NZ765772B2 - Pharmaceutical composition for the treatment of cancer - Google Patents

Abstract

The present disclosure discloses the use of a compound 5-amino-[1,2,4]triazolo[5,1-f]purin-2-one derivatives of Formula I and its pharmaceutically acceptable salt, tautomeric form, stereoisomer, geometrical isomer, polymorph, or hydrate thereof, for the manufacture of a medicament for the treatment of a condition or disorder selected from prostate cancer, rectal cancer, renal cancer, ovarian cancer, endometrial cancer, thyroid cancer, pancreatic cancer, breast cancer, colon cancer, bladder cancer, brain cancer, glial cancer, melanoma cancer, pineal gland cancer, metastatic head and neck cancer, and lung cancer.

Description

The present disclosure discloses the use of a compound o-[1,2,4]triazolo[5,1-f]purinone derivatives of Formula I and its pharmaceutically acceptable salt, tautomeric form, stereoisomer, geometrical isomer, polymorph, or hydrate thereof, for the cture of a medicament for the treatment of a condition or er selected from prostate cancer, rectal cancer, renal cancer, ovarian cancer, endometrial , thyroid cancer, pancreatic cancer, breast cancer, colon cancer, bladder cancer, brain cancer, glial cancer, melanoma cancer, pineal gland cancer, metastatic head and neck cancer, and lung cancer.

NZ 765772 PHARMACEUTICAL ITION FOR THE TREATMENT OF FIELD OF THE ION The present disclosure s to a pharmaceutical ition comprising nds selected from the nd of Formula 1, compound of Formula 11, compound of Formula 111, or Compound of Formula IV for the manufacture of a medicament for the treatment of a condition or disorder ameliorated by tion of the AzA/AzB receptor. In particular, it relates to the use of the pharmaceutical composition for the preparation of a medicament for the treatment of a condition or disorder selected from prostate cancer, rectal , renal cancer, ovarian cancer, endometrial cancer, thyroid cancer, pancreatic cancer, breast cancer, colon cancer, bladder cancer, brain cancer, glial cancer, melanoma , pineal gland cancer, or lung cancer.

BACKGROUND OF INVENTION

[002] Adenosine is an nous tor of a wide range of physiological functions and is implicated in several pathologies. Recent advances in molecular biology coupled with several pharmacological studies have lead to identification of at least four subtypes of adenosine receptors, A1, AzA, A213 and A3. The A1 and A3 receptors down—regulate cellular cAMP levels through their coupling to G protein, which inhibit adenylate cyclase. In contrast, AzA and A213 receptors couple to G protein that activate adenylate cyclase and increase intracellular levels of cAMP.

Advances in understanding the role of adenosine and its receptors in physiology and pathophysiology as well as new developments in medicinal try of these receptors have identified potential therapeutic areas for drug development. With the combination of pharmacological data using selective ligands and genetically modified mice, important progress has been made towards understanding of the role of adenosine receptors (Ars) in a variety of diseases, such as inflammatory conditions, sepsis, heart attack, ischemia—reperfusion injury, vascular injury, spinal cord , chronic obstructive pulmonary disease (COPD), asthma, diabetes, obesity, in?ammatory bowel disease, retinopathy, and Parkinson’s Disease (PD).

In the central nervous system, AzA antagonists can have antidepressant properties and stimulate cognitive functions. Epidemiological evidence shows a protective role for caffeine in Parkinson's disease. Moreover, AzA receptor density is found to be very high in the basal ganglia which regulate motor control function.

Hence, selective AzA antagonists can improve motor impairment due to neurodegenerative diseases such as Parkinson's e (Trends Pharmacol. Sci. 1997, 18, 338—344), senile dementia as in Alzheimer's disease, psychoses, stroke and be potentially effective in the treatment of cerebral ischaemia (Life Sci. 1994, 55, 61—65). Aza antagonists may also be employed for the treatment or management of attention d disorders such as attention deficit disorder and attention deficit hyperactivity disorder, extra pyramidal syndrome, e.g., ia, akathisia, pseudoparkinsonism and tardive dyskinesia, and disorders of abnormal movement such as restless leg syndrome and ic limb movement in sleep. Several of these indications have been disclosed in patent applications (eg. WO 02/055083, WO 05/044245 and WO 06/132275). Adenosine AzA antagonists could also be useful in the ent of amyotrophic lateral sis, cirrhosis, and fibrosis and fatty liver (US2007037033, WO 01/058241). AzA receptor antagonists are also useful for the mitigation of addictive behavior (WO 06/009698) and for the treatment and prevention of dermal is in diseases such as derma (Arthritis & Rheumatism, 54(8), 2632-2642, 2006).

Parkinson’s disease (PD) is a progressive, incurable disorder with no definite tive treatment, although drugs are ble to alleviate the symptoms and/or slow down the progress of the disease. Among the various strategies, AzA AR blockers are considered a potential approach to treatment of the e. Within the brain AzA ARs are richly expressed in the striatum, s accumbens, and olfactory tubercle. Co—expression of AzA with D2 dopamine receptors has been reported in the GABAergic striatopallidal neurons where adenosine and dopamine ts exert antagonistic effects in the tion of locomotor activity. Activation of AzA ARs in striatopallidal neurons decreases the affinity of D2 ors for dopamine, antagonizing the effects of D2 ors.

The negative interaction between AzA and D2 receptors is at the basis of the use of AzA nists as a novel therapeutic approach in the treatment of PD acol.

Ther. 2005, 105, 267). The recent discovery that the AzA can form functional heteromeric receptor complexes with other Gprotein—coupled receptors such as D2 receptors and the mGlu5 receptors has also suggested new opportunities for the potential of AzA antagonists in PD (J. Mol. Neurosci. 2005, 26, 209).

Adenosine signaling is known to serve apoptotic, angiogenic and pro— inflammatory functions and might be relevant to the pathogenesis of asthma and chronic obstructive pulmonary disease (Trends in Pharmacological Sciences, 2003, 24, 8). Extracellular adenosine acts as a local modulator with a generally cytoprotective function in the body. Its effects on tissue protection and repair fall into four categories: increasing the ratio of oxygen supply to demand; protecting against ischaemic damage by cell conditioning; triggering anti—in?ammatory responses; and the ion of angiogenesis.

In recent years, AzA receptor has shown exciting ss in the development of immunotherapy for the treatment of cancer (Cancer Immunol Res. 2015, 3, 506—517). Adenosine generation in tumor microenvironment is an active metabolic mechanism used by cancer cells to avoid anti—tumor surveillance and increase metastasis. Ectonucleotidase CD73 and CD39 (highly expressed on tumor cells and stromal cells) convert ATP released by dying tumor cells to adenosine. Adenosine signaling through AzA receptors enhances pro— tumoral responses in the tumor nvironment contributing to tumor growth and metastases. AzA receptors are expressed on several immune cell types— T cytes, dendritic cells, natural killer cells. AzA receptor activation on T cells and NK cells causes immunosuppression by reducing their proliferation, ne production and tumor killing activity. AzA nists could induce anti—tumoral responses in multiple types of cancer when used as stand alone or in combination with existing immunotherapies or herapy or chemotherapy. Cancers that could benefit from AzA antagonist therapy include melanoma, triple negative breast cancer, colon cancer, colorectal cancer, lung cancer, prostate cancer, renal cell cancer, non—small cell lung , bladder cancer, cervical, vulvar or anal cancer, geal cancer, metastatic head and neck , liver cancer, lymphoma, multiple myeloma, ovarian cancer, pancreatic cancer, acute myeloid leukemia, Kaposi sarcoma.

The A23 adenosine receptor subtype (Feoktistov, et al. I. col. Rev. 1997, 49, 381—402) has been identified in a variety of human and murine tissues and is involved in the regulation of vascular tone, smooth muscle growth, angiogenesis, hepatic e production, bowel movement, intestinal secretion, and mast cell degranulation.

A23 receptors have been ated in mast cell activation and , control of vascular tone, cardiac myocyte ctility, cell growth and gene expression, vasodilation, regulation of cell growth, inal function, and modulation of neurosecretion (Pharmacological Reviews, 2003, 49, 4).

A23 receptors modulate mast cell function. Adenosine activates adenylate cyclase and protein kinase C and potentiates stimulated mediator release in mouse bone marrow derived mast cells. Activation of A23 receptors in HMC—l augments IL—S release and potentiates PMA—induced secretion of lL—S. Thus, ine would contribute to the tic response by acting on the mast cell to enhance the release of proinflammatory ors. (Pulmonary Pharmacology & Therapeutics 1999, 12, 111—114). In COPD, transformation of ary fibroblasts into roblasts is considered a major mechanism. Activation of the A23 AR is involved in this process. Selective A23 antagonists are expected to have beneficial effect on pulmonary fibrosis (Curr. Drug Targets, 2006, 7, 699—706; Am.

J. Resper. Cell. Mol. Biol., 2005, 32, 228). A23 antagonists can be used as wound healing agents. Activation of the A23 AR promotes angiogenesis by sing the release of angiogenic factors and A23 antagonists are useful to block angiogenesis (Circ. Res., 2002, 90, 531—538). A23 AR may be involved in the inhibition cardiac fibroblast (CF) proliferation (Am.J. Physiol. Heart Circ. Physiol., 2004, 287, H2478—H2486). Adenosine ates Cl— secretion in the intestinal epithelia ng towards a possible treatment for cystic fibrosis patients with CFTR mutation (Am. J. Respir. Cell Mol. Biol., 2008, 39, 190—197). High affinity A23 antagonists are effective in hot plate model suggestive of the role of A23 in nociception and can be used as potential analgesic agents (The J. of Pharmacol. and Exp. Ther., 2004, 308, 358—366).

A23 receptor is involved in release of IL—6. sing evidence suggests that IL—6 plays a role in Alzheimer’s disease in the context of in?ammatory process associated with disease. Hence A23 receptor antagonist might be useful for Alzheimer’s disease.

The A23 ARs are involved in the stimulation of nitric oxide production during Na+—linked glucose or glutamine absorption. They are involved in glucose production in hepatocytes upon agonist stimulation. A23—receptor nists showed an anti—diabetic potential mainly by increasing plasma n levels under ions when the ine tonus was elevated in—vivo and increased insulin release in—vitro (J Pharm. Pharmacol. 2006 Dec; 58(12):l639—45). Thus, A23 antagonists may serve as a novel target for the treatment of this metabolic e.

It has been demonstrated that adenosine activation of the A23 adenosine receptor increase cAMP accumulation, cell proliferation and VEGF expression in human retinal endothelial cells. Activation of A23AdoR increased vascular endothelial cell growth factor mRNA and n expression in human retinal endothelial cells. Adenosine also has a synergistic effect with VEGF on retinal endothelial cell proliferation and capillary morphogenesis in vitro. Such ty is necessary in healing wounds, but the hyperproliferation of endothelial cells es ic retinopathy. Also, an undesirable increase in blood vessels occurs in neoplasia. Accordingly, inhibition of binding of adenosine to A23 receptors in the endothelium will alleviate or prevent hypervasculation, thus preventing retinopathy and inhibiting tumor formation.

[0014] Adenosine generation in tumor nvironment is an active metabolic mechanism used by cancer cells to avoid anti—tumor immunosurveillance and increase metastasis. Ectonucleotidase CD73 and CD39 (highly sed on tumor cells and stromal cells) convert ATP released by dying tumor cells to adenosine.

A23 receptors are expressed at low levels on multiple cell types under normal conditions, but significantly upregulated under hypoxic conditions that prevail in the tumor microenvironment. Activation of A23 ors promotes angiogenesis and causes T cell and d derived suppressor cell (MDSC) mediated immunosuppression in the tumor microenvironment. A23 nists could induce anti—tumoral responses in multiple types of cancer when used as stand alone or in combination with existing immunotherapies or radiotherapy or chemotherapy.

Cancers that could benefit from A23 antagonist therapy include melanoma, triple negative breast cancer, colon cancer, colorectal , lung cancer, prostate cancer, renal cell , non—small cell lung cancer, bladder cancer, cervical, vulvar or anal cancer, esophageal cancer, metastatic head and neck cancer, liver cancer, lymphoma, multiple myeloma, ovarian cancer, pancreatic cancer, acute myeloid leukemia, Kaposi sarcoma.

Adenosine A23 receptors are ubiquitous and regulate multiple ical activities. For example, adenosine binds to A23 receptors on endothelial cells, thereby stimulating enesis. Adenosine also regulates the growth of smooth muscle cell populations in blood vessels. Adenosine ates A23 receptors on mast cells, thus modulating Type I hypersensitivity reactions. Adenosine also stimulates gastrosecretory ty by ligation with A23 in the intestine.

While many of these biological effects of ine are necessary to maintain normal tissue homeostasis, under certain physiological changes it is desirable to modulate its effects. For example, the binding of A23 receptors stimulates angiogenesis by promoting the growth of elial cells. Such activity is necessary in healing wounds, but the hyperproliferation of endothelial cells promotes diabetic retinopathy. Also, an undesirable increase in blood vessels occurs in sia. Accordingly, inhibition of the binding of adenosine to A23 receptors in the endothelium will alleviate or prevent hypervasculation, thus preventing retinopathy and inhibibiting tumor formation.

A23 receptors are found in the colon in the basolateral domains of intestinal lial cells, and when acted upon by the appropriate ligand act to increase chloride secretion, thus causing diarrhea, which is a common and potentially fatal complication of infectious diseases such as cholera and . A23 nists can therefore be used to block intestinal chloride secretion and are thus useful in the treatment of in?ammatory gastrointestinal tract disorders, including diarrhea.

Another adverse biological effect of adenosine acting at the A213 receptor is the over—stimulation of cerebral IL—6, a cytokine associated with dementias and Alzheimer's disease.

Accordingly, it is d to provide compounds that are potent B nists (i.e., compounds that t the AzA/AzB adenosine receptor), fully or partially selective for the AzA/AzB receptor, useful in the treatment of various e states related to modulation of the AzA/AzB receptor, for example cancer.

SUMMARY OF THE INVENTION In an aspect of the present disclosure, there is provided a pharmaceutical composition comprising compound of Formula I and its pharmaceutically acceptable salt, analog, tautomeric form, stereoisomer, geometrical isomer, polymorph, hydrate, solvate, lite, and prodrug thereof :5»; AN ”it.” ‘3 T' :— as />’_’ 7:33-." .33»,1 Formula I Wherein ——— represents a single bond or a double bond; X is selected from O, S or NRa; Y1 is selected from N or CH; Y2 is selected from NR5, 0 or CRSR"; Y3 is selected from N, CH, CH2, C(20), or C(=S); Y4 is selected from N, C, or CH; R1 and R2 are ndently selected from hydrogen or alkyl; R3 is —A—Z—B—Q; wherein, A is absent or is a group selected from alkylene, alkenylene, or alkynylene; wherein one or more methylene groups is optionally replaced by hetero atoms or groups such as —O—, —S(O)p—, —N(Ra)—, or —C(O); alkylene, alkenylene and alkynylene is optionally substituted with —(CRdRe)nOR7, (CRdRe)nCOOR7, - (CRdRe)nNR8R9, cyano, halogen, haloalkyl, perhaloalkyl, alkoxyalkoxy, alkyl, or cycloalkyl; Z is absent or is selected from a lkyl or a heterocyclyl; wherein cycloalkyl and heterocyclyl are unsubstituted or substituted independently with l, 2, or 3 tuents ndently selected from alkyl, alkenyl, alkynyl, acyl, — (CRdRe)nOR7, (CRdRe)nCOOR7, —(CRdRe)nNR8R9, aminocarbonyl, alkoxycarbonylamino, halogen, haloalkyl, perhaloalkyl, azido, cyano, keto, thiocarbonyl, —SOgH, arbonylamino, nitro, —S(O)2NRaRa, —NRbS(O)2Rb or - 3(O)pRC; B is absent or is a group selected from alkylene, lene or alkynylene; wherein one or more ene groups is optionally replaced by hetero atoms or groups such as —O—, —S(O)p—, —N(Ra)—, or —C(O); alkylene, alkenylene and alkynylene is optionally tuted with y, amino, aminoalkyl, cyano, halogen, haloalkyl, perhaloalkyl, carboxy, carboxyalkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkoxy or alkyl; Q is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or arylalkyl; wherein alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl are unsubstituted or substituted ndently with l, 2, or 3 substituents independently selected from alkyl, alkenyl, alkynyl, halogen, kyl, perhaloalkyl, azido, cyano, nitro, keto, thiocarbonyl, cyanoalkyl, cyanoalkylcarbonyl, —(CRdRe)nOR7, —(CRdRe)nC(O)R7, e)nSR7, — (CRdRe)nCOOR7, -(CRdRe)nNR8R9, —(CRdRe)nC(O)NR8R9, —(CRdRe)nNR8C(O)OR7, —(CRdRe)nNR8C(O)NR8R9, -NRbS(O)2Rb, —S(O)pRC, —SOsH, —S(O)2NRaRa, cycloalkyl, lkenyl, cycloalkylalkyl aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; wherein each substituent is unsubstituted or substituted with l, 2, or 3 substituents independently selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, arnino, substituted amino, cyano or — 3(O)pRC; R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, carboxyalkyl, lkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, aryl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl are unsubstituted or substituted ndently with up to four substituents independently selected from alkyl, alkenyl, alkynyl, acyl, e)nOR7, (CRdRe)nCOOR7, -(CRdRe)nNR8R9, aminocarbonyl, alkoxycarbonylamino, aminocarbonylamino, azido, cyano, halogen, haloalkyl, perhaloalkyl, keto, nitro, —S(O)2NRbRb, —NRbS(O)2Rb or — S(O)pRC, thiocarbonyl, —SOgH, cycloalkyl, lkenyl, aryl, heteroaryl or heterocyclyl; R5 and R6 are independently selected from the group consisting of hydrogen, hydroxy, —(CRdRe)nOR7, (CRdRe)nCOOR7, —(CRdRe)nNR8R9, cyanoalkyl, kyl, alkoxyalkoxyalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroarylalkyl; R7 is selected from hydrogen, alkyl, halogen, kyl, —(CRdRe)nOR7, — (CRdRe)nCOOR7, —(CReRe)nC(O)R7, carbonylamino, cycloalkyl, lkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl; R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, —(CRdRe)nOR7, —(CRdRe)nC(O)R7, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl, or R8 and R9 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S, said ring system is r ally substituted with l to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nitro, cyano, —(CRdRe)nOR7, —(CRdRe)nSR7, —(CRdRe)nNR8R9, oxo, alkylsulfonyl, — (CRdRe)nCOOR7, e)nC(O)NR8R9, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R21 is selected from hydrogen or alkyl; Rb each is independently selected from the group consisting of hydrogen, alkyl, acyl, yalkyl, carbonylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryl, arylalkyl, heterocyclyl and heterocyclylalkyl; RC is selected from alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl; R01 and Re are independently selected from the group consisting of hydrogen, —OR7, halogen, haloalkyl, perhaloalkyl and alkyl; n is 0, 1, 2, 3 or 4, and p is 0, 1 or 2, for the cture of a medicament for the treatment of a condition or disorder ameliorated by inhibition of the A2A/A2B receptor. [00019a] According to a first aspect, the present invention provides the use of a compound of a I and its pharmaceutically acceptable salt, tautomeric form, stereoisomer, geometrical isomer, polymorph, or hydrate f Formula I wherein --- ents a single bond or a double bond; X is selected from O, S or NRa; Y1 is selected from N or CH; Y2 is selected from NR5, O or CR5R6; Y3 is selected from N, CH, CH2, C(=O), or C(=S); Y4 is selected from N, C, or CH; R1 and R2 are independently selected from hydrogen or alkyl; R3 is –A-Z-B-Q; wherein, A is absent or is a group selected from alkylene, alkenylene, or alkynylene; n one or more ene group is optionally replaced by hetero atoms or groups such as –O-, - , -N(Ra)-, or -C(O); alkylene, alkenylene and alkynylene is optionally substituted with - (CRdRe)nOR7, (CRdRe)nCOOR7, -(CRdRe)nNR8R9, cyano, halogen, haloalkyl, oalkyl, alkoxyalkoxy, alkyl, or cycloalkyl; Z is absent or is selected from a cycloalkyl or a heterocyclyl; wherein cycloalkyl and heterocyclyl are unsubstituted or substituted independently with 1, 2, or 3 substituents ndently selected from alkyl, alkenyl, alkynyl, acyl, -(CRdRe)nOR7, (CRdRe)nCOOR7, - (CRdRe)nNR8R9, aminocarbonyl, alkoxycarbonylamino, halogen, haloalkyl, perhaloalkyl, azido, cyano, keto, thiocarbonyl, -SO3H, aminocarbonylamino, nitro, -S(O)2NRaRa, -NRbS(O)2Rb or - S(O)pRc; B is absent or is a group selected from alkylene, alkenylene or alkynylene; wherein one or more methylene groups is optionally replaced by hetero atoms or groups such as –O-, -S(O)p-, - N(Ra)-, or -C(O); alkylene, lene and alkynylene is optionally substituted with hydroxy, amino, aminoalkyl, cyano, halogen, haloalkyl, perhaloalkyl, carboxy, carboxyalkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkoxy or alkyl; Q is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, cyclylalkyl, heteroaryl or heteroarylalkyl; wherein alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, cyclylalkyl, heteroaryl and heteroarylalkyl are unsubstituted or substituted independently with 1, 2, or 3 substituents independently selected from alkyl, alkenyl, alkynyl, halogen, kyl, perhaloalkyl, azido, cyano, nitro, keto, thiocarbonyl, cyanoalkyl, cyanoalkylcarbonyl, -(CRdRe)nOR7, -(CRdRe)nC(O)R7, -(CRdRe)nSR7, -(CRdRe)nCOOR7, -(CRdRe)nNR8R9, -(CRdRe)nC(O)NR8R9, - (CRdRe)nNR8C(O)OR7, -(CRdRe)nNR8C(O)NR8R9, -NRbS(O)2Rb, -S(O)pRc, -SO3H, - RaRa, cycloalkyl, cycloalkenyl, cycloalkylalkyl aryl, arylalkyl, cyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; wherein each substituent is unsubstituted or substituted with 1, 2, or 3 substituents independently ed from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, n, haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, amino, substituted amino, cyano or -S(O)pRc; R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, kyl, yalkyl, carboxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, aryl and heteroarylalkyl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, aryl, heteroaryl, heteroarylalkyl, cyclyl, and heterocyclylalkyl are unsubstituted or substituted independently with up to four substituents independently selected from alkyl, alkenyl, alkynyl, acyl, -(CRdRe)nOR7, (CRdRe)nCOOR7, -(CRdRe)nNR8R9, aminocarbonyl, alkoxycarbonylamino, aminocarbonylamino, azido, cyano, halogen, haloalkyl, perhaloalkyl, keto, nitro, -S(O)2NRbRb, -NRbS(O)2Rb or -S(O)pRc, rbonyl, -SO3H, lkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl; R5 and R6 are independently selected from the group consisting of hydrogen, hydroxy, -(CRdRe)nOR7, (CRdRe)nCOOR7, -(CRdRe)nNR8R9, cyanoalkyl, haloalkyl, alkoxyalkoxyalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and arylalkyl; R7 is selected from hydrogen, alkyl, halogen, haloalkyl, -(CRdRe)nOR7, -(CRdRe)nCOOR7, -(CReRe)nC(O)R7, carbonylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl; R8 and R9 are independently selected from the group ting of hydrogen, alkyl, haloalkyl, - (CRdRe)nOR7, -(CRdRe)nC(O)R7, aryl, arylalkyl, heteroaryl, heteroarylalkyl, lkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl, or R8 and R9 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S, said ring system is further optionally substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nitro, cyano, -(CRdRe)nOR7, -(CRdRe)nSR7, -(CRdRe)nNR8R9, oxo, alkylsulfonyl, -(CRdRe)nCOOR7, -(CRdRe)nC(O)NR8R9, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; Ra is selected from hydrogen or alkyl; Rb each is independently selected from the group consisting of hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; Rc is selected from alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl; Rd and Re are independently selected from the group consisting of hydrogen, -OR7, n, haloalkyl, perhaloalkyl and alkyl; n is 0, 1, 2, 3 or 4, and p is 0, 1 or 2, for the manufacture of a medicament for the treatment of a condition or disorder selected from prostate cancer, rectal cancer, renal cancer, ovarian cancer, endometrial cancer, thyroid cancer, atic cancer, breast cancer, colon cancer, bladder cancer, brain cancer, glial cancer, melanoma cancer, pineal gland , metastatic head and neck cancer, and lung cancer.

In an aspect of the present disclosure, there is provided a pharmaceutical composition comprising compound of Formula II and its ceutically able salts, s, tautomeric forms, isomers, geometrical isomers, polymorphs, hydrates, solvates, metabolites, and gs thereof Formula II wherein, Y is selected from N or CR; R is selected from H, hydroxy, alkoxy, alkyl, or aryl; R1 is selected from a group ting of alkyl, alkenyl and alkynyl, wherein one or more methylene groups are optionally replaced by hetero atoms or groupselected from (O)p-, -N(Ra)-, or -C(O) provided that the heteroatom is not adjacent to N in the ring; p is selected from 0, 1 or 2; wherein alkyl, alkenyl and alkynyl are unsubstituted or substituted independently with alkoxy, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, haloalkyl, hydroxy, yalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, -SO3H, aminocarbonylamino, yamino, alkoxyamino, nitro, -S(O)2NRaRa, -NRaS(O)2Ra, or -S(O)pRa; R2 is selected from a group consisting of hydrogen, halogen, cyano, nitro, carboxy, acyl, aminocarbonyl, alkyl, alkenyl, alkynyl, yalkyl, carboxyalkyl, kyl, haloalkyloxy, alkoxy, -NRbRb, -S(O)pRb, lkyl, cycloalkylalkyl, lkyloxy, aryl, arylalkyl, aryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl, heteroarylalkyl and heteroaryloxy; n alkyl, alkenyl, alkynyl, alkoxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, aryl, arylalkyl, aryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, [continued on page 11] heteroaryl, heteroarylalkyl, heteroaryloxy and Rb are unsubstituted or substituted ndently with alkyl, alkenyl, alkynyl, alkoxy, acyl, acylan1ino, acyloxy, nitro, amino, monoalkylamino, dialkylamino, hydroxyamino, amino, aminocarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, —SOgH, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, cycloalkyl, cycloalkyloxy, cycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, cyclyloxy, —S(O)2NRCRC, — NRCS(O)2RC or —S(O)de; wherein each substituent is unsubstituted or tuted with l, 2, or 3 substituents independently selected from alkyl, carboxy, yalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano or —S(O)de; R3 is selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkyl, cycloalkyl, lkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; wherein alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, kyl, heteroaryl, and heteroarylalkyl are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, , cycloalkyl, cycloalkenyl, acyl, acylan1ino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, lkylamino, arylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, yalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, —SOgH, aryl, aryloxy, lkyloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, S(O)2NRCRC, —NRCS(O)2RC or —S(O)de; wherein each substituent is unsubstituted or substituted with l, 2, or 3 substituents independently selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxyd, alkoxy, halogen, haloalkyl, haloalkoxy, amino, substituted arnino, cyano or —S(O)de; X is either an optionally substituted arylene or an optionally substituted heteroarylene; A is selected from a bond, (C1—C6)alkylene, (C2—C6)alkenylene or (C2— C6)alkynylene group, wherein l to 4 methylene groups are optionally replaced by groups independently ed from O, —S(O)p—, —N(Rb)—, or —C(O)—; wherein alkylene, lene, and alkynylene are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylan1ino, y, amino, kylamino, dialkylamino, arylamino, cycloalkylamino, heteroarylan1ino, cyclylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SOgH, aryl, aryloxy, cycloalkyloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, amino, nitro, S(O)2NRCRC, —NRCS(O)2RC or —S(O)de; wherein each substituent is unsubstituted or substituted with l, 2, or 3 substituents independently selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano or -S(O)de; B is selected from en, heterocyclyl, cycloalkyl, aryl or heteroaryl; wherein heterocyclyl, cycloalkyl, aryl and heteroaryl are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, acyl, acylan1ino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, cycloalkylamino, heteroarylamino, heterocyclylan1ino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SOgH, aryl, arylalkyl, aryloxy, lkyloxy, aryl, heteroarylalkyl, aminocarbonylamino, aryloxy, heterocyclyl, heterocyclylalkyl, cyclyloxy, hydroxyamino, alkoxyamino, nitro, — S(O)2NRbRb, —NRbS(O)2Rb or —S(O)de; wherein each substituent is tituted or substituted with l, 2, or 3 substituents independently selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano or — R21 is independently selected from hydrogen or alkyl; Rb is independently selected from the group consisting of hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and cyclylalkyl; RC is ed from hydrogen, alkyl, aryl, heteroaryl or heterocyclyl; R01 is selected from alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl; and p is 0, l or 2, for the cture of a medicament for the treatment of a condition or disorder ameliorated by inhibition of the AzA/AzB receptor.

