Novel inhibitors of DNA damage repair pathway

Abstract

The present application relates to novel compounds described herein, the method of preparing the same, its pharmaceutical composition and method for use thereof. In particular, the invention relates to compounds of formula (I) or their pharmaceutically acceptable salts thereof as inhibitors of ubiquitin-specific protease 1 (USP1) protein and useful in treatment, prevention and / or amelioration of diseases or disorders associated with ubiquitin-specific protease 1 (USP1) including Cancer.

Description

NOVEL INHIBITORS OF DNA DAMAGE REPAIR PATHWAY

[0001] This application claims the benefit of priority to Indian provisional patent applications numbers 202341081540 filed dated 10 January 2024, 202441009404 filed dated 12 February 2024, and 202341084429 filed dated 10 January 2024, the disclosures of each of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION

[0002] The present application relates to novel compounds described herein, the method of preparing the same, its pharmaceutical composition and method for use thereof. In particular, the invention relates to compounds of formula (I) or their pharmaceutically acceptable salts thereof as inhibitors of ubiquitin-specific protease 1 (USP1) protein and useful in treatment, prevention and / or amelioration of diseases or disorders associated with ubiquitin-specific protease 1 (USP1) including Cancer.BACKGROUND OF THE INVENTION

[0003] Ubiquitin is a small, highly conserved protein of 76 amino acids that is post- translationally conjugated to substrate proteins, including itself, via a three-step enzymatic reaction. The initial covalent attachment primarily occurs between the C-terminal glycine of ubiquitin and the ε-amino group of lysine residue(s) of the target protein. Additional ubiquitin molecules can be ligated to one of the seven internal lysines of ubiquitin, resulting in diverse ubiquitin chain topologies. The biological outcome of ubiquitination is determined by both the length and linkage topology. For example, Lys48-linked polyubiquitin chains are almost exclusively associated with allocating proteins for proteasome-dependent degradation, while monoubiquitination or chains linked through different lysines have been shown to serve multiple nonproteolytic functions. Similar to other types of post-translational modifications, ubiquitination is a reversible process counter-regulated by enzymes known as deubiquitinases (DUBs), which catalyze the removal of ubiquitin from modified proteins. More importantly, dysfunction in ubiquitin-dependent signaling pathways has been linked to various human diseases, suggesting inhibition of ubiquitin pathway components as novel therapeutic targets for drug discovery.

[0004] Pharmacological intervention within the ubiquitin-proteasome system has been well established by the successful use of proteasome inhibitors for anticancer treatment. Nevertheless, the ubiquitin-proteasome system offers additional opportunities for therapeutic intervention that could afford increased specificity and the possibility for improved clinicalefficacy, which proteasome inhibitors are currently lacking. The most apparent targets include enzymes involved in ubiquitin conjugation and deconjugation (i.e., ubiquitin ligases and DUBs), processes upstream of proteasome-mediated protein degradation. Among the DUBs, ubiquitinspecific protease 1 (USP1) has become an attractive anticancer target because of its involvement in regulating DNA damage response pathways. USP1 associates with UAF1 (USPl-associated factor 1), resulting in the heterodimeric USP1 / UAF1 complex that is required for deubiquitinase activity. The USP1 / UAF1 complex has been shown to regulate the tolerance of DNA damage induced by DNA cross-linking agents through deubiquitination of PCNA (proliferating cell nuclear antigen) and FANCD2 (Fanconi anemia complementation group D2), which are proteins that function in translesion synthesis and the Fanconi anemia pathway, respectively. Williams et al. also recently reported that USP1 / UAF1 deubiquitinates and prevents proteasomal degradation of ID (inhibitor of DNAbinding) proteins, which have been shown to activate multiple pathways involved in tumor progression, including preservation of the cancer stem cell phenotype. Moreover, evidence for aberrant overexpression of USP1 in several tumor types suggests that inhibitors of USP1 are likely to provide a therapeutic benefit, (see Thomas S. Dexheimer et.al., J. Med. Chem. 2014, 57, 8099-8110)

[0005] Reversible protein ubiquitination is emerging as a key process for maintaining cell homeostasis, and the enzymes that participate in this process, in particular E3 ubiquitin ligases and deubiquitinases (DUBs), are increasingly being regarded as candidates for drug discovery. Human DUBs are a group of approximately 100 proteins, whose cellular functions and regulatory mechanisms remain, with some exceptions, poorly characterized. One of the best-characterized human DUBs is ubiquitin-specific protease 1 (USP1), which plays an important role in the cellular response to DNA damage. USP1 levels, localization and activity are modulated through several mechanisms, including protein-protein interactions, autocl eavage / degradati on and phosphorylation, ensuring that USP 1 function is carried out in a properly regulated spatio-temporal manner. Importantly, USP1 expression is deregulated in certain types of human cancer, suggesting that USP1 could represent a valid target in cancer therapy, (see Garcia-Santisteban et al. Molecular Cancer 2013, 12:91)

[0006] Various research groups around the world have been working on targeting USP1 andPatent literature targeting USP1 include the following patents and / or patent applications: WO / 2023 / 148643, WO / 2023 / 155866, WO / 2023 / 143424, WO / 2023 / 066299, WO / 2023 / 083285, WO / 2023 / 083297, WO / 2023 / 083286, WO / 2023 / 147311, WO / 2023 / 030295, WO / 2022 / 216820, WO / 2022 / 199652, WO / 2022 / 253188, WO / 2022 / 214053, WO / 2022 / 174184, WO / 2022 / 197892, WO / 2022 / 228399, WO / 2022 / 233263, WO / 2021 / 163530, WO / 2021 / 247606, WO / 2020 / 132269, WO / 2020 / 139988, WO / 2017 / 087837, WO / 2014 / 105952, WO / 2011 / 137320

[0007] Further review and literature disclosure on USP1 inhibitors have been given by see.Thomas S. Dexheimer et.al. J. Med. Chem. 2014, 57, 8099-8110, Qin Liang et.al., Nat Chem Biol. 2014 April; 10(4): 298-304, and Iraia Garcia-Santisteban et.al., Garcia-Santisteban et al. Molecular Cancer 2013, 12:91. All of these patents and / or patent applications and literature disclosures are incorporated herein as reference in their entirety for all purposes.

