Inhibitors of biliverdin reductase b (BLVRB)

Abstract

The invention is directed to compound of formula (I) or formula (II) and compositions containing the compound of formula (I) and / or formula (II). The invention is further directed to methods using the compounds and compositions.

Description

[0001] Inhibitors of biliverdin reductase B (BLVRB) Field of the invention The present invention regards compounds that have an inhibitory activity against biliverdin reductase B (BLVRB). The invention is further directed to methods of using the compounds in the treatment of diseases involving BLVRB, as well as methods of making the compounds. The invention is further directed to methods of treating cancers in which there is an over expression or over function of BLVRB. Background of the Invention Cellular levels of pro-oxidant free heme are regulated by a two-step catabolic process that initially generates carbon monoxide, free ferrous iron (Fe2+), and isomeric biliverdins (BVs) (Abraham, N.G. and Kappas, A. (2008) Pharmacological and clinical aspects of heme oxygenase, Pharmacol. Rev. 60, 79–127; Frankenberg-Dinkel, N. (2004) Bacterial heme oxygenases, Antioxid. Redox Signal.6, 825–834; Tenhunen, R., et al. (1969) Microsomal heme oxygenase characterization of the enzyme, J. Biol. Chem.244, 6388–6394 PMID: 4390967), followed by rapid NAD(P)H-dependent reduction of BVs to corresponding bilirubins (BRs). Although the initial heme oxygenase (HMOX)-mediated cleavage step could occur at any one of the four meso bridge carbons (designated α, β, γ, and δ, Formula (1), below), primary regioselectivity at the α- meso carbon generates BV IXα (to the exclusion of BV IXβ, IXγ, and IXδ) as the primary isomer found in phylogenetic development including adult mammals (Yamaguchi, T., et al. (1994) Biliverdin-IXα reductase and biliverdin-IXβ reductase from human liver, Purification and characterization, J. Biol. Chem.269, 24343–24348 PMID: 7929092; Pereira, P.J.B., et al. (2001) Structure of human biliverdin IXβ reductase, an early fetal bilirubin IXβ producing enzyme, Nat. Struct. Mol. Biol.8, 215–220). In contrast, BR IXβ, which is present in fetal bile (Yamaguchi, T. and Nakajima, H. (1995) Changes in the composition of bilirubin-IX isomers during human prenatal development, Eur. J. Biochem.233, 467–472; Nakajima, H., et al. (1963) Studies on heme α-methenyl oxygenase I. The enzymatic conversion of pyridine-hemichromogen and hemoglobin- haptoglobin into a possible precursor of biliverdin, J. Biol. Chem. 238, 3784–3796 PMID: 14109221), is followed by a gradual increase in the IXα isomer as development proceeds from mid-gestation to near term (Yamaguchi, T. and Nakajima, H. (1995) Changes in the composition of bilirubin-IX isomers during human prenatal development, Eur. J. Biochem.233, 467–472), suggesting that BV IXβ is a predominant isomer during fetal development. The molecular mechanism(s) of dichotomous BV isomeric production in adults and during fetal development remains unestablished, and there is no evidence that BV generation occurs independently from de novo assembly from smaller units (McDonagh, A.F. (2001) Turning green to gold, Nat. Struct. Mol. Biol.8, 198–200). Whether fetal BV isomers (BV IXβ, IXγ, and IXδ) retain function(s) that are distinct from the predominant BV IXα found in adults has been suggested, although this remains speculative (McDonagh, A.F. (2001) Turning green to gold, Nat. Struct. Mol. Biol.8, 198–200). Canonical HMOX-mediated BV generation is conserved in both bacteria and mammals (Lyles, K.V. and Eichenbaum, Z. (2018) From host heme to iron: the expanding spectrum of heme degrading enzymes used by pathogenic bacteria, Front. Cell. Infect. Microbiol.8, 198), although downstream BV metabolism to the potent antioxidant BR is best characterized in mammals. BV reduction is regulated by two non-redundant reductases retaining specificity for their respective isomers (Stocker, R., et al. (1987) Bilirubin is an antioxidant of possible physiological importance, Science 235, 1043–1046). Biliverdin reductase A (BLVRA) displays predominant specificity for BV IXα, whereas BLVRB catalyzes the reduction of the IXβ, Ixγ, and IXδ BV isomers (Yamaguchi, T., et al. (1994) Biliverdin-IXα reductase and biliverdin-IXβ reductase from human liver. Purification and characterization, J. Biol. Chem. 269, 24343–24348 PMID: 7929092; McDonagh, A.F. (2001) Turning green to gold, Nat. Struct. Mol. Biol.8, 198–200).

[0002] Formula (1) Additionally, BLVRB catalyzes the reduction of several flavins, including flavin mononucleotide (FMN) (Cunningham, O., et al. (2000) Initial-rate kinetics of the flavin reductase reaction catalysed by human biliverdin-IXbeta reductase (BVR-B), Biochem. J.345 (Pt 2), 393– 399), pyrroloquinoline quinone (PQQ) (Xu, F., et al. (1993) Pyrroloquinoline quinone acts with flavin reductase to reduce ferryl myoglobin in vitro and protects isolated heart from re- oxygenation injury, Biochem. Biophys. Res. Commun.193, 434–439), dichlorophenolindophenol (DCPIP) (Yubisui, T., (1979) Characterization of the purified NADPH-flavin reductase of human erythrocytes, J. Biochem.85, 719–728 PMID: 34598), and ferric ion as substrates. BLVRB redox activity also includes function as an Nitric Oxide (NO) intermediary, by transferring NO from acyl-coenzyme A (SNO-CoA) to downstream effector proteins, providing an additional mechanism for controlling cellular redox activity and disease pathogenesis including diabetes and obesity (Zhou, H. L., et al. (2023). An enzyme that selectively S-nitrosylates proteins to regulate insulin signaling, Cell 186, 5812-5825). Although BLVRA is well-characterized and has been shown to be important for various cellular processes including regulation of oxidative stress and cellular signaling (Florczyk, U.M., et al. (2008) Biliverdin reductase: new features of an old enzyme and its potential therapeutic significance, Pharmacol. Rep.60, 38–48 PMID: 18276984), the physiological role of BLVRB remains enigmatic, partly due to unavailability of its presumed physiological substrates, (BV IXβ, BV IXγ, BV IXδ) (Yamaguchi, T., et al. (1994) Biliverdin-IXα reductase and biliverdin-IXβ reductase from human liver. Purification and characterization, J. Biol. Chem.269, 24343–24348 PMID: 7929092; McDonagh, A.F. (2001) Turning green to gold, Nat. Struct. Mol. Biol.8, 198–200). Indeed, most biochemical studies designed to characterize BLVRB’s catalytic activity have been conducted using flavin (Cunningham, O., et al. (2000) Initial-rate kinetics of the flavin reductase reaction catalysed by human biliverdin-IXbeta reductase (BVR-B), Biochem. J. 345 (Pt 2), 393–399) and non-physiological synthetic linear tetrapyrroles as substrates (Cunningham, O., et al. (2000) Studies on the specificity of the tetrapyrrole substrate for human biliverdin-IXα reductase and biliverdin-IXβ reductase. structure- activity relationships define models for both active sites, J. Biol. Chem.275, 19009–19017; Franklin, E.M., et al. (2009) The use of synthetic linear tetrapyrroles to probe the verdin sites of human biliverdin-IXα reductase and human biliverdin-IXβ reductase, FEBS J.276, 4405–4413). More recently, expanded BLVRB function (s) have been suggested for various disease states including cancer and thrombosis (Huan, L., et al. (2016) MicroRNA-127-5p targets the biliverdin reductase B / nuclear factor-κB pathway to suppress cell growth in hepatocellular carcinoma cells, Cancer Sci.107, 258–266; Silveira, V.S., et al. (2013) Gene expression pattern contributing to prognostic factors in childhood acute lymphoblastic leukemia, Leuk. Lymphoma 25, 310–314; Pallua, J.D., et al. (2013) MALDI-MS tissue imaging identification of biliverdin reductase B overexpression in prostate cancer. J. Proteom.91, 500–514; Wu, S., et al. (2016) BLVRB redox mutation defines heme degradation in a metabolic pathway of enhanced thrombopoiesis in humans, Blood 128, 699–709), and a loss-of-function redox mutation (BLVRB S111L) has been implicated in a pathogenetically-regulated mechanism of enhanced platelet production in humans (Wu, S., et al. (2016) BLVRB redox mutation defines heme degradation in a metabolic pathway of enhanced thrombopoiesis in humans. Blood 128, 699–709; Chu, W.T., et al.,. (2017) Enzymatic activity and thermodynamic stability of biliverdin IXbeta reductase are maintained by an active site serine, Chemistry 23, 1891–1900), presumably as a ROS-regulated upstream signaling messenger for megakaryocyte differentiation (Wu, S., et al. (2016) BLVRB redox mutation defines heme degradation in a metabolic pathway of enhanced thrombopoiesis in humans, Blood 128, 699–709; Chen, S., et al. (2013) ROS-mediated platelet generation: a microenvironment-dependent manner for megakaryocyte proliferation, differentiation, and maturation, Cell Death Dis.4, e722; Eliades, A., et al. (2012) Oxidases and reactive oxygen species during hematopoiesis: a focus on megakaryocytes, J. Cell Physiol. 227, 3355–3362; Shinohara, A., et al. (2014) Intracellular reactive oxygen species mark and influence the megakaryocyte-erythrocyte progenitor fate of common myeloid progenitors, Stem Cells 32, 548–557). US 2022 / 0339170 A1 discloses several generally disparate compounds to be used in the inhibition of BLVRB activity to treat platelet disorders, wherein the compounds are characterized by not containing a xanthene or acridine moiety. US 10,543,286 discloses methods of increasing platelet count and treating platelet disorders by inhibiting BLVRB activity or the expression of the BLVRB gene. Nesbitt, Natasha M. et al., In silico and crystallographic studies identify key structural features of biliverdin IXβ reductase inhibitors having nanomolar potency, J. Biol. Chem. (2018) 293; 5431-5446, discloses BLVRB inhibitors containing a tricyclic hydrocarbon core structure. Zhang et al., Biochemical characterization of biliverdins IXβ / δ generated by a selective heme oxygenase, Biochem. J. (2020) 447: 501-614, discloses the use of halogenated xanthene- based compounds as inhibitors of BLVRB using BV IXβ as the substrate. The present inventors have developed a novel class of compounds, sharing a common core structure, which have inhibitory activity of the BLVRB redox reaction. Summary of the Invention In one embodiment the invention is directed to a compound of formula (I), wherein, X is a heteroatom; R1is CO2H, halogen, or CN; and R2and R3are each independently H, a lower alkyl having 1-6 carbon atoms, an ester or alkyoxy having 1-6 carbon atoms, an ether having 1-6 carbon atoms, haloalkyl, halogen, CN, NO2, NH2, C(1-6)NH2. With the compound of formula (I), X may be S or O. With the compound of formula (I), at least one of R2and R3may be F, Cl, or Br. With the compound of formula (I), at least one of R2and R3may be CF3. With the compound of formula (I) one of R2and R3may be an alkyl and the other a halogen; one of R2and R3may be a halogen and the other an ether group; one of R2and R3may be a halogen and the other NH2, or one of R2and R3may be a halogen and the other C(1-6)NH2. The invention is further directed to compositions comprising the compound according to formula (I). In an alternative embodiment the invention is directed to a compound of formula (II) wherein, R1is selected from H, OH, CO2H, CO2R, CN, halogen, lower alkyl, hydroxy or tetrazole, wherein R is a lower alkyl, preferably a lower alkyl of 1 to 6 carbon; R2is H, or a lower alkyl of 1 to 6 carbon atoms, (e.g. a methyl, ethyl, butyl, tert-butyl, pentyl, or hexyl group), more preferably R2is a H or a methyl group; A is a cycloalkyl, phenyl, furanyl, thiophene or pyridinyl group; R3and R4are each independently H; halogen; and alkyl group having 1 to 6 carbon atoms; a substituted or unsubstituted alkoxy group having 1 to 6 carbon atoms, which is optionally substituted with 1, 2 or 3 halogen atoms; -when R3and R4are each be an alkyl group, together R3and R4may form a 5- or 6- member saturated or unsaturated ring, which may contain one or more heteroatoms or N, S or O. The invention is further directed to a composition comprising the compound of formula (II). The invention is further directed to methods of treating thrombocytopenia by administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) and / or formula (II) or a composition comprising a compound of formula (I) and / or formula (II). The invention is further directed to methods of increasing platelet production by administering to a patient a compound of formula (I) and / or formula (II) or a composition comprising a compound of formula (I) and / or formula (II). The invention is further directed to methods of inhibiting BLVRB redox function and S- nitrosylation with a compound of formula (I) and / or formula (II) or a composition comprising a compound of formula (I) and / or formula (II). The invention is further directed to methods of reducing the risk of drug-related hemolysis toxicity in a subject receiving primaquine or tafenoquine, by co-administering to the subject an effective amount of a compound of formula (I) and / or formula (II) or a composition comprising a compound of formula (I) and / or formula (II). The invention is further directed to methods of treating any cancer with increased BLVRB expression of function, by administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) and / or formula (II) or a composition comprising a compound of formula (I) and / or formula (II). The invention is further directed to methods of treating cancer, particularly breast or ovarian cancer, by administering to a patient in need thereof a therapeutically effective amount of at least one BLVRB- inhibitor., The invention is further directed to methods of treating cancer, particularly breast or ovarian cancer, by administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) and / or formula (II) or a composition comprising a compound of formula (I) and / or formula (II). Description of the Drawings FIG 1. BLVRB function in breast cancer. (A) Heme is generated as a TCA cycle byproduct from glucose and glutamine one-carbon pools, followed by derivatization to the BR antioxidant using two non-overlapping reductases (BLVRA and BLVRB) with distinct substrate specificities; i.e. BLVRA specifically utilizes BV IXα as substrate, while BLVRB uses non-IXα BVs (IXγ, IXδ, IXβ (IXβ is shown for simplicity). BLVRB upregulation and enhanced cytoprotection in breast cancer cells results in survival benefit(s) (left panel), and in the absence of BLVRB redox function (either genetic ablation or using uniquely-developed BLVRB inhibitors), interruption of the BV / BR antioxidant cycle will result in (i) defective BR generation, (ii) enhanced ROS accumulation, (iii) lipid peroxidation defects, and (iv) cellular death (right panel). FIG 2. BLVRB is overexpressed in cancer but not in normal mammary cells. (A) in human biopsies (Bartha A, Gyorffy dataset). (B) BLVRB is overexpressed across all breast cancer subtypes (GENT2 database, gent2.appex.kr / gent2). (C) BLVRB IHC staining of human breast cancer tissue microarray (TMA) shows the variable intensity (from negative to strong) of nuclear and cytoplasmic BLVRB staining in human breast cancer with no detectable staining in normal mammary tissues. (D) BLVRB is undetectable in MCF10A but shows high levels in breast cancer cell lines of different subtypes. (E) High levels of BLVRB RNA expression predict poor prognosis across all subtypes of breast cancer, with the highest prognostic value in Her2+ BC. BLVRB RNA (F) and protein (G) show higher levels in murine mammary cancer cell (MECs) lines compared to murine mammary epithelial cells using identical genetic backgrounds established from MMTV / ErbB2 mice. P-values: *<0.05; ***<0.001 FIG.3 Shows the expression of BLVRB in the cell lineage involved in clonal breast cancer pathogenesis. FIG.4 BLVRB-mediated redox handling is required for proliferation and survival of breast cancer cells. (A) BLVRB is expressed in nucleus and cytoplasm of SKBR3 cells, with loss in SKBR3 / BLVRB- / -(CC9) cells by IF (A) and immunoblot (B). BLVRB- / -cells demonstrate defective antioxidant handling, evident by ROS accumulation using DHFE fluorescence (C) and ROS-Glo assay (D), that occur with defective lipid peroxidation, MDA assay (E), but maintenance of mitochondrial function (F, JC1 fluorescence). SKBR3 / BLVRB- / -cells show decreased proliferative capacity (G) in conjunction with loss of cell viability (H), and increased G2 / M arrest (I); **p<0.01; ***p<0.001. FIG.5 Shows the ability of BLVRB to confer resistance to oxidative stress. FIG.6 Megakaryocyte-promoting effects of a BLVRB inhibitor BCT1028 in K562 cell model. FIG.6A - Gene expression patterns of cancer cell lines (N = 60) focusing on the heme degradation genes BLVRA, BLVRB, HMOX1, HMOX2. The inset shows the N=6 hematopoietic (leukemic) cell lines and high BLVRB expression in K562 cells which retain megakaryocyte-promoting potential with the proper stimulus. Scale bar (RPKM, log2) is shown. FIG.6B - BLVRB activity in K562, HEL and MOLT4 cells was determined using the BLVRB substrate DCPIP (data expressed as mean ± SEM, N = 3). The inset confirms BLVRB protein expression in K562 and HEL cells (but not MOLT4), corresponding to BLVRB activity. FIG.6C Incubation of K562 cells with BCT1028 (10 µM, 48 hours) shows striking increase in cell size typical of megakaryocytes (arrows, lower panel). The graph shows cell size quantified by image J software, confirming size increase in BCT1028-treated cells. Size bar corresponding to 20 µm is shown. FIG.6D and FIG.6E K562 cells were incubated with various concentrations of BCT1028, and megakaryocyte differentiation (at 24, 48, 72 hours) was quantified by flow cytometry using CD61 as a megakaryocyte-specific marker. Panel D shows dose-dependent CD61 increase (%) by time, and Panel E quantifies time- and dose-dependent CD61 cell-surface expression (abundance). All plots represent the mean ± SEM for N = 3 independent experiments. The phorbol ester PMA (10-6M) which displays known megakaryocyte-promoting features is shown as control. For all panels, P-values (** <0.01; *** <0.001) are shown. FIG.7 Megakaryocyte-promoting effects of BCT1028 are recapitulated in HEL cells and human stem cells. FIG.7A - Dose-dependent BCT1028 was incubated with HEL cells and evaluated for intracellular accumulation by flow cytometry (Ex / Em 350 / 465 nm). Note the clear time- and dose- dependent intracellular accumulation. FIG.7B - Cell-cycle analysis of HEL cells incubated with vehicle control, BCT1028 (10 µM, 48 hours) or saturating PMA (10-6M for 24 hours) shows clear increase in DNA content typical of megakaryocyte differentiation. FIG.7C - HEL cells incubated with dose-dependent BCT1028 for 48 hours were lysed and analyzed by SDS-PAGE and immunoblot analyses (20 µg / lane), followed by immunodetection. Note the clear induction of megakaryocyte marker CD61 (β3integrin), and relative stability of erythroid CD71 (transferrin receptor) except at high (50 µM) dose. BLVRA remains stable at all concentrations although BLVRB immunodetection decreases with progressive BCT1028 concentrations ≥ 20 µM. FIG. 7D - A second megakaryocyte-specific marker (platelet factor 4, PF4) displayed an identical pattern of enhanced megakaryocyte differentiation in BCT1028-supplemented CD34+stem cells. FIG.8 BLVRB inhibitor BCT1028 promotes platelet recovery in mice. FIG.8A - Study schema and timeline of BCT1028-treated mice is shown, highlighting two distinct cohorts differentiated by basal hematopoietic effects (Cohort 2) or stress hematopoietic responses (Cohort 1 induced by 150 mg / kg 5FU as stressor). Following 5FU induction (or not), mice (N = 8-12 / cohort) received either BCT1028 (formulated in PEG400) or vehicle alone (PBS / PEG400) daily for 21 days by oral gavage. FIG.8B and FIG.8C - Hemograms (mean ± SEM) of age- (12 – 16 week old mice) and gender (male)-matched mice show time-dependent platelet recovery (% increase from baseline) and reticulated platelets (%) (Panel B), or RBC (red blood cell) counts and reticulocytes (Panel C); * p<0.05, **p ≤ 0.01; N.S. - not significant. FIG.8D - The platelet mass index (absolute platelet count X mean platelet volume) as a function of time was applied to determine hemostatic coverage period using area under curve analyses in Cohort 1 mice during stress hematopoietic recovery. P-value (<0.0001) determined by unpaired t-test with false discovery rate is shown. Detailed Description of the Invention Platelets, or thrombocytes, are small, colorless cell fragments in our blood that form clots and stop or prevent bleeding. The regulation of platelet population and the control of specific platelet responses are prominent targets for new drugs against platelet disorders. The impairment of platelet regulation leads to various bleeding disorders, including thrombocytopenia, which is characterized by increased bleeding (hemophilia) due to low platelet counts. Typical treatment intervention for thrombocytopenia is to increase platelet counts by inducing platelet generation or platelet transfusion. In contrast, thrombocytosis is characterized by excessive platelets in the blood. Through cohort analysis of thrombocytosis with large-scale platelet transcriptome sequencing in both primary (essential) and secondary (reactive) thrombocytosis cohorts, it was found that BLVRB can control production of platelet through megakaryocyte (MK) differentiation by reactive oxygen species (ROS) control. Furthermore, it has been shown that the loss-of-function mutant (BLVRBS111L) induces more platelets by ROS accumulation (Wu et al. BLOOD, (2016) Vol.128, No.5, pages 699-709), and thus, the inhibition of BLVRB activity represents a novel strategy to increase the platelet generation due to a unique BLVRB specific redox-regulation in the heme degradation pathway. Megakaryocytopoiesis and proplatelet formation represent progressively linked stages of hematopoietic stem cell (HSC) development that maintain the normal circulating pool of platelets (Kaushansky K. (2008) Blood 111(3):981-986). Platelets are critical to normal hemostasis, pathological thrombosis, and host adaptive immunological responses (Bahou W. F. (2006) Genomics and Clinical Medicine, ed. Kumar D (Oxford University Press, Oxford), pp 221-248; Bahou W. F. (2012) Thromb. Res.129 Suppl 1:S38-45). Platelet generation (˜1×1011cells daily) is largely controlled by the thrombopoietin (TPO) gene / c-Mpl (TPO receptor) axis or the (TPO) / c- MPL axis and is a result of the commitment of the common bipotent megakaryocyte-erythrocyte progenitors (MEP) to the MK lineage (Debili N, et al. (1996) Blood 88(4):1284-1296). Although MKs are reduced in MPL-deficient mice, animals still produce MKs and platelets, implying that HSCs maintain the capacity for lineage fate in the absence of MPL. Transcription factors including GATA-1, GATA-2, FOG1 / ZFPM1, RUNX1, and NFE2, are important for MK development (Bahou W F (2006) Genomics and clinical Medicine , ed Kumar D (Oxford University Press, Oxford), pp 221-248), but none exclusively specify MK fate (Kaushansky K (2008) Blood 111(3):981-986). The platelet count (circulating in the bloodstream) is usually about 140,000 to 440,000 per microliter (140×109to 440×109per liter). “Platelet disorder” refers to an abnormal increase or decrease in the count of such platelets or impaired platelet function and includes “thrombocytopenia.” “Thrombocytopenia” is a disease that causes abnormal bleeding symptoms as the count of platelets decreases. Thrombocytopenia may occur even when platelet production in the bone marrow decreases, or platelet destruction in the spleen increases. Leukemia, aplastic anemia, or anti-cancer therapy affects platelet production in the bone marrow. In addition, thrombocytopenia is not known for its exact cause but may occur in the case of developing a regulatory mechanism or metabolic disorder; in the case of exposure to drugs or chemicals; or the presence of a blood disease such as megaloblastic anemia, leukemia or histocytosis, an infectious disease such as hepatitis, and acquired immunodeficiency syndrome (AIDS), or an autoimmune disease such as systemic lupus erythematosus (SLE). In rare cases, thrombocytopenia may occur due to a malignant tumor. The most important function of platelets is hemostasis, so bleeding symptoms develop when thrombocytopenia occurs. If the platelet count is less than 20,000 per 1 mm3, bleeding can occur naturally without damage to the blood vessels, and severe gastrointestinal tract or central nervous system bleeding occurs. Bleeding also occurs on the skin or mucous membranes, which appear as purpura, hematuria, nasal bleeding, etc. Prolonged bleeding leads to anemia. Thus, thrombocytopenia may cause or worsen anemia or cause anemia complications. BLVRB is an enzyme protein known to control platelet count by controlling ROS. The platelet count is expected to be increased by inhibiting the activity of BLVRB. Accordingly, research is being conducted as a target for the treatment of platelet disorders, including thrombocytopenia. Xanthene or acridine-based compounds have been used as inhibitors of BLVRB activity, but there is a concern regarding complications due to cytotoxicity and oligomerization of BLVRB (U.S. Pub. App. No.2022 / 0339170). In some embodiments, the presently disclosed subject matter relates to BLVRB inhibitor compounds and methods for using BlvrB inhibitors to treat thrombocytopenia and avoid the side effects associated with conventional xanthene and acridine-based compounds. Malaria is an infectious disease afflicting hundreds of millions of people annually and causing 1 to 3 million deaths annually, most of which are children under the age of 5. Malaria is caused by protozoan parasites of the Plasmodium genus, five species of which, P. falciparum, P. ovale, P. vivax, P. malariae, and P. knowlesi, are able to cause infection in humans. Upon infection, the parasites (sporozoites) travel to the liver, where they mature and release another form of parasites called merozoites. The parasites enter the bloodstream and multiply inside red blood cells, causing RBC lysis, thereby allowing the parasites to infect more red blood cells. P. vivax and P. ovale form hypnozoites that manifest in a dormant liver stage. This dormancy causes patients who have recovered from an initial infection to have a subsequent relapse, even up to years after the original infection. Primaquine and tafenoquine, both of which are 8-aminoquinolines (8-AQs), are currently the only approved drugs in the United States that can eradicate the liver phase of P. vivax or P. ovale. Unfortunately, primaquine and tafenoquine have significant and potentially lethal side effects in patients with glucose-6-phosphate dehydrogenase (G6PD) enzyme deficiency, a genetic trait common in regions where malaria is endemic. Therefore, it is urgent to identify new treatments to eliminate the parasite during the liver phase of its life cycle. Malaria is a significant health problem worldwide. According to the World Health Organization (WHO), there were an estimated 219 million cases of malaria in 87 countries in 2017. Of these cases, approximately 435,000 deaths were recorded. In addition to the cost to human life, the equivalent of over 3 billion U.S. dollars were spent on malaria control in 2017. Moreover, the WHO 2018 annual report indicated that efforts to control malaria are making little progress overall. Of the five different species of Plasmodium that cause malarial disease in humans, two, P. vivax and P. ovale, are particularly problematic from both a treatment and eradication standpoint, in part, because they form hypnozoites that manifest in a dormant liver stage. It is estimated that 66%-95% of acute episodes of P. vivax are due to relapse rather than primary infection. This is not only a problem for afflicted patients but also represents a problem for general eradication efforts because relapsed patients can serve as a source of infection for whole populations through mosquito-based transmission. As previously mentioned, the only currently approved drugs in the United States that can eradicate the liver phase of P. vivax and P. ovale (i.e., radical cure) are primaquine and tafenoquine, both of which are contraindicated in patients with G6PD deficiency. G6PD is the first and rate- limiting enzyme in the pentose phosphate pathway (PPP). It oxidizes glucose-6-phosphate into 6- phosphogluconate and converts NADP+ to NADPH, the latter being the major electron donor for antioxidant pathways. Insufficient G6PD activity (i.e., G6PD deficiency (G6PDd)) is the most common enzymopathy known in humans, affecting between 400 and 500 million individuals worldwide. G6PD deficiency can be assayed by enzymatic activity, level of enzyme expression, RBC hemolysis to phenylhydrazine or similar oxidant stresses, reduction of methylene blue, and / or genotyping. Affected individuals can present with acute hemolysis when exposed to sources of oxidant stress, including illnesses and consumption of certain foods or drugs.. Many countries where G6PD deficiency is common do not have the resources to adequately determine if a patient presents with G6PD deficiency. Therefore, in areas where populations where G6PD deficiency is common, primaquine and tafenoquine treatment are not used as treatments for malaria. Primaquine, also known as N-(6-methoxyquinolin-8-yl)pentane- 1,4-diamine phosphate, is known to cause hemolytic anemia in persons deficient in G6PD(Beutler, 1969; Capote et al., 1997). Patients with hemolysis may present with acute anemia, pallor, jaundice, hematuria, dyspnea, fatigue, lightheadedness, dizziness, tachycardia, and possibly hypotension. Laboratory test results that may confirm hemolysis include reticulocytosis, increased lactate dehydrogenase, increased unconjugated bilirubin, and decreased haptoglobin levels. A peripheral blood smear should be performed when hemolysis is present to identify abnormal red blood cell morphologies. Treatment for hemolytic anemia includes a red blood cell transfusion or intravenously administered immunoglobulin. Moreover, methemoglobin toxicity is another predictable dose-related adverse effect associated with primaquine. Methemoglobin toxicity, or methemoglobinemia, can be assayed by a complete blood count, an enzyme test, an examination of blood color, an examination of blood levels or other drugs, pulse oximetry to check the saturation of oxygen, and / or genotyping. Methemoglobinemia can be treated either with methylene blue, which is contraindicated for people with a congenital type of methemoglobinemia, or with a blood transfusion. The mechanism of 8-AQ-induced hemolysis in G6PDd humans has long been appreciated to consist of redox cycling. Two active metabolites, 5-hydroxy primaquine and primaquine-5, 6- ortho-quinone, are produced by hepatic metabolism of primaquine. Redox cycling occurs when primaquine metabolites (PMs) catalyze the transfer of electrons (e-) from NADPH to molecular oxygen (O2) to generate superoxide. It has been recognized that redox cycling does not happen spontaneously and requires an enzymatic reductase to transfer an e- from NADPH to the PMs (Baird. Front Cell Infect Microbiol 2021; 11;696598). Characteristics of the reductase (called Diaphorase II) include the ability to reduce methylene blue 8 and an approximate molecular weight of 18 kiloDaltons (kDa; Fisher et al., 1977). BLVRB has been shown to reduce methylene blue and have a similar molecular weight as Diaphorase II (Komoro et al., 1996; Shalloe, 1996). Finally, BlvrB is known to be able to reduce other quinoline orthoquinones (i.e., pyrroloquinoline quinone; Xu et al., 1993. BlvrB has now been cloned and characterized (Komoro et al., 1996). Tafenoquine is disclosed in U.S. Patent No. 4,617,394. Though more effective than primaquine, the drug was found to cause methemoglobin toxicity almost three times more than that of primaquine (Anders et al., 1988), hence has drawbacks in terms of safety. Because 8-AQs are the only known drugs that can eradicate the liver phase of P. vivax and P. ovale, but also cause hemolysis in patients with G6PD deficiency, these drugs cannot safely be used to cure P. vivax or P ovale in this patient population without the ability to transfuse during therapy and hospitalize if necessary. Because hemolysis can have negative sequelae in addition to anemia (e.g ., kidney damage), even with transfusion support, 8-AQ therapy may not be entirely safe in patients with G6PD deficiency. Ironically, because G6PD deficiency evolved as a natural resistance to malaria, it is particularly prevalent in populations indigenous to malaria-endemic regions, increasing the percentage of malaria-infected people in whom 8-AQs are toxic. Primaquine and tafenoquine cause hemolysis in G6PD deficient subjects because they induce oxidative stress; G6PD RBCs have diminished antioxidant capacity. The mechanisms by which primaquine and tafenoquine generate oxidative stress is by generating ROS by redox cycling. In particular, an electron is transferred to primaquine and tafenoquine (i.e., chemical reduction) by an enzymatic reductase to give rise to primaquine and tafenoquine radicals, which then transfers electrons to O2 to generate superoxide (O2-). The compounds of the present invention may be used to treat patients receiving primaquine or tafenoquine with a BLVRB inhibitor to enhance the safety profile of these drugs, e.g., by reducing or preventing dangerous side effects (e.g, hemolysis), especially in patients deficient in G6PD activity. Enhanced metabolic and mitochondrial activity inherent in actively proliferating cancer cells generates excessive ROS, associated with intracellular redox imbalance that impacts cellular viability. To survive chronic oxidative stress, cancer cells evolve to activate scavenging / anti- oxidant enzymes to restore redox balance. This differential activation of antioxidant pathways compared to normal cells provides a therapeutic window for novel cellular targets. Moreover, the effects of chemo- and radiotherapy (in part) are attributed to oxidative stress that causes irreversible oxidative damage and cell death, and activation of redox-regulating pathways is thought to promote chemoresistance. The obligatory dependence of cancer cells on antioxidant defense pathways as a fundamental pro-survival mechanism suggests the broad translational utility of their targeting in cancer. Modulation of redox-adaptation mechanisms represents a