In an aspect of the present sure there is ed a pharmaceutical composition comprising compound of Formula III or IV and its pharmaceutically acceptable salts, analogs, tautomeric forms, stereoisomers, geometrical isomers, polymorphs, hydrates, solvates, metabolites, and prodrugs thereof R! § ‘ll I-FR o n a‘ a,“ 3, R “a \ 3;: 34., —p X— 3* i A I i“ | 9—K—A—E '2 R 3%Y x weA ~ ““ E .. x; [ i l ,5- Formula III Formula IV wherein, R1 is an alkyl wherein one or more methylene groups are optionally replaced by hetero atoms or group selected from —O—, —S(O)p—, —N(Ra)—, or —C(O), provided that the heteroatom is not adjacent to N in the ring; p is selected from 0, l or 2; n alkyl is unsubstituted or substituted with alkoxy, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, haloalkyl, y, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, — arbonylamino, hydroxyamino, alkoxyamino; R2 is selected from the group consisting of en, halogen, cyano, nitro, carboxy, acyl, aminocarbonyl, alkyl, alkenyl, alkynyl, hydroxyalkyl, carboxyalkyl, haloalkyl, haloalkyloxy, alkoxy, —NRbRb, —S(O)pr, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, aryl, arylalkyl, aryloxy, cyclyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl, arylalkyl and heteroaryloxy; wherein alkyl, l, alkynyl, alkoxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, aryl, arylalkyl, aryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy and Rb are unsubstituted or substituted independently with alkyl, alkenyl, l, alkoxy, acyl, acylamino, acyloxy, nitro, amino, monoalkylamino, dialkylamino, hydroxyamino, amino, aminocarbonylamino, azido, cyano, halogen, y, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, —SOgH, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, cycloalkyl, cycloalkyloxy, cycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, —S(O)2NRCRC, — )2RC or —S(O)de; wherein each substituent is unsubstituted or substituted with l, 2, or 3 substituents independently selected from alkyl, y, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano or —S(O)de; R’ and R” are independently selected from hydrogen, or alkyl; or R’ and R” taken together may represent 0, or a lower cycloalkyl ring system which is saturated or partially unsaturated; R3 is selected from the group ting of alkyl, aryl, —C(O)R4 and —P(O)(OR5)2; R4 is selected from alkyl, alkoxy, aryl, heteroaryl, cyclyl, or —NR6R7; R5 is selected from hydrogen, alkyl, aryl, arylalkyl, —CHzOC(O)alkyl, or — CH20C(O)Oalkyl; or two R5 groups taken together form a five or six membered ring system which is ted or partially unsaturated and is optionally tuted with l to 4 tuents independently selected from halo, alkyl, aryl or heteroaryl; R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, heterocyclyl and heterocyclylalkyl; or R6 and R7 taken together form a monocyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S, wherein the ring system is optionally substituted with l to 4 substituents independently selected from halo, alkyl, alkoxy, or —NR8R9; R4, R5, R6 and R7 is optionally substituted with l to 4 substituents independently selected from hydroxyl, halogen, alkyl, alkoxy, haloalkyl, —NR8R9, —C(O)OR10, — OC(O)R10 or —NC(O)R10; R8 and R9 are independently selected from the group consisting of en and alkyl; R10 is selected from hydrogen, hydroxy, halogen, amino, substituted amino, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, carboxy, carboxyalkyl, aminocarbonyl, aryl or arylalkyl; X is an optionally substituted arylene or an optionally substituted heteroarylene; A is selected from a bond, or )alkylene, wherein l to 4 methylene groups are optionally replaced by group independently selected from O, —S(O)p—, —N(Rb)—, or — C(O)—; wherein alkylene is tituted or tuted independently with alkyl,alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, carbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SOgH, aryl, aryloxy, lkyloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, S(O)2NRCRC, —NRCS(O)2RC or -S(O)de; wherein each tuent is unsubstituted or substituted with l, 2, or 3 substituents ndently selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano or —S(O)de; B is selected from hydrogen, heterocyclyl, cycloalkyl, aryl or heteroaryl; wherein cyclyl, cycloalkyl, aryl and heteroaryl are tituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, lkylalkyl, cycloalkenyl, acyl, acylan1ino, acyloxy, amino, monoalkylamino, lamino, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, carbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SOgH, aryl, arylalkyl, aryloxy, cycloalkyloxy, heteroaryl, heteroarylalkyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclylalkyl, cyclyloxy, hydroxyamino, alkoxyamino, nitro, — S(O)2NRbRb, —NRbS(O)2Rb or —S(O)de; wherein each substituent is unsubstituted or substituted with l, 2, or 3 tuents independently selected from alkyl, carboxy, carboxyalkyl, arbonyl, hydroxy, alkoxy, alkoxyalkoxy, alkyl, halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano or — 3(O)de; D is selected from —O—, —S(O)p—, or —N(Ra)-; R21 is hydrogen or an alkyl; Rb is selected from the group consisting of hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; RC is selected from hydrogen, alkyl, aryl, aryl or cyclyl; R01 is selected from alkyl, lkyl, aryl, heterocyclyl or heteroaryl; p is 0, l or 2; and t is l or 2, for the manufacture of a medicament for the ent of a condition or disorder ameliorated by inhibition of the AzA/AzB receptor.

In an aspect of the present disclosure there is provided a method of using the pharmaceutical composition of the present disclosure comprising a compound selected from compound of Formula 1, Formula II, Formula 111, or Formula IV and their pharmaceutically acceptable salt, analog, tautomeric form, stereoisomer, geometrical isomer, polymorph, hydrate, solvate, metabolite, and prodrug thereof, in the treatment of a disease or condition in a mammal that is amenable to treatment with an AzA/AzB receptor antagonist, the method sing: administering to a mammal in need thereof a therapeutically effective dose of the ceutical composition of the present dislcosure.

In an aspect of the present disclosure there is provided a method of treatment of a disorder or condition ameliorated by antagonizing the AzA/AzB receptor, the method comprising: administering an effective amount of the pharmaceutical composition of the present disclosure comprising a compound selected from compound of Formula 1, Formula II, Formula 111, or Formula IV and their pharmaceutically acceptable salts, analog, tautomeric form, stereoisomer, geometrical isomer, rph, hydrate, solvate, metabolite, and prodrug thereof, to a patient in need of such treatment.

In an aspect of the present disclosure there is provided use of the ceutical composition of the present disclosure sing compound selected from compound of Formula I, Formula II, Formula III, or Formula IV and their pharmaceutically acceptable salt, analog, tautomeric form, stereoisomer, geometrical isomer, polymorph, hydrate, solvate, metabolite, and prodrug thereof, for the preparation of a medicament for the treatment of a condition or disorder selected from prostate cancer, rectal cancer, renal cancer, ovarian , endometrial cancer, thyroid cancer, pancreatic , breast , colon cancer, bladder cancer, brain cancer, glial cancer, melanoma cancer, pineal gland cancer, or lung cancer.

These and other es, aspects, and advantages of the present subject matter will become better understood with reference to the following description.

This y is provided to introduce a selection of concepts in a simplified form.

This summary is not intended to identify key features or essential features of the disclosure, nor is it intended to be used to limit the scope of the t matter.

DETAILED DESCRIPTION

[0026] Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those ically described. It is to be understood that the present sure includes all such variations and modifications. The sure also includes all such steps, features, compositions and compounds referred to or indicated in this ication, dually or collectively, and any and all combinations of any or more of such steps or features.

De?nitions For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have the meanings recognized and known to those of skill in the art, however, for convenience and teness, particular terms and their meanings are set forth below.

The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.

Throughout the description and the claims which follow, unless the context requires otherwise, the word (L comprise”, and variations such as “comprises” and “comprising”, will be tood to imply the inclusion of a stated integer or step or group of integers but not to the exclusion of any other integer or step or group of integers or steps.

The term “including” is used to mean “including but not limited to”.

“Including” and “including but not limited to” are used interchangeably.

In the structural formulae given herein and throughout the present disclosure, the following terms have been ted meaning, unless specifically stated otherwise.

The term "alkyl" refers to a monoradical ed or unbranched saturated hydrocarbon chain having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably 1, 2, 3, 4, 5 or 6 carbon atoms. This term is ified by groups such as methyl, ethyl, n—propyl, iso—propyl, n—butyl, iso—butyl, t—butyl, n— hexyl, n—decyl, tetradecyl, and the like.

The term "alkylene" refers to a diradical of a branched or unbranched saturated arbon chain, having 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11,12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably 1, 2, 3, 4, 5 or 6 carbon atoms. This term is ified by groups such as methylene (—CH2—), ethylene (—CH2CH2—), the propylene isomers (e. g., 2CH2— and —CH(CH3)CH2—) and the like.

The term "substituted alkyl" or “substituted alkylene” refers to: 1) an alkyl group or alkylene group as defined above, having 1, 2, 3, 4 or 5 substituents, preferably 1, 2 or 3 substituents, selected from the group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, kylamino, dialkylamino, arylamino, heteroarylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, y, carboxyalkyl, —SOgH, aryl, aryloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, —S(O)2NRaRa, —NR*‘S(O)2Ra and —S(O)pr, where each R21 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl, heterocyclyl and heterocyclylalkyl; heterocyclyloxy where Rb is hydrogen, alkyl, aryl, aryl or heterocyclyl. Unless ise constrained by the definition, all substituents may optionally be further substituted by l, 2, or 3 tuents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and —S(O)pRC, where RC is alkyl, aryl, or heteroaryl and p is 0,1 or 2; or 2) an alkyl group or alkylene group as defined above that is upted by l, 2, 3, 4, 5, 6, 7, 8, 9 or 10 atoms independently selected from oxygen, sulfur and NRd, where R01 is selected from hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl, ylalkyl, carboxyester, carboxyamide and sulfonyl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or —S(O)pRC, in which RC is alkyl, aryl, or heteroaryl and p is 0, l, or 2; or 3) an alkyl or ne as defined above that has 1, 2, 3, 4 or 5 substituents as defined above, as well as interrupted by l, 2, 3, 4, 5, 6, 7, 8, 9 or 10 atoms as defined above.

The term yl" refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2, 3, 4, 5, 6, 7, 8, 9, 10, ll, l2, l3, 14, 15, l6, 17, 18, 19 or 20 carbon atoms, more preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and even more preferably 2, 3, 4, 5 or 6 carbon atoms and having 1, 2, 3, 4, 5 or 6 double bond (vinyl), ably 1 double bond. Preferred alkenyl groups include ethenyl or —CH=CH2), l—propylene or allyl (— CH2CH=CH2), isopropylene (—C(CH3)=CH2), bicyclo [2.2. l] heptene, and the like.

The term "alkenylene" refers to a diradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, more ably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and even more preferably 2, 3, 4, 5 or 6 carbon atoms and having 1, 3, 4, 5 or 6 double bond (vinyl), ably 1 double bond.

The term "substituted alkenyl" refers to an alkenyl group as defined above having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, lkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, thiocarbonyl, carboxy, carboxyalkyl, —SOgH, aryl, y, aryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, —S(O)2NRaRa, — NRZ‘S(O)2Ra and 6(0)pr Where each R21 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl arylalkyl, heterocyclyl and cyclylalkyl; heterocyclyloxywhere Rb is alkyl, aryl, heteroaryl or heterocyclyl and p is 0, 1 or 2.

Unless otherwise constrained by the definition, all substituents may optionally be further substituted by l, 2, or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, n, CF3, amino, substituted amino, cyano, and —S(O)pRC, Where RC is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.

The term "alkynyl" refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or carbon atoms, more preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and even more preferably 2, 3, 4, 5 or 6 carbon atoms and having 1, 2, 3, 4, 5 or 6 sites of acetylene (triple bond) unsaturation, preferably 1 triple bond. red alkynyl groups include ethynyl, (—CECH), propargyl (or prop—l—yn-3—yl,—CH2CECH), homopropargyl (or but—l—yn—4—yl, —CH2CH2CECH) and the like.

The term "alkynylene" refers to a diradical of a ed or unbranched unsaturated hydrocarbon group preferably having from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, more preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and even more preferably 2, 3, 4, 5 or 6 carbon atoms and having 1, 3, 4, 5 or 6 sites of acetylene (triple bond) unsaturation, preferably 1 triple bond.

The term "substituted alkynyl" refers to an alkynyl group as d above having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3 substituents, selected from the group consisting of alkyl, alkenyl, l, , lkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, —SOgH, aryl, aryloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, — S(O)2NRaRa, -NR*‘S(O)2Ra and —S(O)pr, where each R21 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl, cyclyl and heterocyclylalkyl; heterocyclyloxy where Rb is alkyl, aryl, heteroaryl or heterocyclyl and p is 0, l or 2. Unless otherwise constrained by the definition, all substituents may optionally be further tuted by l, 2, or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, , halogen, CF3, amino, substituted amino, cyano, and—S(O)pRC where RC is alkyl, aryl, or heteroaryl and p is 0, l or 2.

The term alkyl" refers to carbocyclic groups of from 3 to 20 carbon atoms haVing a single cyclic ring or multiple condensed rings which may be partially unsaturated. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, bicyclo[2.2.l]heptane, l,3,3—trimethylbicyclo[2.2.l]hept—2—yl, (2,3,3—trimethylbicyclo[2.2.l]hept—2—yl), or carbocyclic groups to which is fused an aryl group, for example indane, and the like.

The term "substituted cycloalkyl" refers to cycloalkyl groups having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3 substituents, selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, carbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, cyclyl, cyclyloxy, hydroxyamino, alkoxyamino, nitro, — C(O)R and —S(O)pr, where R is hydrogen, hydroxyl, alkoxy, alkyl and cyclocalkyl, heterocyclyloxy where Rb is alkyl, aryl, heteroaryl or heterocyclyl and p is 0, l or 2. Unless otherwise ained by the definition, all substituents may optionally be further tuted by l, 2, or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and—S(O)pRC, where RC is alkyl, aryl, or heteroaryl and p is 0, l or 2.

“Halo” or “Halogen”, alone or in combination with any other term means halogens such as chloro (Cl), ?uoro (F), bromo (Br) and iodo (I).

[0044] “Haloalkyl” refers to a straight chain or branched chain kyl group with l to 6 carbon atoms. The alkyl group may be partly or totally halogenated.

Representative examples of haloalkyl groups include but are not limited to fluoromethyl, chloromethyl, bromomethyl, di?uoromethyl, dichloromethyl, omethyl, tri?uoromethyl, trichloromethyl, oethyl, 2—chloroethyl, 2— bromoethyl, tri?uoroethyl, 3—?uoropropyl, 3—chloropropyl, 3—bromopropyl and the like.

The term "alkoxy" refers to the group R"'—O—, where R'" is optionally substituted alkyl or optionally substituted cycloalkyl, or optionally substituted alkenyl or ally substituted alkynyl; or optionally substituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl are as defined herein.

Representative examples of alkoxy groups include but are not d to y, ethoxy, n—propoxy, iso—propoxy, n—butoxy, tert—butoxy, sec—butoxy, n—pentoxy, n— hexoxy, l,2—dimethylbutoxy, trifluoromethoxy, and the like.

The term "aminocarbonyl" refers to the group —C(O)NR'R' where each R' is ndently hydrogen, alkyl, aryl, heteroaryl, heterocyclyl or both R' groups are joined to form a heterocyclic group (e. g. morpholino). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1—3 substituents selected from alkyl, carboxy, yalkyl, aminocarbonyl, hydroxy, alkoxy, n, CF3, amino, substituted amino, cyano, and —S(O)pRC, where RC is alkyl, aryl, or heteroaryl and p is 0, l or 2.

The term "acylamino" refers to the group —NR"C(O)R" where each R" is independently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. Unless ise constrained by the definition, all substituents may optionally be further substituted by 1—3 tuents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, O)pRC, where RC is alkyl, aryl, or heteroaryl and p is 0, l or 2.

The term "acyloxy" refers to the groups —OC(O)—alkyl, —cycloalkyl, — OC(O)—aryl, —OC(O)—heteroaryl, and —OC(O)—heterocyclyl. Unless otherwise constrained by the tion, all substituents may be optionally further substituted by alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, or —S(O)pRC, where RC is alkyl, aryl, or heteroaryl andp is 0, l or 2.

The term “alkoxyalkyl” refers to alkyl groups as defined above wherein at least one of the hydrogen atoms of the alkyl group is replaced by an alkoxy group as defined above. Representative examples of alkyl groups include but are not limited to methoxymethyl, methoxyethyl, ethoxymethyl and the like.

The term “aryloxyalkyl” refers to the group —alkyl—O—aryl. Representative examples of aryloxyalkyl include but are not limited to phenoxymethyl, naphthyloxymethyl, phenoxyethyl, naphthyloxyethyl and the like.

[0051] The term “di alkylamino” refers to an amino group, to which two same or different straight chain or branched chain alkyl groups with l to 6 carbon atoms are bound. entative examples of di alkylamino include but are not limited to dimethylamino, diethylamino, methylethylamino, dipropylamino, dibutylamino and the like.

[0052] The term alkylalkyl” refers to an alkyl radical as defined above which is substituted by a cycloalkyl radical as defined above. Representative examples of cycloalkylalkyl include but are not limited to ropylmethyl, cyclobutylmethyl, entylmethyl, cyclohexylmethyl, l—cyclopentylethyl, l— cyclohexylethyl, 2—cyclopentylethyl, 2—cyclohexylethyl, cyclobutylpropyl, cyclopentylpropyl, cyclohexylbutyl and the like.

The term “aminoalkyl” refers to an amino group that is ed to (C1- 6)alkylene as defined herein. Representative examples of aminoalkyl include but are not limited to aminomethyl, aminoethyl, l—aminopropyl, 2—aminopropyl, and the like. The amino moiety of aminoalkyl may be substituted once or twice with alkyl to provide alkylaminoalkyl and dialkylaminoalkyl respectively.

Representative examples of alkylaminoalkyl include but are not limited to methylaminomethyl, methylaminoethyl, methylaminopropyl, ethylaminoethyl and the like. Representative examples of dialkylaminoalkyl include but are not limited to dimethylaminomethyl, dimethylaminoethyl, ylaminopropyl, N—methyl—N— ethylaminoethyl and the like.

The term "aryl" refers to an aromatic carbocyclic group of 6 to 20 carbon atoms having a single ring (e.g. phenyl) or multiple rings (e.g. biphenyl), or multiple condensed ) rings (e.g. yl or anthranyl). Preferred aryls include , naphthyl and the like.

[0055] The term "arylene" refers to a diradical of an aryl group as defined above.

This term is exemplified by groups such as l,4—phenylene, enylene, 1,2— phenylene, l,4'—biphenylene, and the like.

Unless otherwise constrained the aryl or arylene groups may optionally be substituted with l, 2, 3 4 or 5 substituents, ably 1, 2 or 3 substituents, ed from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, carboxy, carboxyalkyl, —SOgH, aryl, y, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, —S(O)2NRaRa, —NR*‘S(O)2Ra and 6(0)pr where each R21 is independently selected from the group consisting of hydrogen, alkyl, lkyl, cycloalkylalkyl, aryl, arylalkyl, aryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; where Rb is hydrogen, alkyl, aryl, heterocyclyl or heteroaryl and p is 0, l or 2. Unless otherwise ained by the definition, all substituents may optionally be further substituted by l, 2 or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and —S(O)pRC where RC is hydrogen, alkyl, aryl, or heteroaryl and p is 0, 1 or 2.

The term lkyl" refers to an aryl group covalently linked to an alkylene group, where aryl and alkylene are defined herein.

The term "optionally substituted arylalkyl" refers to an optionally substituted aryl group covalently linked to an ally substituted alkylene group.

Such arylalkyl groups are exemplified by benzyl, phenethyl, naphthylmethyl, and the like.

The term "aryloxy" refers to the group —O—aryl, n the aryl group is as d above and includes optionally substituted aryl groups as also defined above.

The term "arylthio" refers to the group —S—aryl, where aryl group is as defined herein including optionally substituted aryl groups as also defined above.

The term ituted amino" refers to the group —NR'R' where each R' is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, carboxyalkyl, alkoxycarbonyl, aryl, heteroaryl and heterocyclyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by l, 2 or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, n, CF3, amino, substituted amino, cyano, and —S(O)pRC, where RC is alkyl, aryl, or aryl and p is 0, 1 or 2.

The term "carboxyalkyl" refers to the group —alkylene—C(O)OH.

The term "alkylcarboxyalkyl" refers to the group —alkylene—C(O)ORG1 where R01 is alkyl, lkyl, where alkyl, cycloalkyl are as defined herein, and may be optionally further substituted by alkyl, halogen, CF3, amino, substituted amino, cyano, or —S(O)pRC, in which RC is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.

The term "heteroaryl" refers to an aromatic cyclic group having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 carbon atoms and l, 2, 3 or 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring. Such heteroaryl groups can have a single ring (e.g. l or furyl) or multiple condensed rings (e. g. indolizinyl, benzothiazolyl, or benzothienyl). Examples of heteroaryls include, but are not limited to, [1,2,4] zole, [1,3,4] oxadiazole, [1,2,4] thiadiazole, [1,3,4] thiadiazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, ole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, ine, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, furan, thiophene, oxazole, thiazole, triazole, ne and the like.

The term "heteroarylene" refers to a diradical of a heteroaryl group as defined above.

Unless otherwise constrained the heteroaryl or heterarylene groups can be optionally substituted with l, 2, 3, 4 or 5 substituents, preferably 1, 2 or 3 substituents selected from the group ting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, thiocarbonyl, carboxy, carboxyalkyl, —SOgH, aryl, aryloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, — S(O)2NRaRa, -NR*‘S(O)2Ra and —S(O)pr, Where each R21 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryl heteroarylalkyl, heterocyclyl and heterocyclylalkyl; Where Rb is hydrogen, alkyl, aryl, heterocyclyl or heteroaryl, and p is 0, l or 2. Unless otherwise constrained by the definition, all substituents may optionally be further tuted by 1—3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, , halogen, CF3, amino, substituted amino, cyano, and—S(O)nRC, Where RC is alkyl, aryl, or heteroaryl and n is 0,1 or 2.

The term "heteroarylalkyl" refers to a heteroaryl group covalently linked to an alkylene group, Where heteroaryl and alkylene are defined herein.

The term "optionally tuted heteroarylalkyl" refers to an ally substituted aryl group covalently linked to an optionally substituted alkylene group. Such heteroarylalkyl groups are exemplified by 3—pyridylmethyl, in— hyl, 4—methoxythiazol—2—ylpropyl, and the like.

[0069] The term "heterocyclyl" refers to a saturated or partially unsaturated group having a single ring or multiple condensed rings, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1, 2, 3 or 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring. Heterocyclic groups can have a single ring or multiple condensed rings, and include tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl, tetrahydroquinolinyl and the like. Unless ise constrained by the definition for the heterocyclic substituent, such cyclic groups can be optionally substituted with l, 2, 3, 4 or , and preferably 1, 2 or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, arbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, —C(O)R where R is hydrogen, hydroxyl, , alkyl and alkyl, thiocarbonyl, carboxy, carboxyalkyl, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, and —S(O)pr, where Rb is hydrogen, alkyl, aryl, heterocyclyl or heteroaryl and p is 0, l or 2. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1—3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, , halogen, CF3, amino, substituted amino, cyano, and —S(O)RC, where RC is alkyl, aryl, or heteroaryl and n is 0, l or 2.

The term "heterocyclylalkyl" refers to a heterocyclyl group ntly linked to an alkylene group, where heterocyclyl and alkylene are defined herein.

The term nally substituted heterocyclylalkyl" refers to an optionally substituted cyclyl group covalently linked to an optionally substituted ne group.

The term "heteroaryloxy" refers to the group eroaryl.

[0073] The term "thiol" refers to the group —SH.

The term "substituted alkylthio" refers to the group —S—substituted alkyl.

The term "heteroarylthio" refers to the group —S—heteroaryl wherein the heteroaryl group is as defined above including optionally substituted heteroaryl groups as also defined above.

[0076] The term "sulfoxide" refers to a group —S(O).

WO 23482 2018/050859 The term "substituted sulfoxide" refers to a group , in which R is substituted alkyl, substituted aryl, or substituted heteroaryl, as defined above.

The term "sulfone" refers to a group —S(O)2R, where R is alkyl, aryl, or heteroaryl.

The term “substituted e” refers to a group R, in which R is alkyl, aryl, or heteroaryl.

The term "disorder or condition ameliorated by the inhibition of the AzA receptor" will be understood by those skilled in the art to include: cancer such as prostate, rectal, renal, ovarian, trial, thyroid, pancreatic, particularly breast, colon, bladder, brain, glia, melanoma, pineal gland and, more particularly, lung cancer (e.g. Lewis lung carcinoma).

The nds of the present disclosure may have the ability to crystallize in more than one form, a characteristic known as polymorphism, and all such polymorphic forms ("polymorphs") are encompassed within the scope of the invention. Polymorphism generally can occur as a response to changes in temperature or pressure or both and can also result from ions in the crystallization process. Polymorphs can be distinguished by various physical characteristics, and typically the x—ray diffraction patterns, lity behavior, and melting point of the compound are used to distinguish polymorphs.

[0082] The compounds described herein may contain one or more chiral centers and/or double bonds and therefore, may exist as “stereoisomers”, such as double— bond isomers (i.e., “geometric isomers” enantiomers or , regioisomers, diastereomers. Accordingly, the chemical structures depicted herein encompass all possible enantiomers and isomers of the illustrated or identified compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and isomeric mixtures can be resolved into their component enantiomers or stereoisomers using tion techniques or chiral synthesis techniques well known to the person skilled in the art. The compounds may also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof.

Accordingly, the al structures depicted herein encompass all possible tautomeric forms of the rated or identified compounds.

Compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms and as N—oxides. In general, compounds may be ed, ed or N—oxides. Certain compounds may exist in multiple crystalline or amorphous forms. Also contemplated within the scope of the ion are congeners, s, hydrolysis products, metabolites and precursor or prodrugs of the compound. In general, unless otherwise indicated, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present invention.

The term “prodrug” refers to a derivative of a drug molecule as, for example, esters, carbonates, carbamates, ureas, amides or phosphates that requires a transformation within the body to release the active drug. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the parent drug. Prodrugs may be obtained by g a promoiety (defined herein) typically via a functional group, to a drug.

The term "therapeutically effective dose" means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be 10 treated (e.g., provide a positive clinical response). The effective amount of an active ient for use in a ceutical composition will vary with the ular condition being treated, the severity of the condition, the on of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically— acceptable excipient(s)/carrier(s) utilized, the route of administration, and like factors within the knowledge 15 and expertise of the attending physician.

The term “promoiety” refers to a group bonded to a drug, typically to a functional group of the drug, via bond(s) that are cleavable under specified conditions of use. The bond(s) between the drug and promoiety may be cleaved by enzymatic or non—enzymatic means. Under the ions of use, for example following administration to a patient, the bond(s) between the drug and promoiety may be cleaved to release the parent drug. The cleavage of the promoiety may proceed spontaneously, such as via a hydrolysis reaction, or it may be catalyzed or induced by another agent, such as by an enzyme, by light, by acid, or by a change of or re to a physical or environmental ter, such as a change of temperature, pH, etc. The agent may be endogenous to the conditions of use, such as an enzyme t in the systemic ation to which the prodrug is administered or the acidic conditions of the stomach or the agent may be supplied exogenously.

The phrase “pharmaceutically acceptable excipient” refers to compounds or compositions that are physiologically tolerable and do not typically produce allergic or similar untoward reactions, including but not limited to gastric upset or dizziness when administered to mammal.

The term aceutically acceptable salt” embraces salts with a ceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid and c acids, for example citric, fumaric, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p— toluenesulphonic acid. Pharmaceutically acceptable bases include alkali metal (e. g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases, for example alkyl amines, arylalkyl amines and heterocyclic amines.

Other preferred salts according to the invention are quaternary ammonium compounds wherein an lent of an anion (X—) is associated with the ve charge of the N atom. X— may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, te, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, tri?uoroacetate, methanesulphonate and p— toluenesulphonate. X— is preferably an anion ed from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, ate or tri?uoroacetate.

More preferably X— is chloride, bromide, trifluoroacetate or methanesulphonate.

Furthermore, the compound of Formula I, Formula II, Formula III, or a IV can be its tives, analogs, stereoisomer’s, diastereomers, geometrical isomers, polymorphs, solvates, stals, intermediates, hydrates, metabolites, prodrugs or pharmaceutically acceptable salts and compositions.

It is understood that included in the family of compounds of Formula I, Formula II, Formula III, or Formula IV are isomeric forms ing diastereoisomers, enantiomers, tautomers, and geometrical isomers in “E” or “Z” configurational isomer or a mixture of E and Z s. It is also understood that some isomeric forms such as diastereomers, enantiomers and geometrical isomers can be separated by physical and/or chemical methods by those skilled in the art.

Compounds disclosed herein may exist as single stereoisomers, racemates and or mixtures of enantiomers and/or diastereomers, All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the subject matter described.

[0094] Compounds sed herein include isotopes of hydrogen, carbon, oxygen, ?uorine, chlorine, iodine and sulfur which can be incorporated into the compounds, such as, but not limited to, 2H (D), 3H (T), 11C, 13C, 14C, 15N, 18F, 353, 36Cl, and 125I. Compounds of this disclosure wherein atoms were isotopically labeled for e radioisotopes such as 3H, 13C, 14C, and the like can be used in metabolic studies, kinetic studies, and imaging ques such as positron emission tomography used in understanding the tissue distribution of the drugs.

Compounds of the disclosure where hydrogen is replaced with deuterium may improve the metabolic stability, and cokinetics properties of the drug such as in vivo half—life.

[0095] The pharmaceutical composition comprising compounds of Formula I, Formula II, Formula III, or Formula IV and their s, tautomeric forms, stereoisomers, geometrical isomers, polymorphs, hydrates, es, ceutically acceptable salts, pharmaceutical compositions, metabolites, and prodrugs thereof can also be referred as “composition of the present disclosure”.