[0008] We believe, Cancer in general have very few options of treatment, especially when the cancer is a result of metastasis and is unresectable. On one end there have been several advancements in options of treatment for example use of chemotherapy either alone or in combination with radiation and / or surgery however on the other side there has been a significant number of challenges with prognosis especially for the cancers such as the breast cancer, ovarian cancer, prostate cancer, lung cancer, gastric cancer, endometrial cancer, colorectal cancer.

[0009] Accordingly, there do exists an unmet medical need for treatments for such cancers and the present invention aims to address the same.SUMMARY OF THE INVENTION

[0010] The present invention relates to a compound of formula (I), or pharmaceutically acceptable salts or compositions and methods of treatment with them, in particular the present invention relates to a compound of formula (I) and their pharmaceutically acceptable salts thereof useful in the treatment of USP1 mediated cancer.

[0011] In one embodiment of the invention, the present invention is related to a compound of Formula (I):or a tautomer thereof, prodrug thereof, N-oxide thereof, a pharmaceutically acceptable ester thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, whereinCy is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;Cy1is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; each occurrence of L, L1and L2are independently absent or independently selected from substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, substituted or unsubstituted C3-10 cycloalkyl, substituted or unsubstituted C3-10heterocycloalkyl, -(CRbRc)n-. O, S, -S(=O)P-, -C(=O)- ,-NRx- , -S(=O)P-NH-, - NH-S(=O)P-, -CO-NRX- and -NRX-CO-;Cy2is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl; each occurrence of R and R5are independently selected from hydrogen, hydroxy, halogen, CN (Cyano), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkenyl, substituted or unsubstituted haloalkynyl, substituted or unsubstituted haloalkoxy, -C(=O)ORb, -C(=O)Rb, -C(=S)Rb, -C(=O)NRbRc, -C(=O)ONRbRc, - NRbRc, -NRb-ORc, -NRbC(=O)NRbRc, -NRbS(=O)Rc, -NRbS(=O)2Rc, -NRb-ORc, =N-NRbRc, - NRbC(=O)ORc, -NRbC(=O)Rc, -NRbC(=S)Rc,-NRbC(=S)NRbRc, -SONRbRc, -SO2NRbRc, -ORb, - ORbC(=O)NRbRc, -ORbC(=O)ORc, -OC(=O)Rb, -OC(=O)NRbRc, -RbNRcC(=O)Rb, -RbORc, - RbC(=O)ORc, -RbC(=O)NRbRc, -RbC(=O)Rc, -RbOC(=O)Rc, -SRb, -SORC, -SO2Rb, - CRbRcC(=O)Rbor -CRbRcC(=S)Rz, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino or any two Rb and Rc may be joined to a form a substituted or unsubstituted saturated or unsaturated 3-6 member ring, which may optionally include heteroatoms which may be same or different and are selected from O, NRa or S; each occurrence of Rband Rcis independently selected from hydrogen, hydroxy, halogen, CN (Cyano), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkenyl, substituted or unsubstituted haloalkynyl, substituted or unsubstituted haloalkoxy, -C(=O)ORf, -C(=O)Rf, -C(=S)Rf, -C(=O)NRfRg, -C(=O)ONRfRg, - NRfRg, -NRf-ORg, -NRfC(=O)NRfRg, -NRfS(=O)Rg, -NRfS(=O)2Rg, -NRf-ORg, =N-NRfRg, - NRfC(=O)ORg, -NRfC(=O)Rg, -NRfC(=S)Rg,-NRfC(=S)NRfRg, -SONRfRg, -SO2NRfRg, -ORf, - ORfC(=O)NRfRg, -ORfC(=O)ORg, -OC(=O)Rf, -OC(=O)NRfRg, -RfNRgC(=O)Rf, -RfORc, - RfC(=O)ORg-RfC(=O)NRfRg, -RfC(=O)Rg, -RfOC(=O)Rg-SRf, -SORg, -SO2Rg, - CRfRgC(=O)Rg, -CRfRgC(=S)Rz, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino or any two Ramay be joined to a form a substituted or unsubstituted saturated or unsaturated 3-6 member ring, which may optionally include heteroatoms which may be same or different and are selected from O, NRaor S or any two of Rband Rcwhen bound to a common atom may be joined to form (i) a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NRXor S, or (ii)an oxo (=0), thio (=S) or imino (=NRX) group; each occurrence of Rxand Rzare independently selected from hydrogen, hydroxy, cyano, halogen, -ORf, -C0ORf, -S(=O)q-Rf, -NRfRg, -C(=Z’)-Rf, substituted or unsubstituted alkyl group, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted Cycloalkyl; each occurrence of Rfand Rgis independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkenyl, substituted or unsubstituted haloalkynyl, substituted or unsubstituted haloalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino;Z’ is selected from O, S or =N; and each occurrence of n is 0,1, 2, 3, 4, 5, 6, 7 or 8; and each occurrence of p and q are independently 0,1 or 2.

