of 90 μL of cells (4.4 x 10⁴ cells/mL) was added to a well of a 96-well microtiter plate containing 5 μL of a 10 % DMSO in RPMI- 1640 media solution containing 10 nM to 100 μM of N-(A- methoxyphenyl)-N,3,6-trimethylisoxazolo[5,4-rf]pyrimidin-4-amine or other test compounds (1 nM to 10 μM final). An aliquot of 45 μL of cells was added to a well of a 96-well microtiter plate containing 5 μL of a 10 % DMSO in RPMI-1640 media solution without compound as the control sample for maximal cell proliferation (Livia_x)- The samples were mixed by agitation and then incubated at 37 ⁰C for 48 h in a 5% CO₂-95% humidity incubator. After incubation, the samples were removed from the incubator and 25 μL of CellTiter-Glo ^1M reagent (Promega) was added. The samples were mixed by agitation and incubated at room temperature for 10-15 min. Plates were then read using a luminescent plate reader (Model SPECTRAfluor Plus, Tecan) to give L_test values.

[00188] Baseline for GI₅₀ (dose for 50% inhibition of cell proliferation) of initial cell numbers was determined by adding an aliquot of 45 μL of cells or 45 μL of media, respectively, to wells of a 96-well microtiter plate containing 5 μL of a 10% DMSO in RPMI- 1640 media solution. The samples were mixed by agitation and then incubated at 37 ⁰C for 0.5 h in a 5% Cθ₂-95% humidity incubator. After incubation, the samples were removed from the incubator and 25 μL of CellTiter-Glo ^τ reagent (Promega) was added. The samples were mixed by agitation and incubated at 37 ⁰C for 10-15 min at room temperature in a 5% Cθ₂-95% humidity incubator. Fluorescence was read as above, (Ls_tau) defining luminescence for initial cell number used as baseline in

GI₅₀ determinations. [00189] Calculation:

[00190] GI₅₀ (dose for 50% inhibition of cell proliferation) is the concentration where [(L-_{l es}t - L_Start) / (L_Maχ- Lstau)] = 0.5. [00191] The GI₅₀ (nM) are summarized in Table II:

Table III. GI₅₀ in Cancer Cells

[00192] Thus, 7V-(4-methoxyphenyl)-/V,3,6-trimethylisoxazolo[5,4-(i]pyrimidin-

4-amine (Example 7) and related compounds are identified as antineoplastic compound that inhibits cell proliferation. More importantly, N-(4- methoxyphenyl)-N,3,6-trimethylisoxazolo[5,4-c/]pyrimidin-4-amine (Example 7) was found to have similar activity against MES-SA and its corresponding multi-drug resistant cell MES-SA/ ADR, as well as P388 and its corresponding multi-drug resistant cell P388/ADR.

[00193] Having now fully described this invention, it will be understood by those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, foπnulations and other parameters without affecting the scope of the invention or any embodiment thereof. All patents, patent applications and publications cited herein are fully incorporated by reference herein in their entirety.

Claims

WHAT IS CLAIMED IS:

1. A method of treating a disorder responsive to the induction of apoptosis in an animal suffering therefrom, comprising administering to an animal in need of such treatment an effective amount of a compound having the Formula I:

or pharmaceutically acceptable salts or prodrugs or tautomers thereof, wherein:

Ar is optionally substituted aryl or optionally substituted heteroaryl;

A, B and D are independently carbon, nitrogen, oxygen or sulfur, wherein when A, B or D are nitrogen, oxygen or sulfur, then there is no substituent at the nitrogen, oxygen or sulfur; with the proviso that when one of A or D is sulfur, then the other of A or D is not carbon;

E and F are independently carbon or nitrogen;

H is an aromatic ring, and the line between A and B, B and D, D and E, E and F, E and A can be a single bond or a double bond.