[0096] In an embodiment of the present disclosure, there is provided a pharmaceutical composition comprising compound of Formula I and its pharmaceutically acceptable salt, analog, tautomeric form, stereoisomer, geometrical isomer, polymorph, hydrate, solvate, lite, and prodrug thereof 333.,. N’". a Firs—as Rita?»MN Formula I wherein ——— represents a single bond or a double bond; X is ed from O, S or NRa; Y1 is selected from N or CH; Y2 is selected from NR5, 0 or CRSR"; Y3 is selected from N, CH, CH2, C(20), or C(=S); Y4 is selected from N, C, or CH; R1 and R2 are independently selected from hydrogen or alkyl; R3 is —A—Z—B—Q; n, A is absent or is a group selected from alkylene, alkenylene, or alkynylene; wherein one or more methylene groups is ally replaced by hetero atoms or groups such as —O—, —S(O)p—, —N(Ra)—, or —C(O); alkylene, alkenylene and lene is optionally substituted with —(CRdRe)nOR7, (CRdRe)nCOOR7, - (CRdRe)nNR8R9, cyano, halogen, haloalkyl, perhaloalkyl, alkoxyalkoxy, alkyl, or cycloalkyl; Z is absent or is selected from a cycloalkyl or a heterocyclyl; wherein lkyl and heterocyclyl are unsubstituted or substituted independently with l, 2, or 3 substituents independently selected from alkyl, alkenyl, alkynyl, acyl, — (CRdRe)nOR7, (CRdRe)nCOOR7, —(CRdRe)nNR8R9, aminocarbonyl, alkoxycarbonylamino, halogen, haloalkyl, perhaloalkyl, azido, cyano, keto, thiocarbonyl, —SOgH, aminocarbonylamino, nitro, NRaRa, —NRbS(O)2Rb or - 3(O)pRC; B is absent or is a group selected from ne, alkenylene or alkynylene; wherein one or more methylene groups is optionally replaced by hetero atoms or groups such as —O—, —S(O)p—, —N(Ra)—, or —C(O); alkylene, alkenylene and alkynylene is optionally tuted with hydroxy, amino, aminoalkyl, cyano, halogen, haloalkyl, perhaloalkyl, carboxy, carboxyalkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkoxy or alkyl; Q is ed from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; wherein alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, cyclylalkyl, heteroaryl and heteroarylalkyl are unsubstituted or tuted independently with l, 2, or 3 substituents independently selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, perhaloalkyl, azido, cyano, nitro, keto, rbonyl, cyanoalkyl, cyanoalkylcarbonyl, —(CRdRe)nOR7, —(CRdRe)nC(O)R7, —(CRdRe)nSR7, — (CRdRe)nCOOR7, -(CRdRe)nNR8R9, —(CRdRe)nC(O)NR8R9, —(CRdRe)nNR8C(O)OR7, —(CRdRe)nNR8C(O)NR8R9, -NRbS(O)2Rb, —S(O)pRC, —SOsH, —S(O)2NRaRa, cycloalkyl, cycloalkenyl, cycloalkylalkyl aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; wherein each substituent is unsubstituted or tuted with l, 2, or 3 substituents independently selected from alkyl, y, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, haloalkyl, oalkyl, haloalkoxy, perhaloalkoxy, arnino, substituted amino, cyano or — 3(O)pRC; R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, carboxyalkyl, lkyl, cycloalkylalkyl, aryl, kyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, lkylalkyl, arylalkyl, aryl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl are unsubstituted or substituted independently with up to four substituents independently selected from alkyl, l, alkynyl, acyl, —(CRdRe)nOR7, (CRdRe)nCOOR7, -(CRdRe)nNR8R9, aminocarbonyl, alkoxycarbonylamino, aminocarbonylamino, azido, cyano, halogen, kyl, perhaloalkyl, keto, nitro, —S(O)2NRbRb, —NRbS(O)2Rb or — C, thiocarbonyl, —SOgH, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl; R5 and R6 are independently selected from the group consisting of hydrogen, hydroxy, —(CRdRe)nOR7, (CRdRe)nCOOR7, —(CRdRe)nNR8R9, cyanoalkyl, haloalkyl, alkoxyalkoxyalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; R7 is selected from hydrogen, alkyl, halogen, haloalkyl, e)nOR7, — (CRdRe)nCOOR7, —(CReRe)nC(O)R7, carbonylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or cyclylalkyl; R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, e)nOR7, —(CRdRe)nC(O)R7, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl, or R8 and R9 taken er form a monocyclic or a bicyclic ring system which is saturated or partially rated and optionally have additional heteroatoms selected from O, N or S, said ring system is further ally substituted with l to 4 substituents independently selected from halo, alkyl, alkenyl, l, nitro, cyano, —(CRdRe)nOR7, —(CRdRe)nSR7, —(CRdRe)nNR8R9, oxo, alkylsulfonyl, — (CRdRe)nCOOR7, —(CRdRe)nC(O)NR8R9, cycloalkyl, lkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R21 is selected from hydrogen or alkyl; Rb each is independently selected from the group consisting of hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; RC is selected from alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl; R01 and Re are independently selected from the group consisting of en, —OR7, halogen, haloalkyl, perhaloalkyl and alkyl; n is 0, l, 2, 3 or 4, and p is 0, l or 2, for the manufacture of a medicament for the treatment of a condition or disorder ameliorated by inhibition of the AzA/AzB receptor.

In an embodiment of the present disclosure, there is provided a pharmaceutical composition comprising compound of Formula I and its pharmaceutically acceptable salt, analog, tautomeric form, stereoisomer, geometrical , rph, hydrate, solvate, lite, and prodrug thereof, wherein ——— represents a double bond; X is selected from O, S or NRa; Y1 is selected from N or CH; Y2 is selected from NR5 or CR5R6; Y3 is selected from N, CH or CH2; Y4 is selected from N or C; R1 and R2 are independently selected from hydrogen or alkyl; R3 is —Q; wherein, A is absent or is alkylene wherein one or more methylene groups is optionally replaced by hetero atoms or groups selected from the group consisting of —O—, —S(O)p— or —C(O); alkylene is optionally substituted with — , —N(Ra)— , (CRdRe)nOR7, cyano, n, haloalkyl, perhaloalkyl, alkyl or cycloalkyl; Z is absent or is selected from a cycloalkyl or a heterocyclyl; wherein cycloalkyl and heterocyclyl are unsubstituted or substituted independently with l, 2, or 3 substituents ndently selected from alkyl, acyl, — (CRdRe)nOR7, (CRdRe)nCOOR7, —(CRdRe)nNR8R9, aminocarbonyl, carbonylamino, halogen, haloalkyl, perhaloalkyl, azido, cyano, halogen, keto, thiocarbonyl, —SOgH, aminocarbonylamino, nitro, —S(O)2NRaRa, — NRbS(O)2Rb or —S(O)pRC; B is absent or is alkylene wherein one or more methylene groups is optionally replaced by hetero atoms or groups selected from the group consisting of —O—, —S(O)p— or —C(O); alkylene is optionally substituted with hydroxy, , —N(Ra)— , amino, aminoalkyl, cyano, halogen, kyl, perhaloalkyl, carboxy, carboxyalkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkoxy or alkyl; Q is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, aryl or heteroarylalkyl; wherein alkyl, cycloalkyl, cycloalkylalkyl, aryl, kyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl are unsubstituted or substituted independently with l, 2, or 3 substituents independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkyl, oalkyl, azido, cyano, nitro, halogen, keto, thiocarbonyl, cyanoalkyl, cyanoalkylcarbonyl, —(CRdRe)nOR7, — (CRdRe)nC(O)R7, —(CRdRe)nSR7, e)nCOOR7, —(CRdRe)nNR8R9, — (CRdRe)nC(O)NR8R9, —(CRdRe)nNR8C(O)OR7, —(CRdRe),NR8C(O)NR8R9, — NRbS(O)2Rb, —S(0)pRC, —SOgH, NRaRa, cycloalkyl, cycloalkenyl, cycloalkylalkyl aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; wherein each substituent is unsubstituted or substituted with l, 2, or 3 substituents independently selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, n, haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, amino, substituted amino, cyano or —S(O)pRC; R4 is ed from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; wherein alkyl, cycloalkyl, cycloalkylalkyl, kyl, aryl, heteroaryl, heteroarylalkyl, cyclyl, and heterocyclylalkyl are unsubstituted or independently substituted with up to four substituents independently selected from alkyl, acyl, —(CRdRe)nOR7, )nCOOR7, e)nNR8R9, aminocarbonyl, alkoxycarbonylamino, aminocarbonylamino, azido, cyano, halogen, haloalkyl, perhaloalkyl, keto, nitro, —S(O)2NRbRb, —NRbS(O)2Rb or —S(O)pRC, thiocarbonyl, —SOgH, cycloalkyl, lkenyl, aryl, heteroaryl or heterocyclyl ; R5 and R6 are independently selected from the group consisting of hydrogen, hydroxy, —(CRdRe)nOR7, )nCOOR7, —(CRdRe)nNR8R9, cyanoalkyl, haloalkyl, alkoxyalkoxyalkyl, alkyl, alkenyl, alkynyl, lkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; R7 is selected from hydrogen, alkyl, halogen, haloalkyl, ylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, arylalkyl, heterocyclyl or heterocyclylalkyl; R8 and R9 are ndently selected from the group consisting of hydrogen, alkyl, haloalkyl, —(CRdRe)nOR7, —(CRdRe)nC(O)R7, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl, or R8 and R9 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S, said ring system is further optionally substituted with l to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nitro, cyano, —(CRdRe)nOR7, —(CRdRe)nSR7, —(CRdRe)nNR8R9, oxo, ulfonyl, — (CRdRe)nCOOR7, e)nC(O)NR8R9, cycloalkyl, lkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R21 is selected from hydrogen or alkyl; Rb each is independently selected from the group consisting of hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, lkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; RC is selected from alkyl, cycloalkyl, aryl, cyclyl or heteroaryl; R01 and Re are independently selected from the group consisting of hydrogen, — 0R7, halogen, haloalkyl, perhaloalkyl and alkyl; nis0, 1,2, 3 or4and p is 0, l or 2, for the manufacture of a medicament for the treatment of a condition or disorder ameliorated by inhibition of the AzA/AzB receptor.

[0098] In an embodiment of the present sure, there is provided a ceutical composition comprising compound of Formula I and its pharmaceutically acceptable salt, analog, tautomeric form, stereoisomer, geometrical isomer, polymorph, hydrate, solvate, metabolite, and prodrug thereof, ——— represents a double bond; X is selected from O or S; Y1 represents N; Y2 represents NR5; Y3 represents N; Y4 represents C; R1 and R2 are independently selected from hydrogen or alkyl; R3 is —A—Z—B—Q; wherein, A is absent or is alkylene wherein one or more methylene groups is optionally replaced by hetero atoms or groups selected from the group consisting of —O—, —S(O)p—, —N(Ra)—, or —C(O); Z is absent or is a heterocyclyl; wherein the heterocyclyl is unsubstituted or substituted independently with l, 2, or 3 substituents independently selected from alkyl, acyl, —(CRdRe)n0R7, (CRdRe)nCOOR7, —(CRdRe)nNR8R9, haloalkyl, perhaloalkyl, cyano, halogen, keto, thiocarbonyl, —SOgH, nitro, —S(O)2NRaRa, —NRbS(O)2Rb or —S(O)pRC; B is absent or is alkylene wherein one or more methylene groups is ally replaced by hetero atoms or groups selected from the group consisting of —O—,— 3(O)P-, —N(Ra)-, 0r —C(O); Q is selected from hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl; wherein alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl are unsubstituted or ndently substituted with l, 2, or 3 substituents independently selected from alkyl, alkoxy, alkyl, haloalkyl, perhaloalkyl, azido, cyano, nitro, halogen, keto, thiocarbonyl, cyanoalkyl, cyanoalkylcarbonyl, —(CRdRe)nOR7, — (CRdRe)nC(O)R7, —(CRdRe)nSR7, —(CRdRe)nCOOR7, —(CRdRe)nNR8R9, — (CRdRe)nC(O)NR8R9, —(CRdRe)nNR8C(O)OR7, —(CRdRe)nNR8C(O)NR8R9, — NRbS(O)2Rb, —S(0)pRC, —SOgH, —S(O)2NRaRa, cycloalkyl, cycloalkenyl, cycloalkylalkyl aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; wherein each substituent is unsubstituted or substituted with l, 2, or 3 substituents independently selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, n, haloalkyl, perhaloalkyl, koxy, perhaloalkoxy, amino, substituted amino, cyano or —S(O)pRC; R4 is ed from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, carboxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; wherein alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, aryl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl are unsubstituted or independently substituted with up to four substituents independently selected from alkyl, acyl, e)nOR7, (CRdRe)nCOOR7, —(CRdRe)nNR8R9, aminocarbonyl, carbonylamino, aminocarbonylamino, azido, cyano, halogen, kyl, oalkyl, keto, nitro, —S(O)2NRbRb, O)2Rb or —S(O)pRC, thiocarbonyl, —SOgH, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl; R5 and R6 are independently selected from the group consisting of hydrogen, hydroxy, —(CRdRe)nOR7, (CRdRe)nCOOR7, —(CRdRe)nNR8R9, cyanoalkyl, haloalkyl, alkoxyalkoxyalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; R7 is selected from hydrogen, alkyl, halogen, haloalkyl, carbonylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl; R8 and R9 are ndently selected from the group consisting of en, alkyl, haloalkyl, —(CRdRe)nOR7, —(CRdRe)nC(O)R7, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl, or R8 and R9 taken together form a monocyclic or a ic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S, said ring system is r optionally substituted with l to 4 substituents ndently selected from halo, alkyl, alkenyl, alkynyl, nitro, cyano, —(CRdRe)nOR7, —(CRdRe)nSR7, e)nNR8R9, oxo, alkylsulfonyl, — (CRdRe)nCOOR7, —(CRdRe)nC(O)NR8R9, cycloalkyl, cycloalkylalkyl, aryl, kyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R21 is selected from hydrogen or alkyl; Rb each is independently selected from the group consisting of hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; RC is selected from alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl; R01 and Re are ndently selected from the group consisting of hydrogen, — 0R7, halogen, haloalkyl, oalkyl or alkyl; nis0, 1,2, 3 or4and p is 0, l or 2, for the manufacture of a medicament for the treatment of a condition or disorder ameliorated by inhibition of the AzA/AzB receptor.

In an embodiment of the present sure, there is provided a pharmaceutical composition comprising compound of a I and its pharmaceutically acceptable salt, , tautomeric form, stereoisomer, rical isomer, polymorph, hydrate, e, lite, and g thereof, wherein ——— represents a double bond; X selected from O or S; Y1 represents N; Y2 represents NR5; Y3 represents N; Y4 ents C; R1 and R2 are independently selected from hydrogen or alkyl; R3 is —A—Z—B—Q; wherein, A is absent or is alkylene n one or more methylene groups is optionally replaced by hetero atoms or groups ed from the group consisting of —O—or —N(Ra)—; Z is absent or is a heterocyclyl; wherein the heterocyclyl is unsubstituted or substituted independently with l, 2, or 3 substituents independently selected from alkyl, —(CRdRe)nOR7, (CRdRe)nCOOR7, haloalkyl, perhaloalkyl, cyano, halogen, keto or thiocarbonyl; B is absent or is alkylene wherein one or more methylene groups is optionally replaced by hetero atoms or groups selected from the group consisting of —O—,— N(Ra)—, or —C(O); Q is selected from hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl; wherein alkyl, cycloalkyl, aryl, cyclyl and heteroaryl are unsubstituted or independently substituted with l, 2, or 3 substituents independently selected from alkyl, alkoxy, alkoxyalkyl, haloalkyl, perhaloalkyl, cyano, halogen, keto, thiocarbonyl, cyanoalkyl, —(CRdRe)nOR7, —(CRdRe)nC(O)R7, —(CRdRe)nCOOR7, —(CRdRe)nNR8R9, —(CRdRe)nC(O)NR8R9, —(CRdRe)nNR8C(O)OR7, —S(0)pRC, —SOgH, NRaRa, cycloalkyl, lkenyl, aryl, heterocyclyl or heteroaryl; wherein each substituent is unsubstituted or substituted with l, 2, or 3 substituents independently selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, amino, substituted amino, cyano or —S(O)pRC; R4 is selected from the group consisting of hydrogen, alkyl, kyl, hydroxyalkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl; wherein alkyl, lkyl, aryl, heteroaryl and heterocyclyl are unsubstituted or independently substituted with up to four substituents independently selected from alkyl, —(CRdRe)nOR7, (CRdRe)nCOOR7, —(CRdRe)nNR8R9,cyano, halogen, haloalkyl, perhaloalkyl, nitro, —S(O)2NRbRb, —NRbS(O)2Rb, —S(0)pRC, thiocarbonyl, —SOgH, cycloalkyl, aryl, aryl or heterocyclyl; R5 is selected from the group consisting of hydrogen, hydroxy, haloalkyl, — (CRdRe)nOR7, —(CRdRe)nCOOR7, alkoxyalkoxyalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; R7 is selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, e)nOR7, —(CRdRe)nC(O)R7, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl and cyclylalkyl, or R8 and R9 taken er form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S, said ring system is further optionally substituted with l to 4 tuents independently selected from halo, alkyl, nitro, cyano, — (CRdRe)nOR7, —(CRdRe)nNR8R9, oxo, alkylsulfonyl, e)nCOOR7 or — (CRdRe)nC(O)NR8R9; R21 is selected from en or alkyl; Rb each is independently selected from the group consisting of hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, lkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl; RC is selected from alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl; R01 and Re are independently selected from the group consisting of en, — 0R7, halogen, haloalkyl, perhaloalkyl and alkyl; nis0, l,2,3or4and p is 0, l or 2, for the manufacture of a medicament for the treatment of a condition or disorder ameliorated by inhibition of the AzA/AzB receptor.

] In an embodiment of the present disclosure, there is provided a pharmaceutical composition comprising compound of Formula I and its pharmaceutically acceptable salt, , tautomeric form, stereoisomer, geometrical isomer, polymorph, hydrate, solvate, metabolite, and prodrug thereof, wherein ——— represents a double bond; X is selected from O or S; Y1 represents N; Y2 represents NR5; Y3 represents N; 4represents C; R1 and R2 are independently selected from hydrogen or alkyl; R3 is —A—Z—B—Q; wherein, A is absent or is alkylene wherein one or more methylene groups is optionally replaced by hetero atoms or groups selected from the group consisting of —O—or —N(Ra)—; Z is absent or is a heterocyclyl selected from dihydrofuranyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, dihydropyrrole, dihydropyranyl, tetrahydropyranyl, pyrazolidinyl, imidazolidinyl, dihydropyridinyl, ydropyridinyl, piperidinyl, dihydropyrazinyl, tetrahydropyrazinyl, piperazinyl or opyridinyl; wherein the heterocyclyl is tituted or substituted independently with l, 2, or 3 substituents independently selected from alkyl, —(CRdRe)nOR7, )nCOOR7, haloalkyl, perhaloalkyl, cyano or halogen; B is absent or is alkylene wherein one or more methylene groups is optionally replaced by hetero atoms or groups selected from the group consisting of —O—,— N(Ra)—, or —C(O); Q is selected from hydrogen, alkyl, cyclopropyl, entyl, cyclohexyl, phenyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyridinyl, tetrahydropyranyl, piperazinyl, iaxolyl, tetrahydroquinolinyl, linyl, tetrahydronaphthyridinyl, tetrahydrothienopyridinyl, furanyl, pyridinyl, pyrimidinyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, indolyl, quinolinyl, nolinyl or benzooxazolyl; wherein Q is unsubstituted or substituted with l, 2, or 3 substituents independently selected from alkyl, alkoxy, alkoxyalkyl, haloalkyl, perhaloalkyl, cyano, halogen, keto, thiocarbonyl, cyanoalkyl, e)nOR7, e)nC(O)R7, — (CRdRe)nCOOR7, —(CRdRe)nNR8R9, e)nC(O)NR8R9, — (CRdRe)nNR8C(O)OR7, —S(O)pRC, —SO3H, —S(O)2NRaRa, cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl; wherein each substituent is unsubstituted or substituted with l, 2, or 3 substituents ndently selected from alkyl, carboxy, carboxyalkyl, arbonyl, hydroxy, alkoxy, halogen, haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, amino, substituted amino, cyano or RC; R4 is ed from the group consisting of hydrogen, alkyl, phenyl, naphthyl, furanyl, thiazolyl, oxazolyl, azolyl, oxadiazolyl, pyrazinyl, pyridinyl and pyrimidinyl; wherein R4 is unsubstituted or substituted with up to four substituents independently selected from alkyl, —(CRdRe)nOR7, (CRdRe)nCOOR7, — (CRdRe)nNR8R9, cyano, n, haloalkyl, perhaloalkyl or cycloalkyl; R5 is selected from the group consisting of hydrogen, hydroxy, haloalkyl, — (CRdRe)nOR7, —(CRdRe)nCOOR7, alkoxyalkoxyalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, cyclylalkyl, heteroaryl and heteroarylalkyl; R7 is selected from hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, —(CRdRe)nOR7, —(CRdRe)nC(O)R7, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl, or R8 and R9 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms ed from O, N or S, said ring system is further optionally substituted with l to 4 substituents independently selected from halo, alkyl, nitro, cyano, — (CRdRe)nOR7, —(CRdRe)nNR8R9, oxo, alkylsulfonyl, —(CRdRe)nCOOR7 or — (CRdRe)nC(O)NR8R9; R21 is selected from hydrogen or alkyl; Rb at each occurrence is independently selected from the group consisting of hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, lkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl; RC is selected from alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl; R01 and Re are independently selected from the group consisting of hydrogen, — 0R7, halogen, haloalkyl, perhaloalkyl and alkyl; nis0, 1,2, 3 or4and p is 0, l or 2, for the manufacture of a ment for the treatment of a condition or disorder ameliorated by inhibition of the AzA/AzB or.

In an embodiment of the present disclosure, there is provided a ceutical ition comprising nd of Formula I and its pharmaceutically acceptable salt, analog, eric form, stereoisomer, geometrical isomer, polymorph, hydrate, solvate, metabolite, and prodrug thereof as disclosed herein, for use in the treatment of a condition or disorder selected from prostate cancer, rectal cancer, renal cancer, ovarian cancer, endometrial , thyroid , pancreatic , breast cancer, colon cancer, bladder cancer, brain cancer, glial cancer, melanoma cancer, pineal gland cancer, or lung cancer.

In an embodiment of the present disclosure, there is provided a method of using the pharmaceutical composition comprising compound of Formula I and its pharmaceutically acceptable salt, , tautomeric form, stereoisomer, rical isomer, polymorph, hydrate, solvate, metabolite, and prodrug thereof as disclosed herein, in the treatment of a disease or condition in a mammal that is amenable to treatment with an B receptor antagonist, the method sing: administering to a mammal in need thereof a therapeutically effective dose of the pharmaceutical composition comprising compound of Formula 1, its ceutically acceptable salt, analog, tautomeric form, stereoisomer, geometrical isomer, polymorph, hydrate, solvate, metabolite, and prodrug thereof.

In an embodiment of the present disclosure, there is provided a method of treatment of a disorder or condition ameliorated by antagonizing the AzA/AzB receptor, the method sing: administering an effective amount of the pharmaceutical composition comprising compound of Formula I, its pharmaceutically acceptable salt, analog, tautomeric form, stereoisomer, geometrical isomer, rph, e, e, metabolite, and prodrug thereof as disclosed herein to a patient in need of such treatment.

In an embodiment of the present disclosure, there is provided a use of the pharmaceutical composition comprising compound of Formula I, its pharmaceutically acceptable salt, analog, tautomeric form, isomer, geometrical isomer, polymorph, hydrate, solvate, metabolite, and prodrug thereof as disclosed herein, for the preparation of a medicament for the treatment of a condition or disorder selected from prostate , rectal cancer, renal cancer, ovarian cancer, endometrial cancer, thyroid cancer, pancreatic cancer, breast cancer, colon cancer, bladder cancer, brain cancer, glial cancer, melanoma cancer, pineal gland cancer, or lung cancer.

In an embodiment of the present disclosure, there is provided a pharmaceutical composition comprising compound of Formula I, its pharmaceutically acceptable salt, analog, tautomeric form, stereoisomer, geometrical isomer, polymorph, hydrate, solvate, lite, and prodrug thereof as disclosed , in ation with at least one PD—Ll antibody for use in the treatment of a ion or disorder selected from prostate cancer, rectal cancer, renal cancer, n , endometrial cancer, thyroid cancer, pancreatic , breast cancer, colon cancer, bladder , brain cancer, glial cancer, melanoma cancer, pineal gland , or lung cancer.

In an embodiment of the t disclosure, there is provided a use of the pharmaceutical composition comprising compound of Formula I, its pharmaceutically acceptable salt, analog, tautomeric form, stereoisomer, geometrical isomer, polymorph, e, solvate, metabolite, and prodrug thereof as disclosed herein, in combination with at least one PD—Ll antibody for use in the treatment of a condition or disorder selected from prostate cancer, rectal cancer, renal cancer, ovarian cancer, endometrial cancer, thyroid cancer, pancreatic cancer, breast cancer, colon cancer, bladder cancer, brain cancer, glial cancer, melanoma cancer, pineal gland cancer, or lung cancer.