feasible strategy to eradicate cancer cells and / or restore chemosensitivity to conventional therapies. FIG. 1 shows Heme degradation and cytoprotection with the non-redundant BLVRB pathway. Heme (Fe2+-protoporphyrin IX) synthesis and catabolism are contextually placed at the interface of bioenergetics and cellular antioxidant handling, converging in a linear pathway that utilizes tricarboxylic acid (TCA) cycle-derived carbon (glucose or glutamine) in cataplerotic reactions of tetrapyrrole (heme) biosynthesis, linked to the cytoprotective heme degradation pathway critical to mitigating against cellular stress (Heme → BV (biliverdin) → BR (bilirubin), with the generation of the potent BR antioxidant. Heme synthesis and degradation collectively provide key components for (i) maintenance of ETC functionality; (ii) generation of mitochondrial NADH, and (iii) generation of the potent antioxidant bilirubin (BR). The present inventors have demonstrated that a Blvrb- / -mouse model displays no organ pathology in males or females over 18 months, establishing a non-requisite function in normal organs or tissue development (Nesbitt et al. Free Radical Biology and Medicine, (2021) Vol.164, pages 164-174). Furthermore, it has been shown have shown that an intact Hmox / Blvra pathway is insufficient to rescue the stress phenotype in Blvrb- / -mice, in genetically deficient induced pluripotent stem cells (iPSC / BLVRB- / -), and BLVRB-deficient breast cancer cells (vide infra), highlighting the critical and non-overlapping function of the HMOX / BLVRB pathway in redox function and cytoprotection. For the first time, the inventors have identified BLVRB as a requisite component of pro- survival antioxidant defense in breast cancer cells, leading to exaggerated ROS accumulation and cell death. Prior to the work of the inventors, BLVRB’s function was considered superfluous to heme degradation. Unlike BLVRA, the first physiologically-relevant function for BLVRB in human cancer has been defined. Thus, in one embodiment, the invention is directed to a method of using a BLVRB- inhibitor(s) as a potentially non-toxic strategy for cancer treatment with minimal predicted off- target effects in normal cells. In particular, an embodiment the invention is directed to a method of using a BLVRB- inhibitor(s) of the invention as a potentially non-toxic strategy for cancer treatment with minimal predicted off-target effects in normal cells. The cancer treated with the BLVRB inhibitor may be, in particular, breast or ovarian cancer. This description lists several embodiments of the presently disclosed subject matter and in many cases, lists variations and permutations of these embodiments of the presently disclosed subject matter. This Summary is merely exemplary of the numerous and varied embodiments. Mention of one or more representative features of a given embodiment is likewise exemplary. Such an embodiment can typically exist with or without the feature(s) mentioned; likewise, those features can be applied to other embodiments of the presently disclosed subject matter, whether listed in this Summary or not. To avoid excessive repetition, this Summary does not list or suggest all possible combinations of such features. In some embodiments, the present invention is directed to methods of increasing platelet counts in a subject by administering to a human or animal patient a therapeutically effective amount of a compound of the invention that inhibits Biliverdin reductase B (BLVRB) activity. In some embodiments, the invention is directed to methods of treating thrombocytopenia or other platelet-related disorders by administering to a human or animal patient a therapeutically effective amount of a compound of the invention that inhibits Biliverdin reductase B (BLVRB) activity. In some embodiments, the presently disclosed subject matter relates to methods for using BlvrB inhibitors to permit malaria eradication in patients with G6PD deficiency when treated with 8-Aminoquinoline-containing compounds such as but not limited to primaquine and / or tafenoquine. In some embodiments, there is a method of reducing the risk of drug-related hemolysis toxicity in a subject receiving a drug selected from the group consisting of primaquine and tafenoquine, comprising co-administering to the subject an effective amount of a BLVRB inhibitor. In some embodiments, there is a method of improving the therapeutic index of a drug selected from the group consisting of primaquine and tafenoquine in a subject, comprising co- administering to the subject an effective amount of a BLVRB inhibitor. In some embodiments, there is a method of reducing the production of reactive oxygen species in a subject receiving a drug selected from the group consisting of primaquine and tafenoquine comprising co-administering to the subject an effective amount of a BLVRB inhibitor. In some embodiments, the subject has a G6PD deficiency. In some embodiments, the subject’s red blood cells are deficient in G6PD activity. In some embodiments, the G6PD deficiency is established by measurement of enzymatic activity, level of enzyme expression, RBC hemolysis to phenylhydrazine, reduction of methylene blue, or genotyping. As used herein, the term “therapeutically effective amount” refers to an amount of a compound sufficient to show a desired biological response or the development or relief of symptoms or indications. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of the disease or disorder. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent. As used herein, the terms “treat,” “treating,” “treatment,” and the like refer to eliminating, reducing, or ameliorating a disease or condition and / or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated. As used herein, the terms “treat,” “treating,” “treatment,” and the like may include “prophylactic treatment,” which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously- controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition. The term “treat” and synonyms contemplate administering a therapeutically effective amount of a compound of the invention to an individual in need of such treatment. Within the meaning of the invention, “treatment” also includes relapse prophylaxis or phase prophylaxis, as well as the treatment of acute or chronic signs, symptoms and / or malfunctions. The treatment can be orientated symptomatically, for example, to suppress symptoms. It can be effected over a short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy. The use of the terms “a”, “an”, “the”, and similar referents in the context of describing the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated. Recitation of ranges of values herein merely are intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended to better illustrate the invention and is not a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention. A compound of structural formula (I) used in a method of the present invention can be administered in an amount of about 0.005 to about 500 milligrams per dose, about 0.05 to about 250 milligrams per dose, or about 0.5 to about 100 milligrams per dose. For example, a compound of structural formula (I) can be administered, per dose, in an amount of about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 milligrams, including all doses between 0.005 and 500 milligrams. The dosage of a compound of Formula I or Formula II, or a composition containing the same, can be from about 1 ng / kg to about 200 mg / kg, about 1 µg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg. The dosage of a composition can be at any dosage including, but not limited to, about 1 µg / kg. The dosage of a composition may be at any dosage including, but not limited to, about 1 µg / kg, 10 µg / kg, 25 µg / kg, 50 µg / kg, 75 µg / kg, 100 µg / kg, 125 µg / kg, 150 µg / kg, 175 µg / kg, 200 µg / kg, 225 µg / kg, 250 µg / kg, 275 µg / kg, 300 µg / kg, 325 µg / kg, 350 µg / kg, 375 µg / kg, 400 µg / kg, 425 µg / kg, 450 µg / kg, 475 µg / kg, 500 µg / kg, 525 µg / kg, 550 µg / kg, 575 µg / kg, 600 µg / kg, 625 µg / kg, 650 µg / kg, 675 µg / kg, 700 µg / kg, 725 µg / kg, 750 µg / kg, 775 µg / kg, 800 µg / kg, 825 µg / kg, 850 µg / kg, 875 µg / kg, 900 µg / kg, 925 µg / kg, 950 µg / kg, 975 µg / kg, 1 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, or 200 mg / kg. The above dosages are exemplary of the average case, but there can be individual instances in which higher or lower dosages are merited, and such are within the scope of this invention. In practice, the physician determines the actual dosing regimen that is most suitable for an individual patient, which can vary with the age, weight, and response of the particular patient. The compounds of the present invention of Formula I or Formula II typically are administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use in accordance with the present invention are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate processing of compounds of Formula I or Formula II. These pharmaceutical compositions can be manufactured, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping, or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen. When a therapeutically effective amount of a compound of Formula I or Formula II is administered orally, the composition typically is in the form of a tablet, capsule, powder, solution, or elixir. When administered in tablet form, the composition additionally can contain a solid carrier, such as a gelatin or an adjuvant. The tablet, capsule, and powder contain about 0.01% to about 95%, and preferably from about 1% to about 50%, of a compound of Formula I or Formula II. When administered in liquid form, a liquid carrier, such as water, petroleum, or oils of animal or plant origin, can be added. The liquid form of the composition can further contain physiological saline solution, dextrose or other saccharide solutions, or glycols. When administered in liquid form, the composition contains about 0.1% to about 90%, and preferably about 1% to about 50%, by weight, of a compound of Formula I or Formula II. When a therapeutically effective amount of a compound of Formula I or Formula II is administered by intravenous, cutaneous, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art. A preferred composition for intravenous, cutaneous, or subcutaneous injection typically contains, an isotonic vehicle. Compounds of Formula I or Formula II can be readily combined with pharmaceutically acceptable carriers well-known in the art. Such carriers enable the active agents to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by adding the compound of Formula I or Formula II to a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. If desired, disintegrating agents can be added. A compound of Formula I or Formula II can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampules or in multidose containers, with an added preservative. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form. Additionally, suspensions of a compound of Formula I or Formula II can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension. Optionally, the suspension also can contain suitable stabilizers or agents that increase the solubility of the compounds and allow for the preparation of highly concentrated solutions. Alternatively, a present composition can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. A compound of Formula I or Formula II also can be formulated in rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases. In addition to the formulations described previously, the compound of Formula I or Formula II also can be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of Formula I or Formula II can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins. In particular, the compounds of Formula I or Formula II can be administered orally, buccally, or sublingually in the form of tablets containing excipients, such as starch or lactose, or in capsules or ovules, either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. Such liquid preparations can be prepared with pharmaceutically acceptable additives, such as suspending agents. The compounds of Formula I or Formula II also can be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronarily. For parenteral administration, the compounds of Formula I or Formula II are best used in the form of a sterile aqueous solution which can contain other substances, for example, salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood. As an additional embodiment, the present invention includes kits which comprise one or more compounds or compositions packaged in a manner that facilitates their use to practice methods of the invention. In one simple embodiment, the kit includes a compound or composition described herein as useful for practice of a method (e.g., a composition comprising a compound of Formula I or Formula II and an optional second therapeutic agent), packaged in a container, such as a sealed bottle or vessel, with a label affixed to the container or included in the kit that describes use of the compound or composition to practice the method of the invention. Preferably, the compound or composition is packaged in a unit dosage form. The kit further can include a device suitable for administering the composition according to the intended route of administration. Compound forms The compound according to the present disclosure may be used in the form of a pharmaceutically acceptable salt. The “pharmaceutically acceptable salt” refers to a salt of a compound that maintains the pharmacological activity of the parent compound, and includes, but is not limited to, for example, (i) a salt formed with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; (ii) a salt formed with organic acids such as acetic acid, propionic acid, isobutyric acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid; (iii) a salt formed when acidic protons present in the parent compound are replaced by metal ions, for example, alkali metal ions, alkaline earth metal ions, or aluminum ions; or (iv) a coordination with an organic base such as ethanolamine, diethanolamine, triethanolamine, or N-methylglucamine. Also contemplated are polymorph forms of the compound of the invention. In addition, in the method according to the present invention, the compound or a pharmaceutically acceptable salt thereof may be used alone, but in addition to this, a composition further comprising a pharmaceutically acceptable carrier, specifically in the form of a pharmaceutical composition may be used. The pharmaceutically acceptable carrier may be one commonly used in the pharmaceutical field, and an excipient (e.g., starch, calcium carbonate, sucrose, lactose, sorbitol, mannitol, cellulose, etc.) or a diluent (e.g., physiological saline, purified water, etc.). In addition, if necessary, the composition of the present disclosure may further comprise pharmaceutically acceptable additives other than the pharmaceutically acceptable carrier, for example, a binder, a disintegrant, a lubricant, a coating agent, a film coating base, an enteric film coating base, a soft capsule base, a solubilizing aid, an emulsifying agent, a suspending agent, a stabilizer, a buffering agent, an antioxidant, a surfactant, a sweetening agent, a flavoring agent, a preservative, a thickening agent, a fragrance, or a coloring agent. The compound of the present disclosure may be administered orally or parenterally. The parenteral administration may be intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, endothelial administration, topical administration, intranasal administration, intrapulmonary administration, and rectal administration, etc. When administered orally, the compound of the present disclosure may be formulated in the form of a solid or liquid formulation. The solid formulation may be, for example, tablets, capsules (soft & hard capsules), powders, granules, pills, troches, etc., and the liquid formulation may be, for example, elixirs, suspensions, emulsions, solutions, syrups, lemonades, etc. In the case of tablets, in addition to the active ingredient, carriers such as lactose and corn starch, etc., lubricants such as magnesium stearate, etc., binders such as methylcellulose, microcrystalline cellulose, etc., polyvinyl alcohol, and disintegrants such as bentonite, sodium alginate, etc. may be usually added. In the case of a liquid formulation, the active ingredient may be formulated with a carrier such as purified water or physiological saline, and a dissolution aid such as sucrose monostearate, or a stabilizer such as polyvinylpyrrolidone, etc., if necessary. In the case of oral aqueous suspension, the active ingredient may be formulated with a suspending agent and, if necessary, a surfactant, a preservative, a stabilizer, etc. The dosage of the compound may be determined in consideration of the method of administration, the age and sex of the subject, the severity, the condition, the inactivation rate, and the drug to be used in combination, and may be administered once or more a day. In one embodiment, a compound of the invention is a compound of formula (I), wherein, X is a heteroatom. R1is CO2H, halogen, or CN. R2and R3are each independently H, a lower alkyl having 1-6 carbon atoms, an ester or alkyoxy having 1-6 carbon atoms, an ether having 1-6 carbon atoms, haloalkyl, halogen, CN, NO2, NH2, C(1-6)NH2. X is a preferably S or O. When R1is a halogen, it is preferably Br. When either of R2and R3are each independently is halogen, it is preferably F, Cl, or Br. When either of R2and R3are each independently is a haloalkyl, it is preferably CF3. When either of R2and R3are each independently an alkoxy it is preferably methoxy. When either of R2and R3are each independently an ether it is preferably -O-CH3. When R2and R3are independently an alkyl or a halogen, e.g. one of R2and R3may be a halogen and the other a methyl group, or one of R2and R3may be a halogen and the other an ether group, or one of R2and R3may be a halogen and the other NH2, or one of R2and R3may be a halogen and the other C(1-6)NH2. When either of R2 and R3 are each independently C(1-6)NH2, the carbon chain may have 1, 2, 3, 4, 5, or 6 carbon atoms. In one embodiment, a compound of the invention is a compound of formula (II) (II) wherein, R1is selected from H, OH, CO2H, CO2R, CN, halogen, lower alkyl, hydroxy or tetrazole, wherein R is a lower alkyl, preferably a lower alkyl of 1 to 6 carbon atoms (e.g. a methyl, ethyl, butyl, tert-butyl, pentyl, or hexyl group), more preferably R is a methyl group. When R1is a halogen group it may be fluorine, chlorine, bromine, or iodine, preferably Br. R1is preferably hydrogen, CN, methyl, tetrazole, COOH, or CO2CH3. R2is H, or a lower alkyl of 1 to 6 carbon atoms, (e.g. a methyl, ethyl, butyl, tert-butyl, pentyl, or hexyl group), more preferably R2is a H or a methyl group; A is a cycloalkyl, phenyl, furanyl, thiophene or pyridinyl group; R3and R4are each independently H; halogen selected from fluorine, chlorine, bromine, and iodine, preferably F or Cl; and alkyl group having 1 to 6 carbon atoms; a substituted or unsubstituted alkoxy group having 1 to 6 carbon atoms, preferably a methoxy, which is optionally substituted with 1, 2 or 3 halogen atoms, preferably F, -when R3and R4are each be an alkyl group, together may form a 5- or 6- member saturated or unsaturated ring, which may contain one or more heteroatoms or N, S or O, preferably O. Preferably, R3and R4are both hydrogen or one of R3and R4is hydrogen and the other is a methoxy, which may be substituted with fluorine; bromine; or chlorine. Examples The enzymatic activity in Tables 1 and 2 was determined in assays performed using a Cary 60 UV-visible spectrophotometer. Enzymatic activity was measured at 25°C in 100 mM HEPES, pH 7.0, containing 50 µM 2,6-Dichlorophenolindophenol (DCPIP; Sigma), 100 µM NADPH (Sigma), and 250 nM inhibitor. Assays lacking inhibitor (DMSO solvent only) and enzyme served as positive and negative controls, respectively. Reactions were initiated by the addition of 100 nM BLVRB, and reductase activity was measured by following the decrease in absorbance at 600 nm corresponding to the reduction of DCPIP (ε = 20.7 M-1cm-1) (Hägerhall C., Aasa R., von Wachenfeldt C., and Hederstedt L. (1992) Two hemes in Bacillus subtilis succinate:menaquinone oxidoreductase (complex II), Biochemistry 31, 7411–742110.1021 / bi00147a028. Potent inhibitors from the single point primary screen at 250 nM (defined by a reduction of enzymatic activity of at least 50%) were assayed again to determine the concentration of inhibitor required to inhibit enzymatic activity by 50% (IC50). A ten-point dose response was generated by adding 0, 100, 200, 300, 400, 500, 750, 1000, 2000, and 5000 nM of inhibitor to reaction mixtures at fixed concentrations of substrate DCPIP (50 µM) and NADPH (100 µM). The total amount of organic solvent added was kept constant at a final concentration of 2% (v / v). IC50 values were determined by non-liner regression fits of data using GraphPad Prism 9.4.0. The following are exemplified compounds of formula (I) General Synthetic scheme for 6-Thia-1,3-diazabicyclo[3.3.0]octa-2,4,7-triene derivatives of Formula (I) Scheme 1: Synthesis of cyano-N-(thiazol-2-ylmethyl)benzamide (3) derivative was obtained using cyanobenzoic acid and [(1,3-thiazol-2-yl)methyl]amine 1 with triethylamine and [(1,3-thiazol-2- yl)methyl]amine. Synthesis of 4-(imidazo[5,1-b]thiazol-5-yl)benzonitrile (4) was obtained by treating a solution of 4-cyano-N-(thiazol-2-ylmethyl)benzamide in toluene with POCl3. The reaction mixture was stirred for 5hr at 120°C. Synthesis of 4-(7-iodoimidazo[5,1-b]thiazol-5-yl)benzonitrile (5, Step 3) was obtained by treatment of intermediate 4 (scheme 2) with1-iodopyrrolidine-2,5-dione in DMF at room temperature. Synthesis of 4-(7-(3-chloro-2-fluorophenyl)imidazo[5,1-b]thiazol-5- yl)benzonitrile (7, Step 4) was obtained by Suzuki reaction using an boronic acid derivatives 6. The final Target product was obtained by saponification reaction using NaOH. Synthesis of 5-(3-bromophenyl)-7-(2-fluorophenyl)imidazo[5,1-b]thiazole (Compound 77): Step-1: Synthesis of 3-bromo-N-(thiazol-2-ylmethyl)benzamide (3) To a stirred solution of 3-bromobenzoic acid (1 g, 4.98 mmol, 1 eq) in dichloromethane (12 mL) was added [(1,3-thiazol-2-yl)methyl]amine (0.85 g, 7.46 mmol, 1.5 eq) at room temperature with triethylamine (2.07 mL, 14.92 mmol, 3 eq) followed by the addition of CDI (1.21 g, 7.46 mmol, 1.5 eq) at 0°C. After that, reaction mixture was allowed to stir at room temperature for 16 h. Progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (4 x 25 mL). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography, eluted at 0-30% ethyl acetate in hexane to afford desired compound 3-bromo-N-(thiazol-2-ylmethyl)benzamide (810 mg, 54.7% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6): δ 8.09 (m, 1H), 7.95-7.90 (m, 1H), 7.80-7.77 (m, 1H), 7.75 (d, J = 3.2 Hz, 1H), 7.64 (d, J = 3.2 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 4.76 (d, J = 6.0 Hz, 2H). Step-2: Synthesis of 5-(3-bromophenyl)imidazo[5,1-b]thiazole (4) To a stirred solution of 3-bromo-N-(thiazol-2-ylmethyl)benzamide (800 mg, 2.69 mmol, 1.0 eq) in toluene (10 mL), POCl3(8 mL) was added drop wise at room temperature. The reaction mixture was stirred at 120°C for 6 h, then reaction mixture was quenched by cold water (15 mL) and pH ~8 adjusted with NaHCO3solution, then aqueous layer extract with EtOAc (4 x 30 mL). Combined organic layer dried over sodium sulfate and distill off under reduced pressure to get crude compound. The crude compound was purified by combi-flash using 5-40% EA in hexane as eluent to afford desired product 5-(3-bromophenyl)imidazo[5,1-b]thiazole (105 mg, 14.0% yield) as yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.29 (d, J = 4.0 Hz, 1H), 8.01 (t, J = 1.6 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.58-7.56 (m, 1H), 7.47-7.42 (m, 2H), 7.26 (s, 1H). Step-3: Synthesis of 5-(3-bromophenyl)-7-iodoimidazo[5,1-b]thiazole (5) To a stirred solution of 5-(3-bromophenyl)imidazo[5,1-b]thiazole (100 mg, 0.36 mmol, 1.0 eq) in dry DMF (15 mL), was added 1-iodopyrrolidine-2,5-dione (136 mg, 0.54 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred for 2 h. Progress of reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with room temperature ice cold water (10 mL) thus precipitated solid was filtered and dried under vacuum to afford desired compound 5-(3-bromophenyl)-7-iodoimidazo[5,1-b]thiazole (85 mg, yield: 62.5%) as an off- white solid.1H NMR (400 MHz, DMSO-d6): δ 8.43 (d, J = 3.2 Hz, 1H), 7.98 (t, J = 1.6 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.62-7.60 (m, 1H), 7.50-7.44 (m, 2H). Step-4: Synthesis of 5-(3-bromophenyl)-7-(2-fluorophenyl)imidazo[5,1-b]thiazole (Compound 77): To a stirred solution of 5-(3-bromophenyl)-7-iodoimidazo[5,1-b]thiazole (80 mg, 197 µmol, 1.0 eq), 3-chloro-2-fluorophenylboronic acid (33 mg, 237 µmol, 1.2 eq) and dipotassium carbonate (81 mg, 591 µmol, 3 eq) in distilled water (0.5 mL) and 1,4-dioxane (5 mL), argon gas was purged for 10 min. After that [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (16.1 mg, 19.7 µmol, 0.1 eq) was added and again purged under argon gas for 5 min. Then reaction mixture was stirred for overnight at 100 °C in a sealed tube. After the completion of the reaction on TLC, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (4 x 10 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography, eluted at 0-20% ethyl acetate in hexane to obtain desired compound Compound 77 (25 mg, 33.9% yield) as a pale-yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.35–8.33 (m, 1H), 8.11-8.10 (m, 2H), 7.96 (d, J = 8.0 Hz, 1H), 7.63 (m, 1H), 7.52–7.48 (m, 2H), 7.31-7.28 (m, 3H). LCMS (m / z): 373.0 (M+H)+,HPLC purity: 96.02%. Synthetic Scheme for synthesis of 3-(7-(2-fluorophenyl)imidazo[5,1-b]thiazol-5- yl)benzonitrile (Compound 85) & 3-(7-(2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 87): Step-1: Synthesis of 3-cyano-N-(thiazol-2-ylmethyl)benzamide (3) To a stirred solution of 3-cyanobenzoic acid (3 g, 20.40 mmol, 1 eq) in dichloromethane (30 mL) was added [(1,3-thiazol-2-yl)methyl]amine (3.48 g, 30.60 mmol, 1.5 eq) at room temperature with triethylamine (8.52 mL, 61.20 mmol, 3 eq) followed by the addition of CDI (4.98 g, 30.60 mmol, 1.5 eq) at 0°C. After that, reaction mixture was allowed to stir at room temperature for 16 h. Progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (4 x 50 mL). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography, eluted at 0-30% ethyl acetate in hexane to afford desired compound 3-cyano-N-(thiazol-2-ylmethyl)benzamide (2.71 g, 55.15% yield) as a brown solid. LCMS (m / z): 244.1 (M+H)+. Step-2: Synthesis of 3-(imidazo[5,1-b]thiazol-5-yl)benzonitrile (4) To a stirred solution of 3-cyano-N-(thiazol-2-ylmethyl)benzamide (2.7 g, 11.10 mmol, 1.0 eq) in toluene (30 mL), POCl3 (30 mL) was added drop wise at room temperature. The reaction mixture was stirred at 120°C for 6 h, then reaction mixture was quenched by cold water (50 mL) and pH ~8 adjusted with NaHCO3solution, then aqueous layer extract with EtOAc (4 x 50 mL). Combined organic layer dried over sodium sulfate and distill off under reduced pressure to get crude compound. The crude compound was purified by combi-flash using 5-40% EA in hexane as eluent to afford desired product 3-(imidazo[5,1-b]thiazol-5-yl)benzonitrile (1.05 g, 42.0% yield) as yellow solid. LCMS (m / z): 226.1 (M+H)+. Step-3: Synthesis of 3-(7-iodoimidazo[5,1-b]thiazol-5-yl)benzonitrile (5) To a stirred solution of 3-(imidazo[5,1-b]thiazol-5-yl)benzonitrile (1.0 g, 4.45 mmol, 1.0 eq) in dry DMF (7 mL), was added 1-iodopyrrolidine-2,5-dione (607 mg, 6.67 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred for 2 h at room temperature. Progress of reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with ice cold water (50 mL) thus precipitated solid was filtered and dried under vacuum to afford desired compound 3-(7-iodoimidazo[5,1-b]thiazol-5-yl)benzonitrile (465 mg, yield: 48.7%) as an off- white solid.1H NMR (400 MHz, DMSO-d6): δ 8.52 (d, J = 4.0 Hz, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 4.0 Hz, 1H). Step-4: Synthesis of 3-(7-(2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (Compound 85): To a stirred solution of 3-(7-iodoimidazo[5,1-b]thiazol-5-yl)benzonitrile (150 mg, 427 µmol, 1.0 eq), 2-fluorophenylboronic acid (72 mg, 513 µmol, 1.2 eq) and dipotassium carbonate (141 mg, 1026 µmol, 3 eq) in distilled water (0.5 mL) and 1,4-dioxane (7 mL), argon gas was purged for 10 min. After that [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (35 mg, 42.7 µmol, 0.1 eq) was added and again purged under argon gas for 5 min. Then reaction mixture was stirred for overnight at 100 °C in a sealed tube. After the completion of the reaction on TLC, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (4 x 10 mL). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography, eluted at 0-20% ethyl acetate in hexane to obtain desired Compound 85 (115 mg, 84.5% yield) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.49–8.47 (m, 1H), 8.37 (s, 1H), 8.31-8.29 (m, 1H), 8.19-8.14 (m, 1H), 7.91- 7.99 (m, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 4.0 Hz, 1H), 7.34-7.27 (m, 3H), LCMS (m / z): 320.31 (M+H)+, HPLC purity: 99.41%. Step-5: Synthesis of 3-(7-(2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 87) Compound 85 (100 mg, 313 µmol) was dissolved in ethanol (5 mL) and water (1.5 mL) (3:1). To the above solution, sodium hydroxide (37.6 mg, 940 µmol, 3 eq) was added and the reaction mixture was stirred at reflux for overnight. The reaction mixture was acidified with 1N HCl thus solid obtained was filtered and washed with n-pentane (10 mL) to afford desired Compound 87 (73 mg, 68.9% yield) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 13.24 (s, 1H), 8.49 (s, 1H), 8.32-8.30 (m, 1H), 8.20-8.14 (m, 2H), 8.00 (d, J = 7.6 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.51 (d, J = 4.4 Hz, 1H), 7.32-7.27 (m, 3H), LCMS (m / z): 339.1 (M+H)+, HPLC purity: 99.53%. Synthesis of 3-(7-(2-methoxyphenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (Compound 86) & 3-(7-(2-methoxyphenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 90): Step-4: Synthesis of 3-(7-(2-methoxyphenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (Compound 86): To a stirred solution of 3-(7-iodoimidazo[5,1-b]thiazol-5-yl)benzonitrile (150 mg, 427 µmol, 1.0 eq), 2-methoxyphenylboronic acid (78 mg, 513 µmol, 1.2 eq) and dipotassium carbonate (141 mg, 1026 µmol, 3 eq) in distilled water (0.5 mL) and 1,4-dioxane (7 mL), argon gas was purged for 10 min. After that [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (35 mg, 42.7 µmol, 0.1 eq) was added and again purged under argon gas for 5 min. Then reaction mixture was stirred for overnight at 100 °C in a sealed tube. After the completion of the reaction on TLC, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (4x 10 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography, eluted at 0-20% ethyl acetate in hexane to obtain desired Compound 86 (115 mg, 81.2% yield) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.40 (d, J = 4.4 Hz, 1H), 8.34 (s, 1H), 8.29 (d, J = 8.4 Hz, 1H), 8.13 (dd, J = 2.0 Hz, 6.0 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.46 (d, J = 4.0 Hz, 1H), 7.26-7.24 (m, 1H), 7.09-7.03 (m, 2H), 3.95 (s, 3H), LCMS (m / z): 332.37 (M+H)+, HPLC purity: 98.63%. Step-5: Synthesis of 3-(7-(2-methoxyphenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 90) Compound 86 (100 mg, 302 µmol) was dissolved in ethanol (5 mL) and water (1.5 mL) (3:1). To the above solution, sodium hydroxide (36 mg, 905 µmol, 3 eq) was added and the reaction mixture was stirred at reflux for overnight. The reaction mixture was acidified with 1N HCl thus solid obtained was filtered and washed with n-pentane (10 mL) to afford desired Compound 90 (62 mg, 58.48% yield) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 13.23 (s, 1H), 8.48 (s, 1H), 8.23-8.11 (m, 3H), 7.98 (d, J = 8.0 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.44 (d, J = 4.4 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.08-7.03 (m, 2H), 3.95 (s, 3H), LCMS (m / z): 351.25 (M+H)+, HPLC purity: 98.84%. Synthesis of 3-(7-(2-chlorophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (Compound 89) & 3-(7-(2-chlorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 91): Step-4: Synthesis of 3-(7-(2-chlorophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (Compound 89): To a stirred solution of 3-(7-iodoimidazo[5,1-b]thiazol-5-yl)benzonitrile (150 mg, 427 µmol, 1.0 eq), 2-chlorophenylboronic acid (80 mg, 513 µmol, 1.2 eq) and dipotassium carbonate (141 mg, 1026 µmol, 3 eq) in distilled water (0.5 mL) and 1,4-dioxane (7 mL), argon gas was purged for 10 min. After that [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (35 mg, 42.7 µmol, 0.1 eq) was added and again purged under argon gas for 5 min. Then reaction mixture was stirred for overnight at 100 °C in a sealed tube. After the completion of the reaction on TLC, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (4x 10 mL). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography, eluted at 0-20% ethyl acetate in hexane to obtain desired Compound 89 (115 mg, 80.2% yield) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.50 (d, J = 4.4 Hz, 1H), 8.37 (s, 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.95 (dd, J = 2.0 Hz, 6.4 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.56-7.54 (m, 2H), 7.48-7.36 (m, 2H), LCMS (m / z): 336.41 (M+H)+, HPLC purity: 97.00%. Step-5: Synthesis of 3-(7-(2-chlorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 91) Compound 89 (100 mg, 298 µmol) was dissolved in ethanol (5 mL) and water (1.5 mL) (3:1). To the above solution, sodium hydroxide (36 mg, 893 µmol, 3 eq) was added and the reaction mixture was stirred at reflux for overnight. The reaction mixture was acidified with 1N HCl thus solid obtained was filtered and washed with n-pentane (10 mL) to afford desired Compound 91 (13 mg, 12.3% yield) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 8.41 (s, 1H), 8.20 (d, J = 4.4 Hz, 1H), 7.97 (d, J = 7.2 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.49-7.34 (m, 4H), LCMS (m / z): 355.0 (M+H)+, HPLC purity: 98.27%. Synthesis of 4-(7-(2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (Compound 92) & 4-(7-(2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 97):