Ri is hydrogen, halo, optionally substituted amino, optionally substituted alkoxy, optionally substituted C_{M O} alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl alkyl, heteroaryl alkenyl, heteroaryl alkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano, acylamido, hydroxy, thiol, sulfone, sulfoxide, acyloxy, azido, carboxy, carbonylamido or optionally substituted alkylthiol;

R₂ is hydrogen or optionally substituted alkyl; R₃-R₅ independently are hydrogen, halo, amino, alkoxy, Ci-_{I 0} alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano, acylamido, hydroxy, thiol, sulfone, sulfoxide, acyloxy, azido, carboxy, carbonylamido, alkylthiol, or any two adjacent substituents form methylenedioxy.

2. The method of claim 1 , wherein said animal is a mammal.

3. The method of claim 1 , wherein R| is hydrogen, halo, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkylthiol or optionally substituted Ci.₁₀ alkyl.

4. The method of claim 1 , wherein Ar is optionally substituted and is phenyl or pyridyl.

5. The method of claim 1 , wherein R₂ is hydrogen.

6. The method of claim 1, wherein R₂ is methyl or ethyl.

7. A method of treating a disorder responsive to the induction of apoptosis in an animal suffering therefrom, comprising administering to an animal in need of such treatment an effective amount of a compound having the Formulae H-VI:

(H)

or a pharmaceutically acceptable salt or prodrug or tautomer thereof, wherein:

Ar is optionally substituted aryl or optionally substituted heteroaryl;

Ri is hydrogen, halo, optionally substituted amino, optionally substituted alkoxy, optionally substituted C_{M 0} alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano, acylamido, hydroxy, thiol, sulfone, sulfoxide, acyloxy, azido, carboxy, carbonylamido or optionally substituted alkylthiol;

R.₂ is hydrogen or optionally substituted alkyl; R₃-R₅ independently are hydrogen, halo, amino, alkoxy, C_{M 0} alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano, acylamido, hydroxy, thiol, sulfone, sulfoxide, acyloxy, azido, carboxy, carbonylamido, alkylthiol or any two adjacent substituents form methylenedioxy;

8. The method of claim 7, wherein R| is hydrogen, halo, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkylthiol or optionally substituted Ci_-I0 alkyl.

9. The method of claim 7, wherein R₂ is hydrogen.

10. The method of claim 7, wherein R₂ is methyl or ethyl.

1 1. The method of claim 7, wherein A is optionally substituted phenyl or pyridyl.

12. A method of treating a disorder responsive to the induction of apoptosis in an animal suffering therefrom, comprising administering to an animal in need of such treatment an effective amount of a compound selected from the group consisting of: yV-(4-Methoxyphenyl)-N,3-dimethylisoxazolo[5,4-(/]pyrimidin-4- amine;

/V-(4-Methoxyphenyl)-N,3,6-trimethylisoxazolo[5,4-c/]pyrimidin-4- amine;

Af-(2,5-Dimethoxyphenyl)-2,5-dirnethyloxazolo[5,4-rf]pyrimidin-7- amine;

N-(3,5-Dimethoxyphenyl)-2,5-dimethyloxazolo[5,4-t/]pyrimidin-7- amine; N-(4-Methoxyphenyl)-/V,2,5-trimethyloxazolo[5,4-(f]pyrimidin-7- amine; jV-(2,5-Dimethoxyphenyl)-2-methyloxazolo[5,4-rf]pyrimidin-7-amine;

N-(3,5-Dimethoxyphenyl)-2-methyloxazolo[5,4-(/)pyrimidin-7-amine;

N-(3,5-Dimethoxyphenyl)thiazolo[5,4-(f|pyrimidin-7-amine;

N-(2,5-Dimethoxyphenyl)thiazolo[5,4-(/]pyrimidin-7-amine;

7V-(4-Methoxyphenyl)-N-methylthiazolo[5,4-(/]pyrimidin-7-amine;

N-(3,5-Dimethoxy-phenyl)-5-methylimidazo[5,l-/l[l ,2,4]triazin-4- amine;

N-(3,5-Dimethoxyphenyl)-2-methylpyrazolo[l,5-α][l ,3,5]triazin-4- amine;

N-(4-Methoxyphenyl)-Λf,2-dimethylpyrazolo[l ,5-tf][l,3,5]triazin-4- amine; or a pharmaceutically acceptable salt or prodrug thereof.