[0012] Further preferred are compounds having the formula (I) wherein Cy1is selected from substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0013] Further preferred are compounds having the formula (I), wherein Cy1is substituted or unsubstituted heteroaryl.

[0014] In one embodiment of the invention, the present invention Cy1in compound of the formula (I) is selected fromwherein Cy1is optionally substituted with one or more Rband Rbis as defined below in relation to a compound of formula (IA).

[0015] In one embodiment of the invention, the present invention R-Cy in compound of the formula (I) is selected fromX1is absent, O, S, CR1, NR1orN;X2is absent, O, S, CR2, NR2or N;X3is absent, O, S, CR3, NR3or N;X4is absent, O, S, CR4, NR4orN;X3is absent, O, S, CR6, NR6or N;Y1is -CRd, -NRd, CRdRe-CRdRe, CRdRe-N , N-CRdRe, XRd-XRd-, CRdCRd, -CRd=N-, - N=CRd-, -N=N-, -O-, -S- or -N-;Y2is -CRd, -NRd, CRdRe-CRdRe. CRdRe-N , N-CRdRe. \RdAIC. ( Rd( RdCRaX , - N=CRa, -N=N-, -O-, -S- or -N~;Y3is -CRd, -NRd, -CRdRe-CRdRe-, - CRdRe-N- - N-CRdRe-, -N Rd-X Rd-, CRdCRd- CRdX , X CRd, -N=N-, -O-, -S- or -N-; or wherein each of the variables including X1, X2, X3, X4, X5, Y1, Y2and Y3are as defined below in relation to a compound of formula (IA).