[0003] Step-1: Synthesis of 4-cyano-N-(thiazol-2-ylmethyl)benzamide (3) To a stirred solution of 4-cyanobenzoic acid (3 g, 20.40 mmol, 1 eq) in dichloromethane (30 mL) was added [(1,3-thiazol-2-yl)methyl]amine (3.48 g, 30.60 mmol, 1.5 eq) at room temperature with triethylamine (8.52 mL, 61.20 mmol, 3 eq) followed by the addition of CDI (4.98 g, 30.60 mmol, 1.5 eq) at 0°C. After that, reaction mixture was allowed to stir at room temperature for 16 h. Progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (4 x 50 mL). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography, eluted at 0-30% ethyl acetate in hexane to afford desired compound 4-cyano-N-(thiazol-2-ylmethyl)benzamide (2.71 g, 55.15% yield) as a brown solid. LCMS (m / z): 244.1 (M+H)+. Step-2: Synthesis of 4-(imidazo[5,1-b]thiazol-5-yl)benzonitrile (4) To a stirred solution of 4-cyano-N-(thiazol-2-ylmethyl)benzamide (2.7 g, 11.10 mmol, 1.0 eq) in toluene (30 mL), POCl3(30 mL) was added drop wise at room temperature. The reaction mixture was stirred at 120°C for 6 h, then reaction mixture was quenched by cold water (50 mL) and pH ~8 adjusted with NaHCO3solution, then aqueous layer extract with EtOAc (4 x 50 mL). Combined organic layer dried over sodium sulfate and distill off under reduced pressure to get crude compound. The crude compound was purified by combi-flash using 5-40% EA in hexane as eluent to afford desired product 4-(imidazo[5,1-b]thiazol-5-yl)benzonitrile (1.05 g, 42.0% yield) as yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.40 (d, J = 4.4 Hz, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 4.4 Hz, 1H), 5.35 (s, 1H). Step-3: Synthesis of 4-(7-iodoimidazo[5,1-b]thiazol-5-yl)benzonitrile (5) To a stirred solution of 4-(imidazo[5,1-b]thiazol-5-yl)benzonitrile (1,0 g, 4.45 mmol, 1.0 eq) in dry DMF (7 mL), was added 1-iodopyrrolidine-2,5-dione (1.1 g, 6.67 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred for 2 h at room temperature. Progress of reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with ice cold water (50 mL) thus precipitated solid was filtered and dried under vacuum to afford desired compound 4-(7-iodoimidazo[5,1-b]thiazol-5-yl)benzonitrile (465 mg, yield: 48.7%) as an off- white solid.1H NMR (400 MHz, DMSO-d6): δ 8.52 (d, J = 4.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 4.4 Hz, 1H). Step-4: Synthesis of 4-(7-(2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (Compound 92): To a stirred solution of 4-(7-iodoimidazo[5,1-b]thiazol-5-yl)benzonitrile (150 mg, 427 µmol, 1.0 eq), 2-fluorophenylboronic acid (72 mg, 513 µmol, 1.2 eq) and dipotassium carbonate (141 mg, 1026 µmol, 3 eq) in distilled water (0.5 mL) and 1,4-dioxane (7 mL), argon gas was purged for 10 min. After that [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (35 mg, 42.7 µmol, 0.1 eq) was added and again purged under argon gas for 5 min. Then reaction mixture was stirred for overnight at 100 °C in a sealed tube. After the completion of the reaction on TLC, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (4x 10 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography, eluted at 0-20% ethyl acetate in hexane to obtain desired Compound 92 (115 mg, 84.5% yield) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.47–8.45 (m, 1H), 8.19-8.13 (m, 3H), 7.98 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 4.4 Hz, 1H), 7.35-7.29 (m, 3H), LCMS (m / z): 320.1 (M+H)+, HPLC purity: 98.57%. Step-5: Synthesis of 4-(7-(2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 97) Compound 92 (90 mg, 282 µmol, 1 eq) was dissolved in ethanol (5 mL) and water (1.5 mL) (3:1). To the above solution, sodium hydroxide (34 mg, 845 µmol, 3 eq) was added and the reaction mixture was stirred at reflux for overnight. The reaction mixture was acidified with 1N HCl thus solid obtained was filtered and washed with n-pentane (10 mL) to afford desired Compound 97 (25 mg, 68.9% yield) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 13.08 (s, 1H), 8.43-8.41 (m, 1H), 8.18-8.08 (m, 5H), 7.55 (d, J = 4.0 Hz, 1H), 7.33-7.30 (m, 3H), LCMS (m / z): 339.41 (M+H)+, HPLC purity: 99.58%. Synthesis of 4-(7-(2-methoxyphenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (Compound 93) & 4-(7-(2-methoxyphenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 96): Step-4: Synthesis of 4-(7-(2-methoxyphenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (Compound 93): To a stirred solution of 4-(7-iodoimidazo[5,1-b]thiazol-5-yl)benzonitrile (150 mg, 427 µmol, 1.0 eq), 2-methoxyphenylboronic acid (78 mg, 513 µmol, 1.2 eq) and dipotassium carbonate (141 mg, 1026 µmol, 3 eq) in distilled water (0.5 mL) and 1,4-dioxane (7 mL), argon gas was purged for 10 min. After that [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (35 mg, 42.7 µmol, 0.1 eq) was added and again purged under argon gas for 5 min. Then reaction mixture was stirred for overnight at 100 °C in a sealed tube. After the completion of the reaction on TLC, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (4x 10 mL). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography, eluted at 0-20% ethyl acetate in hexane to obtain desired Compound 93 (115 mg, 81.6% yield) as pale yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.38 (d, J = 4.4 Hz, 1H), 8.16-8.11 (m, 3H), 7.95 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 4.4 Hz, 1H), 7.26-7.24 (m, 1H), 7.09-7.02 (m, 2H), 3.95 (s, 3H), LCMS (m / z): 332.38 (M+H)+, HPLC purity: 98.67%. Step-5: Synthesis of 4-(7-(2-methoxyphenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 96) The Compound 93 (90 mg, 272 µmol, 1 eq) was dissolved in ethanol (5 mL) and water (1.5 mL) (3:1). To the above solution, sodium hydroxide (33 mg, 814 µmol, 3 eq) was added and the reaction mixture was stirred at reflux for overnight. The reaction mixture was acidified with 1N HCl thus solid obtained was filtered and washed with n-pentane (10 mL) to afford desired Compound 96 (25 mg, 26.3% yield) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 13.18 (s, 1H), 8.36 (d, J = 4.4 Hz, 1H), 8.14-8.09 (m, 5H), 7.51 (d, J = 4.4 Hz, 1H), 7.28-7.26 (m, 1H), 7.10-7.04 (m, 2H), 3.96 (s, 3H), LCMS (m / z): 351.34 (M+H)+, HPLC purity: 99.71%. Synthesis of 4-(7-(2-chlorophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (Compound 94) & 4-(7-(2-chlorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 95): Step-4: Synthesis of 4-(7-(2-chlorophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (Compound 94): To a stirred solution of 4-(7-iodoimidazo[5,1-b]thiazol-5-yl)benzonitrile (150 mg, 427 µmol, 1.0 eq), 2-chlorophenylboronic acid (80 mg, 513 µmol, 1.2 eq) and dipotassium carbonate (141 mg, 1026 µmol, 3 eq) in distilled water (0.5 mL) and 1,4-dioxane (7 mL), argon gas was purged for 10 min. After that [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (35 mg, 42.7 µmol, 0.1 eq) was added and again purged under argon gas for 5 min. Then reaction mixture was stirred for overnight at 100 °C in a sealed tube. After the completion of the reaction on TLC, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (4x 10 mL). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography, eluted at 0-20% ethyl acetate in hexane to obtain desired Compound 94 (115 mg, 80.4% yield) as pale yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.48 (d, J = 4.4 Hz, 1H), 8.18 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 7.2 Hz, 1H), 7.61-7.55 (m, 2H), 7.49-7.38 (m, 2H), LCMS (m / z): 336.35 (M+H)+, HPLC purity: 96.21%. Step-5: Synthesis of 4-(7-(2-chlorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 95) The Compound 94 (90 mg, 269 µmol, 1 eq) was dissolved in ethanol (5 mL) and water (1.5 mL) (3:1). To the above solution, sodium hydroxide (32 mg, 806 µmol, 3 eq) was added and the reaction mixture was stirred at reflux for overnight. The reaction mixture was acidified with 1N HCl thus solid obtained was filtered and washed with n-pentane (10 mL) to afford desired Compound 95 (25 mg, 26.3% yield) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 13.01 (s, 1H), 8.45 (d, J = 4.0 Hz, 1H), 8.13-8.08 (m, 4H), 7.95 (d, J = 7.6 Hz, 1H), 7.60-7.55 (m, 2H), 7.47 (t, J = 7.6 Hz, 1H), 7.41-7.37 (m, 1H), LCMS (m / z): 355.38 (M+H)+, HPLC purity: 95.96%. Synthesis of 4-(7-(3-chloro-2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 100): Step-1: Synthesis of 4-cyano-N-(thiazol-2-ylmethyl)benzamide (3) To a stirred solution of p-cyanobenzoic acid (1 g, 1 eq., 6.8 mmol) in dichloromethane (6.67 mL, 104 mmol) was added [(1,3-thiazol-2-yl)methyl]amine (1.16 g, 1.5 eq., 10.2 mmol) at rt and stirred for 20 min. After 20 min, added triethylamine (2.87 mL, 3 eq., 20.4 mmol) followed by the addition of [(1,3-thiazol-2-yl)methyl]amine (1.16 g, 1.5 eq., 10.2 mmol) at rt and stirred for 16 h. The reaction mixture was extracted with ethyl acetate and distilled water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography, eluted at 30% ethyl acetate: hexane to get the pure compound 4-cyano-N- (thiazol-2-ylmethyl)benzamide as a brown solid.1H NMR (400 MHz, DMSO-d6): δ 9.66 (t, J = 6.8 Hz, 1H), 8.04 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 3.2 Hz, 1H), 7.64 (d, J = 3.2 Hz, 1H), 4.77 (d, J = 6.0 Hz, 1H). Step-2: Synthesis of 4-(imidazo[5,1-b]thiazol-5-yl)benzonitrile (4) To a stirred solution of 4-cyano-N-(thiazol-2-ylmethyl)benzamide in toluene, and POCl3 was added drop wise at room temperature. The reaction mixture was stirred for 5hr at 120°C then reaction mixture was quenched by cold water and PH adjusted with NaHCO3 up to 8, then aqueous layer extract with EtOAc, organic layer dried over sodium sulfate distill off under reduced pressure, afford desired product 44-(imidazo[5,1-b]thiazol-5-yl)benzonitrile as a pale green color solid obtained. Crude compound was carried to next step without purification.1H NMR (400 MHz, DMSO-d6): δ 8.46 (d, J = 4.4 Hz, 1H), 8.11 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 3.2 Hz, 1H), 7.64 (d, J = 3.2 Hz, 1H), 4.77 (d, J = 6.0 Hz, 1H). Step-3: Synthesis of 4-(7-iodoimidazo[5,1-b]thiazol-5-yl)benzonitrile (5) To a stirred solution of 4-(imidazo[5,1-b]thiazol-5-yl)benzonitrile (1.0 g, 4.44 mmol) in dry DMF (15 mL), was added 1-iodopyrrolidine-2,5-dione (1.5 g, 6.66 mmol) at room temperature. The reaction mixture was stirred for 2h at room temperature, After 1 h checked TLC reaction was completed then reaction mixture was quenched with ice cold water, precipitated solid was filtered and dried under vaccum to afford 4-(7-iodoimidazo[5,1-b]thiazol-5-yl)benzonitrile (1.2 g, yield: 76.98%) as off-white solid.1H NMR (400 MHz, DMSO-d6): δ 8.52 (d, J = 4.0 Hz, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 4.0 Hz, 1H). Step-4: Synthesis of 4-(7-(3-chloro-2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (7) The p-(4-iodo-6-thia-1,3-diazabicyclo[3.3.0]octa-2,4,7-trien-2-yl)benzonitrile (100 mg, 285 µmol) and 3-chloro-2-fluorophenylboronic acid (59.6 mg, 1.2 eq., 342 µmol) were dissolved in 1,4-dioxane (5 mL, 58.6 mmol). To this, a solution of dipotassium carbonate (118 mg, 854 µmol, 3 eq.) in distilled water (0.5 mL, 27.8 mmol) was added and purged under nitrogen atmosphere for 10 min. Finally, [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20.8 mg, 0.1 eq., 28.5 µmol) was added and again purged under nitrogen atmosphere for 10 min. The reaction mixture was stirred for overnight at 100 °C in a sealed tube. After the completion of the reaction, the mixture was extracted with ethylacetate and distilled water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography, eluted at 20% ethylacetate: hexane to obtain 4-(7-(3-chloro-2- fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (58 mg, 57.57% yield) as pale yellow solid as a pure product.1H NMR (400 MHz, DMSO-d6): δ 8.14 – 8.10 (m, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.82 - -7.80 (m, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.32 – 7.28 (m, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.08 (d, J = 4.4 Hz, 1H). LCMS (m / z): 354.1 (M+H)+. Step-5: Synthesis of 4-(7-(3-chloro-2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 100) The p-{4-(3-chloro-2-fluorophenyl)-6-thia-1,3-diazabicyclo[3.3.0]octa-2,4,7-trien-2- yl}benzonitrile (58 mg, 164 µmol) was dissolved in ethanol (5 mL, 85.6 mmol) and water (1.5 mL, 83.3 mmol) (3:1). To this, sodium hydroxide (19.7 mg, 3 eq., 492 µmol) was added and the reaction mixture was stirred for overnight at 100 °C. The reaction mixture was acidified with 1N HCl and filtered it. The yellow solid were obtained which was washed with n-pentane to remove the grease to afford Compound 100 (40 mg, 65.5% yield).1H NMR (400 MHz, DMSO-d6): δ 8.43 – 8.42 (m, 1H), 8.12 - 8.05 (m, 5H), 7.57 (d, J = 4.4 Hz, 2H), 7.50 – 7.46 (m, 1H), 7.32 (t, J = 7.6 Hz, 1H). LCMS (m / z): 373.48 (M+H)+. Synthesis of 4-(7-(2-(trifluoromethyl)phenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 101): Step-4: Synthesis of 4-(7-(2-(trifluoromethyl)phenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile To stirred solution p-(4-iodo-6-thia-1,3-diazabicyclo[3.3.0]octa-2,4,7-trien-2-yl)benzonitrile (100 mg, 0.285 mmol, 1 eq) in 1,4 Dioxane (5 ml) to this add o-(trifluoromethyl)phenylboronic acid (100 mg, 0.285 mmol, 1 eq) and add dipotassium carbonate (118 mg, 0.854 mmol, 3 eq) and water (1 ml). Reaction mixture was degassed with argon gas then add 1,1 -Bis(diphenylphosphino)ferrocene dichloropalladium (23 mg, 0.028 mmol, 0.1 eq), then the reaction was placed in Microwave at 110oC for 120 minutes. After completion of reaction, reaction mixture was concentrated under reduced pressure and crude compound was purified by combi-flash chromatography using 0-50% ethyl acetate: hexane as eluent to afford 4-(7-(2-(trifluoromethyl)phenyl)imidazo[5,1-b]thiazol-5- yl)benzonitrile (80 mg, 76.2% yield) as a brown solid. LCMS (m / z): 370.32 (M+H)+. Step-5: Synthesis of 4-(7-(2-(trifluoromethyl)phenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 101) The 4-(7-(2-(trifluoromethyl)phenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (80 mg, 216 µmol, 1eq) was dissolved in ethanol (5 mL) and water (1.5 mL) (3:1). To this, sodium hydroxide (19.7 mg, 3 eq., 650 µmol) was added and the reaction mixture was stirred for overnight at 100 °C. The reaction mixture was acidified with 1N HCl and filtered it. The yellow solid were obtained which was washed with n-pentane to remove the grease to afford Compound 101 (40 mg, 47.6% yield).1H NMR (400 MHz, DMSO-d6): δ 13.12 (s, 1H), 8.47 (d, J = 4.4 Hz, 1H), 8.09 - 8.07 (m, 4H), 7.88 (d, J = 8.0 Hz, 2H), 7.77 (t, J = 7.6 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.59 – 7.55 (m, 2H). LCMS (m / z): 389.32 (M+H)+. Synthesis of 4-(7-(3-methoxyphenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 102): Step-4: Synthesis of 4-(7-(3-methoxyphenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (7) To stirred solution p-(4-iodo-6-thia-1,3-diazabicyclo[3.3.0]octa-2,4,7-trien-2-yl)benzonitrile (100 mg, 0.285 mmol, 1 eq) in 1,4 Dioxane (5 ml) to this add (3-methoxyphenyl)boronic acid (43.3 mg, 0.285 mmol, 1 eq) and add dipotassium carbonate (118 mg, 0.854 mmol, 3 eq) and water (1 ml). Reaction mixture was degassed with argon gas then add 1,1 -Bis(diphenylphosphino)ferrocene dichloropalladium (23 mg, 0.028 mmol, 0.1 eq). catalyst then keep the reaction in Microwave at 110°C for 120 minutes. After completion of reaction, reaction mixture was concentrated under reduced pressure and crude compound was purified by combiflash chromatography using 0-50% ethyl acetate: hexane as eluent to afford 4-(7-(3-methoxyphenyl)imidazo[5,1-b]thiazol-5- yl)benzonitrile (50 mg, 48% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6): δ 8.02 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 4.4 Hz, 1H), 7.80 - 7.75 (m, 2H), 7.47 (brs, 1H), 7.43 – 7.33 (m, 2H), 7.30 – 7.27 (m, 1H), 7.11 (d, J = 4.4 Hz, 1H), 6.86 – 6.83 (m, 1H), 3.92 (s, 3H). Step-5: Synthesis of 4-(7-(3-methoxyphenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 102) The 4-(7-(3-methoxyphenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (50 mg, 137 µmol, 1eq) was dissolved in ethanol (5 mL and water (1.5 mL) (3:1). To this, sodium hydroxide (11 mg, 3 eq., 273 µmol) was added and the reaction mixture was stirred for overnight at 100 °C. The reaction mixture was acidified with 1N HCl and filtered it. The yellow solid were obtained which was washed with n- pentane to remove the grease to afford 4-(7-(3-methoxyphenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (13 mg, 37% yield) as yellow solid.1H NMR (400 MHz, DMSO-d6): δ 13.08 (brs, 1H), 8.48 (d, J = 4.4 Hz, 1H), 8.11 (d, J = 8.4 Hz, 2H), 8.07 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 4.4 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.33 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 6.87 – 6.84 (m, 1H), 3.84 (s, 3H). LCMS (m / z): 351.32 (M+H)+. Synthesis of 4-(7-(4-chloro-2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 103): Step-4: Synthesis of 4-(7-(4-chloro-2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (7) To stirred solution p-(4-iodo-6-thia-1,3-diazabicyclo[3.3.0]octa-2,4,7-trien-2-yl)benzonitrile (100 mg, 0.285 mmol, 1 eq) in 1,4 Dioxane (5 ml) to this add 4-chloro-2-fluorophenylboronic acid (75 mg, 0.427 mmol, 1.5 eq) and add dipotassium carbonate (118 mg, 0.854 mmol, 3 eq) and water (1 ml). Reaction mixture was degassed with argon gas then add 1,1 -Bis(diphenylphosphino)ferrocene dichloropalladium (23 mg, 0.028 mmol, 0.1 eq), then keep the reaction in Microwave at 110°C for 120 minutes. After completion of reaction, reaction mixture was concentrated under reduced pressure and crude compound was purified by combiflash chromatography using 0-50% ethyl acetate: hexane as eluent to afford 4-(7-(4-chloro-2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (50 mg, 47.5% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6): δ 8.16 (t, J = 8.4 Hz, 1H), 7.97 (d, J = 8.8 Hz, 2H), 7.84 – 7.81 (m, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 2.0 Hz, 1H), 7.15 (dd, J = 9.6 Hz, 2.0 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H). Step-5: Synthesis of 4-(7-(4-chloro-2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 103) The 4-(7-(4-chloro-2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (50 mg, 141 µmol, 1eq) was dissolved in ethanol (5 mL) and water (1.5 mL) (3:1). To this, sodium hydroxide (19.7 mg, 3 eq., 424 µmol) was added and the reaction mixture was stirred for overnight at 100 °C. The reaction mixture was acidified with 1N HCl and filtered it. The yellow solid were obtained which was washed with n-pentane to remove the grease to afford Compound 103 (12 mg, 22.75% yield).1H NMR (400 MHz, DMSO-d6): δ 13.12 (brs, 1H), 8.42 -8.41 (m, 1H), 8.15 (t, J = 8.4 Hz, 1H), 8.07 (brs, 4H), 7.55 – 7.52 (m, 2H), 7.39 (d, J = 8.4 Hz, 1H). LCMS (m / z): 373.32 (M+H)+. Synthesis of 4-(7-(4-chloro-2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 104): Step-4: Synthesis of 4-(7-(2-chloro-4-methylphenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (7) To stirred solution p-(4-iodo-6-thia-1,3-diazabicyclo[3.3.0]octa-2,4,7-trien-2-yl)benzonitrile (100 mg, 0.285 mmol, 1 eq) in 1,4 Dioxane (5 ml) to this add (2-Chloro-4-tolyl) boranediol (58 mg, 0.342 mmol, 1.2 eq) and add dipotassium carbonate (118 mg, 0.854 mmol, 3 eq) and water (1 ml). Reaction mixture was degassed with argon gas then add 1,1 -Bis(diphenylphosphino)ferrocene dichloropalladium (23 mg, 0.028 mmol, 0.1 eq). catalyst then keep the reaction in Microwave at 110°C for 120 minutes. After completion of reaction, reaction mixture was concentrated under reduced pressure and crude compound was purified by combiflash chromatography using 0-50% ethyl acetate: hexane as eluent to afford 4-(7-(2-chloro-4-methylphenyl)imidazo[5,1-b]thiazol-5- yl)benzonitrile (100 mg, 100.4% yield).1H NMR (400 MHz, DMSO-d6): δ 8.43 (d, J = 4.4 Hz, 1H), 8.10 – 8.06 (m, 3H), 7.81 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 4.4 Hz, 1H), 7.32 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 2.35 (s, 3H). Step-5: Synthesis of 4-(7-(2-chloro-4-methylphenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 104) The 4-(7-(2-chloro-4-methylphenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (100 mg, 164 µmol, 1eq) was dissolved in ethanol (5 mL, 85.6 mmol) and water (1.5 mL, 83.3 mmol) (3:1). To this, sodium hydroxide (19.7 mg, 3 eq., 492 µmol, 1eq) was added and the reaction mixture was stirred for overnight at 100 °C. The reaction mixture was acidified with 1N HCl and filtered it. The yellow solid were obtained which was washed with n-pentane to remove the grease to afford Compound 104 (40 mg, 38% yield).1H NMR (400 MHz, DMSO-d6): δ 13.08 (brs, 1H), 8.44 (d, J = 4.4 Hz, 1H), 8.11 – 8.07 (m, 3H), 7.83 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 4.0 Hz, 1H), 7.38 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 2.36 (s, 3H). LCMS (m / z): 369.1 (M+H)+. Synthesis of 4-(7-phenylimidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 105): Step-4: Synthesis of 4-(7-phenylimidazo[5,1-b]thiazol-5-yl)benzonitrile (7) To stirred solution p-(4-iodo-6-thia-1,3-diazabicyclo[3.3.0]octa-2,4,7-trien-2-yl)benzonitrile (100 mg, 0.285 mmol, 1 eq) in 1,4 Dioxane (5 ml) to this add Phenylboronic acid (35 mg, 0.285 mmol, 1 eq) and add dipotassium carbonate (118 mg, 0.854 mmol, 3 eq) and water (1 ml). Reaction mixture was degassed with argon gas then add 1,1 -Bis(diphenylphosphino)ferrocene dichloropalladium (23 mg, 0.028 mmol, 0.1 eq), then keep the reaction in Microwave at 110°C for 120 minutes. After completion of reaction, reaction mixture was concentrated under reduced pressure and crude compound was purified by combiflash chromatography using 0-50% ethyl acetate: hexane as eluent to afford 4-(7-phenylimidazo[5,1-b]thiazol-5-yl)benzonitrile (80 mg, 93% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6): δ 8.03 -8.01 (m, 2H), 7.86 – 7.84 (m, 3H), 7.80 – 7.73 (m, 2H), 7.52 – 7.46 (m, 2H), 7.44 – 7.42 (m, 1H), 7.27 (d, J = 4.4 Hz, 1H). Step-5: Synthesis of 4-(7-phenylimidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 105) The 4-(7-phenylimidazo[5,1-b]thiazol-5-yl)benzonitrile (80 mg, 272 µmol, 1eq) was dissolved in ethanol (5 mL) and water (1.5 mL) (3:1). To this, sodium hydroxide (19.7 mg, 3 eq., 817 µmol, 1eq) was added and the reaction mixture was stirred for overnight at 100 °C. The reaction mixture was acidified with 1N HCl and filtered it. The yellow solid were obtained which was washed with n- pentane to remove the grease to afford Compound 105 (65 mg, 76.4% yield).1H NMR (400 MHz, DMSO-d6): δ 13.08 (s, 1H), 8.48 (d, J = 4.0 Hz, 1H), 8.11 (d, J = 8.4 Hz, 2H), 8.07 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 7.6 Hz, 2H), 7.62 (d, J = 4.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.27 (t, J = 7.6 Hz, 1H). LCMS (m / z): 321.1 (M+H)+. Synthesis of 4-(7-(2-chloro-3-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 106): Step-4: Synthesis of 4-(7-(2-chloro-3-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (7) To stirred solution p-(4-iodo-6-thia-1,3-diazabicyclo[3.3.0]octa-2,4,7-trien-2-yl)benzonitrile (100 mg, 0.285 mmol, 1 eq) in 1,4 Dioxane (5 ml) to this add 2-Chloro-3-fluorophenylboronic acid (50 mg, 0.285 mmol, 1 eq) and add dipotassium carbonate (118 mg, 0.854 mmol, 3 eq) and water (1 ml). Reaction mixture was degassed with argon gas then add 1,1 -Bis(diphenylphosphino)ferrocene dichloropalladium (23 mg, 0.028 mmol, 0.1 eq), then keep the reaction in Microwave at 110oC for 120 minutes. After completion of reaction, reaction mixture was concentrated under reduced pressure and crude compound was purified by combiflash chromatography using 0-50% ethyl acetate: hexane as eluent to afford 4-(7-(2-chloro-3-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (80 mg, 79.4% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6): δ 8.02 – 8.00 (m, 1H), 7.86 (d, J = 4.4 Hz, 1H), 7.81 (d, J = 6.8 Hz, 2H), 7.34 – 7.33 (m, 2H), 7.12 (d, J = 4.4 Hz, 1H). Step-5: Synthesis of 4-(7-(2-chloro-3-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 106) The 4-(7-(2-chloro-3-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (80 mg, 226 µmol, 1eq) was dissolved in ethanol (5 mL) and water (1.5 mL) (3:1). To this solution sodium hydroxide (19.7 mg, 678 µmol, 3 eq.) was added and the reaction mixture was stirred for overnight at 100 °C. The reaction mixture was acidified with 1N HCl and filtered it. The yellow solid were obtained which was washed with n-pentane to remove the grease to afford Compound 106 (40 mg, 38% yield).1H NMR (400 MHz, DMSO-d6): δ 13.09 (s, 1H), 8.46 (d, J = 4.4 Hz, 1H), 8.11 - 8.06 (m, 4H), 7.77 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 4.4 Hz, 1H), 7.51 – 7.46 (m, 1H), 7.39 (t, J = 8.4 Hz, 1H). LCMS (m / z): 373.0 (M+H)+. Synthesis of 4-(7-(5-bromo-2-chlorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 107): Step-4: Synthesis of 4-(7-(5-bromo-2-chlorophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (7) To stirred solution p-(4-iodo-6-thia-1,3-diazabicyclo[3.3.0]octa-2,4,7-trien-2-yl)benzonitrile (100 mg, 0.285 mmol, 1 eq) in 1,4 Dioxane (5 ml) to this add 5-bromo-2-chlorophenylboronic acid (67 mg, 0.285 mmol, 1 eq) and add dipotassium carbonate (118 mg, 0.854 mmol, 3 eq) and water (1 ml). Reaction mixture was degassed with argon gas then add 1,1 -Bis(diphenylphosphino)ferrocene dichloropalladium (23 mg, 0.028 mmol, 0.1 eq), then keep the reaction in Microwave at 110°C for 120 minutes. After completion of reaction, reaction mixture was concentrated under reduced pressure and crude compound was purified by combiflash chromatography using 0-50% ethyl acetate: hexane as eluent to afford 4-(7-(5-bromo-2-chlorophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (85 mg, 72% yield) as a off-white solid.1H NMR (400 MHz, DMSO-d6): δ 8.48 (d, J = 4.4 Hz, 1H), 8.19 (d, J = 8.4 Hz, 2H), 8.09 (d, J = 4.0 Hz, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 4.4 Hz, 1H), 7.56 (m, 1H), 7.52 – 7.50 (m, 1H). Step-5: Synthesis of 4-(7-(5-bromo-2-chlorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 107) The 4-(7-(5-bromo-2-chlorophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (85 mg, 205 µmol, 1eq) was dissolved in ethanol (5 mL, 85.6 mmol) and water (1.5 mL, 83.3 mmol) (3:1). To this, sodium hydroxide (19.7 mg, 615 µmol, 3 eq) was added and the reaction mixture was stirred for overnight at 100 °C. The reaction mixture was acidified with 1N HCl and filtered it. The yellow solid were obtained which was washed with n-pentane to remove the grease to afford Compound 107 (40 mg, 38.4% yield).1H NMR (400 MHz, DMSO-d6): δ 13.10 (s, 1H), 8.45 (d, J = 4.4 Hz, 1H), 8.12 - 8.07 (m, 5H), 7.59 - 7.50 (m, 3H), 7.27 (t, J = 7.6 Hz, 1H). LCMS (m / z): 435.23 (M+H)+. Synthesis of 4-(7-(2-chloro-5-methoxyphenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 110): Step-4: Synthesis of 4-(7-(2-chloro-5-methoxyphenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (7) To stirred solution p-(4-iodo-6-thia-1,3-diazabicyclo[3.3.0]octa-2,4,7-trien-2-yl)benzonitrile (100 mg, 0.285 mmol, 1 eq) in 1,4 Dioxane (5 ml) to this add 2-Chloro-5-methoxyphenyboronic acid (53 mg, 0.285 mmol, 1 eq) and add dipotassium carbonate (118 mg, 0.854 mmol, 3 eq) and water (1 ml). Reaction mixture was degassed with argon gas then add 1,1 -Bis(diphenylphosphino)ferrocene dichloropalladium (23 mg, 0.028 mmol, 0.1 eq), then keep the reaction in Microwave at 110oC for 120 minutes. After completion of reaction, reaction mixture was concentrated under reduced pressure and crude compound was purified by combiflash chromatography using 0-50% ethyl acetate: hexane as eluent to afford 4-(7-(2-chloro-5-methoxyphenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (65 mg, 62.5% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6): δ 8.46 (d, J = 4.4 Hz, 1H), 8.17 (d, J = 8.0 Hz, 2H), 7.97 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 4.4 Hz, 1H), 7.50 – 7.42 (m, 2H), 6.98 (dd, J = 5.6 Hz, 3.2 Hz, 1H), 3.82 (s, 3H). Step-5: Synthesis of 4-(7-(2-chloro-5-methoxyphenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 110) The 4-(7-(2-chloro-5-methoxyphenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (65 mg, 177 µmol, 1eq) was dissolved in ethanol (5 mL) and water (1.5 mL) (3:1). To this, sodium hydroxide (19.7 mg, 533 µmol, 3 eq) was added and the reaction mixture was stirred for overnight at 100 °C. The reaction mixture was acidified with 1N HCl and filtered it. The yellow solid were obtained which was washed with n-pentane to remove the grease to afford Compound 110 (22 mg, 32.3% yield).1H NMR (400 MHz, DMSO-d6): δ 13.08 (brs, 1H), 8.43 (d, J = 4.4 Hz, 1H), 8.10 (d, J = 8.4 Hz, 2H), 8.07 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 4.0 Hz, 1H), 7.45 – 7.43 (m, 2H), 6.97 (dd, J = 5.6 Hz, 3.2 Hz, 1H), 3.82 (s, 3H). LCMS (m / z): 385.3 (M+H)+. Synthesis of 4-(7-(2-chloro-5-nitrophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 115): Step-4: Synthesis of 4-(7-(2-chloro-5-nitrophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (7) To stirred solution p-(4-iodo-6-thia-1,3-diazabicyclo[3.3.0]octa-2,4,7-trien-2-yl)benzonitrile (100 mg, 0.285 mmol, 1 eq) in 1,4 Dioxane (5 ml) to this add 2-chloro-5-nitrophenylboronic acid (57 mg, 0.285 mmol, 1 eq) and add dipotassium carbonate (118 mg, 0.854 mmol, 3 eq) and water (1 ml). Reaction mixture was degassed with argon gas then add 1,1 -Bis(diphenylphosphino)ferrocene dichloropalladium (23 mg, 0.028 mmol, 0.1 eq), then the reaction was placed in Microwave at 110oC for 120 minutes. After completion of reaction, reaction mixture was concentrated under reduced pressure and crude compound was purified by combiflash chromatography using 0-50% ethyl acetate: hexane as eluent to afford 4-(7-(2-chloro-5-nitrophenyl)imidazo[5,1-b]thiazol-5- yl)benzonitrile (60 mg, 55% yield).1H NMR (400 MHz, DMSO-d6): δ 8.73 (d, J = 2.8 Hz, 1H), 8.53 – 8.50 (m, 1H), 8.20 (d, J = 8.0 Hz, 1H), 8.05 – 7.99 (m, 3H), 7.93 – 7.48 (m, 2H), 7.65 – 7.55 (m, 1H). Step-5: Synthesis of 4-(7-(2-chloro-5-nitrophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 115) The 4-(7-(2-chloro-5-nitrophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (60 mg, 157 µmol, 1eq) was dissolved in ethanol (5 mL, 85.6 mmol) and water (1.5 mL, 83.3 mmol) (3:1). To this, sodium hydroxide (19.7 mg, 472 µmol, 3 eq) was added and the reaction mixture was stirred for overnight at 100 °C. The reaction mixture was acidified with 1N HCl and filtered it. The yellow solid were obtained which was washed with n-pentane to remove the grease to afford Compound 115 (15 mg, 23.8% yield).1H NMR (400 MHz, DMSO-d6): δ 13.12 (s, 1H), 8.74 (d, J = 2.4 Hz, 1H), 8.48 (d, J = 4.4 Hz, 1H), 8.17 – 8.15 (m, 2H), 8.13 (d, J = 8.8 Hz, 2H), 8.08 (m, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 4.0 Hz, 1H). LCMS (m / z): 400.44 (M+H)+. Synthesis of 4-(7-(3-cyanophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 116): Step-4: Synthesis of 4-(7-iodoimidazo[5,1-b]thiazol-5-yl)benzoic acid (6) The 4-(7-(2-chloro-5-nitrophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (100 mg, 164 µmol, 1eq) was dissolved in ethanol (5 mL, 85.6 mmol) and water (1.5 mL, 83.3 mmol) (3:1). To this, sodium hydroxide (19.7 mg, 492 µmol, 3 eq) was added and the reaction mixture was stirred for overnight at 100 °C. The reaction mixture was acidified with 1N HCl and filtered it. The yellow solid were obtained which was washed with n-pentane to remove the grease to afford 4-(7-iodoimidazo[5,1- b]thiazol-5-yl)benzoic acid (60 mg, 85.7% yield).1H NMR (400 MHz, DMSO-d6): δ 8.46 (d, J = 4.0 Hz, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.89 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 4.4 Hz, 1H). Step-5: Synthesis of 4-(7-(3-cyanophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 116) To stirred solution 4-(7-iodoimidazo[5,1-b]thiazol-5-yl)benzoic acid (60 mg, 0.162 mmol, 1 eq) in 1,4 Dioxane (5 ml) to this add 3-cyanophenylboronic acid (24 mg, 0.162 mmol, 1 eq) and add dipotassium carbonate (67 mg, 0.486 mmol, 3 eq) and water (1 ml). Reaction mixture was degassed with argon gas then add 1,1 -Bis(diphenylphosphino)ferrocene dichloropalladium (13 mg, 0.016 mmol, 0.1 eq), then the reaction was placed in Microwave at 110°C for 120 minutes. After completion of reaction, reaction mixture was concentrated under reduced pressure and crude compound was purified by combiflash chromatography using 0-50% ethyl acetate: hexane as eluent to afford Compound 116 (10 mg, 18% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6): δ 13.12 (s, 1H), 8.52 (d, J = 4.0 Hz, 1H), 8.14 – 8.06 (m, 5H), 7.99 - 7.97 (m, 1H), 7.72 – 7.71 (m, 2H), 7.67 (d, J = 4.4 Hz, 1H). LCMS (m / z): 346.29 (M+H)+. Synthesis of 4-(7-(1H-pyrazol-3-yl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 120): Step-4: Synthesis of 4-(7-(1H-pyrazol-3-yl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (7) To stirred solution p-(4-iodo-6-thia-1,3-diazabicyclo[3.3.0]octa-2,4,7-trien-2-yl)benzonitrile (100 mg, 0.285 mmol, 1 eq) in 1,4 Dioxane (5 ml) to this add (1H-pyrazol-3-yl)boronic acid (100 mg, 0.285 mmol, 1 eq) and add dipotassium carbonate (118 mg, 0.854 mmol, 3 eq) and water (1 ml). Reaction mixture was degassed with argon gas then add 1,1 -Bis(diphenylphosphino)ferrocene dichloropalladium (23 mg, 0.028 mmol, 0.1 eq), then the reaction was placed in Microwave at 110oC for 120 minutes. After completion of reaction, reaction mixture was concentrated under reduced pressure and crude compound was purified by combiflash chromatography using 0-50% ethyl acetate: hexane as eluent to afford 4-(7-(1H-pyrazol-3-yl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (58 mg, 70% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6): δ 12.95 (s, 1H), 8.48 (d, J = 4.4 Hz, 1H), 8.14 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 8.8 Hz, 2H), 7.80 (s, 1H), 7.60 (d, J = 4.4 Hz, 1H), 6.62 (s, 1H). Step-5: Synthesis of 4-(7-(1H-pyrazol-3-yl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 120) The 4-(7-(1H-pyrazol-3-yl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (58 mg, 199 µmol, 1eq) was dissolved in ethanol (5 mL) and water (1.5 mL) (3:1). To this, sodium hydroxide (19.7 mg, 597 µmol, 3 eq) was added and the reaction mixture was stirred for overnight at 100 °C. The reaction mixture was acidified with 1N HCl and filtered it. The yellow solid were obtained which was washed with n- pentane to remove the grease to afford Compound 120 (11 mg, 18% yield).1H NMR (400 MHz, DMSO-d6): δ 12.87 (s, 1H), 8.42 (d, J = 4.0 Hz, 1H), 8.04 (m, 4H), 7.79 (s, 1H), 7.55 (d, J = 4.0 Hz, 1H), 6.62 (s, 1H). LCMS (m / z): 311.25 (M+H)+. Synthesis of 4-(7-(4-amino-2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 117):