13. The method of claim 1 , 7 or 12, wherein said disorder is cancer.

14. The method according to claim 13, wherein said cancer is Hodgkin's disease, non-Hodgkin's lymphomas, acute or chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, soft-tissue sarcoma, chronic lymphocytic leukemia, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small-cell lung carcinoma, stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, malignant melanoma, choriocarcinoma, mycosis fungoide, head or neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, essential thrombocytosis, adrenal cortex carcinoma, skin cancer, or prostatic carcinoma.

15. The method of claim 13, wherein said cancer is drug resistant cancer.

16. The method of claim 13, further comprising administering at least one known cancer chemotherapeutic agent, or a pharmaceutically acceptable salt of said agent.

17. The method according to claim 13, wherein said compound is administered together with at least one compound selected from the group consisting of busulfan, cis-platin, mitomycin C, carboplatin, colchicine, vinblastine, paclitaxel, docetaxel, camptothecin, topotecan, doxorubicin, etoposide, 5-azacytidine, 5-fluorouracil, methotrexate, 5-fluoro-2'-deoxy- uridine, ara-C, hydroxyurea, thioguanine, melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen, Herceptin , Rituxan", arsenic trioxide, gamcitabine, doxazosin, terazosin, tamsulosin, CB-64D, CB- 184, haloperidol, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, amprenavir, abacavir, CGP- 73547, CGP-61755, DMP-450, indinavir, nelfinavir, tipranavir, ritonavir, saquinavir, ABT-378, AG 1776, BMS-232,632, bexarotene, tretinoin, 13-cis- retinoic acid, 9-cis-retinoic acid, α-difluoromethylornithine, ILX23-7553, fenretinide, N-4-carboxyphenyl retinamide, lactacystin, MG-132, PS-341 , Gleevec®, ZD1839 (Iressa), SH268, genistein, CEP2563, SU6668, SUl 1248, EMD121974, Rl 15777, SCH66336, L-778,123, BAL9611, TAN-1813, flavopiridol, UCN-Ol, roscovitine, olomoucine, celecoxib, valecoxib, rofecoxib and alanosine.

18. The method of claim 13, further comprising treating said animal with radiation-therapy.

19. The method of claim 13, wherein said compound is administered after surgical treatment of said animal for said cancer.

20. The method of claim 1 , 7 or 12, wherein said disorder is an autoimmune disease.

21. The method of claim 1, 7 or 12, wherein said disorder is an infectious viral disease.

22. The method of claim 1 , 7 or 12, wherein said disorder is rheumatoid arthritis.

23. The method of claim 1, 7 or 12, wherein said disorder is an inflammatory disease.

24. The method of claim 1, 7 or 12, wherein said disorder is a skin disease.

25. The method of claim 1, 7 or 12, wherein said disorder is psoriasis.

26. A compound having the Formula VII:

or a pharmaceutically acceptable salt or prodrug or tautomer thereof, wherein:

Ri is hydrogen, halo, optionally substituted amino, optionally substituted alkoxy, optionally substituted Q.io alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano, acylamido, hydroxy, thiol, sulfone, sulfoxide, acyloxy, azido, carboxy, carbonylamido or optionally substituted alkyl thiol;

R.₂ is hydrogen or optionally substituted alkyl;

R₃ and R^-Rio independently are hydrogen, halo, amino, alkoxy, C_Mo alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano, acylamido, hydroxy, thiol, sulfone, sulfoxide, acyloxy, azido, carboxy, carbonylamido, alkylthiol, or any two adjacent substituents form methylenedioxy.