[0016] In one embodiment of the invention, the present invention is related to a compound of Formula (IA):or a tautomer thereof, prodrug thereof, N-oxide thereof, a pharmaceutically acceptable ester thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, whereinR-Cy is selected fromX1is absent, O, S, CR1, NR1orN;X2is absent, O, S, CR2, NR2or N;X3is absent, O, S, CR3, NR3or N;X4is absent, O, S, CR4, NR4or N;X5is absent, O, S, CR6, NR6or N;Y1is -CRd, -NRd, CRdRe-CRdRe. CRdRe~N , \-CRdRc. NRd-NRd-, CRd=CRd-CRd=N~, - N=CRd-, -N=N-, -O-, -S- or -N-;Y2is -CRd, -NRd, CRdR -( RdRcCRdRe-N , N-CRdRe, -NRd-NRe-, CRd( Rd, -CRaN-, - N=CRa~, -N=N-, -O-, -S- or -N-;Y3is -CRd, -\Rd. CRdRe-CRdRe. CRdRe-N . N-CRdRe. NRd-NRd-, ( RdCRd-CRd=N- -N=CRd- -N=N-, -0-, -S- or -N-;Cy1is selected fromwherein Cy1is optionally substituted with one or more Rb. each occurrence of L, L1and L2are independently absent or independently selected from substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, substituted or unsubstituted C3-10 cycloalkyl, substituted or unsubstituted C3-10 heterocycloalkyl, -(CRbRc)n-. O, S, -S(=O)P-, -C(=O)- ,-NRx- , -S(=O)P-NH-, - NH-S(=O)P-, -CO-NRX- and -NRX-CO-; each occurrence of R1, R2, R3, R4, and R6are independently selected from hydrogen, hydroxy, halogen, CN (Cyano), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkenyl, substituted or unsubstituted haloalkynyl, substituted or unsubstituted haloalkoxy, -C(=O)ORb, -C(=O)Rb, -C(=S)Rb, - C(=O)NRbRc, -C(=O)ONRbRc, -NRbRc, -NRb-ORc, -NRbC(=O)NRbRc, -NRbS(=O)Rc, - NRbS(=O)2Rc, -NRb-ORc, =N-NRbRc, -NRbC(=O)ORc, -NRbC(=O)Rc, -NRbC(=S)Rc,- NRbC(=S)NRbRc, -SONRbRc, -SO2NRbRc, -ORb, -ORbC(=O)NRbRc, -ORbC(=O)ORc, - OC(=O)Rb, -OC(=O)NRbRc, -RbNRcC(=O)Rb, -RbORc, -RbC(=O)ORc, -RbC(=O)NRbRc, - RbC(=O)Rc, -RbOC(=O)Rc, -SRb, -SORC, -SO2Rb, -CRbRcC(=O)Rbor -CRbRcC(=S)Rz, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl,substituted or un substituted heteroaryl alkyl, substituted or un substituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino or any two of Rband Rcmay be joined to a form a substituted or un substituted saturated or unsaturated 3-6 member ring, which may optionally include heteroatoms which may be same or different and are selected from O, NRaor S or ; optionally wherein any two variables of R1and R2or R2and R3or R3and R4or R4and R6together with the ring they attached can form a 5 to 8 membered optionally substituted ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NRXor S.Cy2is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl; each occurrence of R and R5are independently selected from hydrogen, hydroxy, halogen, CN (Cyano), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkenyl, substituted or unsubstituted haloalkynyl, substituted or unsubstituted haloalkoxy, -C(=O)ORb, -C(=O)Rb, -C(=S)Rb, -C(=O)NRbRc, -C(=O)ONRbRc, - NRbRc, -NRb-ORc, -NRbC(=O)NRbRc, -NRbS(=O)Rc, -NRbS(=O)2Rc, -NRb-ORc, =N-NRbRc, - NRbC( O)ORc, -NRbC(=O)Rc, -NRbC(=S)Rc,-NRbC(=S)NRbRc, -SONRbRc, -SO2NRbRc, -ORb, - ORbC(=O)NRbRc, -ORbC(=O)ORc, -OC(=O)Rb, -OC(=O)NRbRc, -RbNRcC(=O)Rb, -RbORc, - RbC(=O)ORc, -RbC(=O)NRbRc, -RbC(=O)Rc, -RbOC(=O)Rc, -SRb, -SORC, -SO2Rb, - CRbRcC(=O)Rbor -CRbRcC(=S)Rz, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino or any two Rband Rcmay be joined to a form a substituted or unsubstituted saturated or unsaturated 3-6 member ring, which may optionally include heteroatoms which may be same or different and are selected from O, NRaor S;each occurrence of Rdand Reare independently selected from hydrogen, hydroxy, halogen, CN (Cyano), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -C(=O)ORb, - C(=O)Rb, -C(=S)Rb, -C(=O)NRbRc, -C(=O)ONRbRc, -NRbRc, -NRb-ORc, -NRbC(=O)NRbRc, - NRbS(=O)Rc, -NRbS(=O)2Rc, -NRb-ORc, =N-NRbRc, -NRbC(=O)ORc, -NRbC(=O)Rc, - NRbC(=S)Rc,-NRbC(=S)NRbRc, -SONRbRc, -SO2NRbRc, -ORb, -ORbC(=O)NRbRc, - ORbC(=O)ORc, -OC(=O)Rb, -OC(=O)NRbRc, -RbNRcC(=O)Rb, -RbORc, -RbC(=O)ORc, - RbC(=O)NRbRc, -RbC(=O)Rc, -RbOC(=O)Rc, -SRb, -SORC, -SO2Rb, -CRbRcC(=O)Rbor - CRbRcC(=S)Rz, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino or any two Rdand / or Remay be joined to a form a (i) a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NRXor S, or (ii)an oxo (=0), thio(=S) or imino(=NRx) group; each occurrence of Rband Rcis independently selected from hydrogen, hydroxy, halogen, CN (Cyano), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkenyl, substituted or unsubstituted haloalkynyl, substituted or unsubstituted haloalkoxy, -C(=0)ORf, -C(=0)Rf, -C(=S)Rf, -C(=0)NRfRg, -C(=0)0NRfRg, - NRfRg, -NRf-ORg, -NRfC(=0)NRfRg, -NRfS(=0)Rg, -NRrS( O)2Rg, -NRf-ORg, =N-NRfRg, - NRfC(=0)ORg, -NRfC(=0)Rg, -NRfC(=S)Rg,-NRfC(=S)NRfRg, -SONRfRg, -SO2NRfRg, -ORf, - ORfC(=0)NRfRg, -ORfC(=0)ORg, -0C(=0)Rf, -0C(=0)NRfRg, -RfNRgC(=0)Rf, -RfORc, - RfC(=0)ORg, -RfC(=0)NRfRg, -RfC(=0)Rg, -Rf0C(=0)Rg, -SRf, -SORg, -SO2Rg, - CRfRgC(=0)Rg, -CRfRgC(=S)Rz, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino or any two Rband / or Rcmay be joined to a form a (i) a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, whichmay optionally include one or more heteroatoms which may be the same or different and are selected from O, NRXor S, or (ii)an oxo (=0), thio(=S) or imino(=NRx) group; each occurrence of Rxand Rzare independently selected from hydrogen, hydroxy, cyano, halogen, -OR1, -COORf, -S(=O)q-Rt, -NRfRg, -C(=Z’)-Ri, substituted or unsubstituted alkyl group, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted Cycloalkyl; each occurrence of Rfand Rgis independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkenyl, substituted or unsubstituted haloalkynyl, substituted or unsubstituted haloalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino; each of X1, X2, X3, X4and X5are not absent at the same time; when one or more of X1, X2, X3, X4and X5is or are absent it will always form a stable ring circle represents either saturation, partial unsaturation or unsaturation;Z’ is selected from O, S or =N; each occurrence of n is 0,1, 2, 3, 4, 5, 6, 7 or 8; and each occurrence of p and q are independently 0,1 or 2.

[0017] In one embodiment of the invention, the present invention is related to a compoundor a tautomer thereof, prodrug thereof, N-oxide thereof, a pharmaceutically acceptable ester thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein all the variables (X1, X2, X3, X4, X5, Y1, Y2, Y3, L, L1, L2, R, R5, and Cy2) are as defined above in relation to a compound of formula (I) or (IA)

[0018] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein R is selected from hydrogen, hydroxy, halogen, CN (Cyano), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0019] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein R is selected from substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0020] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA-Ill), (IA-IV), (IA-V), or (IA-VI), wherein R is selected from hydrogen, halogen, substituted or unsubstituted alkyl,wherein R is optionally substituted with one or more Rd;

[0021] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein R is selected from

[0022] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein Rdis selected from hydrogen, hydroxy, halogen, CN (Cyano), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, COOH, CONH2 , -NRbRc, -ORb, -SRb, -SORCor -SO2Rbor any two Rdmay be joined to a form a (i) a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NRXor S, or (ii)an oxo (=0), thio(=S) or imino(=NRx) group;

[0023] Further preferred are compounds having the formula (I), (IA), (TA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein Rdis selected from hydrogen, halogen, -NH2-, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy or substituted or unsubstituted cycloalkyl.