[0004] Step-1: Synthesis of 4-cyano-N-(thiazol-2-ylmethyl)benzamide (3) To a stirred solution of p-cyanobenzoic acid (1 g, 1 eq., 6.8 mmol) in dichloromethane (6.67 mL, 104 mmol) was added [(1,3-thiazol-2-yl)methyl]amine (1.16 g, 1.5 eq., 10.2 mmol) at rt and stirred for 20 min. After 20 min, added triethylamine (2.87 mL, 3 eq., 20.4 mmol) followed by the addition of [(1,3-thiazol-2-yl)methyl]amine (1.16 g, 1.5 eq., 10.2 mmol) at rt and stirred for 16 h. The reaction mixture was extracted with ethyl acetate and distilled water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography, eluted at 30% ethyl acetate: hexane to get the pure compound 4- cyano-N-(thiazol-2-ylmethyl)benzamide as a brown solid.1H NMR (400 MHz, DMSO-d6): δ 9.66 (t, J = 6.8 Hz, 1H), 8.04 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 3.2 Hz, 1H), 7.64 (d, J = 3.2 Hz, 1H), 4.77 (d, J = 6.0 Hz, 1H). Step-2: Synthesis of 4-(imidazo[5,1-b]thiazol-5-yl)benzonitrile (4) To a stirred solution of 4-cyano-N-(thiazol-2-ylmethyl)benzamide in toluene, and POCl3 was added drop wise at room temperature. The reaction mixture was stirred for 5hr at 120°C then reaction mixture was quenched by cold water and PH adjusted with NaHCO3 up to 8, then aqueous layer extract with EtOAc, organic layer dried over sodium sulfate distill off under reduced pressure, afford desired product 44-(imidazo[5,1-b]thiazol-5-yl)benzonitrile as a pale green color solid obtained. Crude compound was carried to next step without purification.1H NMR (400 MHz, DMSO-d6): δ 8.46 (d, J = 4.4 Hz, 1H), 8.11 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 3.2 Hz, 1H), 7.64 (d, J = 3.2 Hz, 1H), 4.77 (d, J = 6.0 Hz, 1H). Step-3: Synthesis of 4-(7-iodoimidazo[5,1-b]thiazol-5-yl)benzonitrile (5) To a stirred solution of 4-(imidazo[5,1-b]thiazol-5-yl)benzonitrile (1.0 g, 4.44 mmol) in dry DMF (15 mL), was added 1-iodopyrrolidine-2,5-dione (1.5 g, 6.66 mmol) at room temperature. The reaction mixture was stirred for 2h at room temperature, After 1 h checked TLC reaction was completed then reaction mixture was quenched with ice cold water, precipitated solid was filtered and dried under vacuum to afford 4-(7-iodoimidazo[5,1-b]thiazol-5-yl)benzonitrile (1.2 g, yield: 76.98%) as off-white solid.1H NMR (400 MHz, DMSO-d6): δ 8.52 (d, J = 4.0 Hz, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 4.0 Hz, 1H). Step-4: Synthesis of 4-(7-(2-fluoro-4-nitrophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (7) To stirred solution p-(4-iodo-6-thia-1,3-diazabicyclo[3.3.0]octa-2,4,7-trien-2-yl)benzonitrile (100 mg, 0.285 mmol, 1 eq) in 1,4 Dioxane (5 ml) to this add (2-fluoro-4-nitrophenyl)boronic acid (100 mg, 0.285 mmol, 1 eq) and add dipotassium carbonate (118 mg, 0.854 mmol, 3 eq) and water (1 ml). Reaction mixture was degassed with argon gas then add 1,1 -Bis(diphenylphosphino)ferrocene dichloropalladium (23 mg, 0.028 mmol, 0.1 eq). catalyst then keep the reaction in Microwave at 110°C for 120 minutes. After completion of reaction, reaction mixture was concentrated under reduced pressure and crude compound was purified by combiflash chromatography using 0-50% ethyl acetate: hexane as eluent to afford 4-(7-(2-fluoro-4-nitrophenyl)imidazo[5,1-b]thiazol-5- yl)benzonitrile (80 mg, 77% yield) as a brown solid. LCMS (m / z): 365.4 (M+H)+. Step-5: Synthesis of 4-(7-(4-amino-2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (8) To a stirred solution 4-(7-(2-fluoro-4-nitrophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (80 mg, 0.219 mmol, 1 eq) in MeOH (5 ml) was added Pd-C (catalytic) under inert atmosphere, then the reaction was stirred at rt under hydrogen atmosphere with balloon pressure for 2 h. After completion of reaction, reaction mixture was diluted with EtOAc and MeOH and filtered through celite pad. Filtrate was concentrated under reduced pressure to afford 4-(7-(4-amino-2- fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (50 mg, 68% yield). LCMS (m / z): 335.4 (M+H)+. Step-6: Synthesis of 4-(7-(4-amino-2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 117) The 4-(7-(4-amino-2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (50 mg, 149 µmol, 1eq) was dissolved in ethanol (5 mL) and water (1.5 mL) (3:1). To this, sodium hydroxide (18 mg, 447 µmol, 3 eq) was added and the reaction mixture was stirred for overnight at 100 °C. The reaction mixture was acidified with 1N HCl and filtered it. The off-white solid were obtained was purified by prep-purification to afford Compound 117 (3 mg, 6.0% yield).1H NMR (400 MHz, DMSO- d6): δ 8.32 (m, 1H), 8.03 – 7.99 (m, 4H), 7.76 (t, J = 8.8 Hz, 1H), 7.43 (d, J = 4.4 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 6.38 (d, J = 12.0 Hz, 1H), 5.52 (s, 2H). LCMS (m / z): 354.1 (M+H)+. Synthesis of 4-(7-(3-amino-2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 119): Step-4: Synthesis of 4-(7-(2-fluoro-3-nitrophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (7) To stirred solution p-(4-iodo-6-thia-1,3-diazabicyclo[3.3.0]octa-2,4,7-trien-2-yl)benzonitrile (100 mg, 0.285 mmol, 1 eq) in 1,4 Dioxane (5 ml) to this add (2-fluoro-3-nitrophenyl)boronic acid (100 mg, 0.285 mmol, 1 eq) and add dipotassium carbonate (118 mg, 0.854 mmol, 3 eq) and water (1 ml). Reaction mixture was degassed with argon gas then add 1,1 -Bis(diphenylphosphino)ferrocene dichloropalladium (23 mg, 0.028 mmol, 0.1 eq). catalyst then keep the reaction in Microwave at 110°C for 120 minutes. After completion of reaction, reaction mixture was concentrated under reduced pressure and crude compound was purified by combiflash chromatography using 0-50% ethyl acetate: hexane as eluent to afford 4-(7-(2-fluoro-4-nitrophenyl)imidazo[5,1-b]thiazol-5- yl)benzonitrile (80 mg, 77% yield). Analytical Data: Data: LCMS (m / z): 365.66 (M+H)+. Step-5: Synthesis of 4-(7-(4-amino-2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (8) To a stirred solution 4-(7-(2-fluoro-4-nitrophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (80 mg, 0.219 mmol, 1 eq) in MeOH (5 ml) was added Pd-C (catalytic) under inert atmosphere, then the reaction was stirred at rt under hydrogen atmosphere with balloon pressure for 2 h. After completion of reaction, reaction mixture was diluted with EtOAc and MeOH and filtered through celite pad. Filtrate was concentrated under reduced pressure to afford 4-(7-(3-amino-2- fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (50 mg, 68% yield). LCMS (m / z): 335.38 (M+H)+. Step-6: Synthesis of 4-(7-(4-amino-2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 119) The 4-(7-(3-amino-2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (50 mg, 149 µmol, 1eq) was dissolved in ethanol (5 mL) and water (1.5 mL) (3:1). To this, sodium hydroxide (18 mg, 447 µmol, 3 eq) was added and the reaction mixture was stirred for overnight at 100 °C. The reaction mixture was acidified with 1N HCl and filtered it. The yellow solid were obtained which was was purified by prep-purification to afford Compound 119 (8 mg, 15% yield).1H NMR (400 MHz, DMSO-d6): δ 8.34 - 8.33 (m, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 4.0 Hz, 1H), 7.28 – 7.25 (m, 1H), 6.94 (t, J = 8.0 Hz, 1H), 6.67 (t, J = 8.0 Hz, 1H), 5.21 (s, 2H). LCMS (m / z): 354.39 (M+H)+. Synthesis of 4-(7-(1H-pyrazol-3-yl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 121): Step-4: Synthesis of 4-(7-iodoimidazo[5,1-b]thiazol-5-yl)benzoic acid (6) The 4-(7-iodoimidazo[5,1-b]thiazol-5-yl)benzonitrile (100 mg, 285 µmol, 1eq) was dissolved in ethanol (5 mL) and water (1.5 mL) (3:1). To this, sodium hydroxide (34.2 mg, 855 µmol, 3 eq) was added and the reaction mixture was stirred for overnight at 100 °C. The reaction mixture was acidified with 1N HCl and filtered it. The off-white solid were obtained which was washed with n- pentane to remove the grease to afford 4-(7-iodoimidazo[5,1-b]thiazol-5-yl)benzoic acid (90 mg, 85.7% yield). Analytical Data:1H NMR (400 MHz, DMSO-d6): δ 8.51 (d, J = 4.0 Hz, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 4.4 Hz, 1H). Step-5: Synthesis of 4-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[5,1- b]thiazol-5-yl)benzoic acid (8) To stirred solution 4-(7-iodoimidazo[5,1-b]thiazol-5-yl)benzoic acid (90 mg, 0.243 mmol, 1 eq) in 1,4 Dioxane (5 ml) to this add (3-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (61 mg, 0.243 mmol, 1 eq) and add dipotassium carbonate (100 mg, 0.729 mmol, 3 eq) and water (1 ml). Reaction mixture was degassed with argon gas then add 1,1 -Bis(diphenylphosphino)ferrocene dichloropalladium (20 mg, 0.024 mmol, 0.1 eq), then the reaction was placed in Microwave at 110°C for 120 minutes. After completion of reaction, reaction mixture was concentrated under reduced pressure and crude compound was purified by combiflash chromatography using 0-50% ethyl acetate: hexane as eluent to afford 4-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl) imidazo[5,1-b]thiazol-5-yl)benzoic acid (50 mg, 45.8% yield). LCMS (m / z): 450.19 (M+H)+. Step-6: Synthesis of 4-(7-(3-(aminomethyl)phenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 121) The 4-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (50 mg, 111 µmol, 1eq) in 1,4-Dioxane (5 ml) was added 4 M HCl in dioxane (1 ml) at rt and then reaction mixture was stir at rt for 10 h. After completion of reaction, reaction mixture was concentrated under reduced pressure. Crude compound obtained was triturated with diethyl ether (20 ml) and the purified by prep purification to afford Compound 121 (11 mg, 28.3% yield).1H NMR (400 MHz, DMSO-d6): δ 8.42 (d, J = 4.0 Hz, 1H), 8.06 – 8.05 (m, 3H), 7.97 (d, J = 8.4 Hz, 2H), 7.57 – 7.46 (m, 3H), 7.28 (d, J = 4.4 Hz, 1H), 4.01 (s, 2H). LCMS (m / z): 350.3 (M+H)+. Synthesis of 4-(7-(1H-pyrazol-3-yl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 122): Step-5: Synthesis of 4-(7-(4-(2-((tert-butoxycarbonyl)amino)ethyl)phenyl)imidazo[5,1- b]thiazol-5-yl)benzoic acid (8) To stirred solution 4-(7-iodoimidazo[5,1-b]thiazol-5-yl)benzoic acid (100 mg, 0.285 mmol, 1 eq) in 1,4 Dioxane (5 ml) to this add (4-(2-((tert-butoxycarbonyl)amino)ethyl)phenyl)boronic acid (76 mg, 0.285 mmol, 1 eq) and add dipotassium carbonate (118 mg, 0.854 mmol, 3 eq) and water (1 ml). Reaction mixture was degassed with argon gas then add 1,1 - Bis(diphenylphosphino)ferrocene dichloropalladium (23 mg, 0.028 mmol, 0.1 eq). catalyst then keep the reaction in Microwave at 100°C for 120 minutes. After completion of reaction, reaction mixture was concentrated under reduced pressure and crude compound was purified by combiflash chromatography using 0-50% ethyl acetate: hexane as eluent to afford 4-(7-(4-(2-((tert- butoxycarbonyl)amino)ethyl)phenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (90 mg, 68.3% yield). LCMS (m / z): 464.4 (M+H)+. Step-6: Synthesis of 4-(7-(4-(2-aminoethyl)phenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid hydrochloride (Compound 122) To the stirred solution of 4-(7-(4-(2-((tert-butoxycarbonyl)amino)ethyl)phenyl)imidazo[5,1- b]thiazol-5-yl)benzoic acid (90 mg, 194 µmol, 1eq) in 1,4-Dioxane (5 ml) was added 4 M HCl in dioxane (1 ml) at rt and then reaction mixture was stir at rt for 10 h. After completion of reaction, reaction mixture was concentrated under reduced pressure. Crude compound obtained was triturated with diethyl ether (20 ml) and pentane and then dried under high vacuum to afford Compound 122 (15 mg, 21.2% yield).1H NMR (400 MHz, DMSO-d6): δ 13.07 (brs, 1H), 8.49 (d, J = 4.4 Hz, 1H), 8.10 (d, J = 8.4 Hz, 2H), 8.07 (d, J = 8.4 Hz, 2H), 7.79 (s, 3H), 7.73 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 4.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 3.11 – 3.06 (m, 2H), 2.91 – 2.87 (m, 2H). LCMS (m / z): 364.42 (M+H)+. Synthesis of 4-(7-(1H-pyrazol-3-yl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 123): Step-1: Synthesis of 3-bromo-2-fluorobenzamide (2) To the stirred solution of 3-bromo-2-fluorobenzoic acid (2.0 g, 9.13 mmol, 1 eq) in DCM (15 ml) was added oxalyl chloride (1.6 mL, 18.26 mmol, 2 eq) and then catalytic DMF was added. Reaction mixture was allowed to stir for 2h at rt. After completion of reaction, reaction mixture was concentrated under reduced pressure and crude compound was dissolved in EtOAc (10 mL) and NH4OH (2 ml) was added to this reaction mixture and allowed to stir at rt for 30 min. After completion of reaction, reaction mixture was quench with water and extracted with EtOAc (100 ml). Organic layer was dried over sodium sulfate and concentrated under reduced pressure. Crude compound was purified by combiflash chromatography using 0-50% ethyl acetate: hexane as eluent to afford 3-bromo-2-fluorobenzamide (1.3 g, 65% yield). LCMS (m / z): 218.00 (M+H)+. Step-2: Synthesis of (3-bromo-2-fluorophenyl)methanamine (3) To the stirred solution of 3-bromo-2-fluorobenzamide (1.3 g, 5.96 mmol, 1 eq) in THF (20 ml) was added Borane-DMS (1M solution) (12 mL, 11.92 mmol, 2.0 eq) at 0oC and then reaction mixture was allowed to come to rt for 10 min and the placed at 60°C for 3 h. After completion of reaction, reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (100 mL). Organic layer was dried over sodium sulfate and concentrated under reduced pressure. Crude compound was purified by combiflash chromatography using 0-50% ethyl acetate: hexane as eluent to afford (3-bromo-2-fluorophenyl)methanamine (1.0 g, 83% yield).1H NMR (400 MHz, DMSO- d6): δ 7.55 – 7.47 (m, 2H), 7.13 (t, J = 8.0 Hz, 1H), 3.76 (s, 2H), 1.98 (brs, 2H). Step-3: Synthesis of tert-butyl (3-bromo-2-fluorobenzyl)carbamate (4) To the stirred solution of (3-bromo-2-fluorophenyl)methanamine (1.0 g, 4.90 mmol, 1 eq) in DCM (15 ml) with sodium carbonate (1.03 g, 9.80 mmol, 2 eq) was added Boc-anhydride (1.13 ml, 4.90 mmol, 1 eq) at 0°C and then reaction mixture was allowed to stir at rt for 2 h. After completion of reaction, reaction mixture was quenched with saturated water and extracted with DCM (100 mL). Organic layer was dried over sodium sulfate and concentrated under reduced pressure. Crude compound was purified by combiflash chromatography using 0-50% ethyl acetate: hexane as eluent to afford tert-butyl (3-bromo-2-fluorobenzyl)carbamate (1.0 g, 66% yield). Analytical Data:1H NMR (400 MHz, CDCl3): δ 7.48 – 7.44 (m, 1H), 7.28 (t, J = 7.6 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 4.93 (s, 1H), 4.37 (d, J = 6.0 Hz, 2H), 1.44 (s, 9H). Step-4: Synthesis of tert-butyl (2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzyl)carbamate (5) To the stirred solution of tert-butyl (3-bromo-2-fluorobenzyl)carbamate (1.0 g, 3.29 mmol, 1 eq) in 1,4-Dioxane (15 ml) with potassium acetate (484 mg, 4.93 mmol, 1.5 eq) was added bis-pinacolato diborone (1.02 g, 3.95 mmol, 1.2 eq) at rt and then reaction mixture was purged with argon gas for 15 min. After argon purging (1,1'-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride (134 mg, 0.16 mmol, 0.05 eq) was added and reaction mixture was allowed to stir at 90°C for 16 h. After completion of reaction, reaction mixture was quenched with saturated water and extracted with EtOAc (100 mL). Organic layer was dried over sodium sulfate and concentrated under reduced pressure. Crude compound was purified by combiflash chromatography using 0-50% ethyl acetate: hexane as eluent to afford tert-butyl (2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzyl)carbamate (500 mg, 43% yield).1H NMR (400 MHz, CDCl3): δ 7.67-7.63 (m, 1H), 7.46 (t, J = 6.00 Hz, 1H), 7.11 (t, J = 7.60 Hz, 1H), 4.94 (s, 1H), 4.34 (d, J = 6.00 Hz, 1H), 1.43 (s, 12H), 0.36 (s, 9H). Step-5: Synthesis of 4-(7-(3-(((tert-butoxycarbonyl)amino)methyl)-2- fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (7) To the stirred solution tert-butyl (2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzyl)carbamate (300 mg, 0.855 mmol, 1.2 eq) in 1,4-Dioxane (15 ml) & water (2 ml) with potassium carbonate (294 mg, 2.13 mmol, 3.0 eq) was added 4-(7-iodoimidazo[5,1-b]thiazol-5- yl)benzoic acid (263 mg, 0.712 mmol, 1.0 eq) at rt and then reaction mixture was purged with argon gas for 15 min. After argon purging (1,1'-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride (29 mg, 0.03 mmol, 0.05 eq) was added and reaction mixture was irradiated at 110°C in microwave for 80 min. After completion of reaction, reaction mixture was quenched with saturated water and extracted with EtOAc (100 mL). Organic layer was dried over sodium sulfate and concentrated under reduced pressure. Crude compound was purified by combiflash chromatography using 0-50% ethyl acetate: hexane as eluent to afford 4-(7-(3-(((tert- butoxycarbonyl)amino)methyl)-2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (150 mg, 45% yield). LCMS (m / z): 468.28 (M+H)+. Step-6: Synthesis of 4-(7-(3-(aminomethyl)-2-fluorophenyl)imidazo[5,1-b]thiazol-5- yl)benzoic acid hydrochloride (Compound 123) To the stirred solution 4-(7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)imidazo[5,1- b]thiazol-5-yl)benzoic acid (150 mg, 0.32 mmol, 1.0 eq) in 1,4-Dioxane (5 ml) was added 4 M HCl in dioxane (1 ml) at rt and then reaction mixture was stir at rt for 10 h. After completion of reaction, reaction mixture was concentrated under reduced pressure. Crude compound obtained was triturated with diethyl ether (20 ml) and the purified by prep purification to afford Compound 123 (11 mg, 8.5% yield).1H NMR (400 MHz, DMSO-d6): 13.10 (s, 1H), 8.45-8.43 (m, 1H), 8.25 (s, 3H), 8.19-8.17 (m, 1H), 8.10 (d, J = 2.40 Hz, 2H), 8.08 (d, J = 2.80 Hz, 2H), 7.57 (d, J = 4.40 Hz, 1H), 7.43-7.36 (m, 2H), 4.19 (s, 2H). LCMS (m / z): 368.1 (M+H)+. Synthesis of 4-(7-(4-amino-2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 124) Step-1: Synthesis of 5-methyl-1,3-thiazole-2-carbaldehyde (2) To stirred a solution of 2-bromo-5-methyl-1,3-thiazole (5.0 g, 28.09 mmol, 1.0 eq) in tetrahydrofuran (50 mL), n-BuLi (1.6 M) (21 mL, 33.71 mmol, 1.2 eq) was added under nitrogen pressure at -70°C temperature for 45 min and then N,N-dimethylformamide (2.16 mL, 28.09 mmol, 1.0 eq) was added. The reaction mixture was maintained at same temperature for 45 min, the brown color precipitate was observed. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was quenched with ammonium chloride solution (50 mL), and extracted with ethyl acetate (4 x 50 mL). Combined organic layer was dried over Na2SO4,and concentrated under reduced pressure to afford product 5-methyl-1,3-thiazole-2- carbaldehyde (4.1 g, crude). The compound obtained was carried to next step as such. GCMS (m / z): 127.1. Step-2: Synthesis of (5-methyl-1,3-thiazol-2-yl)methanol (3) To stirred a solution of 5-methyl-1,3-thiazole-2-carbaldehyde (4.0 g, 31.49 mmol, 1.0 eq) in methanol (50 mL) were added at rt , and sodium borohydride (2.4 g, 62.99 mmol, 2 eq) was added portion wise slowly at -60°C and maintained the reaction for at -60°C 1 h. Progress of the reaction was monitored by TLC. After completion of reaction, the reaction mass was quenched with cold water (50 mL) and extracted with ethyl acetate (4x 50 mL). Combined organic layer was dried over Na2SO4and concentrated under reduced pressure to get crude. The crude compound was purified by flash column chromatography to afford desired product (5-methyl-1,3-thiazol-2- yl)methanol (3.05 g, 75.1% yield).1H NMR (400 MHz, DMSO-d6): δ 7.37 (s, 1H), 4.87 (s, 2H), 2.47 (s, 3H). Step-3: Synthesis of 2-(bromomethyl)-5-methyl-1,3-thiazole (4) To stirred a solution of (5-methyl-1,3-thiazol-2-yl)methanol (3.0 g, 23.26 mmol,1.0 eq) in dichloromethane (30 mL) and triphenylphosphine (12.2 g, 2 eq., 46.4 mmol) was added to reaction mixture at rt. Cooled the reaction mass to 0°C then added perbromomethane (15.4 g, 2 eq., 46.4 mmol) at 0°C. The reaction mixture was allowed to stir at rt for 2 hr. Progress of the reaction was monitored by TLC. After completion of reaction, the reaction mass was quenched with water (30 mL) and extracted with ethyl acetate (3x 30 mL). Combined organic layer was dried over Na2SO4, then solvent was evaporated under reduced pressure to get crude compound. The crude compound obtained was purified by flash column chromatography to afford desired product 2- (bromomethyl)-5-methyl-1,3-thiazole (4.4 g, 98.6% yield). The compound was used as such in next step.1H NMR (400 MHz, DMSO-d6): δ 7.39 (s, 1H), 4.69 (s, 2H), 2.47 (s, 3H). Step-4: Synthesis of 4-cyano-N-(thiazol-2-ylmethyl)benzamide (5) To stirred a solution of 2-(bromomethyl)-5-methyl-1,3-thiazole (4.4 g, 521 µmol, 1.0 eq) , and dimethylformamide (5 mL, 64.6 mmol), sodium azide (102 mg, 3 eq., 1.56 mmol)were added at rt. and temperature raised to 150°C maintained for 3 h. Progress of the reaction was monitored by TLC. After completion of the reaction mass was quenched with cold water and filtered under reduced pressure to afford desired product 1-[(2-methyl-1,3-thiazol-5-yl)methyl]-2λ⁵-triazadiene (4.0 g crude) as solid. Crude compound was carried to next step without purification and without any analysis. Step-5: Synthesis of [(5-methyl-1,3-thiazol-2-yl)methyl]amine (6) To a stirred solution of 1-[(5-methyl-1,3-thiazol-2-yl)methyl]-2λ⁵-triazadiene (4.0 g, 25.97 mmol, 1.0 eq) in ethyl acetate (40 mL), palladium dihydroxide (365 mg, 2.60 mmol.0.1 eq) was added to reaction mixture at rt. Then reaction mixture was allowed to stir for 2 h under hydrogen gas atmosphere. Progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with EtOAc (150 ml) then filtered through celite pad and washed with ethyl acetate (50 mL). Filtrate obtained was distilled off under reduced pressure and dried under high vacuum to afford desired product [(5-methyl-1,3-thiazol-2-yl)methyl]amine (1.16 g, 90.4% yield) as solid. Compound obtained was carried to next step as such.1H NMR (400 MHz, DMSO-d6): δ 7.32 (s, 1H), 3.89 (s, 2H), 2.38 (s, 3H). Step-6: Synthesis of 4-cyano-N-(thiazol-2-ylmethyl)benzamide (8) To a stirred solution of p-cyanobenzoic acid (1.0 g, 1 eq., 6.8 mmol) in dichloromethane (6.67 mL) was added [(1,3-thiazol-2-yl)methyl]amine (1.16 g, 1.5 eq., 10.2 mmol) at rt and stirred for 20 min. After 20 min, added triethylamine (2.87 mL, 3 eq., 20.4 mmol) followed by the addition of [(1,3-thiazol-2-yl)methyl]amine (1.16 g, 1.5 eq., 10.2 mmol) at rt and stirred for 16 h. The reaction mixture was extracted with ethyl acetate and distilled water. The organic layer was dried over Na2SO4and concentrated under reduced pressure to get the crude. The crude was washed with diethyl ether (30 mL) to afford compound 4-cyano-N-(thiazol-2-ylmethyl)benzamide (1.1 g, crude) as a brown solid. Compound obtained was carried to next step as such. LCMS (m / z): 258.1 (M+H)+. Step-7: Synthesis of 4-(imidazo[5,1-b]thiazol-5-yl)benzonitrile (9) To a stirred solution of 4-cyano-N-(thiazol-2-ylmethyl)benzamide (1.1 g, 4.27 mmol) in toluene (10 mL), POCl3(10 mL) was added drop wise at room temperature. The reaction mixture was stirred at 120°C for 5 h. then reaction mixture was quenched by cold water and pH~8 was adjusted with NaHCO3solution, then aqueous layer extract with EtOAc (3x 20 mL). Combined organic layer was dried over sodium sulfate and distill off under reduced pressure, afford desired product 44-(imidazo[5,1-b]thiazol-5-yl)benzonitrile (1.0 g, crude) as a pale green color solid obtained. Crude compound was carried to next step without purification. LCMS (m / z): 240.1 (M+H)+. Step-8: Synthesis of 4-(7-iodoimidazo[5,1-b]thiazol-5-yl)benzonitrile (10) To a stirred solution of 4-(imidazo[5,1-b]thiazol-5-yl)benzonitrile (1.0 g, 4.17 mmol, 1 eq) in dry DMF (15 mL), was added 1-iodopyrrolidine-2,5-dione (1.4 g, 6.25 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred at room temperature for 2 h. After completion of reaction on TLC, the reaction mixture was quenched with ice cold water (30 mL) thus precipitated solid was filtered off and dried under vacuum to afford 4-(7-iodoimidazo[5,1-b]thiazol-5- yl)benzonitrile (1.2 g, yield: 76.98%) as off-white solid. Compound obtained was carried to next step as such. LCMS (m / z): 365.0 (M+H)+. Step-9: Synthesis of 4-(7-(2-fluoro-4-nitrophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (11) To stirred solution p-(4-iodo-6-thia-1,3-diazabicyclo[3.3.0]octa-2,4,7-trien-2-yl)benzonitrile (100 mg, 0.274 mmol, 1 eq) in 1,4 Dioxane (5 ml) to this add (2-fluorophenyl)boronic acid (38 mg, 0.274 mmol, 1 eq) and add dipotassium carbonate (113 mg, 0.822 mmol, 3 eq) and water (1 ml). Reaction mixture was degassed with argon gas then add 1,1 -Bis(diphenylphosphino)ferrocene dichloropalladium (22 mg, 0.027 mmol, 0.1 eq), catalyst then keep the reaction in Microwave at 110°C for 120 minutes. After completion of reaction, reaction mixture was concentrated under reduced pressure and crude compound was purified by combiflash chromatography using 0-50% ethyl acetate: hexane as eluent to afford 4-(7-(2-fluoro-4-nitrophenyl)imidazo[5,1-b]thiazol-5- yl)benzonitrile (55 mg, 77% yield) as a brown solid. LCMS (m / z): 334.1 (M+H)+. Step-10: Synthesis of 4-(7-(4-amino-2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 124) The 4-(7-(4-amino-2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (50 mg, 149 µmol, 1eq) was dissolved in ethanol (3 mL) and water (1 mL) (3:1). To this, sodium hydroxide (18 mg, 449 µmol, 3 eq) was added and the reaction mixture was stirred for overnight at 100 °C. The reaction mixture was acidified with 1N HCl and filtered off and then washed with n-pentane to get crude compound. The crude compound obtained was purified by prep-purification to afford Compound 124 (6 mg, 11.3% yield) as white solid.1H NMR (400 MHz, DMSO-d6): δ 13.07 (s, 1H), 8.27 (s, 1H), 8.14–8.12 (m, 1H), 8.08 (s, 4H), 7.31-7.28 (m, 3H), 2.34 (s, 3H). LCMS (m / z): 353.1 (M+H)+, HPLC purity: 95.19%. Synthesis of 4-(7-(4-amino-2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 125) Step-1: Synthesis of 4-(7-(2-fluoro-4-nitrophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (2) To stirred solution p-(4-iodo-6-thia-1,3-diazabicyclo[3.3.0]octa-2,4,7-trien-2-yl)benzonitrile (100 mg, 0.274 mmol, 1 eq) in 1,4 Dioxane (5 ml) to this add (2-chlorophenyl)boronic acid (39 mg, 0.274 mmol, 1 eq) and add dipotassium carbonate (113 mg, 0.822 mmol, 3 eq) and water (1 ml). Reaction mixture was degassed with argon gas then add 1,1 -Bis(diphenylphosphino)ferrocene dichloropalladium (22 mg, 0.027 mmol, 0.1 eq) catalyst then keep the reaction in Microwave at 110°C for 120 minutes. After completion of reaction, reaction mixture was concentrated under reduced pressure and crude compound was purified by combiflash chromatography using 0-50% ethyl acetate: hexane as eluent to afford 4-(7-(2-fluoro-4-nitrophenyl)imidazo[5,1-b]thiazol-5- yl)benzonitrile (55 mg, 77% yield) as a brown solid. LCMS (m / z): 350.1 (M+H)+. Step-2: Synthesis of 4-(7-(4-amino-2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzoic acid (Compound 125) The 4-(7-(4-amino-2-fluorophenyl)imidazo[5,1-b]thiazol-5-yl)benzonitrile (50 mg, 149 µmol, 1eq) was dissolved in ethanol (5 mL) and water (1.5 mL) (3:1). To this, sodium hydroxide (18 mg, 447 µmol, 3 eq) was added and the reaction mixture was stirred for overnight at 100 °C. The reaction mixture was acidified with 1N HCl thus solid obtained was filtered off and then washed with pentane to get crude compound. The crude compound obtained was purified by prep- purification to afford desired product Compound 125 as white solid.1H NMR (400 MHz, DMSO- d6): δ 13.06 (s, 1H), 8.29 (s, 1H), 8.08 (s, 4H), 7.95-7.93 (m, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 7.2 Hz, 1H), 7.39-7.35 (m, 1H), 2.45 (s, 3H), LCMS (m / z): 369.0 (M+H)+, HPLC purity: 99.33%. Synthesis of 4-(7-(2-chlorophenyl)imidazo[5,1-b]oxazol-5-yl)benzoic acid (Compound 135): Step-1: Synthesis of 4-cyano-N-(oxazol-2-ylmethyl)benzamide (3) To a stirred solution of p-cyanobenzoic acid (1.5 g, 1 eq., 10.2 mmol) and CDI (4.2 mL, 1.2 eq., 12.24 mmol) in dichloromethane (15 mL) was added triethylamine (2.87 mL, 3 eq., 30.6 mmol) and oxazol-2-ylmethanamine (1.2 g, 1.2 eq., 12.24 mmol) at rt and stirred for 16 h. Progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography, eluted at 30% ethyl acetate: hexane to get the desired compound 4-cyano-N-(oxazol-2-ylmethyl)benzamide (1.5 g, 65.2% yield) as an off-white solid. LCMS (m / z): 228.1 (M+H)+. Step-2: Synthesis of 4-(imidazo[5,1-b]oxazol-5-yl)benzonitrile (4) To a stirred solution of 4-cyano-N-(oxazol-2-ylmethyl)benzamide (1.5 g, 6.61 mmol, 1.0 eq) in toluene (10 mL), POCl3 (10 mL) was added drop wise at room temperature. The reaction mixture was stirred at 120°C for 5 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched by cold water (30 mL) and pH~8 was adjusted with NaHCO3, then aqueous layer extract with EtOAc (3 x 50 mL). Combined organic layer dried over sodium sulfate and distill off under reduced pressure to afford desired product 4-(imidazo[5,1- b]oxazol-5-yl)benzonitrile (1.3 g, 94% yield) as a pale green color solid obtained. This crude compound was carried to next reaction as such.1H NMR (400 MHz, DMSO-d6): δ 8.66 (s, 1H), 8.18 (d, J = 1.6 Hz, 1H), 8.06 (d, J = 8.0 Hz, 2H), 7.91 (d, J = 8.4 Hz, 2H), 6.97 (s, 1H). Step-3: Synthesis of 4-(7-iodoimidazo[5,1-b]oxazol-5-yl)benzonitrile (5) To a stirred solution of 4-(imidazo[5,1-b]oxazol-5-yl)benzonitrile (1.3 g, 6.22 mmol, 1.0 eq) in dry DMF (15 mL), was added N-Iodosuccinimide (2.1 g, 9.33 mmol.1.5 eq) at room temperature. The reaction mixture was stirred for 2 h at room temperature. Progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was quenched with ice-cold water (30 mL). The precipitate obtained was filtered through sintered funnel and washed with pentane then dried under high vacuum to afford desired product 4-(7-iodoimidazo[5,1-b]oxazol- 5-yl)benzonitrile (1.5 g, yield: 74.25%) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 8.73 (d, J = 1.6 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 8.4 Hz, 2H). Step-4: Synthesis of 4-(7-(2-chlorophenyl)imidazo[5,1-b]oxazol-5-yl)benzonitrile (7) To the stirred solution of 4-(7-iodoimidazo[5,1-b]oxazol-5-yl)benzonitrile (150 mg, 461 µmol, 1.0 eq) and (2-chlorophenyl)boronic acid (59.6 mg, 554 µmol, 1.2 eq) in 1,4-dioxane (5 mL, 58.6 mmol), was added dipotassium carbonate (191 mg, 1.38 mmol, 3 eq.) in distilled water (0.5 mL). Nitrogen gas was purged to the above reaction mixture for 15 min. Finally, [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37.6 mg, 0.1 eq., 46.1 µmol) was added and again purged under nitrogen atmosphere for 5 min. The reaction mixture was stirred for overnight at 100 °C in a sealed tube. Progress of the reaction was monitored by TLC. After the completion of the reaction, the mixture was quenched with water (15 mL) and extracted with ethyl acetate (3x 30 mL). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography, eluted at 20% ethyl acetate: hexane to afford desired product 4-(7-(2-chlorophenyl)imidazo[5,1-b]oxazol- 5-yl)benzonitrile (80 mg, 55.9% yield) as pale yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.73 (d, J = 1.6 Hz, 1H), 8.28 (d, J = 1.6 Hz, 1H), 8.14 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 1.6 Hz, 6.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.35-7.31 (m, 1H). Step-5: Synthesis of 4-(7-(2-chlorophenyl)imidazo[5,1-b]oxazol-5-yl)benzoic acid (Compound 135) The 4-(7-(2-chlorophenyl)imidazo[5,1-b]oxazol-5-yl)benzonitrile (80 mg, 150 µmol, 1.0 eq) was dissolved in ethanol (5 mL) and water (0.5 mL). To this reaction mixture, sodium hydroxide (30 mg, 450 µmol, 3 eq.) was added and stirred it for overnight at 100 °C. Progress of reaction was monitored by TLC. After completion of reaction, the reaction mixture concentrated under reduced pressure. Thus crude obtained was dissolved in water (8 mL) and acidified with 1N HCl. The yellow solid were obtained was filtered off through sintered funnel and washed with n-pentane to afford desired product Compound 135 (30 mg, 35.4% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 13.04 (s, 1H), 8.68 (d, J = 1.2 Hz, 1H), 8.26 (d, J = 1.2 Hz, 1H), 8.09 (d, J = 8.4 Hz, 2H), 8.04 (d, J = 8.4 Hz, 2H), 7.91 (dd, J = 1.6 Hz, 6.4 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H)), 7.43 (t, J = 7.6 Hz, 1H), 7.34-7.30 (m, 1H), LCMS (m / z): 339.1 (M+H)+, HPLC purity: 99.07%. Synthesis of 4-(7-(2-methoxyphenyl)imidazo[5,1-b]oxazol-5-yl)benzoic acid (Compound 136): Step-4: Synthesis of 4-(7-(2-methoxyphenyl)imidazo[5,1-b]oxazol-5-yl)benzonitrile (7) To the stirred solution of 4-(7-iodoimidazo[5,1-b]oxazol-5-yl)benzonitrile (150 mg, 461 µmol, 1.0 eq) and (2-methoxyphenyl)boronic acid (59.6 mg, 554 µmol, 1.2 eq) in 1,4-dioxane (5 mL, 58.6 mmol), was added dipotassium carbonate (191 mg, 1.38 mmol, 3 eq.) in distilled water (0.5 mL). Nitrogen gas was purged to the above reaction mixture for 15 min. Finally, [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37.6 mg, 0.1 eq., 46.1 µmol) was added and again purged under nitrogen atmosphere for 5 min. The reaction mixture was stirred for overnight at 100 °C in a sealed tube. Progress of the reaction was monitored by TLC. After the completion of the reaction, the mixture was quenched with water (15 mL) and extracted with ethyl acetate (3x 30 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography, eluted at 20% ethyl acetate: hexane to afford desired 4-(7-(2-methoxyphenyl)imidazo[5,1-b]oxazol-5- yl)benzonitrile (80 mg, 56.7% yield) as a pale yellow solid. LCMS (m / z): 316.2 (M+H)+. Step-5: Synthesis of 4-(7-(2-methoxyphenyl)imidazo[5,1-b]oxazol-5-yl)benzoic acid (Compound 136) The 4-(7-(2-methoxyphenyl)imidazo[5,1-b]oxazol-5-yl)benzonitrile (80 mg, 150 µmol, 1.0 eq) was dissolved in ethanol (5 mL) and water (0.5 mL). To this reaction mixture, sodium hydroxide (30 mg, 450 µmol, 3 eq.) was added and stirred it for overnight at 100 °C. Progress of reaction was monitored by TLC. After completion of reaction, the reaction mixture concentrated under reduced pressure Thus crude obtained was dissolved in water (8 mL) and acidified with 1N HCl. The yellow solid were obtained was filtered off through sintered funnel and washed with n-pentane to afford desired product 4-(7-(2-methoxyphenyl)imidazo[5,1-b]oxazol-5-yl)benzoic acid (40 mg, 47.1% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 8.63 (d, J = 2.0 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 8.08 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 8.4 Hz, 2H), 7.94 (dd, J = 1.6 Hz, 6.4 Hz, 1H), 7.27–7.23 (m, 1H), 7.09-7.01 (m, 1H), 3.90 (s, 3H), LCMS (m / z): 335.34 (M+H)+, HPLC purity: 98.95%. Synthesis of 4-(7-(2-fluorophenyl)imidazo[5,1-b]oxazol-5-yl)benzoic acid (Compound 137): Step-4: Synthesis of 4-(7-(2-fluorophenyl)imidazo[5,1-b]oxazol-5-yl)benzonitrile (7) To the stirred solution of 4-(7-iodoimidazo[5,1-b]oxazol-5-yl)benzonitrile (150 mg, 461 µmol, 1.0 eq) and (2-fluorophenyl)boronic acid (59.6 mg, 554 µmol, 1.2 eq) in 1,4-dioxane (5 mL, 58.6 mmol), was added dipotassium carbonate (191 mg, 1.38 mmol, 3 eq.) in distilled water (0.5 mL). Nitrogen gas was purged to the above reaction mixture for 15 min. Finally, [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37.6 mg, 0.1 eq., 46.1 µmol) was added and again purged under nitrogen atmosphere for 5 min. The reaction mixture was stirred for overnight at 100 °C in a sealed tube. Progress of the reaction was monitored by TLC. After the completion of the reaction, the mixture was quenched with water (15 mL) and extracted with ethyl acetate (3x 30 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography, eluted at 20% ethyl acetate: hexane to afford desired product 4-(7-(2-fluorophenyl)imidazo[5,1-b]oxazol- 5-yl)benzonitrile (80 mg, 58.9% yield) as a pale yellow solid. LCMS (m / z): 304.31 (M+H)+. Step-5: Synthesis of 4-(7-(2-fluorophenyl)imidazo[5,1-b]oxazol-5-yl)benzoic acid (Compound 137) The 4-(7-(2-fluorophenyl)imidazo[5,1-b]oxazol-5-yl)benzonitrile (80 mg, 150 µmol, 1.0 eq) was dissolved in ethanol (5 mL) and water (0.5 mL). To this reaction mixture, sodium hydroxide (30 mg, 450 µmol, 3 eq.) was added and stirred it for overnight at 100 °C. Progress of reaction was monitored by TLC. After completion of reaction, the reaction mixture concentrated under reduced pressure Thus crude obtained was dissolved in water (8 mL) and acidified with 1N HCl. The yellow solid were obtained was filtered off through sintered funnel and washed with n-pentane to afford desired product Compound 137 (20 mg, 23.5% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 13.04 (s, 1H), 8.68 (s, 1H), 8.24 (s, 1H), 8.11-8.03 (m, 5H), 7.29-7.25 (m, 3H), LCMS (m / z): 323.3 (M+H)+, HPLC purity: 99.70%. Synthesis of 4-(7-(3-methoxyphenyl)imidazo[5,1-b]oxazol-5-yl)benzoic acid (Compound 138): Step-4: Synthesis of 4-(7-(3-methoxyphenyl)imidazo[5,1-b]oxazol-5-yl)benzonitrile (7) To the stirred solution of 4-(7-iodoimidazo[5,1-b]oxazol-5-yl)benzonitrile (150 mg, 461 µmol, 1.0 eq) and (3-methoxyphenyl)boronic acid (59.6 mg, 554 µmol, 1.2 eq) in 1,4-dioxane (5 mL, 58.6 mmol), was added dipotassium carbonate (191 mg, 1.38 mmol, 3 eq.) in distilled water (0.5 mL). Nitrogen gas was purged to the above reaction mixture for 15 min. Finally, [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37.6 mg, 0.1 eq., 46.1 µmol) was added and again purged under nitrogen atmosphere for 5 min. The reaction mixture was stirred for overnight at 100 °C in a sealed tube. Progress of the reaction was monitored by TLC. After the completion of the reaction, the mixture was quenched with water (15 mL) and extracted with ethyl acetate (3x 30 mL). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography, eluted at 20% ethyl acetate: hexane to afford desired product 4-(7-(3-methoxyphenyl)imidazo[5,1-b]oxazol- 5-yl)benzonitrile (80 mg, 56.7% yield) as pale yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.73 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 1.6 Hz, 1H), 8.14 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 7.41-7.34 (m, 3H), 6.82-6.80 (m, 1H), 3.82 (s, 1H). Step-5: Synthesis of 4-(7-(3-methoxyphenyl)imidazo[5,1-b]oxazol-5-yl)benzoic acid (Compound 138) The 4-(7-(3-methoxyphenyl)imidazo[5,1-b]oxazol-5-yl)benzonitrile (80 mg, 150 µmol, 1.0 eq) was dissolved in ethanol (5 mL) and water (0.5 mL). To this reaction mixture, sodium hydroxide (30 mg, 450 µmol, 3 eq.) was added and stirred it for overnight at 100 °C. Progress of reaction was monitored by TLC. After completion of reaction, the reaction mixture concentrated under reduced pressure Thus crude obtained was dissolved in water (8 mL) and acidified with 1N HCl. The yellow solid were obtained was filtered off through sintered funnel and washed with n-pentane (5 mL) to afford desired product Compound 138 (10 mg, 11.8% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 13.02 (s, 1H), 8.70 (d, J = 1.2 Hz, 1H), 8.29 (d, J = 1.2 Hz, 1H), 8.09 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H), 7.41-7.34 (m, 3H), 6.80 (d, J = 8.0 Hz, 1H), 3.83 (s, 3H), LCMS (m / z): 335.33 (M+H)+, HPLC purity: 9587%. Synthesis of 4-(7-(2-(trifluoromethyl)phenyl)imidazo[5,1-b]oxazol-5-yl)benzoic acid (Compound 139): Step-4: Synthesis of 4-(7-(2-(trifluoromethyl)phenyl)imidazo[5,1-b]oxazol-5-yl)benzonitrile (7) To the stirred solution of 4-(7-iodoimidazo[5,1-b]oxazol-5-yl)benzonitrile (150 mg, 461 µmol, 1.0 eq) and (2-trifluoromethylphenyl)boronic acid (59.6 mg, 554 µmol, 1.2 eq) in 1,4-dioxane (5 mL, 58.6 mmol), was added dipotassium carbonate (191 mg, 1.38 mmol, 3 eq.) in distilled water (0.5 mL). Nitrogen gas was purged to the above reaction mixture for 15 min. Finally, [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37.6 mg, 0.1 eq., 46.1 µmol) was added and again purged under nitrogen atmosphere for 5 min. The reaction mixture was stirred for overnight at 100 °C in a sealed tube. Progress of the reaction was monitored by TLC. After the completion of the reaction, the mixture was quenched with water (15 mL) and extracted with ethyl acetate (3x 30 mL). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography, eluted at 20% ethyl acetate: hexane to afford desired product 4-(7-(2-(trifluoromethyl)phenyl)imidazo[5,1- b]oxazol-5-yl)benzonitrile (80 mg, 50.6% yield) as pale yellow solid. LCMS (m / z): 354.1 (M+H)+. Step-5: Synthesis of 4-(7-(2-(trifluoromethyl)phenyl)imidazo[5,1-b]oxazol-5-yl)benzoic acid (Compound 139) The 4-(7-(2-(trifluoromethyl)phenyl)imidazo[5,1-b]oxazol-5-yl)benzonitrile (80 mg, 150 µmol, 1.0 eq) was dissolved in ethanol (5 mL) and water (0.5 mL). To this reaction mixture, sodium hydroxide (30 mg, 450 µmol, 3 eq.) was added and stirred it for overnight at 100 °C. Progress of reaction was monitored by TLC. After completion of reaction, the reaction mixture concentrated under reduced pressure Thus crude obtained was dissolved in water (8 mL) and acidified with 1N HCl. The yellow solid were obtained was filtered off through sintered funnel and washed with n- pentane to afford desired product Compound 139 (16 mg, 19.0% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 13.07 (s, 1H), 8.71 (d, J = 1.6 Hz, 1H), 8.26 (d, J = 1.6 Hz, 1H), 8.07 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H), 7.88 – 7.83 (m, 2H), 7.74 (t, J = 6.8 Hz, 1H), 7.52 (t, J = 7.2 Hz, 1H), LCMS (m / z): 373.31 (M+H)+, HPLC purity: 95.75%. Synthesis of 4-(7-phenylimidazo[5,1-b]oxazol-5-yl)benzoic acid (Compound 140): Step-4: Synthesis of 4-(7-phenylimidazo[5,1-b]oxazol-5-yl)benzonitrile (7) To the stirred solution of 4-(7-iodoimidazo[5,1-b]oxazol-5-yl)benzonitrile (150 mg, 461 µmol, 1.0 eq) and Phenylboronic acid (59.6 mg, 554 µmol, 1.2 eq) in 1,4-dioxane (5 mL, 58.6 mmol), was added dipotassium carbonate (191 mg, 1.38 mmol, 3 eq.) in distilled water (0.5 mL). Nitrogen gas was purged to the above reaction mixture for 15 min. Finally, [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37.6 mg, 0.1 eq., 46.1 µmol) was added and again purged under nitrogen atmosphere for 5 min. The reaction mixture was stirred for overnight at 100 °C in a sealed tube. Progress of the reaction was monitored by TLC. After the completion of the reaction, the mixture was quenched with water (15 mL) and extracted with ethyl acetate (3x 30 mL). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography, eluted at 20% ethyl acetate: hexane to afford desired product 4-(7-phenylimidazo[5,1-b]oxazol-5- yl)benzonitrile (80 mg, 62.6% yield) as pale yellow solid.1H NMR (400 MHz, DMSO-d6): δ 7.96 – 7.93 (m, 4H), 7.74 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 1.6 Hz, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.17 (t, J = 7.6 Hz, 2H). Step-5: Synthesis of 4-(7-phenylimidazo[5,1-b]oxazol-5-yl)benzoic acid (Compound 140) The 4-(7-phenylimidazo[5,1-b]oxazol-5-yl)benzonitrile (80 mg, 150 µmol, 1.0 eq) was dissolved in ethanol (5 mL) and water (0.5 mL). To this reaction mixture, sodium hydroxide (30 mg, 450 µmol, 3 eq.) was added and stirred it for overnight at 100 °C. Progress of reaction was monitored by TLC. After completion of reaction, the reaction mixture concentrated under reduced pressure Thus crude obtained was dissolved in water (8 mL) and acidified with 1N HCl. The yellow solid were obtained was filtered off through sintered funnel and washed with n-pentane to afford desired product Compound 140 (9 mg, 10.6% yield) as an off-white solid.1H NMR (400 MHz, DMSO- d6): δ 13.01 (s, 1H), 8.71 (d, J = 1.6 Hz, 1H), 8.30 (d, J = 1.6 Hz, 1H), 8.10 (d, J = 8.4 Hz, 2H) 8.04 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.22 (t, J = 7.2 Hz, 1H), LCMS (m / z): 305.31 (M+H)+, HPLC purity: 99.90%. Synthesis of 4-(7-(4-chloro-2-fluorophenyl)imidazo[5,1-b]oxazol-5-yl)benzoic acid (Compound 141): Step-4: Synthesis of 4-(7-(4-chloro-2-fluorophenyl)imidazo[5,1-b]oxazol-5-yl)benzonitrile (7) To the stirred solution of 4-(7-iodoimidazo[5,1-b]oxazol-5-yl)benzonitrile (150 mg, 461 µmol, 1.0 eq) and (4-chloro-2-fluorophenyl)boronic acid (59.6 mg, 554 µmol, 1.2 eq) in 1,4-dioxane (5 mL, 58.6 mmol), was added dipotassium carbonate (191 mg, 1.38 mmol, 3 eq.) in distilled water (0.5 mL). Nitrogen gas was purged to the above reaction mixture for 15 min. Finally, [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37.6 mg, 0.1 eq., 46.1 µmol) was added and again purged under nitrogen atmosphere for 5 min. The reaction mixture was stirred for overnight at 100 °C in a sealed tube. Progress of the reaction was monitored by TLC. After the completion of the reaction, the mixture was quenched with water (15 mL) and extracted with ethyl acetate (3x 30 mL). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography, eluted at 20% ethyl acetate: hexane to afford desired product 4-(7-(4-chloro-2-fluorophenyl)imidazo[5,1- b]oxazol-5-yl)benzonitrile (80 mg, 52.9% yield) as pale yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.07 (t, J = 8.0 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 1.2 Hz, 2H), 7.60 (d, J = 1.6 Hz, 1H), 7.22 (dd, J – 2.0 Hz, 6.4 Hz, 1H), 7.17 (dd, J = 2.0 Hz, 8.4 Hz, 1H). Step-5: Synthesis of 4-(7-(4-chloro-2-fluorophenyl)imidazo[5,1-b]oxazol-5-yl)benzoic acid (Compound 141) The 4-(7-(4-chloro-2-fluorophenyl)imidazo[5,1-b]oxazol-5-yl)benzonitrile (80 mg, 150 µmol, 1.0 eq) was dissolved in ethanol (5 mL) and water (0.5 mL). To this reaction mixture, sodium hydroxide (30 mg, 450 µmol, 3 eq.) was added and stirred it for overnight at 100 °C. Progress of reaction was monitored by TLC. After completion of reaction, the reaction mixture concentrated under reduced pressure Thus crude obtained was dissolved in water (8 mL) and acidified with 1N HCl. The yellow solid were obtained was filtered off through sintered funnel and washed with n- pentane to afford desired product Compound 141 (20 mg, 23.7% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 8.70 (s, 1H), 8.26 (s, 1H), 8.10 - 8.04 (m, 5H), 7.51 (d, J = 10.0 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), LCMS (m / z): 357.1 (M+H)+, HPLC purity: 99.60%. Synthesis of 4-(7-(3-chloro-2-fluorophenyl)imidazo[5,1-b]oxazol-5-yl)benzoic acid (Compound 142): Step-4: Synthesis of 4-(7-(3-chloro-2-fluorophenyl)imidazo[5,1-b]oxazol-5-yl)benzonitrile (7) To the stirred solution of 4-(7-iodoimidazo[5,1-b]oxazol-5-yl)benzonitrile (150 mg, 461 µmol, 1.0 eq) and (3-chloro-2-fluorophenyl)boronic acid (59.6 mg, 554 µmol, 1.2 eq) in 1,4-dioxane (5 mL, 58.6 mmol), was added dipotassium carbonate (191 mg, 1.38 mmol, 3 eq.) in distilled water (0.5 mL). Nitrogen gas was purged to the above reaction mixture for 15 min. Finally, [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37.6 mg, 0.1 eq., 46.1 µmol) was added and again purged under nitrogen atmosphere for 5 min. The reaction mixture was stirred for overnight at 100 °C in a sealed tube. Progress of the reaction was monitored by TLC. After the completion of the reaction, the mixture was quenched with water (15 mL) and extracted with ethyl acetate (3x 30 mL). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography, eluted at 20% ethyl acetate: hexane to afford desired product 4-(7-(3-chloro-2-fluorophenyl)imidazo[5,1- b]oxazol-5-yl)benzonitrile (80 mg, 52.9% yield) as pale yellow solid. LCMS (m / z): 338.38 (M+H)+. Step-5: Synthesis of 4-(7-(3-chloro-2-fluorophenyl)imidazo[5,1-b]oxazol-5-yl)benzoic acid (Compound 142) The 4-(7-(3-chloro-2-fluorophenyl)imidazo[5,1-b]oxazol-5-yl)benzonitrile (80 mg, 150 µmol, 1.0 eq) was dissolved in ethanol (5 mL) and water (0.5 mL). To this reaction mixture, sodium hydroxide (30 mg, 450 µmol, 3 eq.) was added and stirred it for overnight at 100 °C. Progress of reaction was monitored by TLC. After completion of reaction, the reaction mixture concentrated under reduced pressure Thus crude obtained was dissolved in water (8 mL) and acidified with 1N HCl. The yellow solid were obtained was filtered off through sintered funnel and washed with n- pentane to afford desired product Compound 142 (26 mg, 30.8% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 13.03 (s, 1H), 8.70 (s, 1H), 8.27 (s, 1H), 8.11-7.99 (m, 5H), 7.44 (t, J = 7.2 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), LCMS (m / z): 357.31 (M+H)+, HPLC purity: 99.43%. Synthesis of 4-(7-(2-chloro-4-methylphenyl)imidazo[5,1-b]oxazol-5-yl)benzoic acid (Compound 143): Step-4: Synthesis of 4-(7-(2-chloro-4-methylphenyl)imidazo[5,1-b]oxazol-5-yl)benzonitrile (7) To the stirred solution of 4-(7-iodoimidazo[5,1-b]oxazol-5-yl)benzonitrile (150 mg, 461 µmol, 1.0 eq) and (2-chloro-4-methylphenyl)boronic acid (59.6 mg, 554 µmol, 1.2 eq) in 1,4-dioxane (5 mL, 58.6 mmol), was added dipotassium carbonate (191 mg, 1.38 mmol, 3 eq.) in distilled water (0.5 mL). Nitrogen gas was purged to the above reaction mixture for 15 min. Finally, [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37.6 mg, 0.1 eq., 46.1 µmol) was added and again purged under nitrogen atmosphere for 5 min. The reaction mixture was stirred for overnight at 100 °C in a sealed tube. Progress of the reaction was monitored by TLC. After the completion of the reaction, the mixture was quenched with water (15 mL) and extracted with ethyl acetate (3x 30 mL). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography, eluted at 20% ethyl acetate: hexane to afford desired product 4-(7-(2-chloro-4-methylphenyl)imidazo[5,1- b]oxazol-5-yl)benzonitrile (80 mg, 53.7% yield) as pale yellow solid.1H NMR (400 MHz, DMSO- d6): δ 8.71 (d, J = 1.6 Hz, 1H), 8.26 (d, J = 1.6 Hz, 1H), 8.13 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.0 Hz, 1H), 7.36 (s, 1H), 7.24 (d, J = 7.6 Hz, 1H), 2.34 (s, 1H). Step-5: Synthesis of 4-(7-(2-chloro-4-methylphenyl)imidazo[5,1-b]oxazol-5-yl)benzoic acid (Compound 143) The 4-(7-(2-chloro-4-methylphenyl)imidazo[5,1-b]oxazol-5-yl)benzonitrile (80 mg, 150 µmol, 1.0 eq) was dissolved in ethanol (5 mL) and water (0.5 mL). To this reaction mixture, sodium hydroxide (30 mg, 450 µmol, 3 eq.) was added and stirred it for overnight at 100 °C. Progress of reaction was monitored by TLC. After completion of reaction, the reaction mixture concentrated under reduced pressure Thus crude obtained was dissolved in water (8 mL) and acidified with 1N HCl. The yellow solid were obtained was filtered off through sintered funnel and washed with n- pentane to afford desired product Compound 143 (14 mg, 16.56% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 13.08 (s, 1H), 8.69 (d, J = 1.2 Hz, 1H), 8.24 (d, J = 1.6 Hz, 1H), 8.08 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H), 7.79-7.77 (m, 1H), 7.36 (s, 1H), 7.24 (d, J = 7.6 Hz, 1H), 2.34 (s, 1H), LCMS (m / z): 353.31 (M+H)+, HPLC purity: 97.57%. Synthesis of 4-(7-(5-bromo-2-chlorophenyl)imidazo[5,1-b]oxazol-5-yl)benzoic acid (Compound 144): Step-4: Synthesis of 4-(7-(5-bromo-2-chlorophenyl)imidazo[5,1-b]oxazol-5-yl)benzonitrile (7) To the stirred solution of 4-(7-iodoimidazo[5,1-b]oxazol-5-yl)benzonitrile (150 mg, 461 µmol, 1.0 eq) and (5- bromo-2-chlorophenyl)boronic acid (59.6 mg, 554 µmol, 1.2 eq) in 1,4-dioxane (5 mL, 58.6 mmol), was added dipotassium carbonate (191 mg, 1.38 mmol, 3 eq.) in distilled water (0.5 mL). Nitrogen gas was purged to the above reaction mixture for 15 min. Finally, [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37.6 mg, 0.1 eq., 46.1 µmol) was added and again purged under nitrogen atmosphere for 5 min. The reaction mixture was stirred for overnight at 100 °C in a sealed tube. Progress of the reaction was monitored by TLC. After the completion of the reaction, the mixture was quenched with water (15 mL) and extracted with ethyl acetate (3x 30 mL). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to get the crude. The crude was purified by column chromatography, eluted at 20% ethyl acetate: hexane to afford desired product 4-(7-(5-bromo-2-chlorophenyl)imidazo[5,1- b]oxazol-5-yl)benzonitrile (80 mg, 44.94% yield) as pale yellow solid. LCMS (m / z): 398.1 (M+H)+. Step-5: Synthesis of 4-(7-(5-bromo-2-chlorophenyl)imidazo[5,1-b]oxazol-5-yl)benzoic acid (Compound 144) The 4-(7-(5-bromo-2-chlorophenyl)imidazo[5,1-b]oxazol-5-yl)benzonitrile (80 mg, 150 µmol, 1.0 eq) was dissolved in ethanol (5 mL) and water (0.5 mL). To this reaction mixture, sodium hydroxide (30 mg, 450 µmol, 3 eq.) was added and stirred it for overnight at 100 °C. Progress of reaction was monitored by TLC. After completion of reaction, the reaction mixture concentrated under reduced pressure. The crude obtained was dissolved in water (8 mL) and acidified with 1N HCl. The yellow solid was obtained was filtered off through sintered funnel and washed with n- pentane to afford desired Compound 144 (17 mg, 20.4% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 13.04 (s, 1H), 8.71 (d, J = 1.6 Hz, 1H), 8.28 (d, J = 1.6 Hz, 1H), 8.11 (d, J = 8.4 Hz, 2H), 8.07-8.03 (m, 3H), 7.49 (d, J = 1.2 Hz, 1H), 7.36 (s, 1H), 7.24 (d, J = 7.6 Hz, 1H), 2.34 (s, 1H), LCMS (m / z): 417.0 (M+H)+, HPLC purity: 96.86%.