27. The compound of claim 26, wherein said compound is selected from the group consisting of: yV-(4-Methoxyphenyl)-3,6-dimethylisoxazolo[5,4-f/]pyrimidin-4- amine; yV-(4-Methoxyphenyl)-3-methylisoxazolo[5,4-c/]pyrimidin-4-amine; /V-(3,5-Dimethoxyphenyl)-3-methylisoxazolo[5,4-rf]pyrimidin-4- amine;

N-(3-Bromophenyl)-3-methylisoxazolo[5,4-<f]pyrimidm-4-amine;

N-(4-Methoxyphenyl)-N,3-dimethylisoxazolo[5,4-ύf]pyrimidin-4- amine;

/V-(4-Methoxyphenyl)-N,3,6-trimethylisoxazolo[5,4-cT|pyrimidin-4- amine; or a pharmaceutically acceptable salt or prodrug thereof.

28. A compound having the Formula VIIl:

or a pharmaceutically acceptable salt or prodrug or tautomer thereof, wherein:

Ri is hydrogen, halo, optionally substituted amino, optionally substituted alkoxy, optionally substituted Ci_-I0 alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano, acylamido, hydroxy, thiol, sulfone, sulfoxide, acyloxy, azido, carboxy, carbonylamido or optionally substituted alkylthiol;

R₂ is hydrogen or optionally substituted alkyl;

R₄ and R₆-Ri₀ independently are hydrogen, halo, amino, alkoxy, C|.ιo alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano, acylamido, hydroxy, thiol, sulfone, sulfoxide, acyloxy, azido, carboxy, carbonylamido, alkylthiol, or any two adjacent substituents form methylenedioxy.

29. The compound of claim 28, wherein said compound is selected from the group consisting of:

N-(2,5-Dimethoxyphenyl)-2,5-dimethyloxazolo[5,4-(fJpyrimidin-7- amine;

N-(3,5-Dimethoxyphenyl)-2,5-dimethyloxazolo[5,4-(/Jpyrimidin-7- amine;

/V-(3-Bromophenyl)-2,5-dimethyloxazolo[5,4-<f)pyrimidin-7-amine; yV-(4-Methoxyphenyl)-yV,2,5-trimethyloxazolo[5,4-(fJpyrimidin-7- amine; yV-(2,5-Dimethoxyphenyl)-2-methyloxazolo[5,4-(f|pyrimidin-7-amine;

N-(3,5-Dimethoxyphenyl)-2-methyloxazolo[5,4-(/|pyrimidin-7-amine;

Λ/-(3-Bromophenyl)-2-methyloxazolo[5,4-c/]pyrimidin-7-amine;

N-(3-Bromophenyl)-2-phenyloxazolo[5,4-c/]pyrimidin-7-amine;

/V-(4-(2,5-Dimethyloxazolo[5,4-</]pyrimidin-7- ylamino)phenyl)benzamide; or a pharmaceutically acceptable salt or prodrug thereof.

30. A compound having the Formula IX:

or a pharmaceutically acceptable salt or prodrug or tautomer thereof, wherein:

Ri is hydrogen, halo, optionally substituted amino, optionally substituted alkoxy, optionally substituted C_{M 0} alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano, acylamido, hydroxy, thiol, sulfone, sulfoxide, acyloxy, azido, carboxy, carbonylamido or optionally substituted alkylthiol;

R₂ is hydrogen or optionally substituted alkyl;

R₄ and R₆-R₁₀ independently are hydrogen, halo, amino, alkoxy, C_MO alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano, acylamido, hydroxy, thiol, sulfone, sulfoxide, acyloxy, azido, carboxy, carbonylamido, alkylthiol, or any two adjacent substituents form methylenedioxy.

31. The compound of claim 30, wherein said compound is selected from the group consisting of:

N-(3,5-Dimethoxyphenyl)thiazolo[5,4-£/]pyrimidin-7-amine;

N-(3-Bromophenyl)thiazolo[5,4-ύT]pyrimidin-7-amine;

Λ42,5-Dimethoxyphenyl)thiazolo[5,4-c/]pyrimidin-7-amine;

N-(4-(Thiazolo[5,4-c/]pyrimidin-7-ylamino)phenyl)benzamide;

Λ^-(4-Methoxyphenyl)-iV-methylthiazolo[5,4-f/]pyrimidin-7-amine; or a pharmaceutically acceptable salt or prodrug thereof.