] In an ment of the present disclosure, there is provided a pharmaceutical composition comprising compound of Formula 1, its pharmaceutically acceptable salt, analog, tautomeric form, stereoisomer, geometrical isomer, polymorph, hydrate, solvate, metabolite, and prodrug thereof as disclosed herein, wherein the compound of Formula I is ed from the group consisting of: o—8—(2—furyl)—3 — [2— [4— [4—(2—methoxyethoxy)phenyl]piperazin— l—yl] ethyl] — l — methyl—[l,2,4]triazolo[5,l—f]purin—2—one (1), S—Amino—8—(2—furyl)—3—(2—hydroxyethyl)— l—methyl—[ l ,2,4]triazolo[5 , l—f]purin—2—one —Amino—3 — [2— [4—(2,4—difluorophenyl)piperazin— l —yl] ethyl] —8—(2—furyl)— l—methyl— [l,2,4]triazolo[5, l—f]purin—2—one (3), —Amino—8—(2—furyl)—3 — [2— [4—(4—methoxyphenyl)piperazin— l—yl] ethyl] — 1 —methyl— ]triazolo[5, l—f]purin—2—one (4), —Amino—8—(2—furyl)— yl—3—(2—morpholinoethyl)— [ l riazolo[5 , l —f]purin—2— one (5), 5—Amino—3—[2—[4—(2,4—di?uorophenyl)—l—piperidyl]ethyl]—8—(2—furyl)—l—methyl— [l,2,4]triazolo[5, rin—2—one (6), —Amino—8—(2—furyl)— yl—3— [2—[4—(5—methyl—2—pyridyl)piperazin— l—yl]ethyl] — [l,2,4]triazolo[5, l—f]purin—2—one (7), —Amino—8—(2—furyl)— l—methyl—3— [2—[4—(p—tolyl)piperazin— l —yl]ethyl] — [l,2,4]triazolo[5, l—f]purin—2—one (8), —Amino—8—(2—furyl)— l—methyl—3— [2—[4—(3—methyl—2—oxo—butyl)piperazin— l— yl]ethyl]—[l,2,4]triazolo[5, l—f]purin—2—one (9), —Amino—3—[2—[4—(2—fluoro—4—methoxy—phenyl)piperazin—l—yl]ethyl]—8—(2—furyl)—l— methyl—[l,2,4]triazolo[5,l—f]purin—2—one (10), 5—Amino—8—(2—furyl)—3— [2—[4— [4—(2—methoxy— l , l—dimethyl—ethoxy)phenyl] piperazin— thyl] — l—methyl— [ l ,2,4]triazolo[5 , l—f]purin—2—one (11), —Amin0—8—(2—furyl)—3— [2—[4—(6—meth0xy—3—pyridy1)piperazin— 1 —y1]ethy1] — 1—methy1— [1,2,4]triazolo[5, l—?purin—Z—one (12), —Amin0—3—[2—[4—[3—?u0r0—4—(2—methoxyeth0xy)phenyl]piperazin— 1—y1]ethy1]—8—(2— —1—methy1—[1,2,4]triazolo[5,l—?purin—Z—one (13), —Amin0—8—(2—furyl)—3—[2—[4—[4—(1—hydr0xy—1—methy1—ethyl)phenyl]piperazin—1— yl]ethy1]—1—methy1—[1,2,4]triazolo[5, l—?purin—Z—one (14), —Amin0—3—[2— [4—(4—flu0r0phenyl)—4—hydr0xy— 1—piperidyl]ethyl] —8—(2—fury1)— 1 — methy1—[1,2,4]triazolo[5,l—?purin—Z—one (15), —Amin0—8—(2—furyl)—3— [2—[4— [4—(2—meth0xy—2—methy1—prop0xy)phenyl]piperazin— 1 — yl]ethy1]—1—methy1—[1,2,4]triazolo[5, l—?purin—Z—one (16), —Amin0—3—[2—[4—[4—(cyclopropoxy)phenyl]piperazin— 1—y1]ethy1]—8—(2—fury1)— 1— methy1—[1,2,4]triazolo[5,l—?purin—Z—one (17), —Amin0—3—[2— [4—(4—?u0r0phenyl)—3 ydr0—2H—pyridin—1—y1]ethy1]—8—(2—furyl)— 1—methy1—[1,2,4]triazolo[5, l—?purin—Z—one (18), 5—Amin0—8—(2—furyl)—3— [2—[4—hydr0xy—4—(4—methoxyphenyl)— 1 —piperidyl]ethyl] — 1 — methy1—[1,2,4]triazolo[5,l—?purin—Z—one (19), —Amin0—3—[2— [4—[3 u0r0—4—(2—meth0xyeth0xy)pheny1]piperazin— 1 —y1] ethyl] — 8—(2—fury1)—1—methy1—[1,2,4]triazolo[5,l—?purin—Z—one (20), —Amin0—3—[2— [4—[2,5—di?u0r0—4—(2—rnethoxyeth0xy)phenyl]piperazin— 1 —y1] ethyl] — 8—(2—fury1)—1—methy1—[1,2,4]triazolo[5,l—?purin—Z—one (21), —Amin0—3—[2—[4—(2,2—di?uor0— 1 ,3—benzodi0x01—5—y1)piperazin— thy1]—8—(2— fury1)—1—methy1—[1,2,4]triazolo[5,l—?purin—Z—one (22), —Amin0—8—(2—furyl)—3— [2—[4— [4—(2—meth0xyeth0xy)phenyl] —3 ,3—dimethy1—piperazin— 1—y1]ethy1]—1—methy1—[1,2,4]triazolo[5,l—?purin—Z—one (23), 5—Amin0—3—[2—(4—buty1piperazin—1—y1)ethy1]—8—(2—furyl)—1—methy1— [1,2,4]triazolo[5, l—?purin—Z—one (24), —Amin0—8—(2—furyl)—3—[2—(4—hydr0xy—4—methyl— 1—piperidyl)ethyl]—1—methy1— [1,2,4]triazolo[5, l—?purin—Z—one (25), —Amin0—3—[2—[4—[4—[2—(cyclopr0p0xy)eth0xy]phenyl]piperazin— 1—y1]ethy1]—8—(2— fury1)—1—methy1—[1,2,4]triazolo[5,l—?purin—Z—one (26), —Amin0—8—(2—furyl)—3—[2—[4—[(4—methoxyphenyl)methyl]piperazin— 1—y1]ethy1]— 1— methy1—[1,2,4]triazolo[5,l—?purin—Z—one (27), —Amin0—8—(2—furyl)—3— [2—[4—[[4—(2—methoxyeth0xy)phenyl]methyl]piperazin— 1 — yl]ethy1]—1—methy1—[1,2,4]triazolo[5, l—?purin—Z—one (28), —Amin0—8—(2—furyl)—3—[(4—meth0xyphenyl)methyl]— y1—[1,2,4]triazolo[5, 1— f]purin—Z—one (29), —Amin0—8—(2—furyl)—3—[2—[4—(4—methoxyphenyl)piperazin— 1—y1]ethy1]—1—methy1— [1,2,4]triazolo[5, l—?purin—Z—one (30), —Amin0—8—(2—furyl)—3—[2—[4—[3—(2—meth0xyethoxy)phenyl]piperazin— 1—y1]ethy1]— 1— methy1—[1,2,4]triazolo[5,l—?purin—Z—one (31), —Amin0—3—[2—[4—[2—?u0r0—4—(2—methoxyeth0xy)phenyl]piperazin— 1—y1]ethy1]—8—(2— fury1)—1—methy1—[1,2,4]triazolo[5,l—?purin—Z—one (32), 4—[4—[2—[5—Amin0—8—(2—furyl)— 1—methy1—2—ox0—[1,2,4]triazolo[5, 1—f]purin— 3y1] ethyl] piperazin— 1 nzonitrile (33), 4—[4—[2—[5—Amin0—8—(2—furyl)— 1—methy1—2—ox0—[1,2,4]triazolo[5, 1—f]purin—3— yl] ethyl]piperazin— 1 —y1] —2—?u0r0—benzonitrile (34) , —Amin0—8—(2—furyl)— 1—methy1—3— [2—[4— [4—(triflu0romethyl)phenyl]piperazin— 1— y1]ethy1]—[1,2,4]triazolo[5,1—f]purin—2—one (35), —Amin0—8—(2—furyl)— 1—methy1—3— [2—[4— [4—(trifluoromethyl)thiazol—2—y1]piperazin— 1— y1]ethy1]—[1,2,4]triazolo[5,1—f]purin—2—one (36), —Amino—3—[2—[4—(cyclopropylmethyl)piperazin— 1—y1]ethy1]—8—(2—furyl)— 1—methy1— [1,2,4]triazolo[5, l—?purin—Z—one (37), —Amin0—3—[2—(4—ethy1piperazin— 1—y1)ethyl]—8—(2—fury1)—1—methy1— [1,2,4]triazolo[5, l—?purin—Z—one (38), 4—[2—[5—Amin0—8—(2—fury1)— 1—methy1—2—ox0—[1,2,4]triazolo[5, 1—f]purin—3—y1]ethyl]— methy1—piperazine— 1—sulfonamide (39) , —Amin0—8—(2—furyl)—1—methy1—3—[2—[4—(4—tetrahydr0furan—3— henyl)piperazin—1—y1]ethy1]—[1,2,4]triazolo[5,l—?purin—Z—one (40), 0—8—(2—furyl)—1—methy1—3—[2—[4—(4—tetrahydr0pyran—4— yloxyphenyl)piperazin—1—y1]ethy1]—[1,2,4]triazolo[5,l—?purin—Z—one (41), —Amino—8—(2—furyl)—1—methy1—3—[2—[4—[4—(tetrahydr0furan—2— ylmethoxy)phenyl]piperazin—1—y1]ethyl]—[1,2,4]triazolo[5,1—f]purin—2—0ne (42), 0—8—(2—furyl)— 1—methy1—3—[2—(3—methy1—7,8—dihydr0—5H—1,6—naphthyridin—6— y1)ethy1]—[1,2,4]triazolo[5,1—f]purin—2—one (43), —Amin0—3—[2—(6,7—dihydr0—4H—thieno[3 ,2—c]pyridin—S—y1)ethy1] —8—(2—fury1)— 1 — methy1—[1,2,4]triazolo[5,l—?purin—Z—one (44), —Amin0—8—(2—furyl)—3— [2—[4— [4—(2—methoxyeth0xy)phenyl]piperazin— 1—y1]pr0pyl] — 1—methy1—[1,2,4]triazolo[5, l—?purin—Z—one (45), —Amin0—3—[2—[3—(4—?u0r0phenyl)—2,5—dihydr0pyrrol— 1—y1]ethy1]—8—(2—furyl)— 1— methy1—[1,2,4]triazolo[5,l—?purin—Z—one (46), —Amin0—3—[2—[4—[4—(2—methoxyeth0xy)phenyl]piperazin— 1—y1]ethy1]— 1—methy1—8— (5—methy1—2—furyl)—[1,2,4]triazolo[5, l—?purin—Z—one (47), —Amin0—8—(5—cyclopr0py1—2—furyl)—3— [2—[4— [4—(2— methoxyethoxy)phenyl]piperazin— 1—y1]ethy1]—1—methy1—[1,2,4]triazolo[5, 1—f]purin— 2—0ne (48), —Amino—3—[2—(2,4—di?u0r0anilino)ethyl]—8—(2—fury1)—1—methy1—[1,2,4]triazolo[5,1— f]purin—Z—one (49), —Amin0—3—[3—[4—(4—?u0r0phenyl)piperazin—1—y1]pr0py1]—8—(2—furyl)—1—methy1— [1,2,4]triazolo[5, l—?purin—Z—one (50), 0—8—(2—furyl)—3— [3—[4— [4—(2—methoxyeth0xy)phenyl]piperazin— 1—y1]pr0pyl] — y1—[1,2,4]triazolo[5, l—?purin—Z—one (51), —Amin0—8—(2—furyl)—3— [2—[4—(4—meth0xyphenyl)—3 ,6—dihydr0—2H—pyridin— 1 — y1]—1—methy1—[1,2,4]triazolo[5, l—?purin—Z—one (52), o—8—(2—furyl)—3—[2—[4—[4—(2—methoxy—1,1—dimethy1—ethyl)phenyl]piperazin— 1—y1]ethy1]—1—methy1—[1,2,4]triazolo[5,l—?purin—Z—one (53), —Amin0—8—(2—furyl)— 1—methy1—3—(2—piperazin— 1—ylethy1)—[1,2,4]triazolo[5,1— f]purin—Z—one (54), —Amin0—8—(2—furyl)—3—[2—[4—(1H—indole—2—carb0nyl)piperazin— 1—y1]ethy1]— 1— methy1—[1,2,4]triazolo[5,l—?purin—Z—one (55), 5—Amin0—8—(2—furyl)—3—[2—(4—isopropoxyphenyl)ethyl]—1—methy1—[1,2,4]triazolo[5,1— f]purin—Z—one (56), —Amin0—8—(2—furyl)— 1—methy1—3—[2—[4—[(28)—pyrr01idine—2—carbonyl]piperazin— 1— y1]ethy1]—[1,2,4]triazolo[5,1—f]purin—2—one (57), —Amino—8—(2—furyl)—3—[2—(4—meth0xyphenyl)ethy1]—1—methy1—[1,2,4]triazolo[5,1— f]purin—Z—one (58), —amin0—3 — [2— [4— [4—(di?uoromethoxy)phenyl]piperazin— 1—y1] ethyl] —8—(2—fury1)— 1 — methy1—[1,2,4]triazolo[5,l—?purin—Z—one (59), —Amin0—8—(2—furyl)— 1—methy1—3—[2—[4—[3—(5—methyl— 1,3 ,4—0xadiazol—2— yl)phenyl]piperazin—1—y1]ethy1]—[1,2,4]triazolo[5,l—?purin—Z—one (60), —Amin0—3—[2— ?u0r0—4—(5—methy1— 1 xadiazol—3—y1)pheny1]piperazin— 1— yl]ethy1]—8—(2—furyl)—1—methy1—[1,2,4]triazolo[5,l—?purin—Z—one (61), —Amin0—3—[2—[4—(6—?u0r0—2—methy1— 1 ,3—benzoxazol—S—yl)piperazin— 1—y1]ethy1]—8— (2—fury1)—1—methy1—[1,2,4]triazolo[5, l—?purin—Z—one (62), —Amin0—3—[2—[4—(cyclopr0panecarbonyl)piperazin— 1—y1]ethy1]—8—(2—furyl)— 1— methy1—[1,2,4]triazolo[5,l—?purin—Z—one (63), 0—3—[2—[4—(2—cyclopropylacetyl)piperazin— thy1]—8—(2—furyl)— 1—methy1— [1,2,4]triazolo[5, l—?purin—Z—one (64), —Amin0—8—(2—furyl)—3— [2—[4— [4—(2—hydr0xyethoxy)pheny1]piperazin— 1 —y1]ethy1] — 1— methy1—[1,2,4]triazolo[5,l—?purin—Z—one (65), —Amino—8—(2—furyl)—3—[2—[4—(4—hydr0xyphenyl)piperazin— 1—y1]ethy1]— 1—methy1— [1,2,4]triazolo[5, l—?purin—Z—one (66), S—Amino— 1—(cyclopropylmethyl)—3—[2—[4—(4—eth0xyphenyl)piperazin— 1—y1]ethy1]—8— (2—fury1)—[1,2,4]triazolo[5,1—f]purin—2—one (67), S—Amino— 1—(cyclopropylmethyl)—3—[2—[4—(4—?u0r0phenyl)piperazin— 1—y1]ethy1]—8— (2—fury1)—[1,2,4]triazolo[5,1—f]purin—2—one (68), S—Amino— 1—(cyclopropylmethyl)—3—[2—[4—(2,4—difluorophenyl)piperazin— 1—y1]ethy1]— 8—(2—fury1)—[1,2,4]triazolo[5,1—f]purin—2—0ne (69), S—Amino—1—(cyclopr0pylrnethyl)—8—(2—furyl)—3 —[2— [4— [4—(2— methoxyethoxy)phenyl]piperazin—1—y1]ethy1]—[1,2,4]triazolo[5,1—f]purin—2—0ne (70), S—Amino—1—(cyclopr0pylmethyl)—3—[2—(4—flu0r0phenoxy)ethyl]—8—(2—furyl)— [1,2,4]triazolo[5, l—?purin—Z—one (71), —Amin0—8—(2—furyl)— 1—methy1—3— 0x0—5—(tri?u0r0methyl)— 1—pyridyl]ethyl] — [1,2,4]triazolo[5, l—?purin—Z—one (72), —Amin0—3—[2—[4—(2,4—di?u0r0pheny1)pyrazol—1—y1]ethy1]—l—ethyl—S—(Z—furyl)— [1,2,4]triazolo[5, l—?purin—Z—one (73), 1—[2—[5—Amin0— 1—(cyclopr0pylmethyl)—8—(2—fury1)—2—0xo—[1,2,4]triazolo[5, 1— ?purin—3—y1]ethyl]pyrazole—4—carb0xylic acid (74), 1—[2—[5—Amin0—8—(2—fury1)—1—methy1—2—0xo—[1,2,4]triazolo[5,1—f]purin—3— yl]ethyl]pyrazole—4—carb0xylic acid (75), 1—[2—[5—amin0— 1—(cyclopr0pylmethyl)—8—(2—fury1)—2—0x0—[1,2,4]triazolo[5, 1—f]purin— 3—y1]ethy1]—N—cyclopr0py1—pyrazole—4—carboxamide (76), 1—[2—[5—amin0— 1—(cyclopr0pylmethyl)—8—(2—fury1)—2—0x0—[1,2,4]triazolo[5, 1—f]purin— 3—y1]ethy1]—N,N—diethy1—pyrazole—4—carboxamide (77), 1—[2—[5—Amin0— 1—(cyclopr0pylmethyl)—8—(2—fury1)—2—0xo—[1,2,4]triazolo[5, 1— ?purin—3—yl]ethy1]—N—cyclopr0py1—5—methy1—pyrazole—3—carb0xamide (78), 2—[2—[5—Amin0— 1—(cyclopr0pylmethyl)—8—(2—fury1)—2—0xo—[1,2,4]triazolo[5, 1— ?purin—3—yl]ethy1]—N—cyclopr0py1—5—methy1—pyrazole—3—carb0xamide (79), 1—[2—[5—Amin0—8—(2—furyl)— 1—methy1—2—ox0—[1,2,4]triazolo[5, rin—3—y1]ethyl]— N—methyl—pyrazole—3—carb0xamide (80), 1—[2—[5—Amin0—8—(2—furyl)— 1—methy1—2—ox0—[1,2,4]triazolo[5, rin—3—y1]ethyl]— N,N—diethyl—pyrazole—4—carboxamide (81), 1—[2—[5—amino—8—(2—fury1)—1—methy1—2—ox0—[1,2,4]triazolo[5,1—f]purin—3— yl]ethyl]pyrazole—4—carboxamide (82), —Amin0—8—(2—furyl)—3— [2—[4— [(3R)—3—hydr0xypyrr01idine— 1 —carb0nyl]pyrazol— 1 — yl]ethy1]—1—methy1—[1,2,4]triazolo[5, l—?purin—Z—one (83), 1—[2—[5—Amin0—8—(2—furyl)— 1—methy1—2—ox0—[1,2,4]triazolo[5, 1—f]purin—3—y1]ethyl]— N—methyl—pyrazole—4—carboxamide (84), 1—[2—[5—Amin0—8—(2—furyl)— 1—methy1—2—ox0—[1,2,4]triazolo[5, 1—f]purin—3—y1]ethyl]— opropyl—pyrazole—3—carb0xamide (85), 1—[2—[5—Amin0—8—(2—furyl)— 1—methy1—2—ox0—[1,2,4]triazolo[5, 1—f]purin—3—y1]ethyl]— N—cyclopropyl—pyrazole—4—carboxamide (86), —Amino—8—(2—furyl)—3—[2—[4—(3—hydr0xyazetidine— 1—carb0nyl)pyrazol— 1—y1]ethy1]— 1—methy1—[1,2,4]triazolo[5, l—?purin—Z—one (87), S—Amino— 1—ethy1—8—(2—furyl)—3— [2—[4— [4—(2—methoxyeth0xy)phenyl]piperazin— 1— y1]—[1,2,4]triazolo[5,1—f]purin—2—one (88), —Amin0—3—[2—[4—(2,4—di?u0r0pheny1)piperazin—1—y1]ethy1]—1—ethy1—8—(2—fury1)— [1,2,4]triazolo[5, l—?purin—Z—one (89), o— 1—3—{ 2—[4—(4—?u0ro—phenyl)—piperidin— 1—y1]—ethy1}—8—furan—2—y1— 1,3—dihydr0—[1,2,4]triazolo[5,1—f]purin—2—0ne (90), S—Amino— 1—ethy1—8—(2—furyl)—3— [2—(3—methy1—7,8—dihydro—5H— 1 ,6—naphthyridin—6— y1)ethy1]—[1,2,4]triazolo[5,1—f]purin—2—one (91), —Amin0—8—(2—furyl)—3—[2—[4—[4—(2—meth0xyethoxy)phenyl]piperazin— 1—y1]ethy1]— 1— (2,2,2—tri?u0roethyl)—[1,2,4]triazolo[5,1—f]purin—2—0ne (92), —Amin0—3—{ 2—[4—(2,4—di?u0r0—phenyl)—piperazin— 1—y1]—ethy1}—8—furan—2—y1— 1— (2,2,2—trifluoro—ethyl)—1,3—dihydr0—[1,2,4]triazolo[5,l—?purin—Z—one (93), 5—Amin0—8—(2—furyl)—3—[2—[4—[4—(2—meth0xyethoxy)phenyl]piperazin— 1—y1]ethy1]— 1— (2—meth0xyethyl)—[1,2,4]triazolo[5, l—?purin—Z—one (94), —amin0—3—[2—[4—(4—flu0r0phenyl)piperazin— 1—y1]ethy1]—8—(2—furyl)— 1—(2— methoxyethyl)—[1,2,4]triazolo[5, l—?purin—Z—one (95), —Amino—3—[2—[4—(4—?u0r0phenyl)piperazin— 1—y1]ethy1]—8—(2—furyl)— 1—(2— hydroxyethy1)—[ 1 ,2,4]triazolo[5,1—f]purin—Z—one one (96), S—Amino—1—cyclopr0py1—8—(2—fury1)—3—[2—[4—[4—(2— methoxyethoxy)phenyl]piperazin—1—y1]ethy1]—[1,2,4]triazolo[5,1—f]purin—2—0ne (97), —Amin0—8—(2—furyl)—3—[2—[4—[4—(2—meth0xyethoxy)phenyl]piperazin— 1—y1]ethy1]— 1— (2,2,2—tri?u0roethyl)—[1,2,4]triazolo[5,1—f]purin—2—0ne (98), 5—Amin0—3—[2—[4—[4—(2—methoxyeth0xy)phenyl]piperazin— thy1]— 1—methy1—8— thiazol—Z—y1—[1,2,4]triazolo[5, l—?purin—Z—one (99), —Amin0—3—[2—[4—[3—?u0r0—4—(2—methoxyeth0xy)phenyl]piperazin— 1—y1]ethy1]— 1— methyl—8—thiazol—2—yl—[1,2,4]triazolo[5,1—f]purin—2—0ne (100), —Amin0—3—[2—[4—(2—cyc10pr0py1acetyl)piperazin—1—y1]ethy1]—1—methy1—8—thiazol—2— y1—[1,2,4]triazolo[5,1—f]purin—2—0ne (101), —Amin0—3—[2— [4—(4—meth0xyphenyl)piperazin— 1—y1] ethyl] — 1—methy1—8—thiazol—2—yl— [1,2,4]triazolo[5, l—?purin—Z—one (102), —Amino— 1—methy1—3—[2— [4—(p—t01y1)piperazin— 1 —y1] ethyl] —8—thiazol—2—y1— [1,2,4]triazolo[5, l—?purin—Z—one (103), S—Amino—1—methy1—3—[2—(3—methy1—7,8—dihydr0—5H—1,6—naphthyridin—6—yl)ethy1]—8— thiazol—Z—y1—[1,2,4]triazolo[5, in—Z—one (104), 4—[4—[2—(5—Amin0—1—methy1—2—0x0—8—thiazol—2—y1—[1,2,4]triazolo[5,1—f]purin—3— y1)ethy1]piperazin— 1 nzonitrile (105), S—Amino—1—methy1—3—[2—[4—[3—(5—methyl—1,3 ,4—0xadiazol—2—y1)pheny1]piperazin—1— y1]ethy1]—8—thiazol—2—y1—[1,2,4]triazolo[5,l—?purin—Z—one (106), —amino—3—[2— [4—[4—( 1 —hydr0xy— 1—methy1—ethy1)phenyl]piperazin— 1 —y1]ethy1] — 1 — —8—thiazol—2—yl—[1,2,4]triazolo[5,1—f]purin—2—0ne (107), —Amin0—3—[2—[4—[4—(2—methoxyeth0xy)phenyl]piperazin— 1—y1]ethy1]— 1—methy1—8— (2—pyridy1)—[1,2,4]triazolo[5, l—?purin—Z—one (108), 5—Amino—3—[2—[4—(2,4—di?uoropheny1)piperazin—1—y1]ethy1]—1—methy1—8—(2—pyridyl)— [1,2,4]triazolo[5, l—?purin—Z—one (109), 4—[4—[2—[5—Amin0—1—methy1—2—0x0—8—(2—pyridyl)—[1,2,4]triazolo[5,1—f]purin—3— yl] ethyl]piperazin— 1 —y1]benzonitrile (1 10), 0—3—[2— ( 1 —hydr0xy— 1—methy1—ethy1)phenyl]piperazin— 1 hy1] — 1 — methyl—8—(2—pyridyl)—[1,2,4]triazolo[5,1—f]purin—2—0ne (111), —Amin0—3—[2—[4—[4—(2—methoxyeth0xy)phenyl]piperazin— 1—y1]ethy1]— 1—methy1—8— pyrazin—Z—y1—[1,2,4]triazolo[5, l—?purin—Z—one (112), —Amino—3—[2—[4—(2,4—difluorophenyl)piperazin—1—y1]ethy1]—1—methy1—8—pyrazin—2— y1—[1,2,4]triazolo[5,1—f]purin—2—0ne (113), 5—Amin0—3—[2—[4—[2—?u0r0—4—(2—methoxyeth0xy)phenyl]piperazin— 1—y1]ethy1]— 1— methyl—8—pyrazin—2—yl—[1,2,4]triazolo[5, l—?purin—Z—one (114), —Amino—8—(2—furyl)—3—[[1—(4—meth0xyphenyl)pyrrolidin—3—y1]methyl] — 1 —methyl— [1,2,4]triazolo[5, l—?purin—Z—one (115), —Amino—8—(2—furyl)—3—[[1—[4—(2—methoxyeth0xy)phenyl]pyrrolidin—3—y1]methy1]— 1— methy1—[1,2,4]triazolo[5,l—?purin—Z—onehyl}—1—methy1— 1,3 —dihydr0— [1,2,4]triazolo[5,1—i]purin—2—0ne (116), —amin0—8—(2—furyl)—3—[2—[4—[4—(2—methoxyethoxy)phenyl]piperazin— 1—y1]ethy1]— 1— methy1—[1,2,4]triazolo[5,l—?purine—Z—thione (117), 8—(2—fury1)—3—[2—[4—[4—(2—methoxyeth0xy)phenyl]piperazin— 1—y1]ethy1]— 1—methy1—5— (methylamin0)—[1,2,4]triazolo[5, l—?purin—Z—one (118), 0—3—{ 2—[4—(4—?u0r0—phenyl)—piperazin— ethy1}—8—isothiazol—5—y1— 1— methyl—1,3—dihydr0—[1,2,4]triazolo[5,1—i]purin—2—one (119), —Amin0—8—isothiazol—5—y1—3—(2— { 4— [4—(2—meth0xy—eth0xy)—pheny1] —piperazin— 1 — y1}—ethy1)—1—methy1—1,3—dihydr0—[1,2,4]triazolo[5,1—i]purin—2—0ne (120), —Amin0—3—[2—[4—[2—?u0r0—4—(2—methoxyeth0xy)phenyl]piperazin— thy1]—8— isothiazol—S—yl—1—methy1—[1,2,4]triazolo[5,1—f]purin—2—0ne (121), —Amin0—8—isoxazol—5—y1—3—[2— [4—[4—(2—methoxyeth0xy)phenyl]piperazin— 1 — yl]ethy1]—1—methy1—[1,2,4]triazolo[5, l—?purin—Z—one (122), —Amin0—3—[2—[4—[4—(2—methoxyeth0xy)phenyl]piperazin— 1—y1]ethy1]— 1—methy1—8— 0xazol—2—yl—[1,2,4]triazolo[5, l—?purin—Z—one (123), 5—Amin0—3—{ 2—[4—(4—meth0xy—phenyl)—piperazin— 1—y1]—ethy1}— 1—methy1—8—pr0p— 1— ynyl—1,3—dihydr0—[1,2,4]triazolo[5,1—i]purin—2—one (124), —Amin0—3—(2—{ 2—meth0xy—eth0xy)—pheny1]—piperazin— 1—y1}—ethy1)— 1—methy1— 8—pr0p—1—yny1—1,3—dihydr0—[1,2,4]triazolo[5,1—i]purin—2—one (125), —Amino—3—{2—[4—(4—?u0r0—benzoyl)—piperazin— 1—y1]—ethy1}—8—furan—2—y1—1—methyl— 1,3—dihydr0—[1,2,4]triazolo[5,1—i]purin—2—0ne (126), —Amin0—3—(2—dimethylamin0—ethy1)—8—furan—2—y1—1—methy1—1,3—dihydr0— ]triazolo[5,1—i]purin—2—0ne (127), —Amin0—8—furan—2—yl—3 — [3—(4—rnethoxy—pheny1)—pr0pyl] — 1 —methyl— 1 ,3—dihydr0— [1,2,4]triazolo[5,1—i]purin—2—0ne (128), 5—Amino—8—furan—2—yl—1—methy1—3—(2—pyrazol— 1—y1—ethy1)—1,3—dihydr0— [1,2,4]triazolo[5,1—i]purin—2—0ne (129), —Amin0—8—furan—2—yl—3 —(2— { 4—[4—(2—meth0xy—eth0xy)—pheny1]—pyrazol— 1—y1}— ethy1)—1—methy1—1,3—dihydr0—[1,2,4]triazolo[5,1—i]purin—2—0ne (130), 0—8—furan—2—yl—3 —{2—[3—(4—methoxy—phenyl)—pyrr01— 1—y1]—ethy1}—1—methy1— 1,3—dihydr0—[1,2,4]triazolo[5,1—i]purin—2—0ne (131), —Amin0—8—furan—2—yl—3 — { 4—methoxy—phenyl)—imidazol— 1—y1]—ethy1}— 1 — methyl—1,3—dihydr0—[1,2,4]triazolo[5,1—i]purin—2—one (132), —Amin0—8—furan—2—yl—3 —{2—[4—(4—methoxy—phenyl)—[1,2,3]triazol— 1—y1]—ethy1}— 1— methyl—1,3—dihydr0—[1,2,4]triazolo[5,1—i]purin—2—one (133), —Amin0—3—[2—(1,3—dihydr0—isoind01—2—yl)—ethy1]—8—furan—2—y1— 1—methy1— 1,3 — dihydr0—[1,2,4]triazolo[5,1—i]purin—2—one (134), o—S—furan—Z—yl—1—methy1—3—(2—piperidin— 1—y1—ethy1)—1,3—dihydr0— [1,2,4]triazolo[5,1—i]purin—2—0ne (135), S—Amino—S—furan—Z—yl—1—methy1—3—(2—pyrr01idin— 1—y1—ethy1)—1,3—dihydr0— [1,2,4]triazolo[5,1—i]purin—2—0ne (136), S—Amino—S—furan—Z—yl— 1 —methy1—3—[2—(3 —methy1—7,8—dihydro—5H—[1,6]naphthyridin— ethy1]—1,3—dihydr0—[1,2,4]triazolo[5,1—i]purin—2—0ne (137), —Amin0—8—furan—2—yl—3 — { 2—[4—(2—meth0xy—eth0xy)—phen0xy] —ethy1 } — 1 —methyl— 1 ,3— dihydr0—[1,2,4]triazolo[5,1—i]purin—2—one (138), 5—Amin0—8—furan—2—yl—3 — { 2—[4—(2—meth0xy—eth0xy)—pheny1amin0]—ethy1} — y1— 1,3—dihydr0—[1,2,4]triazolo[5,1—i]purin—2—0ne (139), S—Amino—S—furan—Z—yl— 1 —methy1—3—[2—(pyridin—2—y10xy)—ethyl] — 1 ,3—dihydr0— [1,2,4]triazolo[5,1—i]purin—2—0ne (140), S—Amino— 1—ethy1—3—{2—[4—(4—?u0r0—phenyl)—piperazin— 1—y1]—ethy1}—8—isothiazol—5— yl—1,3—dihydr0—[1,2,4]triazolo[5,1—i]purin—2—0ne (141), —Amino— 1—ethy1—8—is0thiazol—5—y1—3—(2— { 4—[4—(2—methoxy—eth0xy)—phenyl] — piperazin—l—y1}—ethyl)—1,3—dihydr0—[1,2,4]triazolo[5,1—i]purin—2—0ne (142), S—Amino— 1—ethy1—8—furan—2—yl—3—(2—piperidin— 1—y1—ethy1)— 1 ,3—dihydr0— [1,2,4]triazolo[5,1—i]purin—2—0ne (143), S—Amino—1—ethy1—8—furan—2—y1—3—[2—(3—methy1—7,8—dihydr0—5H—[1,6]naphthyridin—6— hy1]—1,3—dihydr0—[1,2,4]triazolo[5,1—i]purin—2—0ne (144), —Amin0—3—[2—(2,4—diflu0r0—phen0xy)—ethy1]—1—ethy1—8—furan—2—yl— 1,3—dihydr0— [1,2,4]triazolo[5,1—i]purin—2—0ne (145), —Amin0—3—[2—(2,4—diflu0r0—phenylamino)—ethy1]—1—ethy1—8—furan—2—yl—1,3—dihydr0— [1,2,4]triazolo[5,1—i]purin—2—0ne (146), S—Amino—1—cyclopr0py1methyl—3—[2—(2,4—diflu0r0—pheny1amino)—ethyl]—8—furan—2— yl—1,3—dihydr0—[1,2,4]triazolo[5,1—i]purin—2—0ne (147), S—Amino—1—cyclopr0py1methyl—3—[2—(2,4—diflu0r0—phen0xy)—ethyl]—8—furan—2—y1— 1,3—dihydr0—[1,2,4]triazolo[5,1—i]purin—2—0ne (148), S—Amino— 1—cyclopr0py1methyl—3— { 4—flu0ro—pheny1)—piperidin— 1—y1]—ethy1}—8— furan—Z—yl—1,3—dihydr0—[1,2,4]triazolo[5,1—i]purin—2—0ne (149), —Amin0—3—{2—[4—(4—?u0ro—phenyl)—piperidin— 1—y1]—ethy1}—8—furan—2—y1— 1—(2,2,2— trifluoro—ethyl)—1,3—dihydr0—[1,2,4]triazolo[5,1—i]purin—2—0ne (150), —Amin0—8—furan—2—yl—3 — { 2—[4—(4—meth0xy—phenyl)—piperazin— 1—y1]—ethy1}— 1—(2,2,2— trifluoro—ethyl)—1,3—dihydr0—[1,2,4]triazolo[5,1—i]purin—2—0ne (151), —Amin0—3—[2—(4—cyclopropylmethyl—piperazin—1—y1)—ethy1]—8—isothiazol—5—y1— 1— (2,2,2—tri?uor0—ethyl)—1,3—dihydr0—[1,2,4]triazolo[5,1—i]purin—2—0ne (152), (5—Amino—8—is0thiazol—5—yl—3—{ 2—[4—(4—meth0xy—phenyl)—piperazin— 1—y1]—ethy1}—2— 0x0—2,3—dihydr0—[1,2,4]triazolo[5,1—i]purin—1—y1)—acet0nitrile (153), [5—Amin0—3—{ 2—[4—(2,4—di?u0r0—phenyl)—piperazin— 1—y1]—ethy1}—8—(3—?uoro— )—2—0x0—2,3—dihydr0—[1,2,4]triazolo[5,1—i]purin—1—y1]—acet0nitrile (154), [5—Amin0—8—furan—2—y1—3 —(2—{ 2—meth0xy—eth0xy)—pheny1]—piperazin— 1 —y1}— ethyl)—2—0x0—2,3—dihydr0—[1,2,4]triazolo[5,1—i]purin—1—y1]—acet0nitrile (155), —Amin0—3—(2—{ 4—[4—(2—meth0xy—eth0xy)—pheny1]—piperazin— 1—y1}—ethy1)— yl— 8—pheny1—1,3—dihydr0—[1,2,4]triazolo[5,1—i]purin—2—0ne (156), 3—[5—Amin0—3—(2— { 2—meth0xy—ethoxy)—phenyl]—piperazin— 1—y1}—ethy1)— 1— methyl—2—ox0—2,3—dihydr0— 1H—[1,2,4]triazolo[5, 1—i]purin—8—y1]—benzonitrile (157), 3—[5—Amin0—3—(2— { 4—[4—(2—meth0xy—ethoxy)—phenyl]—piperazin— 1—y1}—ethy1)— 1— methyl—2—ox0—2,3—dihydr0— 1H—[1,2,4]triazolo[5, 1—i]purin—8—y1]—benzonitrile (158), 5—Amino—8—furan—2—yl—1—methy1—3—Viny1— 1,3 —dihydr0—[1,2,4]triazolo[5,1—i]purin—2— one (159) —Amin0—3—[3—(4—?u0r0—phenyl)—pr0p—2—ynyl]—8—furan—2—y1— 1—methy1—1,3—dihydr0— [1,2,4]triazolo[5,1—i]purin—2—0ne (160), S—Amino—S—furan—Z—yl— 1 —rnethy1—3—[4—(4—methy1—piperazin— 1—y1)—but—2—yny1] — 1 ,3— dihydr0—[1,2,4]triazolo[5,1—i]purin—2—one (161), —Amino—8—furan—2—yl— l —isopropyl—3—(2— { 4—[4—(2—methoxy—ethoxy)—phenyl] — piperazin—l—yl}—ethyl)— l ,3—dihydro—[l,2,4]triazolo[5,l—i]purin—2—one (162), —Amino—2—benzyl—7—(2— { 4—[4—(2—methoxy—ethoxy)—phenyl]—piperazin—l—yl}—ethyl)— yl—7,9—dihydro—2H—[l,2,4]triazolo[3,4—i]purine—3,8—dione (163), —Amino—2—benzyl—9—methyl—7—(2—morpholin—4—yl—ethyl)—7,9—dihydro—2H— [l,2,4]triazolo[3,4—i]purine—3,8—dione (164), —Amino—2—(3—chloro—benzyl)—7—[2—(4—isopropyl—piperazin— l—yl)—ethyl] —9—methyl— 7,9—dihydro—2H—[l,2,4]triazolo[3,4—i]purine—3,8—dione (165), —Amino—2—cyclopropylmethyl—9—methyl—7—(2—morpholin—4—yl—ethyl)—7,9—dihydro— 2H—[l,2,4]triazolo[3,4—i]purine—3,8—dione (166), —Amino—2—cyclopropylmethyl—7—(2,4—difluoro—benzyl)—9—methyl—7,9—dihydro—2H— [l,2,4]triazolo[3,4—i]purine—3,8—dione (167), 4—Amino—2—furan—2—yl—6—(2— { 4—[4—(2—methoxy—ethoxy)—phenyl]—piperazin— l—yl}— —6H—8—oxa—l,3,3a,5,6—pentaaza—as—indacen—7—one (168), and 4—Amino—2—furan—2—yl—6—(2— { 4—[4—(2—methoxy—ethoxy)—phenyl]—piperazin— l—yl}— ethyl)—8,8—dimethyl—6,8—dihydro— l ,3 ,3 a,5 ,6—pentaaza—as—indacen—7—one (169).