[0005]

[0006] a: en

[0007] The following are exemplified compounds of formula (II). General Synthetic scheme for Triaza-indenone derivatives of Formula II Scheme 1 Synthesis of the triaza indanone derivatives 7 include the preparation of the 3-Phenyl-5- pyrazolylamine 4 intermediate. This intermediate was obtained by reacting the benzoylacetonitrile derivative 3 with hydrazine (Step 2) in microwave reactor. Synthesis of the benzoylacetonitrile material was obtained by reaction of the corresponding benzyl ester 1 with acetonitrile derivative 2 (Step 1). The triaza indanone ring was obtained by reacting the 3-phenyl-5-pyrazolylamine derivative 4 with ethyl benzoylacetate derivative 5 or 8 in acetic acid and using a microwave reactor (Step 3 or 5). Final basic hydrolysis provided the desired carboxylic acid derivatives 7 (Step 4 or 5) Synthesis of 4-(7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)benzoic acid (Compound 1) & methyl 4-(7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzoate (Compound 14):

[0008] Step-1. Synthesis of 3-phenyl-1H-pyrazol-5-amine (2). Compound 3-oxo-3-phenylpropanenitrile (1) (400 mg, 2.76 mmol), hydrazine hydrate (221 mg, 3.31 mmol) and methanol (4 mL) were charged in a microwave vial. The reaction mixture was stirred in a microwave at 150 °C for 10 min. The completion of the reaction was confirmed by TLC. The reaction mixture was concentrated under reduced pressure to afford crude compound. The crude compound was purified by combi-flash purification using (2 - 8% MeOH in DCM) to afford the desired product 3-phenyl-1H-pyrazol-5-amine (2) (320 mg) as an off-white solid.1H NMR (DMSO-d6): δ 4.94 (s, 1H), 11.42-11.90 (m, 1H), 7.63-7.69 (m, 2H), 7.36 (d, J = 6.40 Hz, 2H), 7.26 (d, J = 6.40 Hz, 1H), 5.77-5.78 (m, 1H), 5.00-4.55 (m, 2H), 5.78 (s, 1H), 4.82 (s, 2H). LCMS (m / z): 160.1 (M+H)+. Step-2. Synthesis of methyl 4-(7-oxo-2-phenyl-4, 7-dihydropyrazolo [1, 5-a] pyrimidin-5-yl) benzoate (Compound 14). The compound 3-phenyl-1H-pyrazol-5-amine (2) (0.1 g, 0.62 mmol) and methyl 4-(3-ethoxy-3- oxopropanoyl) benzoate (Int-A) (0.157 g, 0.62 mmol) was charged along with acetic acid in a MW vial. The reaction mixture was stirred in a MW at 150 °C for 1 h. After completion of the reaction, water was added thus precipitate obtained was filtered and washed with diethyl ether (10 mL), then dried under vacuum to afford the desired product Compound 14 (88 mg) as an off-white solid.1H NMR (DMSO-d6): δ 12.77 (s, 1H), 8.14 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 7.2 Hz, 4 H), 7.50 (t, J = 7.2 Hz, 2H), 7.44 (t, J = 7.2 Hz, 1H), 6.70 (s, 1H), 6.20 (s, 1H), 3.92 (s, 3H). Step-3. Synthesis of 4-(7-oxo-2-phenyl-4, 7-dihydropyrazolo [1, 5-a] pyrimidin-5-yl) benzoic acid. (Compound 1): To a stirred solution of Compound 14 (50 mg, 0.14 mmol) in THF (1 mL) and MeOH (3 mL), added aq. NaOH (16 mg, 2M) solution at room temperature. The reaction mass was stirred at RT for 16 h. After completion of the reaction, reaction mass directly concentrated under reduced pressure and the residue obtained was acidified using 1 N HCl. The precipitate obtained was filtered and washed with diethyl ether (10 mL), followed by washing with hexane (15 mL). The solid was dried under vacuum to afford desired product Compound 1 as an off-white solid.1H NMR (DMSO-d6): δ 13.33 (s, 1H), 12.75 (s, 1H), 8.12 (d, J = 8.4 Hz, 2H), 8.02 (d, J = 8.0 Hz, 2H), 8.99 (d, J = 8.0 Hz, 2H), 7.51 (t, J = 7.6 Hz, 2 H), 7.44 (t, J = 7.2 Hz, 16.70 (s, 1H), 6.19 (s, 1H) ppm; LCMS (m / z): 330.43 (M-H)+. Synthesis of methyl 4-(2-(2-methoxyphenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzoate (Compound 11) & 4-(2-(2-methoxyphenyl)-7-oxo-4,7-dihydropyrazolo[1,5- a]pyrimidin-5-yl)benzoic acid (Compound 15): Step-1: Synthesis of 3-(2-methoxyphenyl)-1H-pyrazol-5-amine (2) To a stirred solution of 3-(2-methoxyphenyl)-3-oxopropanenitrile (500 mg, 2.85 mmol, 1.0 eq) in MeOH (10 mL), N2H4.H2O (0.29 mL, 4.28 mmol, 1.5 eq.) was added dropwise at room temperature. Then reaction mixture was irradiated in microwave at 150°C for 30 min. After completion of the reaction on TLC, excess of solvent was distilled off under reduced pressure. The crude compound obtained was triturated with diethyl ether (10 mL) and pentane (10 mL) to afford desired product 3- (2-methoxyphenyl)-1H-pyrazol-5-amine (255 mg). The compound was used as such for the next reaction.1H NMR (400 MHz, DMSO-d6): δ 11.54 (s, 1H), 6.61 (s, 1H), 7.26 (t, J = 7.60 Hz, 1H), 7.07 (d, J = 8.00 Hz, 1H), 6.96 (t, J = 7.60 Hz, 1H), 5.88 (s, 1H), 3.92 (s, 3H), 4,54 (s, 2H), 3.85 (s, 3H). Step-2: Synthesis of methyl 4-(2-(2-methoxyphenyl)-7-oxo-4,7-dihydropyrazolo[1,5- a]pyrimidin-5-yl)benzoate (Compound 11): To a stirred solution of 3-(2-methoxyphenyl)-1H-pyrazol-5-amine (2) (250 mg, 1.32 mmol, 1.0 eq) in AcOH (8 mL), was added methyl 4-(3-ethoxy-3-oxopropanoyl)benzoate (3) (330 mg, 1.32 mmol, 1.0 eq) at room temperature. The reaction mixture was irradiated in microwave for 2 h at 150°C. After completion of the reaction, the reaction mixture was quenched with ice cold water (20 mL), precipitated solid was filtered and washed with diethyl ether (15 mL). This crude has been purified by combi-flash (1-4% MeOH in DCM) to afford desired product Compound 11 (118 mg, 23.8% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 12.63 (s, 1H), 8.14 (d, J = 8.40 Hz, 2H), 8.07 (dd, J = 1,6 Hz, 6.00 Hz, 1H), 8.02 (d, J = 8.80 Hz, 2H), 7.45-7.40 (m, 1H), 7.18 (d, J = 8.00 Hz, 1H), 7.08 (t, J = 7.60 Hz, 1H), 6.75 (s, 1H), 6.19 (s, 1H), 3.93 (s, 3H), 3.91 (s, 3H), LCMS (m / z): 376.36 (M-H)+, HPLC purity: 98.84%. Step-3: Synthesis of 4-(2-(2-methoxyphenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzoic acid (Compound 15): To a stirred solution of Compound 11 (100 mg, 266 µmol, 1.0 eq) in MeOH (3 mL) and THF (3 mL), a solution of NaOH (43 mg, 4 eq., 1.06 mmol) in distilled water (0.5 mL) was added and reaction mixture was stirred for overnight at RT. After completion of the reaction on TLC, the reaction mixture was concentrated under reduced pressure to get crude compound. The crude compound was dissolved in water (15 mL) and washed with diethyl ether (25 mL). The aqueous layer was separated and acidified with 1N HCl solution thus solid obtained was filtered off and dried under high vacuum to afford desired product Compound 15 (32 mg, 34.7% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): δ 12.63 (s, 1H), 8.12 (d, J = 8.40 Hz, 2H), 8.08 (dd, J = 1,6 Hz, 6.00 Hz, 1H), 7.99 (d, J = 8.40 Hz, 2H), 7.40-7.45 (m, 1H), 7.18 (d, J = 8.40 Hz, 1H), 7.08 (t, J = 7.60 Hz, 1H), 6.75 (s, 1H), 6.18 (s, 1H), 3.93 (s, 3H), LCMS (m / z): 362.36 (M-H)+, HPLC purity: 99.45%. Synthesis of methyl 4-(2-(2-fluorophenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzoate (Compound 13) & 4-(2-(2-fluorophenyl)-7-oxo-4,7-dihydropyrazolo[1,5- a]pyrimidin-5-yl)benzoic acid (Compound 16). Step-1: Synthesis of 3-(2-fluorophenyl)-1H-pyrazol-5-amine (2) To a stirred solution of 3-(2-fluorophenyl)-3-oxopropanenitrile (500 mg, 3.06 mmol, 1.0 eq) in MeOH (5 mL), N2H4.H2O (0.24 mL, 3.68 mmol, 1.2 eq.) was added dropwise at room temperature. Then reaction mixture was irradiated in microwave at 150°C for 10 min. After completion of the reaction on TLC, excess of solvent was distilled off under reduced pressure. The crude compound was dissolved in EtOAc (15 mL), washed with water (10 mL), brine solution (10 mL), and separated organic solvent was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude product. The crude compound was purified by Combi-flash column chromatography and the product was eluted with 3% MeOH in DCM. The collected pure fractions were concentrated under reduced pressure to afford 3-(2-fluorophenyl)-1H-pyrazol-5- amine (330 mg, 60.77%) as an off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 11.80 (s, 1H), 7.82 (s, 1H), 7.31-7.20 (m, 4H), 5.77 (s, 1H), 4.92 (s, 2H), Step-2: Synthesis of methyl 4-(2-(2-fluorophenyl)-7-oxo-4, 7-dihydropyrazolo [1,5- a]pyrimidin-5-yl)benzoate (Compound 13): To a stirred solution of 3-(2-fluorophenyl)-1H-pyrazol-5-amine (150 mg, 0.847 mmol, 1.0 eq) in AcOH (1 mL), was added ethyl 3-(4-cyanophenyl)-3-oxopropanoate (200 mg, 0.847 mmol, 1.0 eq.) at room temperature. The reaction mixture was irradiated in microwave for 2 h at 150°C. After completion of the reaction, the reaction mixture was quenched with ice-cold water (15 mL). Thus precipitated solid was filtered and washed with diethyl ether (10 mL) and purified by combi-flash (1-5% MeOH in DCM) to afford desired product Compound 13 (110 mg, 37.16% yield) as an off- white solid.1H-NMR (400 MHz, DMSO-d6): δ 12.74 (s, 1H), 8.17-8.12 (m, 3H), 7.54 -7.48 (m, 1H), 7.40 -7.34 (m, 1H), 8.03 (d, J = 8.40 Hz, 2H), 6.62 (d, J = 4.00 Hz, 1H), 6.25 (s, 1H), 3.92 (s, 3H), MS (m / z): 364.40 (M+H)+, HPLC purity: 98.98%. Step-3: Synthesis of 4-(2-(2-fluorophenyl)-7-oxo-4, 7-dihydropyrazolo [1, 5-a] pyrimidin-5-yl) benzoic acid (Compound 16): To a stirred solution of Compound 13 (90 mg, 257 µmol, 1.0 eq) in MeOH (2 mL) and THF (4 mL) was added a solution of NaOH (41 mg, 1.03 mmol, 4 eq) in distilled water (1 mL) at rt and stirred for 16 h at room temperature. After completion of the reaction on TLC, the reaction mixture was concentrated under reduced pressure to get crude compound. The crude compound was dissolved in water (10 mL) and washed with diethyl ether (15 mL). The aqueous layer was separated and acidified with 1N HCl solution. The solid obtained was filtered off and dried under high vacuum to afford desired product Compound 16 (24 mg, 20.8% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6): 13.36 (q, J = 8.40 Hz, 1H), 12.76 (s, 1H), 8.13 (q, J = 8.00 Hz, 3H), 7.99 (d, J = 8.40 Hz, 2H), 7.54-7.47 (m, 1H), 7.39-7.18 (m, 2H), 6.61 (d, J = 4.00 Hz, 1H), 6.22 (s, 1H), MS (m / z): 350.35 (M+H)+, HPLC purity: 99.47%. Synthesis of 2, 5-diphenylpyrazolo [1, 5-a] pyrimidin-7(4H)-one (Compound 21). Step-1: Synthesis of 2-methyl-3-oxo-3-phenylpropanenitrile (2) To a stirred solution of sodium hydride (60%) (0.55 g, 13.80 mmol, 2 eq.) at 0 °C in DMF (20 mL), 3-oxo-3-phenylpropanenitrile (1 g, 6.90 mmol, 1 eq.) was added and the reaction mixture was stirred for 30 min. After 30 min., Iodomethane (0.43 ml, 6.90 mmol, 1 eq.) was added to the reaction mixture and allowed to stir at RT for 1 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice water (30 mL) and extracted with ethyl acetate (3x 40 mL). The combined organic layer was distilled under reduced pressure to afford desired compound 2-methyl-3-oxo-3-phenylpropanenitrile (310 mg). The compound was used as such for the next reaction.1H NMR (400 MHz, DMSO-d6): δ 8.02-8.04 (m, 2H), 7.75-7.73 (m, 1H), 7.62-7.59 (m, 2H), 5.16 (q, J = 7.20 Hz, 1H), 1.48 (d, J = 7.20 Hz, 3H). Step-2: Synthesis of 4-methyl-3-phenyl-1H-pyrazol-5-amine (3) To a stirred solution of 2-methyl-3-oxo-3-phenylpropanenitrile (300 mg, 2.51 mmol, 1.0 eq) in MeOH (10 mL), N2H4.H2O (0.33 mL, 5.02 mmol, 2.0 eq) was added dropwise at room temperature. Then reaction mixture was irradiated in microwave at 150°C for 30 min. After completion of the reaction, excess of solvent was distilled off under reduced pressure, thus crude compound obtained was triturated with diethyl ether (10 mL) and pentane (15 mL) to afford desired product 4-methyl- 3-phenyl-1H-pyrazol-5-amine (154 mg). The compound was used as such for the next reaction. LCMS (m / z): 178.2 (M+H)+. Step-3. Synthesis of 3-methyl-2, 5-diphenylpyrazolo [1, 5-a] pyrimidin-7(4H)-one (Compound 21). The compound 4-methyl-3-phenyl-1H-pyrazol-5-amine (3) (150 mg, 0.87 mmol, 1.0 eq) and methyl 3-oxo-3-phenylpropanoate (Int-A) (166 mg, 0.87 mmol, 1.0 eq) was charged along with acetic acid (4 mL) in a MW vial. The reaction mixture was stirred in a MW at 150 °C for 2 h. After completion of the reaction, the precipitate obtained was filtered and washed with diethyl ether (15 mL), dried under vacuum to afford the desired product Compound 21 (65 mg, 25.0%) as an off- white solid.1H-NMR (400 MHz, DMSO-d6): δ 12.13 (s, 1H), 7.84-7.78 (m, 4H), 7.61 (d, J = 6.80 Hz, 3H), 7.55-7.44 (m, 3H), 5.96 (s, 1H), 2.38 (s, 3H), MS (m / z): 300.50 (M-H)+, HPLC purity: 97.90%. Synthesis of 3-(2-(2-fluorophenyl)-3-methyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzonitrile (Compound 22) & 3-(2-(2-fluorophenyl)-3-methyl-7-oxo-4,7- dihydropyrazolo[1,5-a]pyrimidin-5-yl)benzoic acid (Compound 25). Step-1: Synthesis of 3-(2-fluorophenyl)-2-methyl-3-oxopropanenitrile (2) To a stirred solution of sodium hydride (60%) (490 mg, 2 eq., 12.27 mmol) at 0°C in DMF (15 mL), 3-(2-fluorophenyl)-3-oxopropanenitrile (1 g, 6.13 mmol, 1 eq.) was added and the reaction mixture was stirred for 30 min. After 30 min., Iodomethane (0.38 ml, 6.13 mmol, 1 eq.) was added to the reaction mixture and allowed to stir at RT for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture quenched with ice water (15 mL) and aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic layer was distilled under reduced pressure to afford desired compound 3-(2-fluorophenyl)-2-methyl-3- oxopropanenitrile (350 mg). The compound was used as such for the next reaction.1H NMR (400 MHz, DMSO-d6): δ 7.71-7.65 (m, 1H), 7.64-7.49 (m, 1H), 7.44-7.31 (m, 2H), 3.48 (s, 1H), 1.63 (s, 3H). Step-2: Synthesis of 3-(2-fluorophenyl)-4-methyl-1H-pyrazol-5-amine (3) To a stirred solution of 3-(2-fluorophenyl)-2-methyl-3-oxopropanenitrile (350 mg, 1.97 mmol, 1.0 eq) in MeOH (10 mL), N2H4.H2O (0.22 mL, 3.95 mmol, 2.0 eq.) was added dropwise at room temperature. Then reaction mixture was irradiated in microwave at 150 °C for 30 min. After completion of the reaction on TLC, excess of solvent was distilled off under reduced pressure, thus crude compound obtained was triturated with diethyl ether (10 mL) and pentane (15 mL) to afford desired product 3-(2-fluorophenyl)-4-methyl-1H-pyrazol-5-amine (200 mg). The compound was used as such for the next reaction.1H NMR (400 MHz, DMSO-d6): δ 7.50 (dt, J = 2.00, 10.67 Hz, 1H), 7.40-7.38 (m, 1H), 7.23-7.19 (m, 2H), 5.03 (s, 3H), 2.04 (s, 3H), LCMS (m / z): 192.1 (M+H)+. Step-3: Synthesis of 3-(2-(2-fluorophenyl)-3-methyl-7-oxo-4, 7-dihydropyrazolo [1, 5-a] pyrimidin-5-yl) benzonitrile (Compound 22): To a stirred solution of 3-(2-fluorophenyl)-4-methyl-1H-pyrazol-5-amine (200 mg, 1.04 mmol, 1.0 eq) in AcOH (0.2 mL), was added ethyl 3-(3-cyanophenyl)-3-oxopropanoate (227 mg, 1.04 mmol, 1.0 eq) at room temperature. The reaction mixture was irradiated in microwave for 2 h at 150°C. After completion of the reaction on TLC, the reaction mixture was quenched with ice cold water (15 mL) and precipitated solid was filtered, washed with diethyl ether (10 mL) and dried under vacuum to afford product Compound 22 (165 mg, 45.80% ) as an off-white solid. 1H-NMR (400 MHz, DMSO-d6): δ 12.27 (s, 1H), 8.36 (s, 1H), 8.18 (d, J = 8.00 Hz, 1H), 8.08 (d, J = 7.60 Hz, 1H), 7.80 (t, J = 7.60 Hz, 1H), 7.62-7.53 (m, 2H), 7.37 (q, J = 7.20 Hz, 2H), 6.10 (s, 1H), 2.17 (d, J = 2.00 Hz, 3H), LCMS (m / z): 343.58 (M-H)+, HPLC purity: 97.99%. Step-4: Synthesis of 3-(2-(2-fluorophenyl)-3-methyl-7-oxo-4,7-dihydropyrazolo[1,5- a]pyrimidin-5-yl)benzoic acid (Compound 25): To a stirred solution of Compound 22 (150 mg, 436 µmol, 1.0 eq) in EtOH (6.0 mL), a solution of NaOH (87 mg, 5 eq., 2.18 mmol) in distilled water (1.0 mL) was added and reaction mixture was stirred for overnight at 70 °C. After completion of the reaction on TLC, the reaction mixture was concentrated under reduced pressure to get crude compound. The crude compound dissolved in water (10 mL) and washed with diethyl ether (20 mL). The aqueous layer was acidified with 1N HCl solution to obtain solid was filtered off and dried under high vacuum to afford desired product Compound 25 (87 mg, 55.0%) as an off-white solid.1H-NMR (400 MHz, DMSO-d6): δ 13.34 (s, 1H), 12.34 (s, 1H), 8.33 (s, 1H), 8.16 (d, J = 7.60 Hz, 1H), 8.07 (d, J = 7.60 Hz, 1H), 7.73 (t, J = 7.60 Hz, 1H), 7.61-7.53 (m, 2H), 7.37 (q, J = 7.60 Hz, 2H), 6.02 (s, 1H), 2.17 (d, J = 1.60 Hz, 3H), LCMS (m / z): 364.1 (M+H)+, HPLC purity: 98.54%. Synthesis of 3-(3-ethyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzonitrile (Compound 23) & 3-(3-ethyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5- a]pyrimidin-5-yl)benzoic acid (Compound 29): Step-1: Synthesis of 2-benzoylbutanenitrile (3) To a stirred solution of sodium hydride (60%) (551 mg, 13.79 mmol, 2 eq.) at 0°C in DMF (8 mL), 3-oxo-3-phenylpropanenitrile (1) (1 g, 6.89 mmol, 1 eq.) was added and the reaction mixture was stirred for 30 min. After 30 min. Iodoethane (0.55 ml, 6.89 mmol, 1 eq.) was added to the reaction mixture and allowed to stir at RT for 1 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice water (15 mL) and extracted with ethyl acetate (3x 25 mL). The combined organic layer was distilled under reduced pressure to afford desired compound 2-benzoylbutanenitrile (3) (360 mg). The compound was used as such for the next reaction.1H NMR (400 MHz, DMSO-d6): δ 7.98-8.00 (m, 2H), 7.65-7.70 (m, 1H), 7.53- 7.57 (m, 2H), 4.32 (q, J = 5.60 Hz, 1H), 2.02-2.16 (m, 2H), 1.17-1.24 (m, 3H). Step-2: Synthesis of 4-ethyl-3-phenyl-1H-pyrazol-5-amine (4) To a stirred solution of 2-benzoylbutanenitrile (3) (360 mg, 2.08 mmol, 1.0 eq) MeOH (10 mL), N2H4.H2O (0.28 mL, 4.16 mmol, 2.0 eq) was added drop wise at room temperature, then reaction mixture was irradiated in microwave at 150°C for 30 min. After completion of reaction, excess of solvent was distilled off under reduced pressure. Thus, crude compound obtained was triturated with diethyl ether (10 mL) and pentane (15 mL) to afford desired product 4-ethyl-3-phenyl-1H- pyrazol-5-amine (4) (295 mg). The compound was used as such in the next reaction. LCMS (m / z): 188.1 (M+H)+. Step-3: Synthesis of 3-(3-ethyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzonitrile (Compound 23): To a stirred solution of 4-ethyl-3-phenyl-1H-pyrazol-5-amine (4) (290 mg, 1.55 mmol, 1.0 eq) in AcOH (5 mL) was added ethyl 3-(3-cyanophenyl)-3-oxopropanoate (336 mg, 1.55 mmol, 1.0 eq) at room temperature. The reaction mixture was irradiated in microwave for 2 h at 150°C. After completion of reaction, the reaction mixture was quenched with ice cold water (15 mL) thus precipitated solid was filtered and washed with diethyl ether (20 mL) and then dried under vacuum to get crude compound. The crude compound was purified by combi-flash (0-5% MeOH in DCM) to afford desired product Compound 23 (180 mg, 34.1% yield).1H NMR (400 MHz, CD3OD): δ 12.16 (s, 1H), 8.35 (s, 1H), 8.16 (d, J = 7.60 Hz, 1H), 8.09 (d, J = 7.60 Hz, 1H), 7.75-7.83 (m, 3H), 7.47-7.55 (m, 3H), 6.07 (s, 1H), 2.86 (q, J = 7.20 Hz, 2H), 1.14 (t, J = 7.60 Hz, 3H), LCMS (m / z): 341.37 (M-H)+, HPLC purity: 98.20% Step-4: Synthesis of 3-(3-ethyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzoic acid (Compound 29): To a stirred solution of Compound 23 (150 mg, 441 µmol, 1.0 eq) in EtOH (7 mL), a solution of NaOH (88 mg, 2.20 mmol, 5.0 eq) in distilled water (1 mL) was added and reaction mixture was stirred for overnight at 90 °C. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure and crude dissolved in water (15 mL) and then washed with diethyl ether (25 mL). The aqueous layer was separated and acidified with 1N HCl solution thus solid obtained was filtered off and dried under high vacuum to afford Compound 29 (48 mg, 30.3% yield).1H NMR (400 MHz, DMSO-d6): δ 13.36 (s, 1H), 12.23 (s, 1H), 8.31 (s, 1H), 8.16 (d, J = 8.00 Hz, 1H), 8.06 (d, J = 7.60 Hz, 1H), 7.72-7.77 (m, 3H), 7.46-7.55 (m, 3H), 5.99 (s, 1H), 2.87 (q, J = 7.20 Hz, 2H), 1.13 (t, J = 7.20 Hz, 3H), LCMS (m / z): 360.1 (M-H)+, HPLC purity: 99.10% Synthetic Scheme for synthesis of 3-(3-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5- a]pyrimidin-5-yl)benzonitrile (Compound 26) & 3-(3-methyl-7-oxo-2-phenyl-4,7- dihydropyrazolo[1,5-a]pyrimidin-5-yl)benzoic acid (Compound 31):