32. A compound having the Formula X:

or a pharmaceutically acceptable salt or prodrug or tautomer thereof, wherein:

Rι is hydrogen, halo, optionally substituted amino, optionally substituted alkoxy, optionally substituted C_{M 0} alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano, acylamido, hydroxy, thiol, sulfone, sulfoxide, acyloxy, azido, carboxy, carbonylamido or optionally substituted alkylthiol;

R₂ is hydrogen or optionally substituted alkyl;

R₃, R₅ and R₆-RiO independently are hydrogen, halo, amino, alkoxy, Cι-1₀ alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano, acylamido, hydroxy, thiol, sulfone, sulfoxide, acyloxy, azido, carboxy, carbonylamido, alkylthiol, or any two adjacent substituents form methylenedioxy.

33. The compound of claim 32, wherein said compound is selected from the group consisting of:

N-(3,5-Dimethoxy-phenyl)-5-methylimidazo[5,l -/)[l,2,4]triazin-4- amine; N-(4-Methoxyphenyl)-N,5-dimethylimidazo[5,l-/J[l ,2,4]triazin-4- amine; or a pharmaceutically acceptable salt or prodrug thereof.

34. A compound having the Formula XI:

or a pharmaceutically acceptable salt or prodrug or tautomer thereof, wherein:

Ri is hydrogen, halo, optionally substituted amino, optionally substituted alkoxy, optionally substituted C _MO alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano, acylamido, hydroxy, thiol, sulfone, sulfoxide, acyloxy, azido, carboxy, carbonylamido or optionally substituted alkylthiol;

R₂ is hydrogen or optionally substituted alkyl;

R₄-Ri₀ independently are hydrogen, halo, amino, alkoxy, C_{M O} alkyl, haloalkyl, aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, cyano, acylamido, hydroxy, thiol, sulfone, sulfoxide, acyloxy, azido, carboxy, carbonylamido, alkylthiol, or any two adjacent substituents form methylenedioxy.

35. The compound of claim 34, wherein said compound is selected from the group consisting of. yV-(3,5-Dimethoxyphenyl)-2-methylpyrazolo[l,5-Λ][l,3,5]triazin-4- amine; yV-(4-Methoxyphenyl)-N,2-dimethylpyrazolo[l ,5-α][l,3,5]triazin-4- amine; or a pharmaceutically acceptable salt or prodrug thereof.

36. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of any one of claims 26-35.

37. The pharmaceutical composition of claim 36, further comprising at least one known cancer chemotherapeutic agent, or a pharmaceutically acceptable salt of said agent.

38. The pharmaceutical composition of claim 36, further comprising at least one compound selected from the group consisting of busulfan, cis-platin, mitomycin C, carboplatin, colchicine, vinblastine, paclitaxel, docetaxel, camptothecin, topotecan, doxorubicin, etoposide, 5-azacytidine, 5-fluorouracil, methotrexate, 5-fluoro-2'-deoxy-uridine, ara-C, hydroxyurea, thioguanine, melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen, Herceptin" , Rituxan" , arsenic trioxide, gamcitabine, doxazosin, terazosin, tamsulosin, CB-64D, CB- 184, haloperidol, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, amprenavir, abacavir, CGP-73547, CGP- 61755, DMP-450, indinavir, nelfinavir, tipranavir, ritonavir, saquinavir, ABT- 378, AG 1776, BMS-232,632, bexarotene, tretinoin, 13-cis-retinoic acid, 9- cis-retinoic acid, α-difiuoromethylornithine, ILX23-7553, fenretinide, N-4- carboxyphenyl retinamide, lactacystin, MG-132, PS-341 , Gleevec®, ZDl 839 (Iressa), SH268, genistein, CEP2563, SU6668, SUl 1248, EMD121974, R115777, SCH66336, L-778,123, BAL961 1 , TAN-1813, flavopiridol, UCN-Ol, roscovitine, olomoucine, celecoxib, valecoxib, rofecoxib and alanosine.