In an embodiment of the t disclosure there is provided a pharmaceutical composition comprising compound of Formula 11, its pharmaceutically acceptable salts, analogs, tautomeric forms, stereoisomers, rical isomers, polymorphs, hydrates, solvates, metabolites, and prodrugs s T Hseal-LNY‘T‘KJ N:- Rg'? 9"“A“ Y Formula 11 wherein, Y is selected from N or CR; R is selected from H, y, alkoxy, alkyl, or aryl; R1 is selected from a group consisting of alkyl, alkenyl and alkynyl, wherein one or more methylene groups are optionally replaced by hetero atoms or groupselected from —O—, —S(O)p—, —N(Ra)—, or —C(O) provided that the heteroatom is not adjacent to N in the ring; p is selected from 0, l or 2; wherein alkyl, alkenyl and alkynyl are unsubstituted or substituted independently with alkoxy, acyl, 1ino, acyloxy, amino, kylamino, dialkylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, haloalkyl, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, arboxy, carboxyalkyl, —SOgH, arninocarbonylamino, hydroxyamino, alkoxyamino, nitro, —S(O)2NRaRa, —NRaS(O)2Ra, or 'S(O)pRa; R2 is selected from a group ting of hydrogen, halogen, cyano, nitro, carboxy, acyl, aminocarbonyl, alkyl, alkenyl, l, hydroxyalkyl, carboxyalkyl, haloalkyl, haloalkyloxy, alkoxy, —NRbRb, r, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, aryl, arylalkyl, aryloxy, cyclyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl, heteroarylalkyl and heteroaryloxy; wherein alkyl, alkenyl, alkynyl, alkoxy, carboxyalkyl, lkyl, cycloalkylalkyl, lkyloxy, aryl, arylalkyl, aryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy and Rb are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, acyl, acylan1ino, acyloxy, nitro, amino, monoalkylamino, lamino, hydroxyamino, alkoxyamino, aminocarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, —SOgH, arylamino, cycloalkylamino, arylan1ino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, cycloalkyl, cycloalkyloxy, cycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, —S(O)2NRCRC, — NRCS(O)2RC or —S(O)de; wherein each substituent is unsubstituted or substituted with l, 2, or 3 substituents independently selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano or —S(O)de; R3 is selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; wherein alkyl, l, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylan1ino, y, amino, kylamino, dialkylamino, arylamino, cycloalkylamino, arylamino, heterocyclylan1ino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, rbonyl, carboxy, arboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, —SOgH, aryl, aryloxy, cycloalkyloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, S(O)2NRCRC, —NRCS(O)2RC or e; wherein each tuent is unsubstituted or substituted with l, 2, or 3 substituents ndently selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxyd, alkoxy, halogen, haloalkyl, haloalkoxy, amino, substituted arnino, cyano or —S(O)de; X is either an optionally substituted arylene or an ally substituted heteroarylene; A is selected from a bond, (C1—C6)alkylene, (C2—C6)alkenylene or (C2— C6)alkynylene group, n l to 4 methylene groups are optionally replaced by groups independently selected from O, —S(O)p—, —N(Rb)—, or —C(O)—; wherein alkylene, lene, and alkynylene are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylan1ino, acyloxy, amino, monoalkylamino, lamino, arylamino, cycloalkylamino, heteroarylan1ino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, y, hydroxyalkyl, keto, rbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SOgH, aryl, aryloxy, cycloalkyloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, S(O)2NRCRC, O)2RC or —S(O)de; wherein each substituent is unsubstituted or substituted with l, 2, or 3 substituents independently selected from alkyl, carboxy, carboxyalkyl, arbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano or -S(O)de; B is selected from hydrogen, heterocyclyl, cycloalkyl, aryl or heteroaryl; wherein heterocyclyl, cycloalkyl, aryl and heteroaryl are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, , cycloalkyl, cycloalkylalkyl, cycloalkenyl, acyl, acylan1ino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, cycloalkylamino, heteroarylamino, heterocyclylan1ino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, yalkyl, keto, rbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SOgH, aryl, arylalkyl, aryloxy, cycloalkyloxy, heteroaryl, heteroarylalkyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, — S(O)2NRbRb, O)2Rb or —S(O)de; wherein each substituent is unsubstituted or substituted with l, 2, or 3 substituents ndently selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano or — ; R21 is ndently selected from hydrogen or alkyl; Rb is independently selected from the group ting of hydrogen, alkyl, acyl, yalkyl, carbonylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; RC is selected from hydrogen, alkyl, aryl, heteroaryl or heterocyclyl; R01 is selected from alkyl, cycloalkyl, aryl, cyclyl or heteroaryl; and p is 0, l or 2, for the manufacture of a medicament for the treatment of a condition or disorder ameliorated by inhibition of the B receptor.

[00109] In an embodiment of the present disclosure, there is provided a pharmaceutical composition comprising compound of Formula 11, its pharmaceutically acceptable salts, analogs, tautomeric forms, stereoisomers, geometrical isomers, polymorphs, hydrates, solvates, metabolites, and prodrugs thereof, wherein Y is N; R1 is selected from a group ting of alkyl, alkenyl and alkynyl, wherein alkyl, alkenyl and alkynyl are unsubstituted or substituted independently with alkoxy, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, haloalkyl, hydroxyl, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy or carboxyalkyl; R2 is selected from a group consisting of hydrogen, halogen, cyano, nitro, carboxy, acyl, aminocarbonyl, alkyl, alkenyl, l, hydroxyalkyl, carboxyalkyl, haloalkyl, haloalkyloxy, alkoxy, —NRbRb, —S(O)pr, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, aryl, arylalkyl, aryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl, heteroarylalkyl and heteroaryloxy; wherein alkyl, alkenyl, alkynyl, , carboxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, aryl, arylalkyl, aryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy and Rb are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, acyl, acylan1ino, acyloxy, nitro, amino, monoalkylamino, dialkylamino, hydroxyamino, alkoxyamino, aminocarbonylamino, azido, cyano, halogen, hydroxyl, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, —SOgH, arylamino, cycloalkylamino, heteroarylan1ino, heterocyclylamino, arbonyl, alkoxycarbonylamino, cycloalkyl, cycloalkyloxy, cycloalkenyl, aryl, aryloxy, aryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, —S(O)2NRCRC, — NRCS(O)2RC or —S(O)de; wherein each substituent is unsubstituted or substituted with l, 2, or 3 substituents independently selected from alkyl, y, yalkyl, aminocarbonyl, yl, alkoxy, halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano or —S(O)de; R3 is selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkyl, lkyl, cycloalkylalkyl, aryl, kyl, heteroaryl and heteroarylalkyl; wherein alkyl, alkenyl, alkynyl, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryl, and heteroarylalkyl are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylan1ino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, arbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxyl, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, —SOgH, aryl, aryloxy, cycloalkyloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, S(O)2NRCRC, —NRCS(O)2RC or —S(O)de; wherein each substituent is unsubstituted or substituted with l, 2, or 3 substituents independently selected from alkyl, carboxy, yalkyl, aminocarbonyl, hydroxyd, alkoxy, halogen, CF3, amino, substituted amino, cyano or —S(O)de; X is either an optionally substituted arylene or an optionally tuted heteroarylene; A is selected from a bond, (C1—C6)alkylene, (C2—C6)alkenylene or (C2— ynylene group, wherein l to 4 methylene groups are optionally ed by groups independently selected from O, S(O)p N(Rb) or , , C(O) ; n alkylene, alkenylene, and alkynylene are unsubstituted or substituted ndently with alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylan1ino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, arbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxyl, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, yalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SOgH, aryl, aryloxy, cycloalkyloxy, aryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, S(O)2NRCRC, —NRCS(O)2RC or —S(O)de; wherein each substituent is unsubstituted or substituted with l, 2, or 3 substituents independently selected from alkyl, carboxy, yalkyl, aminocarbonyl, hydroxyl, alkoxy, halogen, CF3, amino, substituted amino, cyano or —S(O)de; B is selected from hydrogen, heterocyclyl, cycloalkyl, aryl or heteroaryl; wherein heterocyclyl, cycloalkyl, aryl and heteroaryl are tituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, acyl, acylan1ino, acyloxy, amino, monoalkylamino, lamino, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxyl, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SOgH, aryl, arylalkyl, aryloxy, cycloalkyloxy, heteroaryl, arylalkyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, S(O)2NRbRb, —NRbS(O)2Rb or —S(O)de; wherein each substituent is unsubstituted or substituted with l, 2, or 3 substituents independently selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano or —S(O)de; R21 is independently selected from the group consisting of hydrogen and alkyl; Rb is independently selected from the group consisting of hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, aryl heteroarylalkyl, heterocyclyl and heterocyclylalkyl; RC is selected from hydrogen, alkyl, aryl, heteroaryl or heterocyclyl; R01 is selected from alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl; and p is 0, l or 2, for the manufacture of a medicament for the treatment of a ion or disorder ameliorated by inhibition of the AzA/AzB receptor.

[00110] In an embodiment of the present disclosure, there is provided a ceutical composition comprising nd of Formula 11, its pharmaceutically acceptable salts, analogs, eric forms, stereoisomers, geometrical isomers, polymorphs, hydrates, solvates, metabolites, and prodrugs thereof, wherein Y is CR; R is selected from the group consisting of H, hydroxy, alkoxy, alkyl, and aryl; R1 is selected from the group consisting of alkyl, alkenyl and alkynyl, wherein alkyl, alkenyl and alkynyl are unsubstituted or tuted independently with alkoxy, acyl, acylamino, y, amino, monoalkylamino, dialkylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, haloalkyl, y, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, or carboxyalkyl; Rzis selected from the group consisting of hydrogen, halogen, cyano, nitro, carboxy, acyl, aminocarbonyl, alkyl, l, alkynyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, and —NRbRb; wherein alkyl, alkenyl, alkynyl, alkoxy and Rb are unsubstituted or substituted independently with alkyl, alkenyl, l, alkoxy, acyl, acylamino, y, nitro, amino, monoalkylamino, lamino, hydroxyamino, alkoxyamino, aminocarbonylamino, azido, cyano, n, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, —SOgH, arylamino, cycloalkylamino, heteroarylamino, cyclylamino, aminocarbonyl, carbonylamino, lkyl or cycloalkenyl; R3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, kyl, heteroaryl and heteroarylalkyl; X is optionally substituted heteroarylene; A is selected from the group consisting of a bond, (C1—C6)alkylene, (C2— C6)alkenylene and (C2—C6)alkynylene group, wherein l to 4 methylene groups are optionally replaced by groups independently selected from the group consisting of o,—S(0)p, N(Rb) ,and C(0) ; B is selected from the group consisting of cyclyl, cycloalkyl, aryl and heteroaryl; wherein heterocyclyl, cycloalkyl, aryl and heteroaryl are unsubstituted or substituted ndently with alkyl, alkenyl, alkynyl, alkoxy, lkyl, cycloalkylalkyl, cycloalkenyl, acyl, acylan1ino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SOgH, aryl, arylalkyl, y, cycloalkyloxy, heteroaryl, heteroarylalkyl, aminocarbonylamino, heteroaryloxy, cyclyl, heterocyclylalkyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, S(O)2NRbRb, —NRbS(O)2Rb or —S(O)de; wherein each substituent is unsubstituted or substituted with l, 2, or 3 substituents independently ed from the group consisting of alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano and —S(O)de; Rb is independently selected from the group consisting of en, alkyl, acyl, carboxyalkyl, carbonylan1ino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl, heterocyclyl and heterocyclylalkyl; R01 is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl; and p is 0, l or 2, for the manufacture of a medicament for the treatment of a condition or disorder rated by inhibition of the AzA/AzB receptor.

In an embodiment of the present disclosure, there is provided a pharmaceutical composition sing nd of Formula 11, its pharmaceutically acceptable salts, analogs, tautomeric forms, stereoisomers, geometrical isomers, rphs, hydrates, solvates, metabolites, and prodrugs thereof, wherein Y is N or CR; R is selected from the group consisting of H, hydroxy, alkoxy, alkyl, and aryl; R1 is selected from the group consisting of alkyl, alkenyl and alkynyl; R2 is selected from the group consisting of heterocyclyl, heterocyclyloxy, aryl and heteroaryloxy; n heterocyclyl, heterocyclyloxy, heteroaryl, and heteroaryloxy are unsubstituted or tuted independently with alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, nitro, amino, monoalkylamino, dialkylamino, hydroxyamino, alkoxyamino, arbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, —SOgH, ino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, cycloalkyl or cycloalkenyl; R3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, lkylalkyl, aryl, arylalkyl, aryl and heteroarylalkyl; X is an optionally substituted phenyl; A is selected from the group consisting of a bond, (C1—C6)alkylene, (C2— C6)alkenylene and (C2—C6)alkynylene group, wherein l to 4 methylene groups are optionally replaced by groups independently selected from the group consisting of o, 3(0)p , N(Rb) ,and C(0) ; B is selected from the group consisting of heterocyclyl, cycloalkyl, aryl and heteroaryl; wherein heterocyclyl, cycloalkyl, aryl and heteroaryl are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, acyl, acylamino, y, amino, monoalkylamino, dialkylamino, arylamino, lkylamino, heteroarylamino, cyclylamino, aminocarbonyl, carbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SOgH, aryl, arylalkyl, aryloxy, lkyloxy, heteroaryl, heteroarylalkyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, yamino, alkoxyamino, nitro, S(O)2NRbRb, —NRbS(O)2Rb or —S(O)de; wherein each substituent is unsubstituted or substituted with l, 2, or 3 substituents independently selected from the group consisting of alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, n, haloalkyl, haloalkoxy, amino, substituted amino, cyano and —S(O)de; Rb is independently selected from the group consisting of hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl, heterocyclyl and heterocyclylalkyl; R01 is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl and aryl; and p is 0, l or 2, for the manufacture of a medicament for the treatment of a condition or disorder ameliorated by inhibition of the AzA/AzB receptor.

In an embodiment of the present disclosure, there is provided a pharmaceutical ition comprising compound of Formula 11, its pharmaceutically acceptable salts, analogs, tautomeric forms, stereoisomers, geometrical isomers, polymorphs, hydrates, solvates, metabolites, and prodrugs thereof, wherein Y is N; R1 is an alkyl, n one or more methylene groups are replaced by hetero atoms or groups such as —O—, —S(O)p—, —N(Ra)—, or —C(O) ed that the heteroatom is not adjacent to N in the ring; p is 0, l or 2; wherein alkyl is unsubstituted or tuted independently with alkoxy, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, aminocarbonyl, alkoxycarbonylamino, cyano, halogen, haloalkyl, hydroxy, hydroxyalkyl, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, —SOgH, aminocarbonylamino, yamino, alkoxyamino, —S(O)2NRaRa, O)2Ra, or —S(O)pRa; R2 is selected from the group consisting heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl, heteroarylalkyl and aryloxy; wherein heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl, heteroarylalkyl, and heteroaryloxy are unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, acyl, acylan1ino, acyloxy, nitro, amino, kylamino, dialkylamino, yamino, alkoxyamino, aminocarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, —SOgH, ino, cycloalkylamino, heteroarylamino, heterocyclylamino, arbonyl, alkoxycarbonylamino, lkyl, cycloalkyloxy, cycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, —S(O)2NRCRC, — NRCS(O)2RC or —S(O)de; wherein each substituent is unsubstituted or substituted with l, 2, or 3 substituents independently selected from the group consisting of alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano and —S(O)de; R3 is selected from the group consisting of hydrogen, alkyl and arylalkyl; X is an optionally substituted heteroarylene; A is ed from the group consisting of (C1—C6)alkylene, (C2—C6)alkenylene and (C2—C6)alkynylene group, wherein l to 4 methylene groups are optionally replaced by groups independently selected from the groups consisting of O, —S(O)p—, — N(Rb)—, and —C(O)—; wherein alkylene, alkenylene, and alkynylene are unsubstituted or substituted independently with alkyl, alkoxy, lkyl, halogen, hydroxy, hydroxyalkyl, carboxy, arboxy, carboxyalkyl, carboxyalkyloxy, —SOgH, hydroxyamino, alkoxyamino, S(O)2NRCRC, —NRCS(O)2RC or —S(O)de; B is selected from the group consisting of heterocyclyl, lkyl, aryl and heteroaryl; wherein heterocyclyl, cycloalkyl, aryl and heteroaryl are unsubstituted or tuted independently with alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, acyl, acylamino, y, amino, monoalkylamino, dialkylamino, arylamino, lkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, yalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SOgH, aryl, kyl, aryloxy, cycloalkyloxy, heteroaryl, heteroarylalkyl, arbonylamino, heteroaryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, —S(O)2NRbRb, —NRbS(O)2Rb or —S(O)de; wherein each substituent is unsubstituted or substituted with l, 2, or 3 substituents independently selected from the group consisting of alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano and —S(O)de; R21 is independently selected from the group consisting of hydrogen and alkyl; Rb is independently selected from the group consisting of hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, cycloalkyl, cycloalkylalkyl, aryl, kyl, aryl heteroarylalkyl, cyclyl and heterocyclylalkyl; RC is selected from the group ting of hydrogen, alkyl, aryl, heteroaryl and heterocyclyl; R01 is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl; and p is 0, l or 2, for the manufacture of a medicament for the treatment of a condition or disorder ameliorated by inhibition of the AzA/AzB receptor.

[00113] In an embodiment of the present disclosure, there is provided a pharmaceutical composition comprising compound of Formula 11, its pharmaceutically acceptable salts, analogs, tautomeric forms, isomers, geometrical isomers, polymorphs, es, solvates, metabolites, and prodrugs thereof, for use in the treatment of a condition or disorder selected from prostate cancer, rectal cancer, renal cancer, ovarian cancer, trial cancer, thyroid cancer, pancreatic cancer, breast cancer, colon cancer, bladder , brain cancer, glial cancer, melanoma cancer, pineal gland cancer, or lung cancer.

In an embodiment of the present disclosure, there is provided a method of using the pharmaceutical composition sing compound of Formula II, its pharmaceutically acceptable salts, analogs, eric forms, stereoisomers, rical isomers, polymorphs, hydrates, es, metabolites, and prodrugs thereof, in the treatment of a disease or ion in a mammal that is le to treatment with an AzA/AzB receptor nist, the method comprising: administering to a mammal in need thereof a therapeutically effective dose of the pharmaceutical ition as disclosed herein.

In an embodiment of the present disclosure, there is provided a method of treatment of a disorder or condition ameliorated by antagonizing the AzA/AzB receptor, the method comprising: administering an effective amount of the pharmaceutical composition comprising compound of Formula II, its pharmaceutically acceptable salts, analogs, tautomeric forms, stereoisomers, rical isomers, polymorphs, hydrates, solvates, metabolites, and prodrugs thereof, to a patient in need of such treatment.

In an embodiment of the present disclosure, there is provided a use of the pharmaceutical composition comprising compound of Formula II, its pharmaceutically acceptable salts, s, tautomeric forms, stereoisomers, geometrical isomers, polymorphs, hydrates, solvates, lites, and prodrugs thereof, for the preparation of a medicament for the treatment of a condition or disorder selected from prostate , rectal cancer, renal cancer, ovarian cancer, endometrial cancer, thyroid cancer, pancreatic cancer, breast cancer, colon cancer, bladder , brain cancer, glial cancer, melanoma cancer, pineal gland cancer, or lung cancer.

In an embodiment of the present disclosure, there is provided a pharmaceutical composition comprising compound of Formula II, its pharmaceutically acceptable salts, s, tautomeric forms, stereoisomers, geometrical isomers, polymorphs, es, solvates, metabolites, and prodrugs thereof, in combination with at least one PD—Ll antibody for use in the treatment of a condition or disorder selected from prostate cancer, rectal cancer, renal cancer, ovarian cancer, endometrial cancer, thyroid , pancreatic cancer, breast cancer, colon , r cancer, brain , glial , melanoma cancer, pineal gland , or lung cancer.

In an embodiment of the present disclosure, there is provided a use of the pharmaceutical composition comprising compound of Formula 11, its pharmaceutically acceptable salts, analogs, tautomeric forms, stereoisomers, geometrical isomers, polymorphs, hydrates, solvates, metabolites, and prodrugs thereof, in combination with at least one PD—Ll antibody for use in the treatment of a condition or er selected from prostate cancer, rectal cancer, renal cancer, ovarian cancer, endometrial cancer, d cancer, pancreatic cancer, breast cancer, colon cancer, bladder cancer, brain cancer, glial cancer, melanoma cancer, pineal gland cancer, or lung cancer.