[0009] Step-1: Synthesis of 2-methyl-3-oxo-3-phenylpropanenitrile (2) To a stirred solution of sodium hydride (60%) (1.66 g, 41.38 mmol, 2 eq.) at 0°C in DMF (20 mL), 3-oxo-3-phenylpropanenitrile (3 g, 20.69 mmol, 1 eq.) was added and the reaction mixture was stirred for 30 min. After 30 min. Iodomethane (1.29 ml, 20.69 mmol, 1 eq.) was added to the reaction mixture and allowed to stir at RT for 1 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice water (30 mL) and extracted with ethyl acetate (3x 40 mL). The combined organic layer was distilled under reduced pressure to afford desired compound 2-methyl-3-oxo-3-phenylpropanenitrile (1.2 g). The compound was used as such for the next reaction.1H NMR (400 MHz, DMSO-d6): δ 8.02-8.04 (m, 2H), 7.73-7.75 (m, 1H), 7.59-7.62 (m, 2H), 5.16 (q, J = 7.20 Hz, 1H), 1.48 (d, J = 7.20 Hz, 3H). Step-2: Synthesis of 4-methyl-3-phenyl-1H-pyrazol-5-amine (3) To a stirred solution of 2-methyl-3-oxo-3-phenylpropanenitrile (1.2 g, 7.54 mmol, 1.0 eq) in MeOH (10 mL), N2H4.H2O (0.84 mL, 15.07 mmol, 2.0 eq) was added dropwise at room temperature. Then reaction mixture was irradiated in microwave at 150°C for 30 min. After completion of the reaction, excess of solvent was distilled off under reduced pressure thus crude compound obtained was triturated with diethyl ether (20 mL) and pentane (30 mL) to afford desired product 4-methyl-3- phenyl-1H-pyrazol-5-amine (610 mg). The compound was used as such for the next reaction. LCMS (m / z): 178.2 (M+H)+. Step-3: Synthesis of 3-(3-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzonitrile (Compound 26): To a stirred solution of 4-methyl-3-phenyl-1H-pyrazol-5-amine (200 mg, 1.16 mmol, 1.0 eq) in AcOH (5 mL), was added ethyl 3-(3-cyanophenyl)-3-oxopropanoate (251 mg, 1.16 mmol, 1.0 eq) at room temperature. The reaction mixture was irradiated in microwave for 2 h at 150°C. After completion of the reaction, the reaction mixture was quenched with ice cold water (10 mL) thus precipitated solid was filtered and washed with diethyl ether (10 mL) and purified by combi-flash (2-5% MeOH in DCM) to afford desired product Compound 26 (87 mg) as off-white solid.1H NMR (400 MHz, DMSO-d6): δ 12.17 (s, 1H), 8.36 (s, 1H), 8.17 (d, J = 7.60 Hz, 1H), 8.09 (d, J = 7.20 Hz, 1H), 7.80 (d, J = 6.40 Hz, 3H), 7.47-7.53 (m, 3H), 6.09 (s, 1H), 2.38 (s, 3H), LCMS (m / z): 327.1 (M+H)+, HPLC purity: 96.69%. Step-4: Synthesis of 3-(3-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzoic acid (Compound 31): To a stirred solution of Compound 26 (80 mg, 245 µmol, 1.0 eq) in EtOH (4 mL), a solution of NaOH (49 mg, 5 eq., 1.23 mmol) in distilled water (0.5 mL) was added and reaction mixture was stirred for overnight at 70 °C. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get crude compound. The crude compound was dissolved in water (10 mL) and then washed with diethyl ether (15 mL), then aqueous layer was acidified with 1N HCl solution and solid obtained was filtered off and dried under high vacuum to afford desired product Compound 31 (15 mg) as off-white solid.1H NMR (400 MHz, DMSO-d6): δ 13.32 (s, 1H), 12.22 (s, 1H), 8.35 (s, 1H), 8.15 (d, J = 6.80 Hz, 1H), 8.08 (d, J = 7.60 Hz, 1H), 7.70-7.81 (m, 3H), 7.44-7.55 (m, 3H), 5.99 (s, 1H), 2.38 (s, 3H), LCMS (m / z): 346.1 (M+H)+, HPLC purity: 99.11%. Synthesis of 4-(3-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzonitrile (Compound 27) & 4-(3-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5- a]pyrimidin-5-yl)benzoic acid (Compound 33): Step-3: Synthesis of 4-(3-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzonitrile (Compound 27): To a stirred solution of 4-methyl-3-phenyl-1H-pyrazol-5-amine (3) (200 mg, 1.16 mmol, 1.0 eq) in AcOH (5 mL), was added ethyl 3-(4-cyanophenyl)-3-oxopropanoate (4) (251 mg, 1.16 mmol, 1.0 eq) at room temperature. The reaction mixture was irradiated in microwave for 2 h at 150°C. After completion of the reaction, the reaction mixture was quenched with ice cold water (15 mL) and precipitated solid was filtered and washed with diethyl ether (10 mL) and purified by combi-flash (2-5% MeOH in DCM) to afford desired product Compound 27 (95 mg) as off-white solid.1H NMR (400 MHz, DMSO-d6): δ 12.25 (s, 1H), 8.09 (d, J = 8.40 Hz, 2H), 8.04 (d, J = 8.40 Hz, 2H), 7.79-7.81 (m, 2H), 7.46-7.55 (m, 3H), 6.07 (s, 1H), 2.37 (s, 3H), LCMS (m / z): 327.36 (M+H)+, HPLC purity: 98.60%. Step-4: Synthesis of 4-(3-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzoic acid (Compound 33): To a stirred solution of Compound 27 (70 mg, 214 µmol, 1.0 eq) in EtOH (4 mL), a solution of NaOH (43 mg, 5 eq., 1.07 mmol) in distilled water (0.5 mL) was added and reaction mixture was stirred for overnight at 70 °C. After completion of the reaction on TLC, the reaction mixture was concentrated under reduced pressure to get crude compound. The crude compound was dissolved in water (10 mL) and washed with diethyl ether (20 mL). The aqueous layer was acidified with 1N HCl solution and solid obtained was filtered off and dried under high vacuum to afford desired product Compound 33 (9 mg) as off-white solid.1H NMR (400 MHz, DMSO-d6): δ 12.65 (s, 1H), 8.09 (d, J = 8.40 Hz, 2H), 7.99 (d, J = 8.00 Hz, 2H), 7.79 (d, J = 7.20 Hz, 2H), 7.51 (t, J = 7.20 Hz, 2H), 7.44 (d, J = 7.20 Hz, 1H), 6.01 (s, 1H), 2.37 (s, 3H), LCMS (m / z): 344.6 (M-H)+, HPLC purity: 96.72%. Synthesis of 3-(3,6-dimethyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzonitrile (Compound 30) & 3-(3,6-dimethyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5- a]pyrimidin-5-yl)benzoic acid (Compound 46): Step-1: Synthesis of 3-(3,6-dimethyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzonitrile (Compound 30): To a stirred solution of 4-methyl-3-phenyl-1H-pyrazol-5-amine (3) (200 mg, 1.16 mmol, 1.0 eq) in AcOH (5 mL), was added ethyl 3-(3-cyanophenyl)-2-methyl-3-oxopropanoate (4) (268 mg, 1.16 mmol, 1.0 eq) at room temperature. The reaction mixture was irradiated in microwave for 2 h at 150 °C. After completion of the reaction, the reaction mixture was quenched with ice cold water (15 mL) thus precipitated solid was filtered and washed with diethyl ether (10 mL) and purified by combi- flash (2-5% MeOH in DCM) to afford desired product Compound 30 (130 mg) as off-white solid.1H NMR (400 MHz, DMSO-d6): δ 12.04 (s, 1H), 8.14 (s, 1H), 8.07 (d, J = 7.60 Hz, 1H), 7.94 (d, J = 8.00 Hz, 1H), 7.78-7.82 (m, 3H), 7.43-7.53 (m, 3H), 2.29 (s, 3H), 1.87 (s, 3H), LCMS (m / z): 341.1 (M+H)+, HPLC purity: 96.30%. Step-2: Synthesis of 3-(3,6-dimethyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzoic acid (Compound 46): To a stirred solution of Compound 30 (110 mg, 323 µmol, 1.0 eq) in EtOH (4 mL), a solution of NaOH (65 mg, 5 eq., 1.61 mmol) in distilled water (0.7 mL) was added and reaction mixture was stirred for overnight at 70 °C. After completion of the reaction on TLC, the reaction mixture was concentrated under reduced pressure to get crude compound. The crude compound was dissolved in water (10 mL) and washed with diethyl ether (15 mL). The aqueous layer was acidified with 1N HCl solution and solid obtained was filtered off and dried under high vacuum to afford desired product Compound 46 (76 mg) as off-white solid.1H NMR (400 MHz, DMSO-d6): δ 13.34 (s, 1H), 12.05 (s, 1H), 8.15 (d, J = 8.00 Hz, 1H), 8.09 (s, 1H), 7.84 (d, J = 7.60 Hz, 1H), 7.79-7.81 (m, 2H), 7.74 (t, J = 7.60 Hz, 1H), 7.52 (t, J = 7.60 Hz, 2H), 7.44-7.47 (m, 1H), 2.31 (s, 3H), 1.89 (s, 3H), LCMS (m / z): 360.49 (M+H)+, HPLC purity: 98.42%. Synthesis of 4-(2-(2-fluorophenyl)-3-methyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzonitrile (Compound 32) & 4-(2-(2-fluorophenyl)-3-methyl-7-oxo-4,7- dihydropyrazolo[1,5-a]pyrimidin-5-yl)benzoic acid (Compound 28): Step-1: Synthesis of 3-(2-fluorophenyl)-2-methyl-3-oxopropanenitrile (2) To a stirred solution of sodium hydride (60%) (490 mg, 2 eq., 12.27 mmol) at 0°C in DMF (15 mL), 3-(2-fluorophenyl)-3-oxopropanenitrile (1) (1 g, 6.13 mmol, 1 eq.) was added and the reaction mixture was stirred for 30 min. After 30 min. Iodomethane (0.38 ml, 6.13 mmol, 1 eq.) was added to the reaction mixture and allowed to stir at RT for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture quenched with ice water (15 mL) and aqueous layer was extracted with ethyl acetate (3x 20 mL). The combined organic layer was distilled under reduced pressure to afford desired compound 3-(2-fluorophenyl)-2-methyl-3- oxopropanenitrile (2) (350 mg). The compound was used as such for the next reaction.1H NMR (400 MHz, DMSO-d6): δ 7.65-7.71 (m, 1H), 7.49-7.64 (m, 1H), 7.31-7.44 (m, 2H), 3.48 (s, 1H), 1.63 (s, 3H). Step-2: Synthesis of 3-(2-fluorophenyl)-4-methyl-1H-pyrazol-5-amine (3) To a stirred solution of 3-(2-fluorophenyl)-2-methyl-3-oxopropanenitrile (2) (350 mg, 1.97 mmol, 1.0 eq) in MeOH (10 mL), N2H4.H2O (0.22 mL, 3.95 mmol, 2.0 eq.) was added dropwise at room temperature. Then reaction mixture was irradiated in microwave at 150 °C for 30 min. After completion of the reaction on TLC, excess of solvent was distilled off under reduced pressure thus crude compound obtained was triturated with diethyl ether (10 mL) and pentane (15 mL) to afford desired product 3-(2-fluorophenyl)-4-methyl-1H-pyrazol-5-amine (3) (200 mg). The compound was used as such for the next reaction.1H NMR (400 MHz, DMSO-d6): δ 7.50 (dt, J = 2.00, 10.67 Hz, 1H), 7.40-7.38 (m, 1H), 7.23-7.19 (m, 2H), 5.03 (s, 3H), 2.04 (s, 3H), LCMS (m / z): 192.1 (M+H)+. Step-3: Synthesis of 4-(2-(2-fluorophenyl)-3-methyl-7-oxo-4,7-dihydropyrazolo[1,5- a]pyrimidin-5-yl)benzonitrile (Compound 32): To a stirred solution of 3-(2-fluorophenyl)-4-methyl-1H-pyrazol-5-amine (3) (200 mg, 1.04 mmol, 1.0 eq) in AcOH (5 mL), was added ethyl 3-(4-cyanophenyl)-3-oxopropanoate (4) (227 mg, 1.04 mmol, 1.0 eq) at room temperature. The reaction mixture was irradiated in microwave for 2 h at 150°C. After completion of the reaction on TLC, the reaction mixture was quenched with ice cold water (15 mL) and precipitated solid was filtered through a pad of celite. The solid obtained was washed with diethyl ether (10 mL) and purified by combi-flash (2-5% MeOH in DCM) to afford desired product Compound 32 (210 mg) as off-white solid.1H NMR (400 MHz, DMSO-d6): δ 12.33 (s, 1H), 8.09 (d, J = 8.40 Hz, 2H), 8.03 (d, J = 8.40 Hz, 2H), 7.55-7.59 (m, 2H), 7.34-7.41 (m, 2H), 6.08 (s, 1H), 2.16 (s, 1H), LCMS (m / z): 345.1 (M+H)+, HPLC purity: 99.50%. Step-4: Synthesis of 4-(2-(2-fluorophenyl)-3-methyl-7-oxo-4,7-dihydropyrazolo[1,5- a]pyrimidin-5-yl)benzoic acid (Compound 28): To a stirred solution of Compound 32 (100 mg, 290 µmol, 1.0 eq) in EtOH (4 mL), a solution of NaOH (58 mg, 5 eq., 1.45 mmol) in distilled water (0.5 mL) was added and reaction mixture was stirred for overnight at 70 °C. After completion of the reaction on TLC, the reaction mixture was concentrated under reduced pressure to get crude compound. The crude compound dissolved in water (10 mL) and washed with diethyl ether (20 mL). The aqueous layer was acidified with 1N HCl solution to obtain solid was filtered off and dried under high vacuum to afford desired product Compound 28 (40 mg) as off-white solid.1H NMR (400 MHz, DMSO-d6): δ 12.36 (s, 1H), 8.12 (d, J = 8.40 Hz, 2H), 7.96 (d, J = 8.40 Hz, 2H), 7.59-7.57 (m, 2H), 7.34-7.40 (m, 2H), 2.17 (s, 3H), LCMS (m / z): 362.56 (M-H)+, HPLC purity: 98.61%. Synthesis of 3-methyl-2-phenyl-5-(m-tolyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (Compound 34): Step-1: Synthesis of 2-methyl-3-oxo-3-phenylpropanenitrile (2) To a stirred solution of sodium hydride (60%) (552 mg, 13.79 mmol, 2 eq.) at 0°C in DMF (15 mL), 3-oxo-3-phenylpropanenitrile (1) (1.0 mg, 6.89 mmol, 1 eq.) was added and the reaction mixture was stirred for 30 min. After 30 min. Iodomethane (0.42 ml, 6.89 mmol, 1 eq.) was added to the reaction mixture and allowed to stir at RT for 1 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice water (30 mL) and extracted with ethyl acetate (3x 30 mL). The combined organic layer was distilled under reduced pressure to afford desired compound 2-methyl-3-oxo-3-phenylpropanenitrile (610 mg). The compound was used as such for the next reaction.1H NMR (400 MHz, DMSO-d6): δ 8.02-8.04 (m, 2H), 7.73-7.75 (m, 1H), 7.59-7.62 (m, 2H), 5.16 (q, J = 7.20 Hz, 1H), 1.48 (d, J = 7.20 Hz, 3H). Step-2: Synthesis of 4-methyl-3-phenyl-1H-pyrazol-5-amine (3) To a stirred solution of 2-methyl-3-oxo-3-phenylpropanenitrile (2) (600 mg, 3.77 mmol, 1.0 eq) in MeOH (15 mL), N2H4.H2O (0.42 mL, 7.54 mmol, 2.0 eq.) was added dropwise at room temperature. Then reaction mixture was irradiated in microwave at 150°C for 30 min. After completion of the reaction, excess of solvent was distilled off under reduced pressure thus crude compound obtained was triturated with diethyl ether (10 mL) and pentane (15 mL) to afford desired product 4-methyl- 3-phenyl-1H-pyrazol-5-amine (310 mg). The compound was used as such for the next reaction. LCMS (m / z): 178.2 (M+H)+. Step-3: Synthesis of 3-methyl-2-phenyl-5-(m-tolyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (Compound 34) To a stirred solution of 4-methyl-3-phenyl-1H-pyrazol-5-amine (3) (150 mg, 0.87 mmol, 1.0 eq) in AcOH (5 mL), was added ethyl 3-oxo-3-(m-tolyl)propanoate (4) (179 mg, 0.87 mmol, 1.0 eq) at room temperature. The reaction mixture was irradiated in microwave for 2 h at 150 °C. After completion of the reaction, the reaction mixture was quenched with ice cold water (10 mL) thus precipitated solid was filtered and washed with diethyl ether (10 mL) and purified by combi-flash (1-5% MeOH in DCM) to afford desired product Compound 34 (19 mg, 7.11% yield) as off-white solid.1H NMR (400 MHz, DMSO-d6): δ 12.09 (s, 1H), 7.78-7.80 (m, 2H), 7.61-7.65 (m, 2H), 7.42- 7.54 (m, 5H), 5.93 (s, 1H), 2.44 (s, 3H), 2.37 (s, 3H); LCMS (m / z): 316.1 (M+H)+; HPLC purity: 99.91%. Synthesis of 5-(3-methoxyphenyl)-3-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (Compound 24) & 5-(3-hydroxyphenyl)-3-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)- one (Compound 38): Step-1: Synthesis of 5-(3-methoxyphenyl)-3-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)- one (Compound 24): To a stirred solution of 4-methyl-3-phenyl-1H-pyrazol-5-amine (3) (150 mg, 0.87 mmol, 1.0 eq) in AcOH (5 mL), was added ethyl 3-(3-methoxyphenyl)-3-oxopropanoate (4) (193 mg, 0.87 mmol, 1.0 eq) at room temperature. The reaction mixture was irradiated in microwave for 2 h at 150°C. After completion of the reaction, the reaction mixture was quenched with ice cold water (10 mL) thus precipitated solid was filtered and washed with diethyl ether (10 mL) and purified by combi-flash (1-4% MeOH in DCM) to afford desired product Compound 24 (115 mg, 40.06% yield) as off- white solid.1H NMR (400 MHz, DMSO-d6): δ 12.09 (s, 1H), 7.78 (d, J = 7,2 Hz, 2H), 7.35-7.53 (m, 6H), 7.18 (dd, J = 2.0 Hz, 6.0 Hz, 1H), 5.98 (s, 1H), 3.87 (s, 3H), 2.36 (s, 3H), LCMS (m / z): 332.1 (M+H)+; HPLC purity: 94.59%. Step-2: Synthesis of 5-(3-hydroxyphenyl)-3-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)- one (Compound 38): To a stirred solution of Compound 24 (100 mg, 302 µmol, 1.0 eq) in EtOH (6 mL), a solution of NaOH (60 mg, 5 eq., 1.51 mmol) in distilled water (0.7 mL) was added and reaction mixture was stirred for overnight at 70 °C. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get crude compound. The crude compound was dissolved in water (10 mL) and then washed with diethyl ether (15 mL), then aqueous layer was acidified with 1N HCl solution and solid obtained was filtered off and dried under high vacuum to afford desired product Compound 38 (26 mg, 27.1% yield) as off-white solid.1H NMR (400 MHz, DMSO-d6): δ 12.08 (s, 1H), 9.90 (s, 1H), 7.78 (d, J = 6.80 Hz, 2H), 7.37-7.54 (m, 4H), 7.22 (d, J = 7.60 Hz, 1H), 7.16 (s, 1H), 7.00 (dd, J = 1.6 Hz, 6.0 Hz, 1H), 5.86 (s, 1H), 2.36 (s, 3H); LCMS (m / z): 316.52 (M- H)+; HPLC purity: 99.08%. Synthesis of 4-(2-(2-methoxyphenyl)-3-methyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin- 5-yl)benzonitrile (Compound 37) & 4-(2-(2-methoxyphenyl)-3-methyl-7-oxo-4,7- dihydropyrazolo[1,5-a]pyrimidin-5-yl)benzoic acid (Compound 39): Step-1: Synthesis of 3-(2-methoxyphenyl)-2-methyl-3-oxopropanenitrile (2) To a stirred solution of sodium hydride (60%) (228 mg, 2 eq., 5,71 mmol) at 0°C in DMF (10 mL), 3-(2-methoxyphenyl)-3-oxopropanenitrile (1) (500 mg, 2.85 mmol, 1 eq.) was added and the reaction mixture was stirred for 30 min. After 30 min. Iodomethane (0.18 ml, 2.85 mmol, 1 eq.) was added to the reaction mixture and allowed to stir at RT for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture quenched with ice water (10 mL) and aqueous layer was extracted with ethyl acetate (3x 15 mL). The combined organic layer was distilled under reduced pressure to afford desired compound 3-(2-methoxyphenyl)-2-methyl-3- oxopropanenitrile (2) (300 mg). The compound was used as such for the next reaction. LCMS (m / z): 190.2 (M+H)+. Step-2: Synthesis of 3-(2-methoxyphenyl)-4-methyl-1H-pyrazol-5-amine (3) To a stirred solution of 3-(2-methoxyphenyl)-2-methyl-3-oxopropanenitrile (2) (300 mg, 1.59 mmol, 1.0 eq) in MeOH (8 mL), N2H4.H2O (0.12 mL, 2.38 mmol, 1.5 eq.) was added dropwise at room temperature. Then reaction mixture was irradiated in microwave at 150°C for 30 min. After completion of the reaction on TLC, excess of solvent was distilled off under reduced pressure. The crude compound obtained was triturated with diethyl ether (5 mL) and pentane (10 mL) to afford desired product 3-(2-methoxyphenyl)-4-methyl-1H-pyrazol-5-amine (3) (200 mg). The compound was used as such for the next reaction. LCMS (m / z): 204.2 (M+H)+. Step-3: Synthesis of 4-(2-(2-methoxyphenyl)-3-methyl-7-oxo-4,7-dihydropyrazolo[1,5- a]pyrimidin-5-yl)benzonitrile (Compound 37): To a stirred solution of 3-(2-methoxyphenyl)-4-methyl-1H-pyrazol-5-amine (3) (200 mg, 0.98 mmol, 1.0 eq) in AcOH (6 mL), was added ethyl 3-(4-cyanophenyl)-3-oxopropanoate (4) (213 mg, 0.98 mmol, 1.0 eq) at room temperature. The reaction mixture was irradiated in microwave for 2 h at 150°C. After completion of the reaction, the reaction mixture was quenched with ice cold water (10 mL) and precipitated solid was filtered and washed with diethyl ether (10 mL) and purified by combi-flash (1-4% MeOH in DCM) to afford desired product Compound 37 (145 mg, 41.4% yield) as off-white solid.1H NMR (400 MHz, DMSO-d6): δ 12.19 (s, 1H), 8.08 (d, J = 8.00 Hz, 2H), 8.02 (d, J = 8.40 Hz, 2H), 7.46 (t, J = 7.20 Hz, 1H), 7.35 (d, J = 7.60 Hz, 1H), 7.16 (d, J = 8.40 Hz, 1H), 7.05 (t, J = 7.20 Hz, 1H), 6.02 (s, 1H), 3.79 (s, 3H), 2.05 (s, 3H), LCMS (m / z): 357.40 (M+H)+, HPLC purity: 98.48%. Step-4: Synthesis of 4-(2-(2-methoxyphenyl)-3-methyl-7-oxo-4,7-dihydropyrazolo[1,5- a]pyrimidin-5-yl)benzoic acid (Compound 39): To a stirred solution of Compound 37 (110 mg, 308 µmol, 1.0 eq) in EtOH (6 mL), a solution of NaOH (49 mg, 4 eq., 1.23 mmol) in distilled water (0.5 mL) was added and reaction mixture was stirred for overnight at 70 °C. After completion of the reaction on TLC, the reaction mixture was concentrated under reduced pressure to get crude compound. The crude compound was dissolved in water (15 mL) and washed with diethyl ether (20 mL). The aqueous layer was acidified with 1N HCl solution and solid obtained was filtered off and dried under high vacuum to afford desired product Compound 39 (40 mg, 34.5% yield) as off-white solid.1H NMR (400 MHz, DMSO-d6): δ 12.21 (s, 1H), 8.12 (d, J = 8.40 Hz, 2H), 7.95 (d, J = 8.40 Hz, 2H), 7.45-7.49 (m, 1H), 7.35-7.37 (m, 1H), 7.16 (d, J = 8.00 Hz, 1H), 7.06 (t, J = 7.60 Hz, 1H), 6.00 (s, 1H), 3.80 (s, 3H), 2.07 (s, 3H), LCMS (m / z): 376.39 (M+H)+, HPLC purity: 98.16%. Synthesis of 3-(7-oxo-2-(o-tolyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)benzonitrile (Compound 36) & 3-(7-oxo-2-(o-tolyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)benzoic acid (Compound 40): Step-1: Synthesis of 3-(o-Tolyl)-5-pyrazolylamine (2) To a stirred solution of (o-Toluoyl)acetonitrile (1) (500 mg, 3.14 mmol, 1.0 eq) in MeOH (10 mL), N2H4.H2O (0.42 mL, 6.28 mmol, 2.0 eq.) was added dropwise at room temperature. Then reaction mixture was irradiated in microwave at 150°C for 30 min. After completion of the reaction on TLC, excess of solvent was distilled off under reduced pressure thus crude compound obtained was triturated with diethyl ether (10 mL) and pentane (15 mL) to afford desired product 3-(o-Tolyl)-5- pyrazolylamine (2) (330 mg). The compound was used as such for the next reaction.1H NMR (400 MHz, DMSO-d6): δ 11.56 (s, 1H), 7.22-7.40 (m, 4H), 5.57 (s, 1H), 4.58 (s, 2H), 2.38 (s, 3H). Step-2: Synthesis of 3-(7-oxo-2-(o-tolyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzonitrile (Compound 36): To a stirred solution of 3-(o-Tolyl)-5-pyrazolylamine (2) (320 mg, 1.85 mmol, 1.0 eq) in AcOH (8 mL), was added ethyl 3-(4-cyanophenyl)-3-oxopropanoate (3) (401 mg, 1.85 mmol, 1.0 eq) at room temperature. The reaction mixture was irradiated in microwave for 2 h at 150°C. After completion of the reaction on TLC, the reaction mixture was quenched with ice cold water (15 mL) and precipitated solid was filtered on sintered funnel. The solid obtained was washed with diethyl ether (10 mL) and purified by combi-flash (1-5% MeOH in DCM) to afford desired product Compound 36 (170 mg, 28.2% yield) as off-white solid.1H NMR (400 MHz, DMSO-d6): δ 12.71 (s, 1H), 8.36 (s, 1H), 8.19 (d, J = 8.00 Hz, 1H), 8.07 (d, J = 7.60 Hz, 1H), 7.80 (t, J = 7.60 Hz, 1H), 7.65 (d, J = 6.80 Hz, 1H), 7.28-7.35 (m, 3H), 6.48 (s, 1H), 6.24 (s, 1H), 2.49 (s, 3H), LCMS (m / z): 327.1 (M+H)+, HPLC purity: 98.50%. Step-3: Synthesis of 3-(7-oxo-2-(o-tolyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)benzoic acid (Compound 40): To a stirred solution of Compound 36 (120 mg, 367 µmol, 1.0 eq) in EtOH (4 mL), a solution of NaOH (59 mg, 4 eq., 1.47 mmol) in distilled water (0.5 mL) was added and reaction mixture was stirred for overnight at 70 °C. After completion of the reaction on TLC, the reaction mixture was concentrated under reduced pressure to get crude compound. The crude compound dissolved in water (10 mL) and washed with diethyl ether (20 mL). The aqueous layer was separated and acidified with 1N HCl solution and obtain solid was filtered off then dried under high vacuum to afford desired product Compound 40 (81 mg, 63.7% yield) as off-white solid.1H NMR (400 MHz, DMSO-d6): δ 13.24 (s, 1H), 12.80 (s, 1H), 8.40 (s, 1H), 8.14 (t, J = 7.20 Hz, 2H), 7.73 (t, J = 7.60 Hz, 1H), 7.66 (d, J = 6.80 Hz, 1H), 7.29-7.35 (m, 3H), 6.48 (s, 1H), 6.17 (s, 1H), 2.51 (s, 3H), LCMS (m / z): 346.37 (M+H)+, HPLC purity: 99.14%. Synthesis of 4-(2-(2-chlorophenyl)-3-methyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzonitrile (Compound 41) & 4-(2-(2-chlorophenyl)-3-methyl-7-oxo-4,7- dihydropyrazolo[1,5-a]pyrimidin-5-yl)benzoic acid (Compound 42): Step-1: Synthesis of 2-methyl-3-oxo-3-(o-tolyl)propanenitrile (3) To a stirred solution of propanenitrile (388 mg, 7.06 mmol, 1.2 eq) and potassium tert-butoxide (990 mg, 8.82 mmol, 1.5 eq) in THF (15 mL) at 0°C methyl 2-chlorobenzoate (1) (1.0 g, 5.88 mmol, 1.0 eq) was added. The reaction mass was stirred at RT for 16 h. The progress of reaction was monitored by TLC. The reaction mass was neutralised by 1N HCl and extracted by ethyl acetate (3x 50 mL). The combined organic layer was distilled out under reduced pressure afford desired compound 3-(2-chlorophenyl)-2-methyl-3-oxopropanenitrile (3) (500 mg) without column purification.1H NMR (400 MHz, DMSO-d6): δ 7.84 (dd, J = 1.60, 8.00 Hz, 1H), 7.46-7.49 (m, 1H), 7.41-7.45 (m, 1H), 7.33 (dt, J = 1.60, 10.13 Hz, 1H), 4.43 (q, J = 7.20 Hz, 1H), 1.41-1.45 (m, 3H). Step-2: Synthesis of 3-(2-chlorophenyl)-4-methyl-1H-pyrazol-5-amine (4) To a stirred solution of 3-(2-chlorophenyl)-2-methyl-3-oxopropanenitrile (3) (500 mg, 2.59 mmol, 1.0 eq) MeOH (20 mL), N2H4.H2O (0.37 mL, 5.18 mmol, 2.0 eq) was added drop wise at room temperature, then reaction mixture was irradiated in microwave at 150 °C for 30 min. After completion of reaction excess of solvent was distill off under reduced pressure. Thus crude compound obtained was triturated with diethyl ether (10 mL) and pentane (20 mL) to afford desired product 3-(2-chlorophenyl)-4-methyl-1H-pyrazol-5-amine (4) (300 mg) without column purification. LCMS (m / z): 208.1 (M+H)+. Step-3: Synthesis of 4-(2-(2-chlorophenyl)-3-methyl-7-oxo-4,7-dihydropyrazolo[1,5- a]pyrimidin-5-yl)benzonitrile (Compound 41): To a stirred solution of 3-(2-chlorophenyl)-4-methyl-1H-pyrazol-5-amine (4) (100 mg, 0.48 mmol, 1.0 eq) in AcOH (3 mL) was added ethyl 3-(4-cyanophenyl)-3-oxopropanoate (105 mg, 0.48 mmol, 1.0 eq) at room temperature. The reaction mixture was irradiated in microwave for 2 h at 150°C. After completion of reaction, the reaction mixture was quenched with ice cold water thus precipitated solid was filtered and washed with diethyl ether (10 mL) and then dried under vacuum to get crude compound. Crude compound was purified by combi-flash (0-6% MeOH in DCM) to afford desired product Compound 41 (15 mg).1H NMR (400 MHz, CD3OD): δ 8.00 (d, J = 8.40 Hz, 2H), 7.93 (d, J = 8.00 Hz, 2H), 7.43-7.57 (m, 4H), 6.11 (s, 1H), 2.14 (s, 3H), LCMS (m / z): 359.1 (M-H)+, HPLC purity: 99.57%. Step-4: Synthesis of methyl 4-(2-(2-chlorophenyl)-3-methyl-7-oxo-4,7-dihydropyrazolo[1,5- a]pyrimidin-5-yl)benzoate (7) To a stirred solution of 3-(2-chlorophenyl)-4-methyl-1H-pyrazol-5-amine (4) (200 mg, 0.96 mmol, 1.0 eq) in AcOH (6 mL), was added methyl 4-(3-ethoxy-3-oxopropanoyl)benzoate (6) (241 mg, 0.96 mmol, 1.0 eq) at room temperature. The reaction mixture was irradiated in microwave for 2 h at 150°C. After completion of reaction, reaction mixture was quenched with ice cold water thus precipitated solid was filtered and washed with diethyl ether (10 mL) and then dried under vacuum to get crude compound. Crude compound was purified by combi-flash (2-5% MeOH in DCM) to afford desired product methyl 4-(2-(2-chlorophenyl)-3-methyl-7-oxo-4,7-dihydropyrazolo[1,5- a]pyrimidin-5-yl)benzoate (7) (100 mg). LCMS (m / z): 392.1 (M+H)+. Step-5: Synthesis of 4-(2-(2-chlorophenyl)-3-methyl-7-oxo-4,7-dihydropyrazolo[1,5- a]pyrimidin-5-yl)benzoic acid (Compound 42): To a stirred solution of 4-(2-(2-chlorophenyl)-3-methyl-7-oxo-4,7-dihydropyrazolo[1,5- a]pyrimidin-5-yl)benzonitrile (7) (100 mg, 254 µmol, 1.0 eq) in MeOH (3 mL) and THF (3 mL), a solution of NaOH (40 mg, 1.16 mmol, 4.0 eq) in distilled water (1 mL) was added and reaction mixture was stirred for overnight at rt. After the completion of the reaction, the mixture was concentrated under reduced pressure and crude dissolved in water (10 mL) and then washed with diethyl ether (20 mL). The aqueous layer was acidified with 1N HCl solution thus solid obtained was filtered off to afford Compound 42 (8 mg).1H NMR (400 MHz, DMSO-d6): δ 13.31 (s, 1H), 12.33 (s, 1H), 8.12 (d, J = 8.40 Hz, 2H), 7.96 (d, J = 8.40 Hz, 2H), 7.63 (d, J = 8.00 Hz, 1H), 7.48- 7.54 (m, 3H), 6.04 (s, 1H), 2.09 (s, 3H), LCMS (m / z): 380.1 (M-H)+, HPLC purity: 99.84% Synthesis of 4-(3-methyl-7-oxo-2-(o-tolyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzonitrile (Compound 43) & 4-(3-methyl-7-oxo-2-(o-tolyl)-4,7-dihydropyrazolo[1,5- a]pyrimidin-5-yl)benzoic acid (Compound 47): Step-1: Synthesis of 2-methyl-3-oxo-3-(o-tolyl)propanenitrile (3) To the stirred solution of propanenitrile (176 mg, 3.20 mmol, 1.2 eq) and potassium tert-butoxide (448 mg, 3.99 mmol, 1.5 eq) in THF (10 mL) at 0°C, methyl 2-methylbenzoate (400 mg, 2.67 mmol, 1.0 eq) was added. The reaction mixture was stirred at RT for 16 h. The completion of reaction was monitored by TLC. After completion of reaction, the reaction mass was neutralised by 1N HCl and extracted by ethyl acetate (3x 20 mL). The combined organic layer distilled off under reduced pressure afford desired compound 2-methyl-3-oxo-3-(o-tolyl)propanenitrile (340 mg) without column purification.1H NMR (400 MHz, DMSO-d6): δ 9.78 (s, 1H), 7.39-7.44 (m, 2H), 7.27-7.32 (m, 2H), 2.68 (m, 1H), 2.37 (s, 3H), 1.80 (s, 3H). Step-2: Synthesis of 4-methyl-3-(o-tolyl)-1H-pyrazol-5-amine (4) To a stirred solution of 2-methyl-3-oxo-3-(o-tolyl)propanenitrile (340 mg, 1.96 mmol, 1.0 eq) MeOH (20 mL), and N2H4.H2O (0.28 mL, 3.91 mmol, 2.0 eq) was added drop wise at room temperature. Now reaction mixture was irradiated in microwave at 150 °C for 30 min. After completion of reaction excess of solvent was distill off under reduced pressure. Thus crude compound obtained was triturated with diethyl ether (10 mL) and pentane (15 mL) to get crude compound. The crude compound was purified by combi-flash (2-5% MeOH in DCM) to afford desired product 4-methyl-3-(o-tolyl)-1H-pyrazol-5-amine (310 mg).1H NMR (400 MHz, DMSO- d6): δ 11.28 (s, 1H), 7.16-7.29 (m, 4H), 4.40 (s, 2H), 4.12 (q, J = 5.20 Hz, 1H), 3.18 (d, J = 5.20 Hz, 3H), 2.20 (s, 3H). Step-3: Synthesis of 4-(3-methyl-7-oxo-2-(o-tolyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzonitrile (Compound 43): To a stirred solution of 4-methyl-3-(o-tolyl)-1H-pyrazol-5-amine (310 mg, 1.65 mmol, 1.0 eq) in AcOH (4 mL) was added ethyl 3-(4-cyanophenyl)-3-oxopropanoate (256 mg, 1.65 mmol, 1.0 eq) at room temperature. The reaction mixture was irradiated in microwave for 2 h at 150°C. After completion of reaction, the reaction mixture was quenched with ice cold water (15 mL) thus precipitated solid was filtered and washed with diethyl ether (10 mL) and then dried under vacuum to get crude compound. The crude compound was purified by combi-flash (2-8% MeOH in DCM) to afford desired product Compound 43 (270 mg).1H NMR (400 MHz, DMSO-d6): δ 12.30 (s, 1H), 8.10 (d, J = 8.40 Hz, 2H), 8.04 (d, J = 8.00 Hz, 2H), 7.36-7.39 (m, 2H), 7.29-7.31 (m, 2H), 6.07 (s, 1H), 2.24 (s, 3H), 2.07 (s, 3H), LCMS (m / z): 341.39 (M+H)+, HPLC purity: 96.26%. Step-4: Synthesis of 4-(3-methyl-7-oxo-2-(o-tolyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzoic acid (Compound 47): To a stirred solution of Compound 43 (200 mg, 586 µmol, 1.0 eq) in EtOH (5 mL), a solution of NaOH (117 mg, 5 eq., 2.93 mmol) in distilled water (1 mL) was added and reaction mixture was stirred for overnight at 100 °C. After the completion of the reaction, the mixture was concentrated under reduced pressure and crude dissolved in water (10 mL) and then washed with diethyl ether (20 mL). The aqueous layer was acidified with 1N HCl solution thus solid obtained was filtered off to afford Compound 47 (200 mg).1H NMR (400 MHz, DMSO-d6): δ 13.30 (s, 1H), 12.28 (s, 1H), 8.13 (d, J = 8.00 Hz, 2H), 7.96 (d, J = 8.00 Hz, 2H), 7.37-7.38 (m, 2H), 7.30-7.31 (m, 2H), 6.03 (s, 1H), 2.24 (s, 3H), 2.08 (s, 3H), LCMS (m / z): 358.68 (M-H)+, HPLC purity: 96.88%. Synthesis of 3-(3-methyl-7-oxo-2-(o-tolyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzonitrile (Compound 44) & 3-(3-methyl-7-oxo-2-(o-tolyl)-4,7-dihydropyrazolo[1,5- a]pyrimidin-5-yl)benzoic acid (Compound 48): Step-1: Synthesis of 2-methyl-3-oxo-3-(o-tolyl)propanenitrile (3) To stirred a solution of propanenitrile (176 mg, 1.2 eq., 3.20 mmol) and potassium tert-butoxide (448 mg, 1.5 eq., 3.99 mmol) in THF (15 mL) at 0°C methyl 2-methylbenzoate (400 mg, 2.67 mmol, 1.0 eq.) was added in the reaction mixture. The reaction mass was stirred at RT for 16 h. The completion of reaction was monitored by TLC. According to analytical data desired product was formed. The reaction mass was neutralised by 1N HCl and extracted by ethyl acetate (3x 20 mL). The combined organic layer distilled off under reduced pressure to afford desired compound 2-methyl-3-oxo-3-(o-tolyl)propanenitrile (240 mg) without column purification.1H NMR (400 MHz, DMSO-d6): δ 9.78 (s, 1H), 7.39-7.44 (m, 2H), 7.27-7.32 (m, 2H), 2.68 (m, 1H), 2.37 (s, 3H), 1.80 (s, 3H). Step-2: Synthesis of 4-methyl-3-(o-tolyl)-1H-pyrazol-5-amine (4) To a stirred solution of 2-methyl-3-oxo-3-(o-tolyl)propanenitrile (240 mg, 1.38 mmol, 1.0 eq) MeOH (20 mL), and N2H4.H2O (0.2 mL, 2.77 mmol, 2.0 eq) was added drop wise at room temperature. Now reaction mixture was irradiated in microwave at 150 °C for 30 min. After completion of reaction excess of solvent was distill off under reduced pressure. Thus crude compound obtained was triturated with diethyl ether (10 mL) and pentane (15 mL) to afford desired product 4-methyl-3-(o-tolyl)-1H-pyrazol-5-amine (150 mg) without column purification.1H NMR (400 MHz, DMSO-d6): δ 11.28 (s, 1H), 7.16-7.29 (m, 4H), 4.40 (s, 2H), 4.12 (q, J = 5.20 Hz, 1H), 3.18 (d, J = 5.20 Hz, 3H), 2.20 (s, 3H). Step-3: Synthesis of 3-(3-methyl-7-oxo-2-(o-tolyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzonitrile (Compound 44): To a stirred solution of 4-methyl-3-(o-tolyl)-1H-pyrazol-5-amine (150 mg, 0.80 mmol, 1.0 eq) in AcOH (4 mL), was added ethyl 3-(3-cyanophenyl)-3-oxopropanoate (174 mg, 0.80 mmol, 1.0 eq) at room temperature. The reaction mixture was irradiated in microwave for 2 h at 150°C. After completion of reaction, reaction mixture was quenched with ice cold water, precipitated solid was filtered and washed with diethyl ether and then dried under vacuum to get crude compound. Crude compound was purified by combi-flash to afford desired product Compound 44 (112 mg).1H NMR (400 MHz, DMSO-d6): δ 12.23 (s, 1H), 8.36 (s, 1H), 8.18 (d, J = 7.60 Hz, 1H), 8.08 (d, J = 8.00 Hz, 1H), 7.80 (t, J = 7.60 Hz, 1H), 7.36-7.39 (m, 2H), 7.30-7.31 (m, 2H), 6.09 (s, 1H), 2.24 (s, 3H), 2.08 (s, 3H), LCMS (m / z): 341.42 (M+H)+, HPC purity: 94.34% Step-4: Synthesis of 3-(3-methyl-7-oxo-2-(o-tolyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzoic acid (Compound 48): To a stirred solution of Compound 44 (100 mg, 293 µmol, 1.0 eq) in EtOH (5 mL), a solution of NaOH (59 mg, 5 eq., 1.47 mmol) in distilled water (1 mL) was added and reaction mixture was stirred at 100 °C for 14 h. After the completion of the reaction, the mixture was concentrated under reduced pressure and crude dissolved in water (10 mL) and then washed with diethyl ether (20 mL). The aqueous layer was acidified with 1N HCl solution thus solid obtained was filtered off and dried under high vacuum to afford Compound 48 (20 mg).1H NMR (400 MHz, DMSO-d6): δ 13.36 (s, 1H), 12.28 (s, 1H), 8.35 (s, 1H), 8.15 (d, J = 7.60 Hz, 1H), 8.08 (d, J = 8.00 Hz, 1H), 7.73 (t, J = 8.00 Hz, 1H), 7.37-7.38 (m, 2H), 7.30-7.30 (m, 2H), 6.00 (s, 1H), 2.25 (s, 3H), 2.08 (s, 3H), LCMS (m / z): 360.2 (M+H)+, HPLC purity: 99.64%. Synthesis of 5-(3-(1H-tetrazol-5-yl)phenyl)-3-methyl-2-phenylpyrazolo[1,5-a]pyrimidin- 7(4H)-one (Compound 45):