[0024] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein R is selected from hydrogen, methyl, ethyl, fluorine, chlorine, bromine,

[0025] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein Cy is selected from substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0026] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein Cy is selected from substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0027] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein Cy is selected from

[0028] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein R-Cy- is selected from

[0029] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA-III), (IA-IV), (IA-V), or (IA-VI), wherein Cy1is selected fromwherein Cy1is optionally substituted with one or more Rb.

[0030] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA-III), (IA-IV), (IA-V), or (IA-VI), wherein Cy1is selected from

[0031] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein Cy1is selected from

[0032] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein X1is CR1or N; wherein R1is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, or CN.

[0033] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein X1is CR1, wherein R1is hydrogen, halogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy.

[0034] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein X1is CR1, wherein R1is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, isopropyl or methoxy.

[0035] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein X2is CR2or N; wherein R2is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, or CN.

[0036] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein X2is CR2, wherein R2is hydrogen, halogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy.

[0037] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein X2is CR2, wherein R2is fluorine, chlorine, bromine, methyl, ethyl, isopropyl or methoxy.

[0038] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein X3is CR3or N; wherein R3is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, or CN.

[0039] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein X3is CR3, wherein R3is hydrogen, halogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy.

[0040] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein X3is CR3, wherein R3is fluorine, chlorine, bromine, methyl, ethyl, isopropyl or methoxy.

[0041] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein X4is CR4or N; wherein R4is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, or CN.

[0042] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein X4is CR4, wherein R4is hydrogen, halogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy.

[0043] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein X4is CR4, wherein R4is fluorine, chlorine, bromine, methyl, ethyl, isopropyl or methoxy.

[0044] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein X3is CR6or N; wherein R6is hydrogen, halogen, or CN.

[0045] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein X5is CR6, CN or N, wherein R6is hydrogen or halogen.

[0046] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein X5is CR6, wherein R6is fluorine or chlorine.

[0047] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein L is absent or selected from substituted or unsubstituted C1-4alkyl, O, S, -S(=O)Por NRx.

[0048] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein L is absent or selected from substituted or unsubstituted C1-4alkyl.

[0049] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein L is absent or -CH2-.

[0050] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein L is absent.

[0051] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein L1is absent or selected from substituted or unsubstituted C1-4alkyl, O, S, -S(=O)Por NRX.

[0052] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein L1is absent or selected from substituted or unsubstituted C1-4alkyl.

[0053] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein L1is absent or -CH2-.

[0054] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein L2is absent or selected from substituted or unsubstituted C1-4alkyl, O, S, -S(=O)Por NRX.

[0055] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein L2is absent or selected from substituted or unsubstituted C 1-4 alkyl.

[0056] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein L2is absent or -CH2-.

[0057] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein Cy2is selected from substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0058] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein Cy2is selected fromwherein Cy2is optionally substituted with one or more substituents of variable Rd.

[0059] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA-III), (IA-IV), (IA-V), or (IA-VI), wherein Cy2is selected from

[0060] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA-Ill), (IA-IV), (IA-V), or (IA-VI), wherein R5is selected from substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0061] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), or (IA-VI), wherein R5is selected fromWherein R5is optionally substituted with one or more Rd.

[0062] Further preferred are compounds having the formula (I), (IA), (IA-I), (IA-II), (IA-Ill), (IA-IV), (IA-V), or (IA-VI), wherein R5is selected from