In an embodiment of the present disclosure, there is provided a pharmaceutical composition sing compound of Formula 11, its pharmaceutically acceptable salts, analogs, tautomeric forms, stereoisomers, geometrical isomers, polymorphs, es, es, lites, and prodrugs thereof, wherein the compound of Formula II is selected from the group consisting 8—(4—Benzyloxy—phenyl)— l—propyl— l ,7—dihydro—purin—6—one (170), l—Propyl—S— [ l —(3—tri?uoromethyl—benzyl)— lH—pyrazol—4—yl] — l ,7—dihydro—purin—6— one (171), 8—(l—Benzyl—lH—pyrazol—4—yl)— l—propyl— l ,7—dihydro—purin—6—one (170), 2—Chloro—8—[ l —(2,3—di?uoro—benzyl)— lH—pyrazol—4—yl] — l—propyl— l ,7—dihydro—purin— 6—one (172), 2—Chloro—8—[l—(3—?uoro—4—tri?uoromethyl—benzyl)—lH—pyrazol—4—yl]— l—propyl— 1,7— dihydro—purin—6—one (173), 2—Chloro— l—propyl—8— [ l —(4—tri?uoromethyl—benzyl)— lH—pyrazol—4—yl] — l ,7—dihydro— purin—6—one (174), 8—[ l —(3—Fluoro—4—tri?uoromethyl—benzyl)— lH—pyrazol—4—yl] — l—propyl— l ,7—dihydro— purin—6—one (175), 8—[1—(2,3—Difluoro—benzyl)—1H—pyrazol—4—yl]—1—propyl—1,7—dihydro—purin—6—one (176), 1—Propyl—8—[1—(4—tri?uoron1ethy1—benzy1)—1H—pyrazol—4—yl]—1,7—dihydro—purin—6— one (177), 1—Propyl—8—(1H—pyrazol—4—yl)—1,7—dihydro—purin—6—one (178), 2—Chloro—8—[1—(3—?uoro—benzyl)—1H—pyrazol—4—yl]—1—propyl—1,7—dihydro—purin—6— one (179), 8—[1—(2,4—Difluoro—benzyl)—1H—pyrazol—4—yl]—1—propyl—1,7—dihydro—purin—6—one (180), 2—Chloro— 1—propyl—8—[1—(3—trifluoron1ethy1—benzyl)—1H—pyrazol—4—y1]— 1,7—dihydro— purin—6—one (181), 8—{4—[3—(4—F1uoro—pheny1)—prop—2—ynyloxy]—pheny1}—1—propyl—1,7—dihydro—purin—6— one (182), 8—{ 4—[5—Oxo— 1—(4—trifluoron1ethoxy—pheny1)—pyrrolidin—3—y1n1ethoxy] —pheny1}— 1— —1,7—dihydro—purin—6—one (183), yl—8— { 4—[3—(3—trifluoron1ethy1—phenyl)—prop—2—ynyloxy] —pheny1 } — 1 ,7— dihydro—purin—6—one (184), 8— { 4— [5—Oxo— 1 —(3—trifluoron1ethy1—pheny1)—pyrrolidin—3—y1n1ethoxy] —pheny1 } — 1 — propyl—1,7—dihydro—purin—6—one (185), 2—Chloro—8—[1—(2,4—di?uoro—benzyl)—1H—pyrazol—4—y1]—1—propyl—1,7—dihydro—purin— 6—one (186), 8—[1—(3—F1uoro—benzyl)—1H—pyrazol—4—yl]—1—propyl—1,7—dihydro—purin—6—one (187), 2—Morpholin—4—y1—1—propyl—8—[1—(4—trifluoron1ethyl—benzyl)—1H—pyrazol—4—yl]—1,7— dihydro—purin—6—one (188), N—(4—Cyano—pheny1)—2—[4—(6—oxo—1—propy1—6,7—dihydro— 1H—purin—8—yl)—phenoxy]— acetamide (189), [4—(6—Oxo—1—propy1—6,7—dihydro— 1H—purin—8—y1)—phenoxy]—acetic acid (190), enzy1—1H—pyrazol—4—yl)—2—chloro—1—propyl—1,7—dihydro—purin—6—one (191), 8—(4—{ 2—Oxo—2—[4—(3—tri?uoron1ethy1—phenyl)—piperazin— 1—y1]—ethoxy}—phenyl)— 1 — propyl—1,7—dihydro—purin—6—one (192), enzyl—1H—pyrazol—4—yl)— 1—pr0py1—2—(4—triflu0r0methyl—benzylamino)— 1,7— dihydro—purin—6—one (193), 8—(1—Benzyl—1H—pyrazol—4—yl)— 1—pr0py1—2—(3—triflu0r0methyl—benzylamino)— 1,7— dihydro—purin—6—one (194), 8—(1—Benzyl—1H—pyrazol—4—yl)—2—[2—(4—meth0xy—phenyl)—ethy1amin0]—1—pr0pyl— 1,7— dihydro—purin—6—one (195), 8—(1—Benzyl—1H—pyrazol—4—yl)—2—phenethy1amino—1—pr0pyl—1,7—dihydr0—purin—6—0ne (196), 8—(1—Benzyl—1H—pyrazol—4—yl)—2—(4—methy1—piperazin—1—y1)—1—pr0pyl—1,7—dihydr0— purin—6—0ne (197), 8—(1—Benzyl—1H—pyrazol—4—yl)—2—piperidin—1—y1— 1—pr0py1— 1,7—dihydr0—purin—6—0ne (198), 8—{ 1—[1—(2,4—Di?uoro—phenyl)—5—0x0—pyrr01idin—3—y1methy1]—1H—pyrazol—4—y1}—1— propyl—1,7—dihydro—purin—6—0ne (199), 8—[1—(3—F1u0r0—4—tri?u0r0methy1—benzyl)— 1H—pyrazol—4—yl]—2—(2—hydr0xy— min0)—1—pr0pyl—1,7—dihydr0—purin—6—0ne (200), 0— 1—pr0pyl—8—[1—(3—triflu0r0methy1—benzyl)—1H—pyrazol—4—y1]— 1,7—dihydr0— purin—6—0ne (201), 8—(1—Benzyl—1H—pyrazol—4—yl)—2—methylamino—1—pr0pyl—1,7—dihydr0—purin—6—0ne (202), Benzy1—1H—pyrazol—4—yl)—6—0xo— 1—pr0py1—6,7—dihydr0—1H—purin—2—ylamin0]— acetic acid ethyl ester (203), 8—(1—Benzyl—1H—pyrazol—4—yl)—2—meth0xy— 1—pr0py1—1,7—dihydr0—purin—6—0ne (204) , 1,2—Dipr0py1—8—[1—(3—tri?u0romethy1—benzyl)—1H—pyrazol—4—yl]—1,7—dihydr0—purin— 6—0ne (205), 1—Pr0pyl—8—[1—(3—tri?u0r0methyl—benzyl)—1H—pyrazol—4—yl]—2—(4—triflu0romethyl— pheny1)— 1 ,7—dihydr0—purin—6—0ne (206), 1—Pr0pyl—8—[1—(3—tri?u0r0methyl—benzyl)—1H—pyrazol—4—yl]—2—(3—triflu0romethyl— pheny1)— 1 ,7—dihydr0—purin—6—0ne (207), 2—(3—F1u0r0—phenyl)— 1—pr0pyl—8— [ 1 —(3—tri?u0r0methy1—benzyl)— 1H—pyrazol—4—yl] — 1,7—dihydro—purin—6—0ne (208), 2—Dimethy1amin0— 1 —pr0pyl—8—[ 1—(3 —triflu0r0methy1—benzyl)— 1H—pyrazol—4—yl] — 1 ,7— dihydro—purin—6—one (209), 8—[ 1—(3—Fluoro—4—tri?u0r0methy1—benzyl)— azol—4—y1]—6—0xo— 1—pr0py1—6,7— dihydro—1H—purine—2—carbonitrile (210), 8—[ 1—(3—Fluoro—4—tri?u0r0methy1—benzyl)— 1H—pyrazol—4—y1]—6—0xo— 1—pr0py1—6,7— dihydro—1H—purine—2—carb0xylic acid (21 1), 8—(4—Benzyloxy—phenyl)— 1—pr0py1—2—(3—triflu0romethyl—pheny1)—1,7—dihydr0—purin— 6—0ne (212), 8—{ 4—[3—(4—F1u0r0—pheny1)—prop—2—ynyloxy]—phenyl}— 1—pr0pyl—2—(3— tri?uoromethyl—phenyl)—1,7—dihydr0—purin—6—0ne (213), 8—(4—Methoxy—phenyl)— 1—pr0py1—2—(3—triflu0r0methy1—phenyl)—1,7—dihydr0—purin—6— one (214), 2—Ethy1—1—pr0py1—8—[1—(3 —tri?u0r0methy1—benzyl)— azol—4—yl] — 1 ,7—dihydr0— purin—6—one (215), 2—Benzyl—1—pr0py1—8—[1—(3—tri?u0r0methy1—benzyl)—1H—pyrazol—4—y1]—1,7—dihydr0— purin—6—one (216), { 6—Ox0— 1—pr0py1—8—[ 1—(3 0r0methy1—benzyl)— 1H—pyrazol—4—yl] —6,7—dihydr0— 1H—purin—2—ylamin0 } —acetic acid (217) , (S)—1—{6—Ox0—1—pr0py1—8—[1—(3—tri?u0romethy1—benzyl)—1H—pyrazol—4—yl]—6,7— dihydro—1H—purin—Z—yl}—pyrr01idine—2—carb0xylic acid (218), 1—Pr0pyl—2—pyrrolidin—1—y1—8—[1—(3—triflu0romethy1—benzyl)— 1H—pyrazol—4—yl]— 1,7— o—purin—6—one (219), 2—Methy1amin0— 1—pr0py1—8—[ 1—(3—tri?u0r0methy1—benzyl)— 1H—pyrazol—4—yl]— 1 ,7— o—purin—6—one (220), 2—Cyc10buty1amino— 1—pr0pyl—8—[ 1—(3 —tri?u0r0methy1—benzyl)— 1 H—pyrazol—4—yl] — 1,7—dihydr0—purin—6—0ne (221), 2—Ch10r0—8—[1—(3—?u0r0—4—tri?u0r0methy1—benzyl)—1H—pyrazol—4—y1]—7—methy1— 1— propyl—1,7—dihydr0—purin—6—0ne (222), 2—Meth0xy—1—pr0py1—8—[1—(3—tri?u0r0methy1—benzyl)—1H—pyrazol—4—y1]— 1,7— dihydro—purin—6—one (223), 6—Ox0—1—pr0py1—8—[1—(3—tri?u0r0methy1—benzyl)—1H—pyrazol—4—yl]—6,7—dihydr0—1H— purine—Z—carbonitrile (224), 2—Cyc10pentyloxy—1—pr0py1—8—[1—(3 0r0methy1—benzyl)— 1H—pyrazol—4—yl] — 1 ,7— dihydro—purin—6—one (225), 6—Ox0—1—pr0py1—8—[1—(3—tri?u0r0methy1—benzyl)—1H—pyrazol—4—yl]—6,7—dihydr0—1H— purine—Z—carboxylic acid amide (226) , { 6—Ox0— 1—pr0py1—8—[ 1—(3 —tri?u0r0methy1—benzyl)— 1H—pyrazol—4—yl] —6,7—dihydr0— 1H—purin—2—yloxy } —acetic acid ethyl ester (227), 2—M0rph01in—4—y1—1—pr0pyl—8—[1—(3—triflu0r0methyl—benzyl)—1H—pyrazol—4—yl]—1,7— dihydro—purin—6—one (228), { 6—Ox0— 1—pr0py1—8—[ 1—(3 —tri?u0r0methy1—benzyl)— 1H—pyrazol—4—yl] —6,7—dihydr0— 1H—purin—2—yloxy } —acetic acid (229), 8—{ 1— [3—(4—F1u0r0—pheny1)—pr0p—2—ynyl] — 1H—pyrazol—4—yl } — l—propyl—Z—pyrrolidin— 1— yl—1,7—dihydr0—purin—6—0ne (230), (S)—1—{6—Ox0—1—pr0py1—8—[1—(3—tri?u0romethy1—benzyl)—1H—pyrazol—4—yl]—6,7— dihydro—1H—purin—Z—yl}—pyrr01idine—2—carb0xylic acid amide (231), 1—{ 6—Ox0— 1—pr0pyl—8—[1—(3—tri?u0r0methy1—benzyl)—1H—pyrazol—4—yl]—6,7—dihydr0— 1H—purin—2—yl } —piperidine—3—carb0xylic acid (232), 1—{ 6—Ox0— 1—pr0pyl—8—[1—(3—tri?u0r0methy1—benzyl)—1H—pyrazol—4—yl]—6,7—dihydr0— in—2—yl } —piperidine—4—carb0xylic acid (233), (2R,4R)—4—Hydroxy—1—{6—0x0—1—pr0py1—8—[1—(3—triflu0romethyl—benzyl)—1H— l—4—yl]—6,7—dihydr0—1H—purin—2—y1}—pyrr01idine—2—carboxylic acid (234), 2—(2,3—Dihydr0xy—pr0py1amino)— 1—pr0py1—8—[ 1—(3—triflu0r0methy1—benzyl)— 1H— pyrazol—4—yl]—1,7—dihydr0—purin—6—0ne (235), 2—(2—Meth0xy—ethy1amin0)— 1—pr0pyl—8—[1—(3—tri?u0romethy1—benzyl)—1H—pyrazol— 4—y1]—1,7—dihydr0—purin—6—0ne (236), 2—(4—Hydr0xy—piperidin—1—y1)—1—pr0py1—8—[1—(3—triflu0r0methy1—benzyl)—1H— pyrazol—4—yl]—1,7—dihydr0—purin—6—0ne (237), 2—(3—Hydr0xy—piperidin—1—y1)—1—pr0py1—8—[1—(3—triflu0r0methy1—benzyl)—1H— pyrazol—4—yl]—1,7—dihydr0—purin—6—0ne (238), 2—{ 6—Ox0— 1—pr0pyl—8—[1—(3—tri?u0r0methy1—benzyl)—1H—pyrazol—4—yl]—6,7—dihydr0— 1H—purin—2—ylamin0 } —ethanesu1f0nic acid (239), 2—(3—Hydr0xymethy1—piperidin—1—y1)—1—pr0pyl—8—[1—(3—tri?u0r0methy1—benzyl)—1H— pyrazol—4—yl]—1,7—dihydr0—purin—6—0ne (240), (Methy1—{ 6—0x0— 1—pr0pyl—8—[1—(3—triflu0romethyl—benzyl)— azol—4—yl]—6,7— dihydro—1H—purin—Z—yl}—amin0)—acetic acid (241), 2—(2—Hydr0xy—ethylamin0)—1—pr0py1—8—[1—(3—tri?u0r0methy1—benzyl)—1H—pyrazol—4— y1]— 1 ,7—dihydr0—purin—6—0ne (242), 2—(4—Hydr0xymethyl—piperidin— 1—y1)—1—pr0py1—8—[1—(3—tri?u0r0methy1—benzyl)— 1H— pyrazol—4—yl]—1,7—dihydr0—purin—6—0ne (243), 2—(4—Hydr0xymethy1—piperidin— 1—y1)—1—pr0py1—8—[1—(3—tri?u0r0methy1—benzyl)— 1H— pyrazol—4—yl]—1,7—dihydr0—purin—6—0ne (244), (S)—3—Methy1—2—{ 6—0x0—1—pr0py1—8—[1—(3—tri?u0r0methy1—benzyl)—1H—pyrazol—4—y1]— 6,7—dihydr0—1H—purin—2—y1amino}—butyric acid (245), —2—Meth0xymethy1—pyrr01idin—1—y1)—1—pr0py1—8—[1—(3—tri?u0r0methyl— benzyl)— 1H—pyrazol—4—y1]—1,7—dihydr0—purin—6—0ne (246), 2—((S)—2—Hydroxymethyl—pyrrolidin—1—y1)—1—pr0py1—8—[1—(3—tri?u0romethyl— benzyl)— azol—4—y1]—1,7—dihydr0—purin—6—0ne (247), 2—((R)—3—Hydr0xy—pyrr01idin—1—y1)—1—pr0pyl—8—[1—(3—triflu0r0methy1—benzyl)—1H— pyrazol—4—yl]—1,7—dihydr0—purin—6—0ne (248), 1—Pr0pyl—2—(tetrahydro—pyran—4—ylamin0)—8—[ 1 —(3—tri?u0r0methy1—benzyl)— 1H— l—4—yl]—1,7—dihydr0—purin—6—0ne (249), 2—F1u0r0— 1—pr0py1—8—[1—(3—tri?u0r0methy1—benzyl)—1H—pyrazol—4—yl]—1,7—dihydr0— purin—6—one (250), 1—Pr0pyl—2—(2,2,2—tri?u0r0—eth0xy)—8—[ 1—(3 —tri?u0romethy1—benzyl)—1H—pyrazol—4— y1]— 1 ,7—dihydr0—purin—6—0ne (251), 2—(2—Methoxy—ethoxy)— 1—pr0py1—8—[ 1 —(3—tri?u0r0methy1—benzyl)— 1H—pyrazol—4—yl] — 1,7—dihydr0—purin—6—0ne (252), 7—Methy1—1—pr0py1—8—[1—(3—tri?u0r0methy1—benzyl)—1H—pyrazol—4—yl]—1,7—dihydr0— purin—6—one (253), 2—Ch10r0— 1—pr0pyl—8—[6—(3—triflu0r0methy1—benzylamin0)—pyridin—3—y1]— 1,7— dihydro—purin—6—one (254), 2—Ch10r0—8—[6—(3—?u0r0—benzylamin0)—pyridin—3 —y1]—1—pr0pyl—1,7—dihydr0—purin—6— one (255), 1—Pr0pyl—8—[6—(3—tri?u0r0methy1—benzylamino)—pyridin—3—y1]—1,7—dihydr0—purin—6— one (256), 1—Pr0pyl—8—(1—pyridin—3—ylmethyl—1H—pyrazol—4—yl)—1,7—dihydr0—purin—6—0ne (257), yl—8— [ 1 —(6—tri?u0r0methy1—pyridin—3 —y1methy1)—1H—pyrazol—4—yl]— 1,7— dihydro—purin—6—one (258), 2—Cyclopr0py1—1—pr0pyl—8—[1—(3—tri?u0r0methy1—benzyl)—1H—pyrazol—4—yl]—1,7— dihydro—purin—6—one (259), 2—Diflu0romethoxy— 1—pr0pyl—8—[ 1—(3 —tri?u0r0methy1—benzyl)— 1H—pyrazol—4—yl]— 1,7—dihydro—purin—6—0ne (260), 1—Pr0pyl—2—triflu0romethy1—8—[1—(3 —tri?u0r0methy1—benzyl)— azol—4—yl] — 1 ,7— dihydro—purin—6—one (261), 2—Ch10r0—8—(1—methy1—1H—pyrazol—4—yl)—1—pr0py1—1,7—dihydr0—purin—6—one (262) 8—(1—Methy1—1H—pyrazol—4—yl)—1—pr0py1—1,7—dihydr0—purin—6—0ne (263), 2—Isobutylamino—8—(1—methy1—1H—pyrazol—4—yl)—1—pr0pyl—1,7—dihydr0—purin—6—0ne (264), 8—(l—Methyl—1H—pyrazol—4—yl)—1—pr0py1—2—pyrr01idin—1—y1—1,7—dihydr0—purin—6—one (265), 2—[2—(4—Meth0xy—phenyl)—ethy1amin0]—8—(1—methy1—1H—pyrazol—4—yl)—1—pr0pyl—1,7— dihydro—purin—6—one (266), 2—(4—Methy1—piperazin—1—y1)—8—(1—methy1—1H—pyrazol—4—yl)—1—pr0pyl—1,7—dihydr0— purin—6—0ne (267), 2—[4—(4—F1u0r0—pheny1)—piperazin—1—y1]—8—(1—methy1—1H—pyrazol—4—yl)—1—pr0pyl—1,7— dihydro—purin—6—one (268), 1—[8—(1—Methy1—1H—pyrazol—4—yl)—6—0x0—1—pr0py1—6,7—dihydr0—1H—purin—2—yl]— pyrrolidine—Z—carboxylic acid methyl ester (269) , 2—Benzyl—8—(1—methyl—1H—pyrazol—4—yl)—1—pr0py1—1,7—dihydr0—purin—6—one (270), 2—(3—F1uoro—phenyl)—8—(1—methy1—1H—pyrazol—4—yl)—1—propyl—1,7—dihydro—purin—6— one (271), 8—(l—Methyl—1H—pyrazol—4—yl)— 1—propy1—2—(4—trifluoron1ethy1—phenyl)—1,7—dihydro— purin—6—one (272), ethyl—1H—pyrazol—4—yl)—2—phenethy1an1ino—1—propyl—1,7—dihydro—purin—6—one (273), 8—(l—Methyl—1H—pyrazol—4—yl)— 1—propy1—2—(4—trifluoromethyl—benzylamino)— 1,7— dihydro—purin—6—one (274), 2—Cyclopropylan1ino—8—(1—methy1— 1H—pyrazol—4—yl)— 1—propyl—1,7—dihydro—purin—6— one (275), 2—(3—F1uoro—phenoxy)—8—(1—methy1—1H—pyrazol—4—yl)— yl— 1,7—dihydro—purin—6— one (276), 2—(4—Methoxy—phenylamino)—8—(1—methy1—1H—pyrazol—4—yl)— 1—propy1— 1,7—dihydro— purin—6—one (277), 7—Benzyl—2—chloro—8—(1—methy1—1H—pyrazol—4—yl)—1—propyl—1,7—dihydro—purin—6—one (278), 9—Benzyl—2—chloro—8—(1—methy1—1H—pyrazol—4—yl)—1—propyl—1,9—dihydro—purin—6—one (279), 2—An1ino—7—benzy1—8—(1—n1ethy1—1H—pyrazol—4—yl)—1—propyl—1,7—dihydro—purin—6— one (280), 2—Chloro—8—furan—2—yl—1—propy1—1,7—dihydro—purin—6—one (281), 2—An1ino—8—[1—(4—?uoro—benzyl)—1H—imidazo[1,2—b]pyrazol—7—yl]— 1—propyl— 1,7— dihydro—purin—6—one (282), 2—Chloro—8—[1—(4—?uoro—benzyl)—1H—imidazo[1,2—b]pyrazol—7—yl]— 1—propyl— 1,7— dihydro—purin—6—one (283), 2—Amino—8—(1—n1ethy1—1H—pyrazol—4—yl)—1—propy1—1,7—dihydro—purin—6—one (284) 2—An1ino—7—n1ethy1—8—(1—methy1—1H—pyrazol—4—yl)—1—propyl—1,7—dihydro—purin—6— one (285), 2—An1ino—9—n1ethy1—8—(1—methy1—1H—pyrazol—4—yl)—1—propyl—1,9—dihydro—purin—6— one (286), 7—Methy1—8—(1—n1ethyl—1H—pyrazol—4—yl)—1—propy1—1,7—dihydro—purin—6—one (287), 9—Methy1—8—(1—methyl—1H—pyrazol—4—yl)—1—pr0pyl—1,9—dihydr0—purin—6—0ne (288), 2—Amino—8—furan—2—yl—1—pr0py1—1,7—dihydr0—purin—6—one (289), r0—8—furan—2—yl—7—methyl—1—pr0py1—1,7—dihydro—purin—6—0ne (290), ethyl—1H—pyrazol—4—yl)— 1—pr0py1—2—(3—triflu0r0methyl—benzylamino)— 1,7— dihydro—purin—6—one (291), 2—Furan—2—yl—8—(1—methy1—1H—pyrazol—4—yl)—1—pr0py1—1,7—dihydr0—purin—6—one (292), 8—(1—Benzyl—1H—pyrazol—4—yl)—2—furan—2—y1—1—pr0pyl—1,7—dihydr0—purin—6—0ne (293), 2—Ch10r0—8—(6—ch10r0—pyridin—3—y1)—1—pr0pyl—1,7—dihydr0—purin—6—one (294), 2—Diflu0r0methyl—1—pr0pyl—8—[1—(3—triflu0r0methyl—benzyl)—1H—pyrazol—4—yl]—1,7— dihydro—purin—6—one (295), 2—F1u0r0methy1—1—pr0py1—8—[1—(3—tri?u0r0methy1—benzyl)—1H—pyrazol—4—yl]—1,7— dihydro—purin—6—one (296), romethyl—8—{ 1—[3—(3—meth0xy—phenyl)—pr0p—2—ynyl]—1H—pyrazol—4—y1}—1— propyl—1,7—dihydro—purin—6—0ne (297), 2—Di?u0r0methyl—8—{ 1— [2—0x0—2—(4—m—t01y1—piperazin— 1—y1)—ethyl] — 1H—pyrazol—4— y1}—1—pr0py1—1,7—dihydr0—purin—6—0ne (298), 3—F1u0r0—N—methy1—N—[5—(6—0x0— 1—pr0pyl—6,7—dihydr0—1H—purin—8—yl)—pyridin—2— yl] —benzamide (299), N—[5—(2—Di?u0r0methyl—6—ox0— y1—6,7—dihydr0— 1H—purin—S—y1)—pyridin—2—yl]— 3—meth0xy—N—methyl—benzamide (300), N—[5—(2—Di?u0r0methyl—6—ox0— 1—pr0py1—6,7—dihydr0— 1H—purin—S—y1)—pyridin—2—yl]— 3—meth0xy—benzenesulfonamide (301), 2—Flu0romethy1—1—pr0py1—8—[1—(5—tri?uoromethyl—pyridin—3 —y1methy1)—1H—pyrazol— 4—y1]—1,7—dihydr0—purin—6—0ne (302), 2—F1u0r0methy1— 1—pr0py1—8—[1—(2—trifluoromethyl—pyridin—4—y1methy1)—1H—pyrazol— 4—y1]—1,7—dihydr0—purin—6—0ne (303), 2—F1u0r0methyl—8—[3—(3 —meth0xy—phen0xy)—isoxazol—5—yl]—1—pr0pyl—1,7—dihydr0— purin—6—one (304), 2—Di?u0r0methyl—8—{ 3—[3—(3—?u0r0—phenyl)—pr0p—2—yny10xy]—isoxazol—5—yl}— 1— propyl—1,7—dihydro—purin—6—0ne (305), 2—F1u0r0methy1—1—(2—hydr0xy—ethyl)—8—[3—(3—meth0xy—phen0xy)—isoxazol—5—yl]— 1,7—dihydro—purin—6—0ne (306), 2—Di?u0r0methyl—1—ethy1—8—{3—[3—(3—?u0r0—pheny1)—pr0p—2—yny10xy]—isoxazol—5— y1}—1,7—dihydr0—purin—6—0ne (307), 2—Di?uor0methyl— 1—ethy1—8—(1— { 3—meth0xy—phenyl)—piperazin— 1—y1]—2—0x0— ethyl } — 1H—pyrazol—4—yl)— 1 ,7—dihydr0—purin—6—one (308), 1—Ethy1—8—(1—{2—[4—(3—meth0xy—pheny1)—piperazin—1—y1]—2—0x0—ethy1}—1H—pyrazol— 4—y1)—6—0x0—6,7—dihydr0—1H—purine—2—carb0nitrile (309), N—[5—(2—Cyan0—6—oxo— 1 —pr0pyl—6,7—dihydr0— 1H—purin—8—y1)—pyridin—2—y1] —3— methoxy—benzenesulfonamide (310), N—{ 5—[2—Cyan0—1—(2—hydr0xy—ethyl)—6—0x0—6,7—dihydr0—1H—purin—8—yl]—pyridin—2— yl } —3—meth0xy—benzenesulfonamide (311), 2—Di?u0r0methyl—1—ethy1—8—{4—[3—(3—meth0xy—phenyl)—pr0p—2—yny10xy]—pheny1}— 1,7—dihydro—purin—6—0ne (312), 2—Di?u0r0methyl—1—ethy1—8—{4—[1—(3—?u0r0—pheny1)—5—0x0—pyrrolidin—3— ylmethoxy]—phenyl}—1,7—dihydro—purin—6—0ne (313), 2—Di?u0r0methyl—8—[5—(3 —meth0xy—phenoxy)—1—methy1—1H—pyrazol—3—yl]—1—pr0py1— 1,7—dihydro—purin—6—0ne (314), 2—Di?u0r0methyl—8—{ 5—[ eth0xy—phenyl)—piperidin—4—yloxy]— 1 —methyl— 1H— pyrazol—3—y1}—1—pr0pyl— 1,7—dihydro—purin—6—0ne (315), 2—F1u0romethyl—8—{ 3 —[1—(3—?u0r0—phenyl)—piperidin—4—yloxy]—is0xazol—5—yl}— 1— propyl—1,7—dihydro—purin—6—0ne (316), 1—Ethy1—8—{ 3—?u0r0—phenyl)—5—0x0—pyrr01idin—3—y1meth0xy]—pyridin—3—y1}—6— oxo—6,7—dihydr0—1H—purine—2—carb0nitrile (317) , 1—Ethy1—8—{ 6—[1—(3—meth0xy—phenyl)—pyrr01idin—3—y10xy]—pyridin—3—y1}—6—0x0—6,7— dihydro—1H—purine—2—carbonitrile (318) , 3—[4—(2—Di?u0romethyl— 1 —ethy1—6—0x0—6,7—dihydr0— 1H—purin—8—y1)—pyrazol— 1— ylmethyl]—benzoic acid (319), 2—Di?u0r0methyl— l—ethy1—8—[1—(3—hydr0xymethy1—benzyl)—1H—pyrazol—4—yl]— 1,7— dihydro—purin—6—one (320), 2—Diflu0romethyl—3—ethy1—6—[1—(3—meth0xy—benzyl)—1H—pyrazol—4—yl]—3 ,5—dihydr0— pyrr010[3,2—d]pyrimidin—4—0ne (321), N—[5—(2—Cyan0—4—0x0—3—pr0pyl—4,5—dihydr0—3H—pyrr010[3 ,2—d]pyrimidin—6—yl)— pyridin—Z—yl]—3—methoxy—benzenesulfonamide (322), 2—F1u0romethyl—6—{ 3 —[ u0r0—phenyl)—piperidin—4—y10xy]—isoxazol—5—yl}—3— propy1—3,5—dihydr0—pyrr010[3,2—d]pyrimidin—4—one (323), 2—Di?u0r0methyl—6—{ 5—[1—(3—meth0xy—phenyl)—piperidin—4—yloxy]—1—methy1— 1H— pyrazol—3—yl } py1—3 ,5—dihydr0—pyrr010[3 yrimidin—4—one (324), 3—Ethy1—6—{ 6—[1—(3—meth0xy—phenyl)—pyrr01idin—3—y10xy]—pyridin—3—y1}—4—0x0—4,5— dihydro—3H—pyrrolo[3,2—d]pyriniidine—Z—carbonitrile (325), 2—F1u0romethyl—6—{ 3 —[ 1—(3—?u0r0—phenyl)—piperidin—4—y10xy]—isoxazol—5—yl}—7— hydroxy—3—pr0py1—3 ,5—dihydr0—pyrr010[3 ,2—d]pyrimidin—4—0ne (326), 0r0methyl—3—ethy1—6—[1—(3—methoxy—benzyl)—1H—pyrazol—4—yl]—7—methy1— 3,5—dihydr0—pyrr010[3,2—d]pyrimidin—4—0ne (327), 2—Di?u0r0methyl— l—ethy1—8—[1—(3—meth0xy—benzyl)—1H—pyrazol—4—yl]—7—methy1— 1,7—dihydr0—purin—6—0ne (328), N—[5—(2—Cyan0—7—methy1—6—0x0—1—pr0pyl—6,7—dihydr0—1H—purin—S—y1)—pyridin—2—y1]— 3—meth0xy—benzenesulfonamide (329), 1—(2,2—Di?u0r0—ethy1)—2—ethy1—8—[ 1—(3—meth0xy—benzyl)— 1H—pyrazol—4—yl]— 1 ,7— dihydro—purin—6—one (330), 3—{ 3—[4—(2—Difluoromethy1—6—0x0—1—pr0py1—6,7—dihydr0—1H—purin—8—yl)—pyrazol— 1— y1]—pr0p— 1—yny1}—benzoic acid (331), 3—(3—{ 4—[ 1—(2,2—Difluoro—ethyl)—2—ethy1—6—0x0—6,7—dihydr0— in—8—yl]—pyrazol— 1—y1}—pr0p—1—yny1)—benzoic acid (332), 3—{ 3—[4—(6—Ox0— 1—pr0py1—2—trifluor0methyl—6,7—dihydr0— 1H—purin—8—yl)—pyrazol— 1— y1]—pr0p— 1—yny1}—benzoic acid (333), and 6—Ox0—1—pr0py1—8—[6—(3—tri?u0r0methy1—benzyl)—pyridin—3—y1]—6,7—dihydr0— 1H— purine—Z—carbonitrile (334).

In an embodiment of the present disclosure, there is ed a pharmaceutical composition comprising compound of Formula 111 or IV, its pharmaceutically acceptable salts, analogs, tautomeric forms, stereoisomers, rical isomers, polymorphs, es, solvates, metabolites, and prodrugs thereof 3' & E} El; Rim?“ x I K K_ 31—3 Ri x. E:7 /i\R R : _ I R \ “x R if>_X—A —B AF [ 1: RN Y 3“ '23“ i Formula 111 Formula IV Wherein, R1 is an alkyl wherein one or more ene groups are optionally replaced by hetero atoms or group selected from —O—, —S(O)p—, —N(Ra)—, or —C(O), ed that the heteroatom is not adjacent to N in the ring; p is selected from 0, l or 2; wherein alkyl is unsubstituted or substituted with alkoxy, acyl, acylamino, y, amino, monoalkylamino, dialkylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, haloalkyl, hydroxy, yalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, — aminocarbonylamino, hydroxyamino, alkoxyamino; R2 is selected from the group consisting of hydrogen, halogen, cyano, nitro, carboxy, acyl, aminocarbonyl, alkyl, alkenyl, alkynyl, hydroxyalkyl, carboxyalkyl, haloalkyl, haloalkyloxy, alkoxy, —NRbRb, —S(O)pr, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, aryl, arylalkyl, aryloxy, heterocyclyl, cyclylalkyl, heterocyclyloxy, heteroaryl, heteroarylalkyl and heteroaryloxy; wherein alkyl, alkenyl, alkynyl, alkoxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, aryl, arylalkyl, aryloxy, heterocyclyl, heterocyclylalkyl, cyclyloxy, heteroaryl, heteroarylalkyl, aryloxy and Rb are unsubstituted or substituted independently with alkyl, l, alkynyl, alkoxy, acyl, acylamino, acyloxy, nitro, amino, monoalkylamino, dialkylamino, hydroxyamino, alkoxyamino, aminocarbonylamino, azido, cyano, halogen, y, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, —SOgH, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, aminocarbonyl, alkoxycarbonylamino, lkyl, cycloalkyloxy, cycloalkenyl, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, cyclyloxy, —S(O)2NRCRC, — NRCS(O)2RC or —S(O)de; wherein each substituent is unsubstituted or substituted with l, 2, or 3 substituents independently selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano or —S(O)de; R’ and R” are independently selected from hydrogen, or alkyl; or R’ and R” taken together may represent 0, or a lower cycloalkyl ring system which is ted or partially unsaturated; R3 is selected from the group consisting of alkyl, aryl, —C(O)R4 and OR5)2; R4 is selected from alkyl, alkoxy, aryl, heteroaryl, heterocyclyl, or —NR6R7; R5 is selected from hydrogen, alkyl, aryl, arylalkyl, —CHzOC(O)alkyl, or — O)Oalkyl; or two R5 groups taken together form a five or six ed ring system which is saturated or partially unsaturated and is optionally substituted with l to 4 substituents independently selected from halo, alkyl, aryl or heteroaryl; R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, heterocyclyl and heterocyclylalkyl; or R6 and R7 taken together form a monocyclic ring system which is saturated or partially unsaturated and ally have additional heteroatoms selected from O, N or S, wherein the ring system is optionally substituted with l to 4 substituents independently selected from halo, alkyl, alkoxy, or —NR8R9; R4, R5, R6 and R7 is optionally substituted with l to 4 substituents independently selected from hydroxyl, halogen, alkyl, alkoxy, haloalkyl, —NR8R9, —C(O)OR10, — or —NC(O)R10; R8 and R9 are independently selected from the group consisting of hydrogen and alkyl; R10 is selected from hydrogen, hydroxy, halogen, amino, tuted amino, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, carboxy, carboxyalkyl, aminocarbonyl, aryl or arylalkyl; X is an optionally substituted arylene or an optionally substituted arylene; A is selected from a bond, or (C1—C6)alkylene, wherein l to 4 methylene groups are optionally replaced by group independently selected from O, —S(O)p—, —, or — C(O)—; wherein alkylene is unsubstituted or substituted independently with alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, cycloalkylamino, heteroarylan1ino, cyclylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, arboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SOgH, aryl, aryloxy, cycloalkyloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, S(O)2NRCRC, —NRCS(O)2RC or -S(O)de; wherein each substituent is unsubstituted or substituted with l, 2, or 3 substituents independently selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano or —S(O)de; B is ed from hydrogen, heterocyclyl, cycloalkyl, aryl or heteroaryl; wherein heterocyclyl, lkyl, aryl and heteroaryl are unsubstituted or substituted independently with alkyl, l, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, acyl, acylan1ino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, cycloalkylamino, arylamino, heterocyclylan1ino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy —SOgH, aryl, arylalkyl, aryloxy, cycloalkyloxy, heteroaryl, heteroarylalkyl, arbonylamino, heteroaryloxy, heterocyclyl, cyclylalkyl, heterocyclyloxy, hydroxyamino, amino, nitro, — S(O)2NRbRb, —NRbS(O)2Rb or —S(O)de; wherein each substituent is unsubstituted or substituted with l, 2, or 3 substituents ndently selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, alkoxyalkoxy, alkoxyalkyl, halogen, haloalkyl, haloalkoxy, amino, substituted amino, cyano or — D is selected from —O—, —S(O)p—, or —N(Ra)-; R21 is hydrogen or an alkyl; Rb is selected from the group consisting of hydrogen, alkyl, acyl, yalkyl, ylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; RC is selected from hydrogen, alkyl, aryl, heteroaryl or heterocyclyl; R01 is selected from alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl; p is 0, l or 2; and t is l or 2, for the manufacture of a medicament for the treatment of a condition or disorder ameliorated by inhibition of the AzA/AzB receptor.