[0010] Step-1: Synthesis of 2-methyl-3-oxo-3-phenylpropanenitrile (2) To a stirred solution of sodium hydride (60%) (551 mg, 13.78 mmol, 2 eq.) at 0°C in DMF (8 mL), 3-oxo-3-phenylpropanenitrile (1 g, 6.89 mmol, 1 eq.) was added and the reaction mixture was stirred for 30 min. After 30 min. Iodomethane (0.43 ml, 6.89 mmol, 1 eq.) was added to the reaction mixture and allowed to stir at RT for 1 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3x 15 mL). The combined organic layer was distilled under reduced pressure to afford desired compound 2-methyl-3-oxo-3-phenylpropanenitrile (390 mg). The compound was used as such for the next reaction.1H NMR (400 MHz, DMSO-d6): δ 8.02-8.04 (m, 2H), 7.73-7.75 (m, 1H), 7.59-7.62 (m, 2H), 5.16 (q, J = 7.20 Hz, 1H), 1.48 (d, J = 7.20 Hz, 3H). Step-2: Synthesis of 4-methyl-3-phenyl-1H-pyrazol-5-amine (3) To a stirred solution of 2-methyl-3-oxo-3-phenylpropanenitrile (380 g, 2.39 mmol, 1.0 eq) in MeOH (7 mL), N2H4.H2O (0.32 mL, 4.77 mmol, 2.0 eq) was added dropwise at room temperature. Then reaction mixture was irradiated in microwave at 150°C for 30 min. After completion of the reaction, excess of solvent was distilled off under reduced pressure thus crude compound obtained was triturated with diethyl ether (5 mL) and pentane (10 mL) to afford desired product 4-methyl-3- phenyl-1H-pyrazol-5-amine (210 mg). The compound was used as such for the next reaction. LCMS (m / z): 178.2 (M+H)+. Step-3: Synthesis of 3-(3-methyl-7-oxo-2-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzonitrile (Compound 26): To a stirred solution of 4-methyl-3-phenyl-1H-pyrazol-5-amine (210 mg, 1.19 mmol, 1.0 eq) in AcOH (5 mL), was added ethyl 3-(3-cyanophenyl)-3-oxopropanoate (257 mg, 1.19 mmol, 1.0 eq) at room temperature. The reaction mixture was irradiated in microwave for 2 h at 150°C. After completion of the reaction, the reaction mixture was quenched with ice cold water (10 mL) thus precipitated solid was filtered and washed with diethyl ether (10 mL) and purified by combi-flash (1-5% MeOH in DCM) to afford desired product Compound 26 (119 mg, 30.1% yield) as off-white solid.1H NMR (400 MHz, DMSO-d6): δ 12.17 (s, 1H), 8.36 (s, 1H), 8.17 (d, J = 7.60 Hz, 1H), 8.09 (d, J = 7.20 Hz, 1H), 7.80 (d, J = 6.40 Hz, 3H), 7.47-7.53 (m, 3H), 6.09 (s, 1H), 2.38 (s, 3H), LCMS (m / z): 327.1 (M+H)+, HPLC purity: 96.69%. Step-4: Synthesis of 5-(3-(1H-tetrazol-5-yl)phenyl)-3-methyl-2-phenylpyrazolo[1,5- a]pyrimidin-7(4H)-one (Compound 45): To a stirred solution of Compound 26 (115 mg, 352 µmol, 1.0 eq) in DMF (5 mL) was added NaN3 (275 mg, 12 eq., 4.23 mmol). After that NH4Cl (226 mg, 12 eq., 4.23 mmol) was added to above reaction mixture and irradiated in microwave for 30 min at 120 °C. After completion of the reaction on TLC, the reaction mixture was quenched with water (15 mL) and extracted with EtOAc (3x 25 mL). Organic layer was separated and concentrated under reduced pressure to get crude compound. The crude compound was purified by combi-flash (2-10% MeOH in DCM) to afford desired product Compound 45 (43 mg, 33.07% yield).1H NMR (400 MHz, DMSO-d6): δ 12.27 (s, 1H), 8.46 (s, 1H), 8.26 (d, J = 7.60 Hz, 1H), 8.08 (d, J = 8.00 Hz, 1H), 7.79-7.83 (m, 3H), 7.53 (t, J = 7.2 Hz, 2H), 7.46 (t, J = 7.2 Hz, 1H), 6.53 (s, 1H), 6.05 (s, 1H), 2.39 (s, 3H), LCMS (m / z): 370.29 (M+H)+, HPLC purity: 98.47%. Synthesis of 3-(2-(2-chlorophenyl)-3-methyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzoic acid (Compound 50): Step-1: Synthesis of 2-methyl-3-oxo-3-(o-tolyl)propanenitrile (3) To a stirred solution of propanenitrile (196 mg, 3.52 mmol, 1.2 eq) and potassium tert-butoxide (493 mg, 4.39 mmol, 1.5 eq) in THF (15 mL) at 0°C methyl 2-chlorobenzoate (500 mg, 2.93 mmol, 1.0 eq.) was added. The reaction mass was stirred at RT for 16 h. The progress of reaction was monitored by TLC. After completion of reaction on TLC, the reaction mixture was neutralised by 1N HCl and extracted by ethyl acetate (3x 30 mL). The combined organic layer was distilled off under reduced pressure to afford desired compound 3-(2-chlorophenyl)-2-methyl-3- oxopropanenitrile (256 mg). The compound was used as such in the next reaction.1H NMR (400 MHz, DMSO-d6): δ 7.84 (dd, J = 1.60, 8.00 Hz, 1H), 7.46-7.49 (m, 1H), 7.41-7.45 (m, 1H), 7.33 (dt, J = 1.60, 10.13 Hz, 1H), 4.43 (q, J = 7.20 Hz, 1H), 1.41-1.45 (t, J = 7.20 Hz, 3H). Step-2: Synthesis of 3-(2-chlorophenyl)-4-methyl-1H-pyrazol-5-amine (4) To a stirred solution of 3-(2-chlorophenyl)-2-methyl-3-oxopropanenitrile (250 mg, 1.29 mmol, 1.0 eq) MeOH (8 mL), N2H4.H2O (0.17 mL, 2.58 mmol, 2.0 eq) was added drop wise at room temperature, then reaction mixture was irradiated in microwave at 150 °C for 30 min. After completion of reaction, excess of solvent was distilled off under reduced pressure. Thus crude compound obtained was triturated with diethyl ether (5 mL) and pentane (10 mL) to afford desired product 3-(2-chlorophenyl)-4-methyl-1H-pyrazol-5-amine (155 mg). The compound was used as such in the next reaction. LCMS (m / z): 208.1 (M+H)+. Step-3: Synthesis of 3-(2-(2-chlorophenyl)-3-methyl-7-oxo-4,7-dihydropyrazolo[1,5- a]pyrimidin-5-yl)benzonitrile (6): To a stirred solution of 3-(2-chlorophenyl)-4-methyl-1H-pyrazol-5-amine (150 mg, 0.72 mmol, 1.0 eq) in AcOH (5 mL) was added ethyl 3-(3-cyanophenyl)-3-oxopropanoate (157 mg, 0.72 mmol, 1.0 eq) at room temperature. The reaction mixture was irradiated in microwave for 2 h at 150°C. After completion of reaction, the reaction mixture was quenched with ice cold water (10 mL) thus precipitated solid was filtered and washed with diethyl ether (10 mL) and then dried under vacuum to get crude compound. The crude compound was purified by combi-flash (0-5% MeOH in DCM) to afford desired product 3-(2-(2-chlorophenyl)-3-methyl-7-oxo-4,7- dihydropyrazolo[1,5-a]pyrimidin-5-yl)benzonitrile (124 mg, 47.58% yield).1H NMR (400 MHz, CD3OD): δ 8.00 (d, J = 8.40 Hz, 2H), 7.93 (d, J = 8.00 Hz, 2H), 7.43-7.57 (m, 4H), 6.11 (s, 1H), 2.14 (s, 3H), LCMS (m / z): 359.1 (M-H)+, HPLC purity: 99.57%. Step-4: Synthesis of 3-(2-(2-chlorophenyl)-3-methyl-7-oxo-4,7-dihydropyrazolo[1,5- a]pyrimidin-5-yl)benzoic acid (Compound 50): To a stirred solution of 3-(2-(2-chlorophenyl)-3-methyl-7-oxo-4,7-dihydropyrazolo[1,5- a]pyrimidin-5-yl)benzonitrile (6) (120 mg, 332 µmol, 1.0 eq) in EtOH (6 mL), a solution of NaOH (66 mg, 1.66 mmol, 5.0 eq) in distilled water (1 mL) was added and reaction mixture was stirred for overnight at 90°C. After the completion of the reaction, the mixture was concentrated under reduced pressure and crude dissolved in water (10 mL) and then washed with diethyl ether (20 mL). The aqueous layer was separated and acidified with 1N HCl solution thus solid obtained was filtered off and dried under high vacuum to afford Compound 50 (48 mg, 38.06% yield).1H NMR (400 MHz, DMSO-d6): δ 13.32 (brs, 1H), 12.35 (s, 1H), 8.35 (s, 1H), 8.16 (d, J = 7.60 Hz, 1H), 8.08 (d, J = 8.00 Hz, 1H), 7.73 (t, J = 8.00 Hz, 1H), 7.63 (d, J = 7.60 Hz, 1H), 7.48-7.54 (m, 3H), 6.02 (s, 1H), 2.10 (s, 3H), LCMS (m / z): 380.48 (M-H)+, HPLC purity: 99.68% Synthesis of 3-(3-methyl-2-(naphthalen-1-yl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzonitrile (Compound 55) & 3-(3-methyl-2-(naphthalen-1-yl)-7-oxo-4,7- dihydropyrazolo[1,5-a]pyrimidin-5-yl)benzoic acid (Compound 58): Step-1: Synthesis of 2-methyl-3-(naphthalen-1-yl)-3-oxopropanenitrile (3) To a stirred solution of propiononitrile (220 mg, 1 eq., 4.0 mmol) in THF (15 mL) was added n- BuLi (2.5 mL, 4.0 mmol, 1.0 eq) at -78°C and reaction mixture was stirred for 30 min at same temperature. After that a solution of ethyl 1-naphthoate (800 mg, 4.0 mmol, 1.0 eq.) in THF (5 mL) at same temperature was added and reaction mixture was allowed to stirr for 60 min. Progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quench with saturated NH4Cl solution (10 mL) and extracted with ethyl acetate (3x 20 mL). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to get the crude. The crude compound was purified by column chromatography (0-30% Ethyl acetate in hexane) to afford desired compound 2-methyl-3-(naphthalen-1-yl)-3-oxopropanenitrile (300 mg) as a yellow liquid.1H NMR (400 MHz, DMSO-d6): δ 8.59 (d, J = 8.40 Hz, 1H), 8.11 (d, J = 8.40 Hz, 1H), 7.96-7.93 (m, 2H), 7.70-7.67 (m, 1H), 7.63-7.56 (m, 2H), 4.51 (q, J = 7.20 Hz, 1H), 1.67 (d, J = 18.40 Hz, 3H). Step-2: Synthesis of 4-methyl-3-(naphthalen-1-yl)-1H-pyrazol-5-amine (4) To a stirred solution of 2-methyl-3-(naphthalen-1-yl)-3-oxopropanenitrile (300 mg, 1.43 mmol, 1.0 eq) in MeOH (20 mL), N2H4.H2O (0.2 mL, 2.86 mmol, 2.0 eq) was added dropwise at room temperature. Now the reaction mixture was irradiated in microwave at 150°C for 30 min. After completion of reaction, excess of solvent was distilled off under reduced pressure. Thus crude compound obtained was triturated with diethyl ether (10 mL) and pentane (20 mL) to afford desired product 4-methyl-3-(naphthalen-1-yl)-1H-pyrazol-5-amine (250 mg) without column purification. LCMS (m / z): 224.25 (M+H)+. Step-3: Synthesis of 3-(3-methyl-2-(naphthalen-1-yl)-7-oxo-4,7-dihydropyrazolo[1,5- a]pyrimidin-5-yl)benzonitrile (Compound 55): To a stirred solution of 4-methyl-3-(naphthalen-1-yl)-1H-pyrazol-5-amine (250 mg, 1.11 mmol, 1.0 eq) in AcOH (5 mL) was added ethyl 3-(3-cyanophenyl)-3-oxopropanoate (242 mg, 1.11 mmol, 1.0 eq) at room temperature. Then the reaction mixture was irradiated in microwave for 2 h at 150°C. After completion of reaction, the reaction mixture was quenched with ice cold water (15 mL) thus precipitated solid was filtered and washed with diethyl ether (10 mL) and then dried under vacuum to afford crude compound. The crude compound was purified by flash-chromatography (0-8% MeOH in DCM) to afford desired compound Compound 55 (120 mg). Analytical Data:1H NMR (400 MHz, DMSO-d6): δ 12.30 (brs, 1H), 8.39 (s, 1H), 8.22 (d, J = 7.6 Hz, 1H), 8.03 (t, J = 7.2 Hz, 3H), 7.91 (d, J =7.6 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 6.8 Hz, 1H), 7.55-7.51 (m, 2H), 2.07 (s, 3H), LCMS (m / z): 377.45 (M+H)+. Step-4: Synthesis of 3-(3-methyl-2-(naphthalen-1-yl)-7-oxo-4,7-dihydropyrazolo[1,5- a]pyrimidin-5-yl)benzoic acid (Compound 58): To a stirred solution of Compound 55 (100 mg, 265 µmol, 1.0 eq) in EtOH (5 mL), a solution of NaOH (52 mg, 5 eq., 1.32 mmol) in distilled water (0.5 mL) was added and the reaction mixture was stirred at 100 °C for 14 h. After completion of the reaction, the mixture was concentrated under reduced pressure and crude was dissolved in water (10 mL) and then washed with diethyl ether (20 mL). The aqueous layer was separated and acidified with 1N HCl solution thus solid obtained was filtered off and dried under high vacuum to afford desired product Compound 58 (35 mg).1H NMR (400 MHz, DMSO-d6): δ 13.37 (brs, 1H), 12.37 (brs, 1H), 8.37 (s, 1H), 8.17 (d, J = 7.6 Hz, 1H), 8.13-8.03 (m, 3H), 7.90 (d, J =8.0 Hz, 1H), 7.75 (t, J = 7.6 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.60- 7.52 (m, 3H), 2.08 (s, 3H), LCMS (m / z): 396.4 (M+H)+. Synthesis of 4-(2-(2-(difluoromethoxy)phenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin- 5-yl)benzonitrile (Compound 56) & 4-(2-(2-(difluoromethoxy)phenyl)-3-methyl-7-oxo-4,7- dihydropyrazolo[1,5-a]pyrimidin-5-yl)benzoic acid (Compound 60): Step-1: Synthesis of 3-(2-(difluoromethoxy)phenyl)-2-methyl-3-oxopropanenitrile (3) To a stirred solution of propiononitrile (136 mg, 1 eq., 2.47 mmol) in THF (15 mL) was added n- BuLi (1.54 mL, 2.47 mmol, 1.0 eq) at -78°C and reaction mixture was stirred for 30 min at same temperature. After that a solution of methyl 2-(difluoromethoxy)benzoate (500 mg, 2.47 mmol, 1.0 eq.) in THF (5 mL) at same temperature was added and reaction mixture was allowed to stirred for 4 h. Progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with saturated NH4Cl solution and extracted with ethyl acetate (3x 20 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford desired compound 3-(2-(difluoromethoxy)phenyl)-2-methyl-3-oxopropanenitrile (180 mg) without column purification.1H NMR (400 MHz, DMSO-d6): δ 11.01 (s, 1H), 7.57-7.53 (m, 1H), 7.47 (dd, J = 1.60, 7.20 Hz, 1H), 7.40-7.26 (m, 2H), 1.83 (s, 3H). LCMS (m / z): 224.1 (M-H)+. Step-2: Synthesis of 3-(2-(difluoromethoxy)phenyl)-4-methyl-1H-pyrazol-5-amine (4) To a stirred solution of 3-(2-(difluoromethoxy)phenyl)-2-methyl-3-oxopropanenitrile in (180 mg, 0.80 mmol, 1.0 eq) MeOH (20 mL), and N2H4.H2O (0.11 mL, 1.60 mmol, 2.0 eq) was added drop wise at room temperature. Now reaction mixture was irradiated in microwave at 150°C for 30 min. After completion of reaction, excess of solvent was distill off under reduced pressure, thus crude compound obtained was triturated with diethyl ether (10 mL) and pentane (15 mL) to afford desired product 3-(2-(difluoromethoxy)phenyl)-4-methyl-1H-pyrazol-5-amine (120 mg) without column purification.1H NMR (400 MHz, DMSO-d6): δ 11.41 (s, 1H), 7.45 (t, J = 7.60 Hz, 1H), 7.38 (dd, J = 1.60, 7.60 Hz, 1H), 7.32-7.25 (m, 2H), 4.45 (s, 2H), 1.76 (s, 3H). Step-3: Synthesis of 4-(2-(2-(difluoromethoxy)phenyl)-3-methyl-7-oxo-4,7- dihydropyrazolo[1,5-a] pyrimidin-5-yl)benzonitrile (Compound 56): To a stirred solution of 3-(2-(difluoromethoxy)phenyl)-4-methyl-1H-pyrazol-5-amine (120 mg, 0.50 mmol, 1.0 eq) in AcOH (3 mL), was added ethyl 3-(4-cyanophenyl)-3-oxopropanoate (109 mg, 0.50 mmol, 1.0 eq) at room temperature. The reaction mixture was irradiated in microwave for 2 h at 150°C. After completion of reaction, reaction mixture was quenched with ice cold water (15 mL) thus precipitated solid was filtered and washed with diethyl ether (10 mL) and then dried under high vacuum to afford crude compound. The crude compound was purified by flash- chromatography (0-5% MeOH in DCM) to afford desired product Compound 56 (90 mg). Analytical Data:1H NMR (400 MHz, DMSO-d6): δ 12.30 (s, 1H), 8.09 (d, J = 8.40 Hz, 2H), 8.04 (d, J = 8.40 Hz, 2H), 7.58-7.53 (m, 2H), 7.43-7.34 (m, 2H), 2.11 (s, 3H), LCMS (m / z): 393.2 (M+H)+, HPLC purity: 99.76%. Step-4: Synthesis of 4-(2-(2-(difluoromethoxy)phenyl)-3-methyl-7-oxo-4,7- dihydropyrazolo[1,5-a]pyrimidin-5-yl)benzoic acid (Compound 60): To a stirred solution of Compound 56 (60 mg, 153 µmol, 1.0 eq) in EtOH (3 mL), a solution of NaOH (31 mg, 5 eq., 765 µmol) in distilled water (0.5 mL) was added and reaction mixture was stirred for overnight at 100 °C. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and crude dissolved in water (10 mL) and then washed with diethyl ether (20 mL). The aqueous layer was separated and acidified with 1N HCl solution thus solid obtained was filtered off and dried under high vacuum to afford Compound 60 (10 mg).1H NMR (400 MHz, DMSO-d6): δ 13.31 (s, 1H), 12.29 (s, 2H), 8.12 (d, J = 8.40 Hz, 2H), 7.97 (d, J = 8.00 Hz, 2H), 7.60-7.53 (m, 1H), 7.41-7.26 (m, 2H), 7.01-6.93 (m, 1H), 6.05 (d, J = 10.00 Hz, 1H), 2.30-2.11 (m, 3H), LCMS (m / z): 412.29 (M+H)+, HPLC purity: 99.80%. Synthesis of 4-(2-(2,3-dihydrobenzofuran-7-yl)-3-methyl-7-oxo-4,7-dihydropyrazolo[1,5- a]pyrimidin-5-yl)benzonitrile (Compound 57) & 4-(2-(2,3-dihydrobenzofuran-7-yl)-3- methyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)benzoic acid (Compound 61):