[0063] The non-limiting representative compounds of the present invention are as listed herein below and pharmaceutically acceptable salts thereof. The present invention should not be construed to be limited to these compounds1. 5-(5-bromo-2-fluorophenyl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)- 1,2,4-oxadiazole;2. 5-(2-fluoro-4-methoxyphenyl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)- 1,2,4-oxadiazole;3. 5-(2-bromo-4-fluorophenyl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)- 1,2,4-oxadiazole;4. 3-(5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-2-fluorophenyl)-5-(4-(l-methyl-4-(tri fluoromethyl )- 1 H-imi dazol -2-y l)phenyl )- 1 ,2,4-oxadi azol e;5. 5-(4-fhioro-2'-isopropyl-[1,1'-biphenyl]-3-yl)-3-(4-(l-methyl-4-(trifhioromethyl)-lH- imidazol-2-yl) phenyl)- 1,2,4-oxadiazole;5-(2'-isopropyl-4-(4-methylpiperazin-l-yl)-[1, 1'-biphenyl]-3-yl)-3-(4-(l -methyl -4- (trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole; 5-(2-fluoro-4-methoxyphenyl)-3-(2-methyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)- 1 ,2,4-oxadiazole; 5-(2-bromo-4-fluorophenyl)-3-(2-methyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)-l,2,4-oxadiazole; 4-(4-bromo-2-(3-(4-(l -methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)- 1,2,4- oxadiazol-5-yl)phenyl)morpholine; 5-(5-bromo-2-(4-methylpiperazin-l-yl)phenyl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)- 1 ,2,4-oxadiazole; 5-(2-(azepan-l-yl)-5-bromophenyl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)- 1 ,2,4-oxadiazole; 4-(4-bromo-2-(3 -(4-( 1 -methyl-4-(trifluorom ethyl)- 1 H-imidazol-2-yl)phenyl)- 1,2,4- oxadiazol-5-yl)phenyl)-2,6-dimethylmorpholine; 4-(5-methoxy-2-(3 -(4-(l -methyl -4-(trifluorom ethyl)- 1 H-imidazol-2-yl)phenyl)-l ,2,4- oxadiazol-5-yl)phenyl)-2,6-dimethylmorpholine; 4-(5-methoxy-2-(3-(4-( 1 -methyl -4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l, 2,4- oxadiazol-5-yl)phenyl)morpholine; 5 -(4-methoxy-2-(4-methylpiperazin- 1 -yl)phenyl)-3 -(4-( 1 -methyl-4-(trifluorom ethyl)- 1 H- imidazol-2-yl)phenyl)- 1 ,2,4-oxadiazole; tert-butyl 3-(5-methoxy-2-(3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)- l,2,4-oxadiazol-5-yl)phenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate; 5-(2-(l, 4-diazepan-l-yl)-4-methoxyphenyl)-3-(4-(l -methyl -4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)- 1 ,2,4-oxadiazole; 5-(4-methoxy-2-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)phenyl)-3-(4-(l -methyl- 4-(tri fluoromethyl)- lH-imidazol-2-yl)phenyl)- 1 ,2,4-oxadiazole; 5-(5-fluoro-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)- 1 ,2,4-oxadiazole; 5-(5-fluoro-3',5'-bis(trifluoromethyl)-[l, 1'-biphenyl]-2-yl)-3-(4-(l-methyl-4- (trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole;5-(2',5-difluoro-6'-methoxy-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)- 1 ,2,4-oxadiazole; 5-(5'-chloro-5-fluoro-2'-methoxy-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)- lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole; 5-(3',5'-dichloro-5-fluoro-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)- 1 ,2,4-oxadiazole; 3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-5-(2',3',5-trifluoro-[1,1'- biphenyl]-2-yl)- 1 ,2,4-oxadiazole; 5-(5'-chl oro-2', 5-difluoro-[1,1'-biphenyl]-2 -yl)-3-(4-(l -methyl-4-(trifluoromethyl)- 1H- imidazol-2-yl)phenyl)- 1 ,2,4-oxadiazole; 3,5'-difluoro-2'-(3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4- oxadiazol-5-yl)-[1,1'-biphenyl]-2-carbonitrile; 5-(3'-chl oro-2', 5-difluoro-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)- 1H- imidazol-2-yl)phenyl)- 1 ,2,4-oxadiazole; 5'-fluoro-2'-(3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazol- 5-yl)-[1,1'-biphenyl]-4-carbonitrile; 5-(4'-chl oro-2', 5-difluoro-[1,1'-biphenyl]-2 -yl)-3-(4-(l -methyl-4-(trifluoromethyl)- 1H- imidazol-2-yl)phenyl)- 1 ,2,4-oxadiazole; 5-(4'-ethoxy-5-fluoro-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol- 2-yl)phenyl)-l,2,4-oxadiazole; 5-(5-fluoro-3',5'-dimethyl-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)- 1 ,2,4-oxadiazole; 5-(5-fluoro-3 '-(trifluoromethoxy)-[1,1'-biphenyl]-2-yl)-3-(4-(l -methyl -4-(trifluoromethyl)- lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole; 5-(2'-chloro-5-fluoro-4'-rnethoxy-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)- lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole; 5-(5-fluoro-2',4'-dimethoxy-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)- 1 ,2,4-oxadiazole; 5-(4'-chl oro-3', 5-difluoro-[l, l'-biphenyl]-2 -yl)-3-(4-(l-methyl-4-(trifluoromethyl)- 1H- imidazol-2-yl)phenyl)- 1 ,2,4-oxadiazole;5-(3',5-difluoro-4'-methoxy-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)- 1 ,2,4-oxadiazole; 5-(5-fluoro-3',4'-dimethoxy-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)- 1 ,2,4-oxadiazole; 5-(4'-chloro-5-fluoro-3'-methyl-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)- 1 ,2,4-oxadiazole; 5 -(4', 5 -difluoro-3 '-(trifluoromethyl)- [1,1 '-biphenyl ] -2 -y 1 ) -3 -(4-( 1 -methyl-4- (trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole; 3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-5-(3',5,5'-trifluoro-[1,1'- biphenyl]-2-yl)-l,2,4-oxadiazole; 5-(3',5-difluoro-4'-methoxy-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)- 1 ,2,4-oxadiazole; 5-(2',5'-dichloro-5-fluoro-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)- 1 ,2,4-oxadiazole; 5-(2-(2,6-dimethoxypyridin-3-yl)-4-fluorophenyl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)- 1 ,2,4-oxadiazole; 5-(3'-chloro-5-fluoro-4'-methyl-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)- 1 ,2,4-oxadiazole; 4-(5-methoxy-2-(3-(2-methyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-1.2.4-oxadiazol-5-yl)phenyl)-2,6-dimethylmorpholine; 5-(4-methoxy-2-(4-methyl-l,4-diazepan-l-yl)phenyl)-3-(2-methyl-4-(l-methyl-4- (trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole; 5-(2-(l,4-diazepan-l-yl)-4-methoxyphenyl)-3-(2-methyl-4-(l-methyl-4-(trifluoromethyl)- lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole; 4-(5-methoxy-2-(3-(2-methyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-1.2.4-oxadiazol-5-yl)phenyl)morpholine; 5-(4-methoxy-2-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)phenyl)-3-(2-methyl-4-( 1 -methyl -4-(trifluorom ethyl)- 1 H-imidazol-2-yl)phenyl)- 1 ,2,4-oxadiazole 5 -(5 -(4-cy clopropyl-6-methoxypy rimidin-5 -yl)-2-fluoropheny l)-3 -(4-( 1 -methyl-4- (trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole;3-(5-bromo-2-fluorophenyl)-5-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)- 1 ,2,4-oxadiazole; 3,5-bis(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole; 3-(5-bromo-2-(4-methylpiperazin-l-yl)phenyl)-5-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)-l,2,4-oxadiazole; 5 -(2-(2-i sopropy Iphenyl )py rimidin-4-yl)-3 -(4-( 1 -methyl-4-(trifluorom ethyl )- 1 H- imidazol-2-yl)phenyl)-l,2,4-oxadiazole; 5-(5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)-l,2,4-oxadiazole; 5-(2',5-difluoro-6'-methoxy-[1,1'-biphenyl]-2-yl)-3-(2-methyl-4-(l-methyl-4- (trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole; 5-(4-fluoro-2-(l-methyl-lH-pyrazol-4-yl)phenyl)-3-(2-methyl-4-(l-methyl-4- (trifluorom ethyl)- lH-imidazol-2-yl)phenyl)- 1 ,2,4-oxadiazole; (R)-4-(5-fluoro-2-(3-(4-(l -methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)- 1,2,4- oxadiazol-5-yl)phenyl)but-3-yn-2-ol; (R)-4-(5-fluoro-2-(3-(2-methyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)-l,2,4-oxadiazol-5-yl)phenyl)but-3-yn-2-ol; (S)-4-(5-fluoro-2-(3-(2-methyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)-l,2,4-oxadiazol-5-yl)phenyl)but-3-yn-2-ol; 5-(2-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-methoxyphenyl)-3-(4-(l-methyl-4- (trifluoromethyl)- IH-imidazol -2 -yl)phenyl)- 1 ,2,4-oxadiazole; 5-(2'-isopropyl-[1,1'-biphenyl]-4-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)- 1 ,2,4-oxadiazole; 3-(2'-isopropyl-[1,1'-biphenyl]-4-yl)-5-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)- 1 ,2,4-oxadiazole; 5-(4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)phenyl)-3-(4-(l-methyl-4- (trifluoromethyl)- IH-imidazol -2 -yl)phenyl)- 1 ,2,4-oxadiazole; 5 -(2-(2-i sopropy Iphenyl )pyrimidin-5 -y l)-3 -(4-( 1 -methy l-4-(trifluorom ethyl )- 1 H- imidazol-2-yl)phenyl)-l,2,4-oxadiazole; 3,5-bis(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-lH-l,2,4-triazole;2-amino-4-(3-(4-(l -methyl -4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)- 1,2, 4- oxadiazol-5-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile; 2-amino-4-methyl-4-(3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)- l,2,4-oxadiazol-5-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile; 2-amino-4-(3-(4-(l -methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)- 1,2,4- oxadiazol-5-yl)benzo[b]thiophene-3-carbonitrile; 3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-5-(naphthalen-l-yl)-l,2,4- oxadiazole; 2-amino-5-(3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4- oxadiazol-5-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile; 2-amino-7-(3-(2-fluoro-4-(2-fluoropyridin-3-yl)phenyl)-l,2,4-oxadiazol-5-yl)-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carbonitrile; 2-amino-7-(3-(4-(2-fluoropyri din-3 -yl)benzyl)- 1,2, 4-oxadiazol-5-yl)-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carbonitrile; 5-(isoquinolin-l-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4- oxadi azole; 2-(3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazol-5- yl)naphthalen- 1 -ol; 4-(3-bromo-4-(3-(4-(l -methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)- 1,2,4- oxadiazol-5-yl)phenyl)morpholine; and pharmaceutically acceptable salts thereof.