In an embodiment of the present disclosure, there is provided a pharmaceutical composition comprising nd of Formula 111 or IV, its pharmaceutically acceptable salts, analogs, tautomeric forms, stereoisomers, geometrical s, polymorphs, hydrates, solvates, metabolites, and prodrugs thereof, wherein R1 is an alkyl; R2 is selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, hydroxyalkyl, haloalkyl, haloalkyloxy and alkoxy; R' and R" are ndently selected from hydrogen or alkyl; R3 is selected from the group consi.—tuig of alkyl. —C(0)R4 and —P(0)(OR5)2; R4 is selected from alkyl or alkoxy; R5 is selected from the group consisting of en, alkyl, —CHzOC(0)alkyl or — CH20C(0)Oalkyl; R4 and R5 is optionally substituted with l to 4 substituents independently ed from hydroxyl, n, alkyl, alkoxy, haloalkyl, —NR8R9, —C(0)OR10, —OC(0)R10 or — NC(0)R10; R° and R* are independently selected from the group consisting of hydrogen and alkyl; R10 is selected from the group consisting of hydrogen, hydroxy, n, amino, substituted amino, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, carboxy, carboxyalkyl, aminocarbonyl, aryl and arylalkyl; X is optionally substituted heteroarylene; A is selected from a bond or (Ci—C6)a'kyiene; B is selected from aryl or heteroaryl, wherein aryl and aryl are unsubstituted or substituted independently with alkyl, alkoxy, acyl, acylamino, y, amino, monoalkylamino, dialkylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, n, hydroxy, hydroxyalkyl, haloalkyl, perhaloalkyl, keto, thiocarbonyl, y, alkylcarboxy, yalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy — SO3H, aminocarbonylamino, hydroxyamino, alkoxyamino or nitro; D is selected from —0—, —S (O) p— or —N(Ra)-; R21 is hydrogen or an alkyl; p is 0, l or 2; and

[00122] t is l or 2, for the manufacture of a medicament for the treatment of a condition or disorder ameliorated by inhibition of the AzA/AzB receptor.In an embodiment of the present sure, there is provided a pharmaceutical composition comprising compound of Formula III or IV, its pharmaceutically acceptable salts, analogs, tautomeric forms, stereoisomers, geometrical isomers, polymorphs, hydrates, solvates, metabolites, and prodrugs thereof, for use in the treatment of a condition or disorder selected from te cancer, rectal cancer, renal cancer, ovarian cancer, endometrial cancer, d cancer, pancreatic cancer, breast , colon cancer, bladder cancer, brain cancer, glial , melanoma cancer, pineal gland cancer, or lung cancer.

[00123] In an ment of the present disclosure, there is provided a method of using the pharmaceutical composition comprising compound of Formula III or IV, its pharmaceutically acceptable salts, analogs, tautomeric forms, stereoisomers, geometrical isomers, polymorphs, hydrates, solvates, metabolites, and prodrugs thereof, in the treatment of a disease or condition in a mammal that is amenable to treatment with an AzA/AzB receptor antagonist, the method comprising: stering to a mammal in need thereof a eutically effective dose of the pharmaceutical composition comprising compound of Formula III or IV, its pharmaceutically acceptable salts, analogs, tautomeric forms, stereoisomers, rical isomers, rphs, hydrates, solvates, metabolites, and prodrugs thereof.

In an embodiment of the present disclosure, there is provided a method of ent of a disorder or condition ameliorated by antagonizing the AzA receptor, the method comprising: administering an effective amount of the pharmaceutical composition comprising compound of Formula III or IV, its pharmaceutically acceptable salts, analogs, tautomeric forms, stereoisomers, geometrical isomers, rphs, es, solvates, metabolites, and prodrugs thereof, to a patient in need of such treatment.

In an embodiment of the present sure, there is provided a use of the pharmaceutical composition comprising compound of Formula III or IV, its pharmaceutically acceptable salts, analogs, tautomeric forms, stereoisomers, geometrical isomers, polymorphs, hydrates, solvates, metabolites, and prodrugs thereof, for the preparation of a medicament for the treatment of a condition or disorder ed from prostate cancer, rectal cancer, renal cancer, ovarian cancer, endometrial cancer, thyroid cancer, pancreatic cancer, breast cancer, colon cancer, bladder cancer, brain cancer, glial , ma cancer, pineal gland cancer, or lung cancer.

] In an embodiment of the present disclosure, there is provided a pharmaceutical composition comprising compound of Formula III or IV, its pharmaceutically able salts, s, tautomeric forms, stereoisomers, geometrical isomers, polymorphs, hydrates, solvates, metabolites, and prodrugs thereof, in combination with at least one PD—Ll antibody for use in the treatment of a condition or disorder selected from prostate cancer, rectal , renal cancer, ovarian cancer, endometrial cancer, d cancer, pancreatic cancer, breast cancer, colon cancer, bladder cancer, brain cancer, glial cancer, melanoma cancer, pineal gland cancer, or lung cancer.

[00127] In an embodiment of the present disclosure, there is ed a use of the pharmaceutical composition comprising compound of Formula III or IV, its pharmaceutically acceptable salts, analogs, tautomeric forms, stereoisomers, geometrical isomers, polymorphs, hydrates, solvates, metabolites, and prodrugs thereof, in ation with at least one PD—Ll antibody for use in the treatment of a condition or disorder selected from prostate cancer, rectal cancer, renal cancer, ovarian cancer, endometrial cancer, thyroid cancer, pancreatic cancer, breast cancer, colon cancer, bladder cancer, brain , glial cancer, melanoma cancer, pineal gland cancer, or lung cancer.

In an embodiment of the present disclosure, there is ed a pharmaceutical composition comprising compound of Formula 111 or IV, its pharmaceutically able salts, analogs, tautomeric forms, stereoisomers, geometrical isomers, polymorphs, hydrates, solvates, metabolites, and prodrugs thereof, wherein the compound of Formula 111 or a IV is selected from the group consisting of: Phosphoric acid mono—{ 2—cyano—6—oxo— l—propyl—8—[l—(3—tri?uoromethyl—benzyl)— lH—pyrazol—4—yl]—l,6—dihydro—purin—7—ylmethyl} ester (335), Phosphoric acid mono—{ 2—cyano—6—oxo— l—propyl—8—[l—(3—tri?uoromethyl—benzyl)— lH—pyrazol—4—yl]—l,6—dihydro—purin—9—ylmethyl} ester di sodium salt (336), Phosphoric acid mono—{ 2—chloro—6—oxo— l—propyl—8—[l—(3—tri?uoromethyl— benzyl)— lH—pyrazol—4—yl]—l,6—dihydro—purin—7—ylmethyl} ester (337), oric acid mono—{ 2—chloro—6—oxo— l—propyl—8—[l—(3—tri?uoromethyl— benzyl)— lH—pyrazol—4—yl]—l,6—dihydro—purin—9—ylmethyl} ester (338), 2,2—Dimethyl—propionic acid 6—oxo—l—propyl—8—[l—(3—trifluoromethyl—benzyl)—lH— pyrazol—4—yl]—l,6—dihydro—purin—7—ylmethyl ester (339), methyl—propionic acid l—propyl—8—[l—(3—trifluoromethyl—benzyl)—lH— pyrazol—4—yl]—l,6—dihydro—purin—9—ylmethyl ester (340), 2,2—Dimethyl—propionic acid ro—6—oxo—l—propyl—8—[l—(3—tri?uoromethyl— benzyl)— lH—pyrazol—4—yl]—l,6—dihydro—purin—7—ylmethyl ester (341), 7—Methoxymethyl— l—propyl—8—[ l —(3 —tri?uoromethyl—benzyl)— lH—pyrazol—4—yl] — l ,7— dihydro—purin—6—one (342), 9—Methoxymethyl— l—propyl—8—[ l —(3 —tri?uoromethyl—benzyl)— lH—pyrazol—4—yl] — l ,9— dihydro—purin—6—one (343), 2—Ch10r0—7—rneth0xyrnethy1—1—pr0py1—8—[1—(3—tri?u0r0rnethy1—benzyl)—1H—pyrazol— 4—y1]—1, 7—dihydr0—purin—6—0ne (344), Phosphoric acid m0n0—{ 6—0x0— 1—pr0py1—8—[ 1—(3—triflu0r0rnethy1—benzyl)— 1H— pyrazol—4—y1]—1,6—dihydr0—purin—7—y1rnethy1} ester (345), (2—Dirnethy1arnin0—ethyl)—rnethy1—carbarnic acid 6—0x0— 1—pr0pyl—8—[ 1—(3— tri?uorornethyl—benzyl)—1H—pyrazol—4—yl]—1,6—dihydr0—purin—7—y1rnethy1 ester (346), y1—pyrr01idin—2—ylrnethyl)—carbarnic acid 6—0x0— 1—pr0pyl—8—[ 1—(3— tri?uorornethyl—benzyl)—1H—pyrazol—4—yl]—1,6—dihydr0—purin—7—y1rnethy1 ester (347), Nicotinic acid 6—0x0— 1—pr0pyl—8—[ 1—(3 u0r0methy1—benzyl)—1H—pyrazol—4—y1]— 1,6—dihydr0—purin—7—y1rnethy1 ester (348), Acetic acid 6—0x0—1—pr0pyl—8—[1—(3—triflu0r0methy1—benzyl)—1H—pyrazol—4—yl]—1,6— dihydro—purin—7—y1rnethy1 ester (349), c acid 6—0x0— 1—pr0py1—8—[ 1—(3 —tri?u0r0rnethy1—benzyl)—1H—pyrazol—4—yl]—1,6— dihydro—purin—7—y1rnethy1 ester (350), c acid 2—ch10r0—6—0x0— 1—pr0pyl—8—[ 1—(3 —triflu0r0methy1—benzyl)—1H—pyrazol— 4—y1]—1,6—dihydr0—purin—7—y1rnethy1 ester (351), Nicotinic acid 2—ch10r0—6—0x0— 1—pr0pyl—8—[ 1—(3—triflu0r0methy1—benzyl)— 1H— pyrazol—4—yl]—1,6—dihydr0—purin—7—y1rnethy1 ester (352), nethy1arnin0—ethyl)—rnethy1—carbarnic acid 2—ch10r0—6—0x0— 1—pr0pyl—8—[ 1—(3 — tri?uorornethyl—benzyl)—1H—pyrazol—4—yl]—1,6—dihydr0—purin—7—y1rnethy1 ester (353), (2—Dirnethy1arnin0—ethyl)—rnethy1—carbarnic acid 2—cyan0—6—0xo— 1—pr0pyl—8—[ 1—(3— tri?uorornethyl—benzyl)—1H—pyrazol—4—yl]—1,6—dihydr0—purin—7—y1rnethy1 ester (354), Butyric acid 2—cyan0—6—0x0—1—pr0py1—8—[1—(3—triflu0r0rnethy1—benzyl)—1H—pyrazol— 4—y1]—1,6—dihydr0—purin—7—y1rnethy1 ester (355), 2,2—Dirnethy1—pr0pi0nic acid 2—cyan0—6—0x0—1—pr0py1—8—[1—(3—triflu0r0rnethy1— benzyl)— 1H—pyrazol—4—y1]—1,6—dihydr0—purin—7—y1rnethy1 ester (356), Nicotinic acid 2—cyano—6—oxo— 1—propy1—8—[ rifluorornethy1—benzyl)— 1H— pyrazol—4—yl]—1,6—dihydro—purin—7—y1rnethy1 ester (357), 4—Methy1—piperazine— 1—carboxy1ic acid 2—cyano—6—oxo— 1—propy1—8—[ 1—(3— tri?uorornethyl—benzyl)—1H—pyrazol—4—yl]—1,6—dihydro—purin—7—y1rnethy1 ester (358), 1—{6—Oxo—7—phosphonooxyrnethy1—1—propy1—8—[1—(3—trifluoromethy1—benzyl)—1H— pyrazol—4—yl]—6,7—dihydro—1H—purin—2—y1}—pyrrolidine—2—carboxy1ic acid (359), 1—{7—(2,2—Dirnethy1—propionyloxyrnethyl)—6—oxo—1—propyl—8—[1—(3—tri?uorornethy1— benzyl)—1H—pyrazol—4—yl]—6,7—dihydro—1H—purin—2—yl}—pyrrolidine—2—carboxy1ic acid (360), 2,2—Dirnethy1—propionic acid 2—cyclopropy1—6—oxo— 1—propy1—8—[ 1—(3— tri?uorornethyl—benzyl)—1H—pyrazol—4—yl]—1,6—dihydro—purin—7—y1rnethy1 ester (361), Phosphoric acid mono—{ 2—cyclopropy1—6—oxo—1—propy1—8—[1—(3—tri?uorornethy1— benzyl)—1H—pyrazol—4—y1]—1,6—dihydro—purin—7 —y1rnethy1} ester (362) , Phosphoric acid mono—{ 2—chloro—6—oxo— l—propyl— 8—[1—(6—tri?uorornethy1—pyridin— 3 —y1rnethy1)—1H—pyrazol—4—yl]—1,6—dihydro—purin—7—y1rnethy1} ester (363), oric acid mono—{ 6—oxo—1—propy1—8—[1—(6—tri?uorornethyl—pyridin—3 — hyl)—1H—pyrazol—4—yl]—1,6—dihydro—purin—7—ylrnethy1} ester (364) , c acid 2—cyano—6—oxo— 1—propy1—8—[ 1—(3—trifluorornethy1—benzyl)— 1H—pyrazol— 4—y1]—1,6—dihydro—purin—7—y1rnethy1 ester (365), 7—Methoxyrnethy1—6—oxo—1—propy1—8—[1—(3—tri?uorornethy1—benzyl)—1H—pyrazol—4— yl]—6,7—dihydro—1H—purine—2—carbonitri1e (366), Acetic acid 2—cyano—6—oxo— y1—8—[ 1—(3 —tri?uorornethy1—benzy1)—1H—pyrazol—4— y1]— 1 ,6—dihydro—purin—7—y1rnethy1 ester (367), (S)—Pyrrolidine— 1,2—dicarboxy1ic acid 1—benzy1 ester 2— { 2—cyano—6—oxo— 1 —propyl—8— [1—(3—tri?uorornethy1—benzy1)—1H—pyrazol—4—y1]—1,6—dihydro—purin—7—y1rnethy1} ester (368), Butyric acid 2—cyano—6—oxo— 1—propy1—8—[ 1—(3—trifluorornethy1—benzyl)— 1H—pyrazol— 4—y1]—1,6—dihydro—purin—9—y1rnethy1 ester (369), Butyric acid 2—cyclopropyl—6—oxo—l—propyl—8—[l—(3—trifluoromethyl—benzyl)— lH— pyrazol—4—yl]—l,6—dihydro—purin—9—ylmethyl ester (370), Butyric acid 2—chloro—6—oxo— l—propyl—8—[l—(3 —tri?uoromethyl—benzyl)— lH—pyrazol— 4—yl]—l,6—dihydro—purin—9—ylmethyl ester (371), Butyric acid 6—oxo— l —propyl—8—[ l —(3 —tri?uoromethyl—benzyl)— lH—pyrazol—4—yl] — l ,6— dihydro—purin—9—ylmethyl ester (372), Phosphoric acid mono—{ 2—?uoro—6—oxo—l—propyl—8—[l—(3—tri?uoromethyl—benzyl)— azol—4—yl]—l,6—dihydro—purin—9—ylmethyl} ester (373), Phosphoric acid mono—{ 6—oxo—l—propyl—8—[l—(3—tri?uoromethyl—benzyl)— lH— pyrazol—4—yl]—l,6—dihydro—purin—9—ylmethyl} ester (374), or Phosphoric acid mono—{2—cyclopropyl—6—oxo—l—propyl—8—[l—(3—trifluoromethyl— benzyl)— lH—pyrazol—4—yl]—l,6—dihydro—purin—9—ylmethyl} ester (375).

In an embodiment of the present disclosure there is provided a pharmaceutical composition comprising compounds selected from the compound of Formula 1, nd of Formula 11, compound of Formula 111, or compound of Formula IV for the manufacture of a medicament for the treatment of a condition or disorder ameliorated by tion of the AzA/AzB receptor further comprising a therapeutically ive amount of at least one pharmaceutically acceptable excipient.

Example 1 Synthesis of the nd of a I The compounds of Formula I were synthesized as per the procedures mentioned in W02012038980 which is incorporated herein by nce.

Pharmaceutically acceptable salts of the compounds may be obtained as per procedures reported in literature.

Example 2 Synthesis of the compound of Formula II The compounds of Formula II were synthesized as per the procedures mentioned in W02010103547 which is incorporated herein by nce.

Pharmaceutically acceptable salts of the compounds may be obtained as per ures reported in literature.

Example 3 Synthesis of the nd of Formula 111 and Formula IV The compounds of Formula 111 or IV were synthesized as per the procedures mentioned in W02012035548 which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds may be obtained as per procedures reported in literature.

The compounds of the sure may be prepared by a variety of methods, including standard tic chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated.

Illustrative general synthetic methods are set out in the schemes and can be readily adapted to prepare other compounds of the disclosure.

Example 4 Biological Assay Tumor suppression activity of ine A2A (Compound 31) and A213 (Compound 169) Antagonists in xenograft models of cancer General ol: 6—8 weeks old BALB/c mice were acclimated and on Day 1 of the study, the mice were injected with 50 ML of medium containing 5 X104 4T1 cells (breast ) or 5 X 105 CT26 cells (colon cancer). On day 8 or 9, the mice were segregated into different groups and d orally with either vehicle (1% Tween—80+ 0.5% Carboxymethylcellulose in water) or test compound [(Compound 32 5—Amino—3—[2—[4—[2—?uoro—4—(2—methoxyethoxy)phenyl]piperazin— 1—y1]ethy1]—8—(2—fury1)—1—methy1—[1,2,4]triazolo[5,1—f]purin—2—one (32) & Phosphoric acid mono— { 2—cyano—6—oxo— 1—propy1—8—[ 1—(3—trifluoromethy1—benzy1)— 1H—pyrazol—4—yl]—1,6—dihydro—purin—7—y1methy1} ester (335)] in vehicle. The treatment was BID for 22 days (colon cancer) or 28 days (breast cancer). At the end of the study, the tumor volume was measured as h X breadth)/2. Data were presented as % reduction ed to the tumor volume in vehicle treated animals. 4T1 Breast Cancer Model Treatment Groups (n=12) % decrease in Tumor growth vs. vehicle On Day 28 Compound 32, 1 mg/kg, >“PO, >“*BID 48.30 Compound 335, 3 mg/kg, >“PO, >“*BID 46.40 CT26 Colon Cancer Model % decrease in Tumor growth vs. vehicle Treatment Groups (n=12) On Day 22 Compound 32, , >“PO, >“*BID 54.40 Compound 335, 3mg/kg, >“PO, >“*BID 23.90 >“PO: per os, i.e., by mouth; >“*BIDz bis in die, i.e., twice a day Although the subject matter has been described in considerable detail with reference to certain red embodiments thereof, other embodiments are possible. As such, the spirit and scope of the appended claims should not be limited to the description of the red embodiment contained therein.

I/

Claims (5)

WE CLAIM:

1. Use of a compound of Formula I and its pharmaceutically acceptable salt, tautomeric form, stereoisomer, geometrical isomer, polymorph, or hydrate thereof Formula I wherein --- ents a single bond or a double bond; X is selected from O, S or NRa; Y1 is selected from N or CH; Y2 is selected from NR5, O or CR5R6; Y3 is selected from N, CH, CH2, C(=O), or C(=S); Y4 is selected from N, C, or CH; R1 and R2 are independently selected from hydrogen or alkyl; R3 is -Q; wherein, A is absent or is a group selected from alkylene, alkenylene, or alkynylene; wherein one or more methylene group is optionally replaced by hetero atoms or groups such as –O-, -, -N(Ra)-, or -C(O); alkylene, alkenylene and alkynylene is optionally substituted with -(CRdRe)nOR7, (CRdRe)nCOOR7, -(CRdRe)nNR8R9, cyano, halogen, haloalkyl, perhaloalkyl, alkoxyalkoxy, alkyl, or cycloalkyl; Z is absent or is selected from a cycloalkyl or a heterocyclyl; n cycloalkyl and heterocyclyl are unsubstituted or substituted independently with 1, 2, or 3 substituents independently selected from alkyl, alkenyl, alkynyl, acyl, -(CRdRe)nOR7, )nCOOR7, -(CRdRe)nNR8R9, aminocarbonyl, alkoxycarbonylamino, halogen, haloalkyl, perhaloalkyl, azido, cyano, keto, thiocarbonyl, -SO3H, arbonylamino, nitro, -S(O)2NRaRa, -NRbS(O)2Rb or -S(O)pRc; B is absent or is a group selected from ne, alkenylene or alkynylene; wherein one or more methylene groups is optionally replaced by hetero atoms or groups such as –O-, -S(O)p-, -, or -C(O); alkylene, alkenylene and alkynylene is optionally tuted with hydroxy, amino, aminoalkyl, cyano, halogen, haloalkyl, perhaloalkyl, carboxy, carboxyalkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkoxy or alkyl; Q is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or arylalkyl; wherein alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl are unsubstituted or substituted independently with 1, 2, or 3 substituents independently selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, perhaloalkyl, azido, cyano, nitro, keto, thiocarbonyl, cyanoalkyl, cyanoalkylcarbonyl, -(CRdRe)nOR7, -(CRdRe)nC(O)R7, -(CRdRe)nSR7, -(CRdRe)nCOOR7, -(CRdRe)nNR8R9, - (CRdRe)nC(O)NR8R9, -(CRdRe)nNR8C(O)OR7, -(CRdRe)nNR8C(O)NR8R9, -NRbS(O)2Rb, -S(O)pRc, -SO3H, -S(O)2NRaRa, cycloalkyl, cycloalkenyl, cycloalkylalkyl aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, aryl or heteroarylalkyl; wherein each tuent is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from alkyl, carboxy, yalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, kyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, amino, substituted amino, cyano or -S(O)pRc; R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, carboxyalkyl, lkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, aryl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl are unsubstituted or tuted independently with up to four substituents independently selected from alkyl, alkenyl, alkynyl, acyl, -(CRdRe)nOR7, (CRdRe)nCOOR7, -(CRdRe)nNR8R9, aminocarbonyl, carbonylamino, aminocarbonylamino, azido, cyano, halogen, haloalkyl, perhaloalkyl, keto, nitro, -S(O)2NRbRb, -NRbS(O)2Rb or -S(O)pRc, thiocarbonyl, -SO3H, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl; R5 and R6 are independently selected from the group consisting of hydrogen, hydroxy, e)nOR7, (CRdRe)nCOOR7, -(CRdRe)nNR8R9, cyanoalkyl, haloalkyl, alkoxyalkoxyalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; R7 is selected from hydrogen, alkyl, halogen, haloalkyl, -(CRdRe)nOR7, -(CRdRe)nCOOR7, -(CReRe)nC(O)R7, carbonylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl; R8 and R9 are ndently selected from the group consisting of hydrogen, alkyl, kyl, -(CRdRe)nOR7, -(CRdRe)nC(O)R7, aryl, kyl, heteroaryl, heteroarylalkyl, cycloalkyl, lkylalkyl, cyclyl and heterocyclylalkyl, or R8 and R9 taken together form a monocyclic or a ic ring system which is ted or partially unsaturated and optionally have additional heteroatoms selected from O, N or S, said ring system is further optionally substituted with 1 to 4 substituents independently ed from halo, alkyl, alkenyl, alkynyl, nitro, cyano, -(CRdRe)nOR7, -(CRdRe)nSR7, -(CRdRe)nNR8R9, oxo, alkylsulfonyl, e)nCOOR7, -(CRdRe)nC(O)NR8R9, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, cyclylalkyl, heteroaryl, or heteroarylalkyl; Ra is selected from hydrogen or alkyl; Rb each is independently selected from the group consisting of hydrogen, alkyl, acyl, carboxyalkyl, carbonylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; Rc is selected from alkyl, cycloalkyl, aryl, heterocyclyl or aryl; Rd and Re are independently selected from the group consisting of hydrogen, -OR7, halogen, haloalkyl, perhaloalkyl and alkyl; n is 0, 1, 2, 3 or 4, and p is 0, 1 or 2, for the cture of a medicament for the treatment of a condition or disorder selected from prostate cancer, rectal cancer, renal cancer, ovarian cancer, endometrial cancer, d cancer, pancreatic cancer, breast cancer, colon cancer, bladder cancer, brain cancer, glial cancer, melanoma cancer, pineal gland cancer, metastatic head and neck cancer, and lung cancer.

2. The use of the compound as claimed in claim 1, wherein the compound is ated in ation with at least one PD-Ll antibody.