[0011] Step-1: Synthesis of 3-(2,3-dihydrobenzofuran-7-yl)-2-methyl-3-oxopropanenitrile (3) To a stirred solution of propiononitrile (309 mg, 1 eq., 5.61 mmol) in THF (20 mL) was added n- BuLi (3.5 mL, 5.61 mmol, 1.0 eq) at -78°C and reaction mixture was stirred for 30 min at same temperature. After that a solution of methyl 2,3-dihydrobenzofuran-7-carboxylate (1.0 g, 5.61 mmol, 1.0 eq.) in THF (15 mL) at same temperature was added and reaction mixture was allowed to stir for 4 h. Progress of the reaction was monitored by TLC. After completion of reaction, reaction mixture was quench with saturated NH4Cl solution and extracted with ethyl acetate (3x 30 mL). The organic layer was dried over Na2SO4and concentrated under reduced pressure to afford desired compound 3-(2,3-dihydrobenzofuran-7-yl)-2-methyl-3-oxopropanenitrile (500 mg) without column purification.1H NMR (400 MHz, DMSO-d6): δ 7.75 (d, J = 8.00 Hz, 1H), 7.45 (dd, J = 0.80, 7.20 Hz, 1H), 6.97 (t, J = 7.60 Hz, 1H), 4.81-4.75 (m, 2H), 4.65 (q, J = 7.20 Hz, 1H), 3.31 (t, J = 8.80 Hz, 2H), 1.60 (d, J = 7.20 Hz, 3H). Step-2: Synthesis of 3-(2,3-dihydrobenzofuran-7-yl)-4-methyl-1H-pyrazol-5-amine (4) To a stirred solution of 3-(2,3-dihydrobenzofuran-7-yl)-2-methyl-3-oxopropanenitrile (500 mg, 0.89 mmol, 1.0 eq) in MeOH (20 mL), and N2H4.H2O (0.13 mL, 1.78 mmol, 2.0 eq) was added drop wise at room temperature. Now the reaction mixture was irradiated in microwave at 150°C for 30 min. After completion of reaction, excess of solvent was distilled off under reduced pressure. Thus crude compound obtained was triturated with diethyl ether (10 mL) and pentane (20 mL) to afford desired product 3-(2,3-dihydrobenzofuran-7-yl)-4-methyl-1H-pyrazol-5-amine (200 mg) without column purification.1H NMR (400 MHz, DMSO-d6): δ 10.07 (s, 1H), 7.46 (d, J = 8.40 Hz, 1H), 7.19 (dd, J = 1.20, 7.40 Hz, 1H), 6.97 (t, J = 7.60 Hz, 1H), 4.71 (t, J = 8.80 Hz, 1H), 3.58 (s, 2H), 3.30 (t, J = 8.80 Hz, 2H), 2.19 (s, 3H). Step-3: Synthesis of 4-(2-(2,3-dihydrobenzofuran-7-yl)-3-methyl-7-oxo-4,7- dihydropyrazolo[1,5-a]pyrimidin-5-yl)benzonitrile (Compound 57): To a stirred solution of 3-(2,3-dihydrobenzofuran-7-yl)-4-methyl-1H-pyrazol-5-amine (200 mg, 0.93 mmol, 1.0 eq) in AcOH (5 mL), was added ethyl 3-(4-cyanophenyl)-3-oxopropanoate (202 mg, 0.93 mmol, 1.0 eq) at room temperature. The reaction mixture was irradiated in microwave for 2 h at 150°C. After completion of reaction, reaction mixture was quenched with ice cold water, then precipitated solid was filtered and washed with diethyl ether (10 mL) and then dried under vacuum to afford crude compound. The crude compound was purified by flash-chromatography (2 – 8% MeOH in DCM) to afford desired product Compound 57 (110 mg).1H NMR (400 MHz, DMSO-d6): δ 12.22 (s, 1H), 8.09 (d, J = 8.40 Hz, 2H), 8.03 (d, J = 8.40 Hz, 2H), 7.34 (d, J = 7.20 Hz, 1H), 7.26 (d, J = 7.60 Hz, 1H), 6.95 (t, J = 7.60 Hz, 1H), 6.04 (s, 1H), 4.57 (t, J = 8.40 Hz, 2H), 3.26 (t, J = 8.80 Hz, 2H), 2.16 (s, 3H), LCMS (m / z): 369.37 (M+H)+, HPLC purity: 98.05%. Step-4: Synthesis of 4-(2-(2,3-dihydrobenzofuran-7-yl)-3-methyl-7-oxo-4,7- dihydropyrazolo[1,5-a]pyrimidin-5-yl)benzoic acid (Compound 61): To a stirred solution of Compound 57 (100 mg, 271 µmol, 1.0 eq) in EtOH (3 mL), a solution of NaOH (54 mg, 5 eq., 1.36 mmol) in distilled water (0.5 mL) was added and reaction mixture was stirred for overnight at 100 °C. After the completion of the reaction, the mixture was concentrated under reduced pressure and crude dissolved in water (10 mL) and then washed with diethyl ether (20 mL). The aqueous layer was acidified with 1N HCl solution thus solid obtained was filtered off and dried under high vacuum to afford Compound 61 (10 mg).1H NMR (400 MHz, DMSO- d6): δ 13.28 (s, 1H), 12.19 (s, 1H), 8.11 (d, J = 8.40 Hz, 2H), 7.95 (d, J = 8.40 Hz, 2H), 7.33 (d, J = 7.20 Hz, 1H), 7.25 (d, J = 7.60 Hz, 1H), 6.94 (t, J = 7.60 Hz, 1H), 6.00 (s, 1H), 4.57 (t, J = 8.80 Hz, 2H), 3.27 (t, J = 9.60 Hz, 3H), 2.16 (s, 3H), LCMS (m / z): 388.4 (M+H)+, HPLC purity: 99.88%. Synthesis of 3-(2-cyclohexyl-3-methyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzonitrile (Compound 62) & 3-(2-cyclohexyl-3-methyl-7-oxo-4,7-dihydropyrazolo[1,5- a]pyrimidin-5-yl)benzoic acid (Compound 59):

[0012] Step-1. Synthesis of methyl cyclohexanecarboxylate (2). To a stirred solution of cyclohexane carboxylic acid (500 mg, 3.90 mmol)) in methanol (10 ml) was added sulfuric acid (1 ml) at room temperature and then stirred the reaction mixture at 100°C for 12 h. Progress of the reaction was monitored by TLC. After completion of reaction, excess of solvent was removed under reduced pressure and added water (15 mL) thus precipitate formed was filtered and dried under high vacuum to afford desired product as methyl cyclohexanecarboxylate (2) (500 mg, 90.25%) without column purification.1H NMR (DMSO- d6): δ 3.66 (s, 3H), 2.34-2.27 (m, 1H), 1.92-1.89 (m, 2H), 1.88-1.71 (m, 3H), 1.49-1.42 (m, 2H), 1.32-1.23 (m, 3H). Step-2. Synthesis of 3-cyclohexyl-2-methyl-3-oxopropanenitrile (4) To a stirred solution of propanenitrile (234 mg, 4.22 mmol) in THF (10 ml), Sodium hydride (210 mg, 5.26 mmol) was added portion wise at 0°C under N2atmosphere. The reaction mixture was stirred at RT for 1 h. The reaction mixture was again cooled to 0°C and then a solution of methyl cyclohexane carboxylate (500 mg, 3.51 mmol) in THF (10 mL) was added dropwise. The reaction mass was stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with ice-water (10 mL) and then acidified with 1N HCl to pH 2-3 and then extracted with EtOAc (3x 20 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo to afford desired product 3- cyclohexyl-2-methyl-3-oxopropanenitrile (4) (320 mg) without column purification.1H NMR (DMSO-d6): δ 2.34-2.30 (m, 1H), 2.20-2.10 (m, 1H), 1.96-1.84 (m, 2H), 1.79-1.59 (m, 5H), 1.43- 1.37 (m, 2H), 1.28-1.22 (m, 4H). Step-3. Synthesis of 3-cyclohexyl-4-methyl-1H-pyrazol-5-amine (5). Compound 3-cyclohexyl-2-methyl-3-oxopropanenitrile (4) (300 mg, 1.82 mmol), hydrazine hydrate (164 mg, 3.27 mmol.) and methanol (5 mL) were charged in a microwave vial. The reaction mixture was stirred in a microwave at 150 °C for 30 min. The completion of the reaction was confirmed by TLC. The reaction mixture was concentrated under reduced pressure thus crude obtained was washed with diethyl ether (10 mL), then dried under reduced pressure to afford desired product 3-cyclohexyl-4-methyl-1H-pyrazol-5-amine (5) (150 mg) without column purification. Analytical Data:1H NMR (DMSO-d6): δ 8.87 (s, 1H), 4.11 (s, 2H), 2.07-2.00 (m, 1H), 1.74 (s, 3H), 1.71-1.60 (m, 4H), 1.39-1.28 (m, 3H), 1.21-1.11 (m, 3H). Step-4. Synthesis of 3-(2-cyclohexyl-3-methyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzonitrile (Compound 62): The compound 3-cyclohexyl-4-methyl-1H-pyrazol-5-amine (5) (150 mg, 0.84 mmol) and methyl 4-(3-ethoxy-3-oxopropanoyl) benzoate (6) (170 mg, 0.84 mmol) were charged along with acetic acid in a MW vial. The reaction mixture was irradiated in a MW at 150 °C for 2 h. After completion of the reaction, water (15 mL) was added to reaction mixture thus precipitate obtained was filtered and washed with diethyl ether (10 mL), then dried under vacuum to get crude. The crude compound was purified by combi-flash (2-5% MeOH in DCM) to afford the desired product Compound 62 (90 mg) as an off-white solid.1H NMR (DMSO-d6): δ 8.29 (s, 1H), 8.11 (d, J = 8.00 Hz, 1H), 8.04 (d, J = 7.60 Hz, 1H), 7.76 (t, J = 8.00 Hz, 1H), 5.95 (s, 1H), 2.74-2.67 (m, 1H), 2.15 (s, 3H), 1.85-1.79 (m, 4H), 1.72-1.69 (m, 1H), 1.58-1.50 (m, 2H), 1.42-1.30 (m, 2H), 1.27-1.23 (m, 1H), LCMS (m / z): 333.2 (M-H)+. Step-5. Synthesis of 3-(2-cyclohexyl-3-methyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-5- yl)benzoic acid (Compound 59): To a stirred solution of Compound 62 (80 mg, 0.24 mmol) in EtOH (3 mL), added aq. NaOH (29 mg, 0.72 mmol) solution in water (1 ml) at room temperature. The reaction mass was stirred for overnight at RT. After completion of the reaction, the reaction mass directly concentrated under reduced pressure and the residue obtained was dissolved in water (5 ml), and then acidified using 1 N HCl, thus precipitate obtained was filtered and washed with diethyl ether (5 mL) and hexane (10 mL). The solid was dried under high vacuum to afford desired product Compound 59 (13 mg) as an off-white solid.1H NMR (DMSO-d6): δ 13.34 (s, 1H), 12.02 (s, 1H), 8.29 (s, 1H), 8.13 (d, J = 7.60 Hz, 1H), 8.02 (d, J = 7.60 Hz, 1H), 7.70 (t, J = 7.60 Hz, 1H), 2.75-2.68 (m, 1H), 2.17 (s, 3H), 1.83 (t, J = 14.80 Hz, 4H), 1.72 (d, J = 12.40 Hz, 1H), 1.56 (q, J = 10.80 Hz, 2H), 1.44-1.28 (m, 3H), ; LCMS (m / z): 352.40 (M-H)+.

[0013] Table 2

[0014]

[0015] Studies of BLVRB expression in cancer cells BLVRB was shown to be overexpressed in cancer, but not normal mammary cells as indicated by transcriptome analysis across all human breast cancer subtypes (FIG.2A and FIG 2B). Similarly, BLVRB IHC staining of human breast cancer tissue demonstrated variable intensity (negative to strong) of nuclear and cytoplasmic BLVRB in all subtypes, with no detectable staining in normal mammary tissues (FIG.2C). A similar pattern of BLVRB expression was also evident in human breast cancer cell lines: (i) undetectable BLVRB in MCF10A (immortalized, human non-malignant mammary epithelial cells) and (ii) high levels in breast cancer cell lines of different subtypes: MCF7 (Luminal A), SKBR3 (Her2+), ZR75-1 (Luminal A), BT474 (Luminal B). Notably, high BLVRB RNA expression predicted poor prognosis across all subtypes of breast cancer, with the highest prognostic value in Her2+(HR=1.77) and TNBC (HR=1.48)34(FIG.2E). These collective clinical data support an oncogenic BLVRB function that confers tumor aggression and / or drug resistance in breast cancer. Although in silico analyses require validation, these data support the hypothesis that BLVRB expression is restricted to highly proliferative cancer cells where it plays a cytoprotective function. Similar to human data, higher BLVRB mRNA (FIG.2F) and protein (FIG,.2G) were found in murine mammary cancer cell lines compared to mammary epithelial cells (MECs), using isogenic lines from our MMTV / ErbB2 mouse model. Among heme degradation genes, BLVRB demonstrated the greatest induction, a pattern that parallels that of the major antioxidant transcription factor Nrf237, and was consistent with the acquisition of an antioxidant phenotype during malignant transformation (FIG. 2F). This dichotomous pattern of BLVRB induction imputes a function divergent from that of other heme degradation pathway genes. Differential BLVRB normal mammary / cancer expression provides a therapeutic window for cancer cellular targeting. It has been found that BLVRB is expressed in the cell lineage involved in clonal breast cancer pathogenesis. Single-cell RNA (scRNA) of human TNBC tumors (FIG.3A-C) confirmed enriched BLVRB expression in cycling (Ki67+) epithelial cells compared to non-cycling counterparts (FIG.3C, arrows). Mammary tissue scRNA from MMTV / ErbB2 mice (n=4; 12 weeks age, Figs. 3D-F) paralleled that of human data. Developmental kinetics of mammary tumorigenesis in these mice suggest that at this age, tissue is comprised of (i) normal MECs, (ii) DCIS lesions, and (iii) microscopic low-grade tumors with increased ErbB2 as lesions progress. In contrast to cancer cells, MECs displayed very low ErbB2 and undetectable BLVRB (FIG.2G). Furthermore, a strong correlation between BLVRB and ErbB2 in luminal cells (p < 2.2 X10-16) was observed, synchronous with tumor progression (FIG.3F). Thus, independent of subtype (TNBC or Her2+), BLVRB is developmentally expressed at early stages of malignant transformation in the cell lineage implicated in cancer pathogenesis. It was further demonstrated that BLVRB activity is required for proliferation and breast cancer cell survival. The breast cancer line (SKBR3) was used to generate SKBR3 / BLVRB- / -cells by CRISPR-targeted editing (FIG.4A, B). Immunoblots of three clones confirmed BLVRB loss, with compensatory induction of Nrf2, HMOX2, and BLVRA. Compared to control (empty vector, EV) cells, SKBR3 / BLVRB- / -(CC9) cells demonstrated defective antioxidant handling, as evident by ROS accumulation using both DHFE fluorescence (FIG.4C) and ROS-Glo luciferase assay (p<0.001, FIG.4D). Elevated ROS was associated with defective lipid peroxidation (increased malondialdehyde (MDA) (FIG. 4E), with preservation of mitochondrial function using JC1 fluorescence [a viability marker of the mitochondrial membrane potential (ΔΨm) (FIG. 4F)]. Strikingly, BLVRB- / -cells lose proliferative capacity (FIG. 4G), cell viability (FIG. 4H), and display increased G2 / M arrest (FIG.4I). Thus, BLVRB has an essential non-redundant role in redox homeostasis and cytoprotection independent of other cell antioxidant systems. It was also demonstrated that BLVRB confers resistance to oxidative stress. Oxidative stress was induced with H2O2, irradiation, and 5FU, and observed dose-dependent and synchronized elevation of both ROS and BLVRB, suggesting a role in oxidative stress sensing (FIG.5A-C). Compared to SKBR3 / BLVRB+ / +, H2O2-stressed SKBR3 / BLVRB- / -cells displayed defective antioxidant handling as indicated by exaggerated lipid peroxidation (MDA) (FIG.5E) and increased cell death (FIG. 5F). Similarly, 5FU induced ~6-fold increase in ROS in SKBR3 / BLVRB- / -and aggravated cell death compared to control cells (FIG.5G, and not shown). High BLVRB expression predicted resistance of human breast cancer (independent of subtype) to conventional chemotherapy regimen FAC (5FU, doxorubicin, cyclophosphamide (FIG. 5H). Cancer cells hijack ErbB2 signaling to upregulate antioxidant defense and survive chronic oxidative stress, and previous studies demonstrate that targeted ErbB2 inhibition elevates ROS in human breast cancer cells. ErbB2 was targeted with trastuzumab (Tz) or the ErbB2 inhibitor Lapatinib (Lap), demonstrating elevated ROS in SKBR3 and BT474 cells (FIG.5J and not shown), concomitant with loss of cell viability (FIG.5I and not shown). Moreover, BLVRB deficiency accentuated both cell death and ROS-induced lipid peroxidation (FIG.5I, and FIG.5J). These observations are consistent with clinical data showing that BLVRBhighcohorts display therapeutic resistance to Her2-targeted therapies (Tz and Lap, FIG.5K), manifested by the worse pathological complete response (pCR), supporting that the BLVRB cytoprotectant function(s) confer resistance to conventional therapies. Cellular and megakaryocyte-promoting effects of a selective BLVRB inhibitor Cellular studies of BLVRB inhibitors were done by comparing transcriptomic profiles of heme degradation genes from the NCI60 gene set (Barretina, J. et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603-607, doi:10.1038 / nature11003 (2012); Reinhold, W. C. et al. RNA Sequencing of the NCI-60: Integration into CellMiner and CellMiner CDB. Cancer Res 79, 3514-3524, doi:10.1158 / 0008- 5472.CAN-18-2047 (2019)) and identified K562 (BCR-ABL1+chronic myelogenous leukemia) cells among the four most abundant BLVRB-expressing lines (FIG.6A). Within the 6-member hematopoietic subset, BLVRB expression was greater than that of BLVRA and displayed minimal to absent expression in lymphoid (CCRF and MOLT4)-derived leukemias (log2RPKM <0.1). K562 (and JAK2V617Fhuman erythroleukemia cells, HEL (Martin, P. & Papayannopoulou, T. HEL cells: a new human erythroleukemia cell line with spontaneous and induced globin expression. Science 216, 1233-1235 (1982)) display bilineage potential in models of erythroid / megakaryocyte (E / Meg) differentiation (Cupit, L. D., Schmidt, V. A., Gnatenko, D. V. & Bahou, W. F. Expression of protease activated receptor 3 (PAR3) is upregulated by induction of megakaryocyte phenotype in human erythroleukemia (HEL) cells. Exp Hematol 32, 991-999, doi:10.1016 / j.exphem.2004.07.005 (2004); Long, M. W., Heffner, C. H., Williams, J. L., Peters, C. & Prochownik, E. V. Regulation of megakaryocyte phenotype in human erythroleukemia cells. J.Clin.Invest.85, 1072-1084 (1990)) consistent with RNA expression patterns BLVRB was readily immunodetected in K562 (and HEL, but not MOLT4) cells. Similarly, both K562 and HEL cells displayed concomitant dose-dependent DCPIP reductive capacity compared to BLVRB-negative MOLT4 cells, greatest in K562 cells (FIG.6B). E / Meg lineage potential was studied using BCT1028 which displayed a favorable metabolic profile in MDCK studies (excellent permeability and stability using liver microsomes). K562 incubation with BCT1028 induced morphological changes typical of megakaryocytic differentiation (i.e. increased size and cytoplasmic content, FIG.6C), features comparable to those using phorbol ester (Cupit, L. D., Schmidt, V. A., Gnatenko, D. V. & Bahou, W. F. Expression of protease activated receptor 3 (PAR3) is upregulated by induction of megakaryocyte phenotype in human erythroleukemia (HEL) cells. Exp Hematol 32, 991-999, doi:10.1016 / j.exphem.2004.07.005 (2004); Long, M. W., Heffner, C. H., Williams, J. L., Peters, C. & Prochownik, E. V. Regulation of megakaryocyte phenotype in human erythroleukemia cells. J.Clin.Invest.85, 1072-1084 (1990); Tetteroo, P. A., Massaro, F., Mulder, A., Schreuder-van Gelder, R. & von dem Borne, A. E. Megakaryoblastic differentiation of proerythroblastic K562 cell-line cells. Leuk Res 8, 197-206, doi:10.1016 / 0145-2126(84)90143- 7 (1984)). Flow cytometry confirmed that cellular effects were megakaryocyte-specific, displaying both time- and dose-dependent acquisition of the megakaryocyte-specific marker CD61 (β3 integrin). CD61 acquisition was maximal at 72 hours, a time point when >90% of cells were CD61+, and expressed ~5-fold increase in cell-surface CD61 abundance. MK-promoting effects of BCT1028 were nearly identical to those of a saturating concentration of PMA (10-6M) known to induce maximal megakaryocyte features (FIG.6D). Megakaryocyte-promoting effects of BLVRB inhibition were confirmed in a second cell line (HEL) and in human stem cells. The intrinsic fluorescence properties of BCT1028 (λEx / Em= 350 / 465 nm) allowed precise tracking of cellular drug accumulation, and BCT1028 displayed time- and dose-dependent uptake in HEL cells (FIG.7A); the compound was readily detectable by 1 hour with persistent cellular accumulation at 24 hours, confirming that metabolic characteristics in erythroleukemia cells paralleled those using MDCK cells. BLVRB inhibition using BCT1028 (10 µM, 48 hours) in HEL cells induced ~3-fold increase in DNA content by PI staining, a feature characteristic of megakaryocyte differentiation and polyploidization (>4N DNA content, FIG.7B). Megakaryocyte phenotypic features were clearly evident by immunoblot which confirmed dose-dependent CD61 induction. Reciprocal loss of the erythroid CD71 (transferrin receptor) marker at 50 µM suggests that megakaryocyte-promoting effects of BCT may be associated with reciprocal effects on erythroid maturation (FIG.7C). BCT1028 was associated with diminished BLVRB expression at MK-enhancing concentrations (≥ 20 µM) suggesting that inhibitor may partially affect enzymatic cellular stability. Studies were extended in cell lines to human hematopoietic stem cells (CD34+) by using thrombopoietin-directed cultures to promote megakaryocyte differentiation. Consistent with the results in K562 and HEL, BCT1028 enhanced megakaryocyte differentiation in human stem cells as established by progressively greater CD61 and actin expression. A second megakaryocyte- specific marker (platelet factor 4, PF4) displayed an identical pattern of enhanced megakaryocyte differentiation in BCT1028-supplemented CD34+stem cells (FIG. 7D). Megakaryocyte- differentiation markers were maximal at a time point (Day 11) at which >90% of cells expressed cell-surface CD61 by flow cytometry. Consistent with results in HEL-treated BCT1028 (FIG. 7C), megakaryocyte-promoting effect of BCT1028 in CD34+stem cells were associated with dose- dependent decrease in BLVRB expression. BLVRB inhibition enhances platelet recovery during stress thrombopoiesis in mice Based on pharmacokinetic studies, BCT1028 showed moderate clearance, very good oral bioavailability (61 %) and plasmatic exposure, and was used at once daily dosing for in vivo studies. Effects of Blvrb inhibition on platelet responses was established in murine models of quiescent and stress hematopoietic recovery (FIG.8A). Cohorts were either pre-treated (or not) with 5-fluoruracil (5FU, 150 mg / kg) as stressor, followed by a 21-day course of BCT1028 (formulated in polyethylene glycol, PEG) by oral gavage using a dose (100 mg / kg) predicted to achieve steady-state plasmatic concentration ~10 µM. Serial hemograms identified no differences in blood counts in non-5FU treated mice (Cohort 2) irrespective of BCT1028 exposure (not shown). In contrast, 5FU-stressed mice treated with BCT1028 displayed highly-significant increases in peak (Day 10 / 11) platelet recovery (P = 0.004) (FIG.8B). This pattern of exaggerated thrombocytosis at peak platelet recovery (Day 10 / 11) is nearly identical to that of Blvrb-deficient mice, establishing phenotypic recapitulation using a small molecule Blvrb inhibitor. Persistently exaggerated differences at Day 17 were evident although not statistically significant (p = 0.1). Exaggerated platelet recovery in the BCT1028-treated mouse cohort was associated with statistically-greater reticulated (newly formed) platelets (RP%) at all time points post-platelet nadir (Day 3), suggesting that the exaggerated platelet recovery was explained by enhanced megakaryocytopoiesis or proplatelet formation. Results evident in platelet recovery were distinct from those affecting erythropoiesis (FIG.8C). Although red blood count (RBC) nadirs (Day 10) were exaggerated in BCT1028-treated mice, differences were not significant and RBC counts were fully recovered by Day 20; the exaggerated anemia was associated with rebound reticulocytosis at Day 17 although not statistically significant. Since newly-formed reticulated platelets are larger and display exaggerated functional reactivity, the platelet mass index (PMI) (which incorporates the mean platelet volume) was quantified as an optimal parameter of hemostatic coverage during thrombopoietic recovery (Liu, Z. J. et al. Expansion of the neonatal platelet mass is achieved via an extension of platelet lifespan. Blood 123, 3381-3389, doi:10.1182 / blood-2013-06-508200 (2014)). The platelet mass index of 5FU / BCT1028-treated mice was considerably enhanced compared to non-treated control cohorts (P<0.0001), specifically highlighting the predicted improvement in hemostasis post- chemotherapeutic stress.

Claims

Claims 1. A compound of formula (I),wherein, X is a heteroatom; R1is CO2H, halogen, or CN; and R2and R3are each independently H, a lower alkyl having 1-6 carbon atoms, an ester or alkyoxy having 1-6 carbon atoms, an ether having 1-6 carbon atoms, haloalkyl, halogen, CN, NO2, NH2, C(1-6)NH2.

2. The compound according to claim 1, wherein X is S or O.

3. The compound according to claim 1, wherein R1is a halogen.

4. The compound according to claim 3, wherein the halogen is Br.

5. The compound according to claim 1, wherein at least one of R2and R3is F, Cl, or Br.

6. The compound according to claim 1, wherein at least one of R2and R3is a haloalkyl.

7. The compound according to claim 6, wherein the haloalkyl is CF3.

8. The compound according to claim 1, wherein at least one of R2and R3is methoxy.

9. The compound according to claim 1, wherein at least one of R2and R3is -O-CH3.

10. The compound according to claim 1, wherein one of R2and R3is an alkyl and the other a halogen; one of R2and R3is a halogen and the other an ether group; one of R2and R3is a halogen and the other NH2, or one of R2and R3is a halogen and the other C(1-6)NH2.

11. The compound according to claim 1, wherein at least one of R2and R3is C(1-6)NH2.

12. A composition comprising the compound according to any one of claims 1-11.

13. A method of treating thrombocytopenia, which comprises administering to a patent in need thereof, a therapeutically effective amount of a compound of any one of claims 1-11 or the composition of claim 12.

14. A method increasing platelet production by administering to a patient a compound of any one of claims 1-11 or the composition of claim 12.

15. A method of inhibiting Biliverdin reductase B (BLVRB) redox and / or nitrosylation activity by contacting said Biliverdin reductase B (BLVRB) with a compound of any one of claims 1-11 or the composition of claim 12.

16. A method of reducing the risk of drug-related hemolysis toxicity in a subject receiving a drug selected from the group consisting of primaquine and tafenoquine, comprising co- administering to the subject an effective amount of a compound of any one of claims 1- 11 or the composition of claim 12.

17. A compound of formula (II)wherein, R1is selected from H, OH, CO2H, CO2R, CN, halogen, lower alkyl, hydroxy or tetrazole, wherein R is a lower alkyl; R2is H, or a lower alkyl of 1 to 6 carbon atoms; A is a cycloalkyl, phenyl, furanyl, thiophene or pyridinyl group; R3and R4are each independently H; halogen; and alkyl group having 1 to 6 carbon atoms; a substituted or unsubstituted alkoxy group having 1 to 6 carbon atoms, which is optionally substituted with 1, 2 or 3 halogen atoms; -when R3and R4are each be an alkyl group, together R3and R4may form a 5- or 6- member saturated or unsaturated ring, which may contain one or more heteroatoms or N, S or O.

18. The compound according to claim 17, wherein R is a lower alkyl selected from methyl, ethyl, butyl, tert-butyl, pentyl, and hexyl group.

19. The compound according to claim 17, wherein R is methyl.

20. The compound according to claim 17, wherein R1is a halogen and is fluorine, chlorine, bromine, or iodine.

21. The compound according to claim 20, wherein R1 is Br.

22. The compound according to claim 17, wherein at least one of R3and R4is Fl, Cl, Br or I.

23. The compound according to claim 22, wherein at least one of R3and R4is F or Cl.

24. The compound according to claim 22, wherein at least one of R3and R4is methoxy.

25. The compound according to claim 17, wherein at least one of R3and R4is a substituted alkoxy group, which is substituted with at leas one F.

26. The compound according to claim 17, wherein R3 and R4 are both hydrogen or one of R3and R4is hydrogen and the other is a methoxy, which is optionally substituted with fluorine, bromine, or chlorine.

27. A composition comprising the compound of any of claims 17-26 and one or more pharmaceutically acceptable carriers.

28. A method of treating thrombocytopenia, which comprises administering to a patent in need thereof, a therapeutically effective amount of a compound of any of claims 17-26 or the composition of claim 27.

29. A method increasing platelet production by administering to a patient a compound of any of claims 17-26 or the composition of claim 27.

30. A method of inhibiting Biliverdin reductase B (BLVRB) redox and / or nitrosylation activity by contacting said Biliverdin reductase B (BLVRB) with a compound of any of claims 17-26 or the composition of claim 27.

31. A method of reducing the risk of drug-related hemolysis toxicity in a subject receiving a drug selected from the group consisting of primaquine and tafenoquine, comprising co- administering to the subject an effective amount of a compound of any of claims 17-26 or the composition of claim 27.

32. Use of a compound of any of claims 17-26 or the composition of claim 27 for treating thrombocytopenia.

33. Use of a compound of any of claims 17-26 or the composition of claim 27 for increasing platelet production.

34. Use of a compound of any of claims 17-26 or the composition of claim 27 for inhibiting Biliverdin reductase B (BLVRB).

35. Use of a compound of any of claims 17-26 or the composition of claim 27 for reducing the risk of drug-related hemolysis toxicity in a subject receiving a drug selected from the group consisting of primaquine and tafenoquine.

36. Use of a compound of any of claims 17-26 or the composition of claim 27 for treating cancer.

37. The use according to claim 35, wherein the cancer is breast cancer or ovarian cancer.

38. A method of treating cancer by administering to a patient in need thereof a therapeutically effective amount of a compound of any of claims 1-11 or the composition of claim 12.

39. The method according to claim 37, wherein the cancer is breast cancer or ovarian cancer.

40. The method according to claim 36, wherein the cancer displays increased expression of BLVRB or BLVRB function.

41. The method according to claim 38, wherein the cancer displays increased expression of BLVRB or BLVRB function.

42. Use of a BLVRB inhibitor for treating cancer.

43. The use according to claim 42, wherein the cancer is breast cancer or ovarian cancer.

44. Use of a compound of any of claims 1-11 or the composition of claim 12 for treating cancer.

45. The use according to claim 44, wherein the cancer is breast cancer or ovarian cancer.

46. The use according to claim 42, wherein the cancer displays increased expression of BLVRB or BLVRB function.

47. The use according to claim 44, wherein the cancer displays increased expression of BLVRB or BLVRB function.

48. Use of a compound of any of claims 1-11 or the composition of claim 12 for treating thrombocytopenia.

49. Use of a compound of any of claims 1-11 or the composition of claim 12 for increasing platelet production.

50. Use of a compound of any of claims 1-11 or the composition of claim 12 for inhibiting Biliverdin reductase B (BLVRB).

51. Use of a compound of any of claims 1-11 or the composition of claim 12 for reducing the risk of drug-related hemolysis toxicity in a subject receiving a drug selected from the group consisting of primaquine and tafenoquine.

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