[0064] The list of compounds used for preparation of compounds of the present invention are as listed herein below a. 4-(4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile: b. 2-methyl-4-(4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile: c. 4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile: d. 2-methyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile: e. N-hydroxy-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzimidamide.' f N-hydroxy-2-methyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzimidamide: g. 4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzoic acid: h. N-((5-bromo-2-fluorobenzoyl)oxy)-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)benzimidamide: / . N-((2-fluoro-4-methoxybenzoyl)oxy)-4-(l -methyl -4-(trifluoromethyl)-lH-imidazol -2- yl)benzimidamide: j. N-((2-bromo-4-fluorobenzoyl)oxy)-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)benzimidamide: k. 5-bromo-2-fluoro-N-((4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)benzoyl)oxy)benzimidamide: / . 4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)-N-((4-(l-methyl-4-(trifluoromethyl)- lH-imidazol-2-yl)benzoyl)oxy)benzimidamide: m. N-((2-fluoro-4-methoxybenzoyl)oxy)-2-methyl-4-(l -methyl -4-(trifluoromethyl)-lH- imidazol-2-yl)benzimidamide: n. N-((2-bromo-4-fluorobenzoyl)oxy)-2-methyl-4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)benzimidamide: o. N-((2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-4-carbonyl)oxy)-4-(l-methyl- 4-(trifluoromethyl)-lH-imidazol-2-yl)benzimidamide: p. N-((2-amino-3-cyano-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-4-carbonyl)oxy)-4- (l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzimidamide: q. N-((2-amino-3-cyanobenzo[b]thiophene-4-carbonyl)oxy)-4-(l-methyl-4- (trifluoromethyl)-lH-imidazol-2-yl)benzimidamide: r. N-(( 1 -naphthoyl)oxy)-4-( 1 -methyl-4-(trifluorom ethyl)- lH-imidazol-2-yl)benzimidamide: s. 3-(4-bromophenyl)-5-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4- oxadi azole: t. 5-(4-bromophenyl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4- oxadi azole: u. 5-(2-chloropyrimidin-4-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)- 1 ,2,4-oxadiazole: v. 5-(2-chloropyrimidin-5-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)- 1 ,2,4-oxadiazole: w. 4-bromo-2-fluoro-N-hydroxybenzimidamide: x. 2-(4-bromophenyl)-N-hydroxyacetimidamide: y. N-((2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-4-carbonyl)oxy)-4-bromo-2- fluorobenzimidamide:z. N-((2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-4-carbonyl)oxy)-2-(4- bromophenyl)acetimidamide: aa. 2-amino-4-(3-(4-bromo-2-fluorophenyl)- 1,2, 4-oxadiazol-5-yl)-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carbonitrile: bb. 2-amino-4-((3-(4-bromophenyl)-l,2,4-oxadiazol-5-yl)methyl)-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carbonitrile: cc. l-(4-(4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)ethan-l-one: dd. 1 -(4-( 1 -methyl-4-(trifluorom ethyl)- lH-imidazol-2-yl)phenyl)ethan- 1 -one: ee. 4-(l-methyl-4-(trifluorornethyl)-lH-imidazol-2-yl)benzohydrazide