3. The use of the compound as claimed in claim 1, wherein the compound of Formula I is selected from the group consisting of: 5-Amino(2-furyl)[2-[4-[4-(2- methoxyethoxy)phenyl]piperazinyl]ethyl]methyl-[l,2,4]triazolo[5, l-f]purinone 5-Amino(2-furyl)(2-hydroxyethyl)-l-methyl-[l,2,4]triazolo[5, l­ f]purinone (2), 5-Amino[2-[4-(2,4-difluorophenyl)piperazinyl]ethyl](2-furyl)-l­methyl- [l,2,4]triazolo[5,l-f]purinone (3), 5-Amino(2-furyl)[2-[4-(4-methoxyphenyl)piperazinyl]ethyl]-l­methyl- ]triazolo[5,l-f]purinone (4), 5-Amino(2-furyl)-l-methyl(2-morpholinoethyl)-[l,2,4]triazolo[5, l­ f]purinone 5-Amino[2-[4-(2,4-difluorophenyl)-l-piperidyl]ethyl](2-furyl)-l-methyl- [l,2,4]triazolo[5,l-f]purinone (6), 5-Amino(2-furyl)-l-methyl[2-[4-(5-methylpyridyl)piperazinyl]ethyl]- [l,2,4]triazolo[5,l-f]purinone (7), 5-Amino(2-furyl)-l-methyl[2-[4-(p-tolyl)piperazinyl]ethyl]­[l,2,4]triazolo[5,lf ]purinone (8), 5-Amino(2-furyl)-l-methyl[2-[4-(3-methyloxo-butyl)piperazinyl]ethyl]- [l,2,4]triazolo[5,l-f]purinone (9), 5-Amino[2-[4-(2-fluoromethoxy-phenyl)piperazinyl]ethyl](2-furyl)-l-methyl- ]triazolo[5, l-f]purinone (10), 5-Amino(2-furyl)[2-[4-[4-(2-methoxy-1,l-dimethyl-ethoxy)phenyl]piperazin yl]ethyl]-l-methyl-[l,2,4]triazolo[5, l-f]purin one (11), 5-Amino(2-furyl)[2-[4-(6-methoxypyridyl)piperazin-l-yl]ethyl]-l­methyl- [l,2,4]triazolo[5,l-f]purinone (12), 5-Amino[2-[4-[3-fluoro(2-methoxyethoxy)phenyl]piperazin-l­yl]ethyl](2-furyl)- l-methyl-[l,2,4]triazolo[5, l-f]purinone (13), 5-Amino(2-furyl)[2-[4-[4-(1-hydroxy-l-methyl­ethyl)phenyl]piperazin-l-yl]ethyl]-lmethyl- [l,2,4]triazolo[5, rin one (14), 5-Amino[2-[4-(4-fluorophenyl)hydroxy-l-piperidyl]ethyl](2-furyl)-l-methyl- [l,2,4]triazolo[5, l-f]purinone (15), 5-Amino(2-furyl)[2-[4-[4-(2-methoxymethyl­ propoxy)phenyl]piperazin-lyl ]ethyl]-l-methyl-[l,2,4]triazolo[5,l-f]purin- 2-one (16), 5-Amino[2-[4-[4-(cyclopropoxy)phenyl]piperazin-l-yl]ethyl](2-furyl)-l-methyl- [l,2,4]triazolo[5, l-f]purinone (17), 5-Amino[2-[4-(4-fluorophenyl)-3,6-dihydro-2H-pyridin-l-yl]ethyl](2-furyl)-lmethyl- [l,2,4]triazolo[5, l-f]purinone (18), 5-Amino(2-furyl)[2-[4-hydroxy(4-methoxyphenyl)piperidyl]ethyl]-l-methyl- [l,2,4]triazolo[5, rinone (19), 5-Amino[2-[4-[3,5-difluoro(2-methoxyethoxy)phenyl]piperazin-l-yl]ethyl](2- -l-methyl-[l,2,4]triazolo[5, l-f]purinone (20), 5-Amino[2-[4-[2,5-difluoro(2-methoxyethoxy)phenyl]piperazin-l­yl]ethyl](2- -l-methyl-[l,2,4]triazolo[5, l-f]purinone (21), 5-Amino[2-[4-(2,2-difluoro-l,3-benzodioxolyl)piperazin-l-yl]ethyl](2-furyl)-lmethyl- [l,2,4]triazolo[5,l-f]purinone (22), 5-Amino(2-furyl)[2-[4-[4-(2-methoxyethoxy)phenyl]-3,3-dimethyl­piperazin-lyl ]ethyl]-l-methyl-[l,2,4]triazolo[5,l-f]purinone (23), 5-Amino[2-(4-butylpiperazin-l-yl)ethyl](2-furyl)-l-methyl- [l,2,4]triazolo[5, lf ]purinone (24), 5-Amino(2-furyl)[2-(4-hydroxymethyl-l-piperidyl)ethyl]-l-methyl- [l,2,4]triazolo[5,l-f]purinone (25), 5-Amino[2-[4-[4-[2-(cyclopropoxy)ethoxy]phenyl]piperazin-l-yl]ethyl](2-furyl)-lmethyl- [l,2,4]triazolo[5, l-f]purinone (26), 5-Amino(2-furyl)[2-[4-[(4-methoxyphenyl)methyl]piperazinyl]ethyl]­l-methyl- [l,2,4]triazolo[5, l-f]purinone (27), 5-Amino(2-furyl)[2-[4-[[4-(2-methoxyethoxy)phenyl]methyl]piperazin-l­yl]ethyl]- l-methyl-[l,2,4]triazolo[5, l-f]purinone (28), 5-Amino(2-furyl)[(4-methoxyphenyl)methyl]-l-methyl-[l,2,4]triazolo[5, l-f]purin- 2-one (29), 5-Amino(2-furyl)[2-[4-(4-methoxyphenyl)piperazin-l-yl]ethyl]methyl- [l,2,4]triazolo[5,l-f]purinone (30), 5-Amino(2-furyl)[2-[4-[3-(2-methoxyethoxy)phenyl]piperazin-l­yl]ethyl]-l-methyl- [l,2,4]triazolo[5, l-f]purinone (31), 5-Amino[2-[4-[2-fluoro(2-methoxyethoxy)phenyl]piperazinyl]ethyl](2-furyl)- yl-[l,2,4]triazolo[5, l-f]purinone (32),

4-[4-[2-[5-Amino(2-furyl)-l-methyloxo-[l,2,4]triazolo[5,l-f]purin- 3yl]ethyl]piperazin-l-yl]benzonitrile (33), 4-[4-[2-[5-Amino(2-furyl)-l-methyloxo-[l,2,4]triazolo[5,l-f]purin yl]ethyl]piperazin-l-yl]fluoro-benzonitrile (34),

5-Amino(2-furyl)-l-methyl[2-[4-[4-(trifluoromethyl)phenyl]piperazinyl]ethyl]- [l,2,4]triazolo[5,l-f]purinone (35), 5-Amino(2-furyl)-l-methyl[2-[4-[4-(trifluoromethyl)thiazolyl]piperazin-lyl ]ethyl]-[l,2,4]triazolo[5, l-f]purinone (36), 5-Amino[2-[4-(cyclopropylmethyl)piperazin-l-yl]ethyl](2-furyl)-l­methyl- [l,2,4]triazolo[5,l-f]purinone (37), 5-Amino[2-(4-ethylpiperazin-l-yl)ethyl](2-furyl)-l-methyl­ [l,2,4]triazolo[5, lf ]purinone (38), 4-[2-[5-Amino(2-furyl)-l-methyloxo-[1,2,4]triazolo[5,l-f]purinyl]ethyl]-N,N- dimethyl-piperazine- l-sulfonamide (39), 5-Amino(2-furyl)-l-methyl[2-[4-(4-tetrahydrofuran yloxyphenyl)piperazin yl]ethyl]-[l,2,4]triazolo[5,l-f]purinone (40), 5-Amino(2-furyl)-l-methyl[2-[4-(4-tetrahydropyranyloxyphenyl)piperazin-lyl ]ethyl]-[l,2,4]triazolo[5,l-f]purinone (41), 5-Amino(2-furyl)-l-methyl[2-[4-[4-(tetrahydrofuran ylmethoxy)phenyl]piperazin-l-yl]ethyl]-[l,2,4]triazolo[5, l-f]purinone (42), 5-Amino(2-furyl)-l-methyl[2-(3-methyl-7,8-dihydro-5H-l,6-naphthyridin yl)ethyl]-[1,2,4]triazolo[5, rinone (43), 5-Amino[2-(6,7-dihydro-4H-thieno[3,2-c]pyridinyl)ethyl](2-furyl)-l-methyl- [l,2,4]triazolo[5,l-f]purinone (44), 5-Amino(2-furyl)[2-[4-[4-(2-methoxyethoxy)phenyl]piperazinyl]propyl] methyl-[l,2,4]triazolo[5,l-f]purinone (45), o[2-[3-(4-fluorophenyl)-2,5-dihydropyrrol-l-yl]ethyl](2-furyl)-l­methyl- [l,2,4]triazolo[5,l-f]purinone (46), 5-Amino[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin-l-yl]ethyl]-l-methyl(5- methylfuryl)-[l,2,4]triazolo[5, l-f]purinone (47), 5-Amino(5-cyclopropylfuryl)[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin-lyl ]ethyl]-l-methyl-[l,2,4]triazolo[5,l­ f]purinone (48), 5-Amino[2-(2,4-difluoroanilino)ethyl](2-furyl)- l-methyl­ [l,2,4]triazolo[5, l- f]purinone (49), 5-Amino[3-[4-(4-fluorophenyl)piperazin-l-yl]propyl](2-furyl)-lmethyl­ [l,2,4]triazolo[5, l-f]purinone (50), 5-Amino(2-furyl)[3-[4-[4-(2-methoxyethoxy)phenyl]piperazin-l­yl]propyl]-lmethyl- ]triazolo[5,l-f]purinone (51), 5-Amino(2-furyl)[2-[4-(4-methoxyphenyl)-3,6-dihydro-2H-pyridin-l-yl]ethyl] methyl-[l,2,4]triazolo[5, l-f]purinone (52), 5-Amino(2-furyl)[2-[4-[4-(2-methoxy-l,l-dimethyl­ ethyl)phenyl]piperazin-lyl ]ethyl]-l-methyl-[l,2,4]triazolo[5, l-f]purinone (53), 5-Amino(2-furyl)-l-methyl(2-piperazin-l-ylethyl)-[l,2,4]triazolo[5,1-f]purinone (54), 5-Amino(2-furyl)[2-[4-(lH-indolecarbonyl)piperazin-l-yl]ethyl]-l­methyl- [l,2,4]triazolo[5,l-f]purinone (55), 5-Amino(2-furyl)[2-(4-isopropoxyphenyl)ethyl]-l-methyl- [l,2,4]triazolo[5, lf one (56), 5-Amino(2-furyl)-l-methyl[2-[4-[(2S)-pyrrolidinecarbonyl]piperazin­l-yl]ethyl]- [l,2,4]triazolo[5,l-f]purinone (57), 5-Amino(2-furyl)[2-(4-methoxyphenyl)ethyl]-l-methyl- [l,2,4]triazolo[5, rin- 2-one (58), 5-amino[2-[4-[4-(difluoromethoxy)phenyl]piperazin-l-yl]ethyl](2-furyl)methyl- [l,2,4]triazolo[5, l-f]purinone (59), 5-Amino(2-furyl)-l-methyl[2-[4-[3-(5-methyl-1,3,4-oxadiazol yl)phenyl]piperazin-l-yl]ethyl]-[l,2,4]triazolo[5,l-f]purinone (60), 5-Amino[2-[4-[2-fluoro(5-methyl-l,2,4-oxadiazolyl)phenyl]piperazin-l-yl]ethyl]- 8-(2-furyl)- l-methyl-[l,2,4]triazolo[5, 1-f]purinone (61), 5-Amino[2-[4-(6-fluoromethyl-l,3-benzoxazolyl)piperazin-l­yl]ethyl](2- furyl)-l-methyl-[l,2,4]triazolo[5, l-f]purinone (62), 5-Amino[2-[4-(cyclopropanecarbonyl)piperazin-l-yl]ethyl](2-furyl)-l­methyl- [l,2,4]triazolo[5,l-f]purinone (63), 5-Amino[2-[4-(2-cyclopropylacetyl)piperazin-l-yl]ethyl](2-furyl)-l­methyl- [l,2,4]triazolo[5,l-f]purinone (64), 5-Amino(2-furyl)[2-[4-[4-(2-hydroxyethoxy)phenyl]piperazin-l­yl]ethyl]-l-methyl- [l,2,4]triazolo[5, l-f]purinone (65), 5-Amino(2-furyl)[2-[4-(4-hydroxyphenyl)piperazin-l-yl]ethyl]methyl- [l,2,4]triazolo[5,l-f]purinone (66), 5-Amino(cyclopropylmethyl)[2-[4-(4-ethoxyphenyl)piperazin-l­yl]ethyl](2- furyl)-[1,2,4]triazolo[5, l-f]purinone (67), 5-Amino(cyclopropylmethyl)[2-[4-(4-fluorophenyl)piperazin-l­yl]ethyl](2- furyl)-[1,2,4]triazolo[5, l-f]purinone (68), 5-Amino(cyclopropylmethyl)[2-[4-(2,4-difluorophenyl)piperazin-l­yl]ethyl](2- furyl)-[1,2,4]triazolo[5, rinone (69), 5-Amino(cyclopropylmethyl)(2-furyl)[2-[4-[4-(2- methoxyethoxy)phenyl]piperazinyl]ethyl]-[1,2,4]triazolo[5, l-f]purinone (70), 5-Amino(cyclopropylmethyl)[2-(4-fluorophenoxy)ethyl](2-furyl)- [l,2,4]triazolo[5,l-f]purinone (71), 5-Amino(2-furyl)-l-methyl[2-[2-oxo(trifluoromethyl)-l­pyridyl]ethyl]- [1,2,4]triazolo[5,l-f]purinone (72), 5-Amino[2-[4-(2,4-difluorophenyl)pyrazolyl]ethyl]-l-ethyl(2- furyl)­[l,2,4]triazolo[5,l-f]purinone (73), l-[2-[5-Amino(cyclopropylmethyl)(2-furyl)oxo-[l,2,4]triazolo[5,l­f]purin yl]ethyl]pyrazolecarboxylic acid (74), 5-Amino(2-furyl)-l-methyloxo-[l,2,4]triazolo[5,l-f]purinyl]ethyl]pyrazole- 4-carboxylic acid (75), 5-amino(cyclopropylmethyl)(2-furyl)oxo-[l,2,4]triazolo[5,l-f]purin yl]ethyl]-N-cyclopropyl-pyrazolecarboxamide (76), l-[2-[5-amino(cyclopropylmethyl)(2-furyl)oxo-[l,2,4]triazolo[5,l­f]purin yl]ethyl]-N,N-diethyl-pyrazolecarboxamide (77), l-[2-[5-Amino(cyclopropylmethyl)(2-furyl)oxo-[l,2,4]triazolo[5,l­f]purin yl]-N-cyclopropylmethyl-pyrazolecarboxamide (78), 2-[2-[5-Amino(cyclopropylmethyl)(2-furyl)oxo-[l,2,4]triazolo[5,l­f]purin yl]ethyl]-N-cyclopropylmethyl-pyrazolecarboxamide (79), l-[2-[5-Amino(2-furyl)-l-methyloxo-[l,2,4]triazolo[5,l-f]purinyl]ethyl]-N- methyl-pyrazolecarboxamide (80), 5-Amino(2-furyl)-l-methyloxo-[l,2,4]triazolo[5,l-f]purinyl]ethyl]-N,N- diethyl-pyrazolecarboxamide (81), l-[2-[5-amino(2-furyl)-l-methyloxo-[l,2,4]triazolo[5,l-f]purinyl]ethyl]pyrazole carboxamide (82), 5-Amino(2-furyl)[2-[4-[(3R)hydroxypyrrolidine-l-carbonyl]pyrazol­l-yl]ethyl]-lmethyl- [l,2,4]triazolo[5, l-f]purinone (83), l-[2-[5-Amino(2-furyl)-l-methyloxo-[l,2,4]triazolo[5,l-f]purinyl]ethyl]-N- methyl-pyrazolecarboxamide (84), l-[2-[5-Amino(2-furyl)-l-methyloxo-[l,2,4]triazolo[5,l-f]purinyl]ethyl]-N- cyclopropyl-pyrazolecarboxamide (85), l-[2-[5-Amino(2-furyl)-l-methyloxo-[l,2,4]triazolo[5,l-f]purinyl]ethyl]-N- cyclopropyl-pyrazolecarboxamide (86), 5-Amino(2-furyl)[2-[4-(3-hydroxyazetidine-l-carbonyl)pyrazolyl]ethyl]-lmethyl- [l,2,4]triazolo[5, l-f]purinone (87), o-l-ethyl(2-furyl)[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin­l-yl]ethyl]- [l,2,4]triazolo[5,l-f]purinone (88), 5-Amino[2-[4-(2,4-difluorophenyl)piperazinyl]ethyl]-l-ethyl(2-furyl)- [l,2,4]triazolo[5,l-f]purinone (89), 5-Amino-l-ethyl{2-[4-(4-fluoro-phenyl)-piperidinyl]-ethyl}furanyl-1,3- dihydro-[l,2,4]triazolo[5, l-f]purinone (90), 5-Amino-l-ethyl(2-furyl)[2-(3-methyl-7,8-dihydro-5H-l,6-naphthyridinyl)ethyl]- [l,2,4]triazolo[5,l-f]purinone (91), 5-Amino(2-furyl)[2-[4-[4-(2-methoxyethoxy)phenyl]piperazinyl]ethyl]-l-(2,2,2- trifluoroethyl)-[l,2,4]triazolo[5,l-f]purinone (92), 5-Amino{2-[4-(2,4-difluoro-phenyl)-piperazinyl]-ethyl}furanyl(2,2,2- trifluoro-ethyl)-l,3-dihydro-[l,2,4]triazolo[5, l-f]purinone (93), 5-Amino(2-furyl)[2-[4-[4-(2-methoxyethoxy)phenyl]piperazinyl]ethyl](2- methoxyethyl)-[1,2,4]triazolo[5, l-f]purinone (94), 5-amino[2-[4-(4-fluorophenyl)piperazinyl]ethyl](2-furyl)-l-(2-methoxyethyl)- [l,2,4]triazolo[5, rinone (95), 5-Amino[2-[4-(4-fluorophenyl)piperazinyl]ethyl](2-furyl)-l-(2-hydroxyethyl)- [l,2,4]triazolo[5, l-f]purinone one (96), 5-Amino-l-cyclopropyl(2-furyl)[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin yl]ethyl]-[1,2,4]triazolo[5, l-f]purinone (97), 5-Amino(2-furyl)[2-[4-[4-(2-methoxyethoxy)phenyl]piperazinyl]ethyl]-l-(2,2,2- trifluoroethyl)-[l,2,4]triazolo[5,l-f]purinone (98), 5-Amino[2-[4-[4-(2-methoxyethoxy)phenyl]piperazinyl]ethyl]-l-methylthiazol- 2-yl-[l,2,4]triazolo[5, l-f]purinone (99), 5-Amino[2-[4-[3-fluoro(2-methoxyethoxy)phenyl]piperazinyl]ethyl]­l-methyl thiazolyl-[l,2,4]triazolo[5, l-f]purinone (100), 5-Amino[2-[4-(2-cyclopropylacetyl)piperazin-l-yl]ethyl]-l-methylthiazolyl- [l,2,4]triazolo[5, l-f]purinone (101), 5-Amino[2-[4-(4-methoxyphenyl)piperazin-l-yl]ethyl]-l-methylthiazolyl- [l,2,4]triazolo[5,l-f]purinone (102), 5-Amino-l-methyl[2-[4-(p-tolyl)piperazin-l-yl]ethyl]thiazolyl­[l,2,4]triazolo[5,lf ]purinone (103), 5-Amino-l-methyl[2-(3-methyl-7,8-dihydro-5H-l,6-naphthyridinyl)ethyl]thiazol- 2-yl-[1,2,4]triazolo[5, l-f]purinone (104), 4-[4-[2-(5-Amino-l-methyloxothiazolyl-[l,2,4]triazolo[5,l-f]purin yl]piperazin-l-yl]benzonitrile (105), 5-Amino-l-methyl[2-[4-[3-(5-methyl-1,3,4-oxadiazolyl)phenyl]piperazin-lyl ]ethyl]thiazolyl-[1,2,4]triazolo[5, l-f]purinone (106), 5-amino[2-[4-[4-(1-hydroxy-l-methyl-ethyl)phenyl]piperazin-l-yl]ethyl]-l­methyl thiazolyl-[1,2,4]triazolo[5, l-f]purinone (107), 5-Amino[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin-l-yl]ethyl]-l-methyl(2- pyridyl)-[l,2,4]triazolo[5, l-f]purinone (108), 5-Amino[2-[4-(2,4-difluorophenyl)piperazin-l-yl]ethyl]-l-methyl(2-pyridyl)- [l,2,4]triazolo[5,l-f]purinone (109), 4-[4-[2-[5-Amino-l-methyloxo(2-pyridyl)-[l,2,4]triazolo[5,l-f]purin yl]ethyl]piperazin-l-yl]benzonitrile (110), 5-Amino[2-[4-[4-(l-hydroxy-l-methyl-ethyl)phenyl]piperazin-l-yl]ethyl]-l-methyl (2-pyridyl)-[1,2,4]triazolo[5, l-f]purinone (111), 5-Amino[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin-l-yl]ethyl]-l-methylpyrazin- 2-yl-[1,2,4]triazolo[5, l-f]purinone (112), 5-Amino[2-[4-(2,4-difluorophenyl)piperazin-l-yl]ethyl]-l-methylpyrazinyl- [l,2,4]triazolo[5, l-f]purinone (113), 5-Amino[2-[4-[2-fluoro(2-methoxyethoxy)phenyl]piperazin-l-yl]ethyl]­l-methyl pyrazinyl-[l,2,4]triazolo[5,l-f]purinone (114), 5-Amino(2-furyl)[[l-(4-methoxyphenyl)pyrrolidinyl]methyl]-l­methyl- [l,2,4]triazolo[5,l-f]purinone (115), 5-Amino(2-furyl)[[1-[4-(2-methoxyethoxy)phenyl]pyrrolidinyl]methyl]-lmethyl- [l,2,4]triazolo[5,l-f]purinonehyl}-l-methyl-1,3-dihydro-[l,2,4]triazolo[5,li one (116), 5-amino(2-furyl)[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin-l­yl]ethyl]-l-methyl- [l,2,4]triazolo[5, rinethione (117), uryl)[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin-l-yl]ethyl]-l­methyl (methylamino)-[1,2,4]triazolo[5, l-f]purinone (118), 5-Amino{2-[4-(4-fluoro-phenyl)-piperazinyl]-ethyl}isothiazolyl-l­methyl- 1,3-dihydro-[l,2,4]triazolo[5, l-i]purinone (119), 5-Aminoisothiazolyl(2-{4-[4-(2-methoxy-ethoxy)-phenyl]-piperazinyl}- ethyl)-l-methyl-1,3-dihydro-[l,2,4]triazolo[5, l-i]purinone (120), 5-Amino[2-[4-[2-fluoro(2-methoxyethoxy)phenyl]piperazinyl]ethyl] isothiazolyl-l-methyl-[l,2,4]triazolo[5, l-f]purinone (121), 5-Aminoisoxazolyl[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin-l­yl]ethyl]-lmethyl- [l,2,4]triazolo[5, l-f]purinone (122), 5-Amino[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin-l-yl]ethyl]-l-methyloxazol yl-[l,2,4]triazolo[5, l-f]purinone (123), 5-Amino{2-[4-(4-methoxy-phenyl)-piperazinyl]-ethyl}-l-methylprop-l-ynyl-1,3- o-[l,2,4]triazolo[5, l-i]purinone (124), 5-Amino(2-{4-[4-(2-methoxy-ethoxy)-phenyl]-piperazin-l-yl}-ethyl)-l­methylpropl-ynyl-1 ,3-dihydro-[l,2,4]triazolo[5, l-i]purinone (125), o{2-[4-(4-fluoro-benzoyl)-piperazinyl]-ethyl}furanylmethyl-1,3- dihydro-[l,2,4]triazolo[5, l-i]purinone (126), 5-Amino(2-dimethylamino-ethyl)furanyl-l-methyl-l,3-dihydro­[l,2,4]triazolo[5,li ]purinone (127), 5-Aminofuranyl[3-(4-methoxy-phenyl)-propyl]-l-methyl-1,3-dihydro- [l,2,4]triazolo[5,l-i]purinone (128), 5-Aminofuranyl-l-methyl(2-pyrazol-l-yl-ethyl)-l,3-dihydro-[l,2,4]triazolo[5,li ]purinone (129), ofuranyl(2-{4-[4-(2-methoxy-ethoxy)-phenyl]-pyrazol-l-yl}­ethyl)-lmethyl-1 ,3-dihydro-[l,2,4]triazolo[5,l-i]purinone (130), 5-Aminofuranyl{2-[3-(4-methoxy-phenyl)-pyrrolyl]-ethyl}-l­methyl-1,3- dihydro-[l,2,4]triazolo[5,l-i]purinone (131), 5-Aminofuranyl{2-[4-(4-methoxy-phenyl)-imidazolyl]-ethyl}-l­methyl-1,3- dihydro-[l,2,4]triazolo[5,l-i]purinone (132), 5-Aminofuranyl{2-[4-(4-methoxy-phenyl)-[l,2,3]triazol-l-yl]­ethyl}-l-methyl- 1,3-dihydro-[l,2,4]triazolo[5, l-i]purinone (133), 5-Amino[2-(l,3-dihydro-isoindolyl)-ethyl]furanyl-l-methyl-1,3-dihydro- [l,2,4]triazolo[5,l-i]purinone (134), 5-Aminofuranyl-l-methyl(2-piperidin-l-yl-ethyl)-l,3-dihydro­[l,2,4]triazolo[5,li ]purinone (135), 5-Aminofuranyl-l-methyl(2-pyrrolidin-l-yl-ethyl)-l,3-dihydro­[l,2,4]triazolo[5,li ]purinone (136), 5-Aminofuranyl-l-methyl[2-(3-methyl-7,8-dihydro-5H-[l,6]naphthyridinyl)- ethyl]-l,3-dihydro-[1,2,4]triazolo[5, l-i]purinone (137), ofuranyl{2-[4-(2-methoxy-ethoxy)-phenoxy]-ethyl}-l­methyl-1,3- dihydro-[l,2,4]triazolo[5,l-i]purinone (138), 5-Aminofuranyl{2-[4-(2-methoxy-ethoxy)-phenylamino]-ethyl}-l­methyl-1,3- dihydro-[l,2,4]triazolo[5,l-i]purinone (139), 5-Aminofuranyl-l-methyl[2-(pyridinyloxy)-ethyl]-1,3- dihydro­[l,2,4]triazolo[5,l-i]purinone (140), 5-Amino-l-ethyl{2-[4-(4-fluoro-phenyl)-piperazinyl]-ethyl}isothiazolyl-l,3- dihydro-[l,2,4]triazolo[5,l-i]purinone (141), 5-Amino-l-ethylisothiazolyl(2-{4-[4-(2-methoxy-ethoxy)-phenyl]­piperazin-lyl }-ethyl)-1,3-dihydro-[l,2,4]triazolo[5, l-i]purinone (142), 5-Amino-l-ethylfuranyl(2-piperidin-l-yl-ethyl)-l,3-dihydro­[l,2,4]triazolo[5,li one (143), 5-Amino-l-ethylfuranyl[2-(3-methyl-7,8-dihydro-5H-[1,6]naphthyridinyl)- ethyl]-l,3-dihydro-[1,2,4]triazolo[5, l-i]purinone (144), 5-Amino[2-(2,4-difluoro-phenoxy)-ethyl]-l-ethylfuranyl-l,3-dihydro- [l,2,4]triazolo[5,l-i]purinone (145), 5-Amino[2-(2,4-difluoro-phenylamino)-ethyl]-l-ethylfuranyl-1,3-dihydro- ]triazolo[5,l-i]purinone (146), 5-Amino-l-cyclopropylmethyl[2-(2,4-difluoro-phenylamino)-ethyl]furanyl-1,3- dihydro-[1,2,4]triazolo[5,l-i]purinone (147), 5-Amino-l-cyclopropylmethyl[2-(2,4-difluoro-phenoxy)-ethyl]furanyl-1,3- dihydro-[l,2,4]triazolo[5,l-i]purinone (148), 5-Amino-l-cyclopropylmethyl{2-[4-(4-fluoro-phenyl)-piperidinyl]­ethyl}furan- 2-yl-1,3-dihydro-[l,2,4]triazolo[5,l-i]purinone (149), 5-Amino{2-[4-(4-fluoro-phenyl)-piperidinyl]-ethyl}furanyl(2,2,2- trifluoro-ethyl)-l,3-dihydro-[1,2,4]triazolo[5, rinone (150), ofuranyl{2-[4-(4-methoxy-phenyl)-piperazinyl]-ethyl}(2,2,2- trifluoro-ethyl)-l,3-dihydro-[1,2,4]triazolo[5,l-i]purinone (151), 5-Amino[2-(4-cyclopropylmethyl-piperazinyl)-ethyl]isothiazolyl(2,2,2- trifluoro-ethyl)-l,3-dihydro-[l,2,4]triazolo[5, l-i]purinone (152), (5-Aminoisothiazolyl{2-[4-(4-methoxy-phenyl)-piperazinyl]­ethyl}oxo- 2,3-dihydro-[l,2,4]triazolo[5, l-i]purinyl)-acetonitrile (153), [5-Amino{2-[4-(2,4-difluoro-phenyl)-piperazinyl]-ethyl}(3-fluoro­phenyl) oxo-2,3-dihydro-[1,2,4]triazolo[5, l-i]purinyl]-acetonitrile (154), [5-Aminofuranyl(2-{4-[4-(2-methoxy-ethoxy)-phenyl]-piperazinyl}-ethyl) oxo-2,3-dihydro-[1,2,4]triazolo[5, l-i]purinyl]-acetonitrile (155), 5-Amino(2-{4-[4-(2-methoxy-ethoxy)-phenyl]-piperazinyl}-ethyl)methyl phenyl-1,3-dihydro-[l,2,4]triazolo[5, l-i]purinone (156), 3-[5-Amino(2-{4-[4-(2-methoxy-ethoxy)-phenyl]-piperazin-l-yl}-ethyl)­l-methyl oxo-2,3-dihydro-lH-[l,2,4]triazolo[5,l-i]purinyl]­ benzonitrile (157), 3-[5-Amino(2-{4-[4-(2-methoxy-ethoxy)-phenyl]-piperazin-l-yl}-ethyl)-l-methyl oxo-2,3-dihydro-lH-[l,2,4]triazolo[5,l-i]purinyl]- benzonitrile (158), 5-Aminofuranyl-l-methylvinyl-1,3-dihydro-[l,2,4]triazolo[5,l­ i]purinone (159) 5-Amino[3-(4-fluoro-phenyl)-propynyl]furanyl-l-methyl-1,3-dihydro- [l,2,4]triazolo[5,l-i]purinone (160), 5-Aminofuranyl-l-methyl[4-(4-methyl-piperazin-l-yl)-butynyl]-1,3-dihydro- ]triazolo[5, l-i]purinone (161), 5-Aminofuranyl-l-isopropyl(2-{4-[4-(2-methoxy-ethoxy)-phenyl]­piperazin-lyl }-ethyl)-1,3-dihydro-[l,2,4]triazolo[5,l-i]purinone (162), 5-Aminobenzyl(2-{4-[4-(2-methoxy-ethoxy)-phenyl]-piperazin-l-yl}­ethyl) methyl-7,9-dihydro-2H-[1,2,4]triazolo[3,4-i]purine-3,8-dione (163), 5-Aminobenzylmethyl(2-morpholinyl-ethyl)-7,9-dihydro- 2H­[1,2,4]triazolo[3,4-i]purine-3,8-dione (164), 5-Amino(3-chloro-benzyl)[2-(4-isopropyl-piperazin-l-yl)-ethyl]methyl-7,9- dihydro-2H-[1,2,4]triazolo[3,4-i]purine-3,8-dione (165), 5-Aminocyclopropylmethylmethyl(2-morpholinyl-ethyl)-7,9-dihydro-2H- [1,2,4]triazolo[3,4-i]purine-3,8-dione (166), Aminocyclopropylmethyl(2,4-difluoro-benzyl)methyl-7,9-dihydro-2H- [l,2,4]triazolo[3,4-i]purine-3,8-dione (167), 4-Aminofuranyl(2-{4-[4-(2-methoxy-ethoxy)-phenyl]-piperazin-l-yl}-ethyl)-6H- l,3,3a,5,6-pentaaza-as-indacenone (168), and 4-Aminofuranyl(2-{4-[4-(2-methoxy-ethoxy)-phenyl]-piperazin-l-yl}- ethyl)-8,8-dimethyl-6,8-dihydro- l,3,3a,5,6-pentaaza-as-indacenone (169). Impetis Biosciences Ltd. By the Attorneys for the Applicant SPRUSON & FERGUSON