[0065] The non-limiting representative compounds of the present invention as listed herein below, and pharmaceutically acceptable salts thereof areTable-2zz □OO N d (^j} Vo j 1Q

[0066] Another embodiment of the invention is a composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0067] Yet another embodiment of the invention is a method for treating cancer in a subj ect in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0068] Without being bound by a particular theory, provided herewith are the compounds that can modulate (e.g., inhibit) one or more members of the USP family. More specifically,and without being bound by a particular theory, it is believed that the compounds described herein can bind to one or more USP1.[691 As such, in another embodiment, the invention is a method of treating a USP1 mediated disorder in a subject in need thereof, in particular— USP1 mediated disorder comprising administering to the subject in need thereof a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0070] Another embodiment of the invention is use of a compound of the invention for treating cancer or a USP-mediated disorder, in particular USP1, mediated disorder in a subject.

[0071] Another embodiment of the invention is use of a compound of the invention for treating cancer or a USP-mediated disorder, in particular USP1 mediated disorder in a subject.

[0072] Another embodiment of the invention is use of a compound of the invention for the manufacture of a medicament for treating cancer or a USP mediated disorder, in particular USP1 mediated disorder in a subject.

[0073] Another embodiment of the invention is use of a compound of the invention for the manufacture of a medicament for treating cancer or a USP mediated disorder, in particular USP1 mediated disorder in a subject.

[0074] Compounds of the present invention, and pharmaceutically acceptable salts and / or compositions thereof, are useful for treating a variety of cancers, such as solid cancer and, more specifically, USP1 associated solid cancers.DETAILED DESCRIPTION

[0075] A description of example embodiments of the invention follows. Definitions

[0076] Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 7 5th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith,M B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0077] Unless specified otherwise within this specification, the nomenclature used in this specification generally follows the examples and rules stated in Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979, which is incorporated by reference herein for its exemplary chemical structure names and rules on naming chemical structures. Optionally, a name of a compound may be generated using a chemical naming program: ACD / Chem Sketch, Version 5.09 / September 2001, Advanced Chemistry Development, Inc., Toronto, Canada.

[0078] Compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (e.g., as described in: E. L. Eliel and S. H. Wilen, Stereo-chemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, racemic mixtures, and as individual diastereomers or enantiomers, with all possible isomers and mixtures thereof, including optical isomers, being included in the present invention.

[0079] As used herein the following definitions shall apply unless otherwise indicated. Further many of the groups defined herein can be optionally substituted. The listing of substituents in the definition is exemplary and is not to be construed to limit the substituents defined elsewhere in the specification.

[0080] The term ’’alkyl”, unless otherwise specified, refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1 -methylethyl (isopropyl), n-butyl, n- pentyl, and 1,1 -dimethylethyl (t-butyl). The term “C1-3alkyl” refers to an alkyl group as defined above having up to 3 carbon atoms. The term “C1-6alkyl” refers to an alkyl group as defined above having up to 6 carbon atoms. In appropriate circumstances, the term “alkyl” refers to a hydrocarbon chain radical as mentioned above which is bivalent.

[0081] The term “alkenyl”, unless otherwise specified, refers to an aliphatic hydrocarbon group containing one or more carbon-carbon double bonds and which may be a straight or branched or branched chain having about 2 to about 10 carbon atoms, e.g., ethenyl, 1 -propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l -propenyl, 1-butenyl, and 2-butenyl. The term “C2- salkenyl” refers to an alkenyl group as defined above having up to 6 carbon atoms. Inappropriate circumstances, the term “alkenyl” refers to a hydrocarbon group as mentioned above which is bivalent.

[0082] The term “alkynyl”, unless otherwise specified, refers to a straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond, and having in the range of 2 to up to 12 carbon atoms (with radicals having in the range of 2 to up to 10 carbon atoms presently being preferred) e.g., ethynyl, propynyl, and butnyl. The term “C2-6 alkynyl” refers to an alkynyl group as defined above having up to 6 carbon atoms. In appropriate circumstances, the term “alkynyl” refers to a hydrocarbyl radical as mentioned above which is bivalent.

[0083] The term “alkoxy” unless otherwise specified, denotes an alkyl, cycloalkyl, or cycloalkylalkyl group as defined above attached via an oxygen linkage to the rest of the molecule. The term “substituted alkoxy” refers to an alkoxy group where the alkyl constituent is substituted (i.e., -©-(substituted alkyl). For example “alkoxy" refers to the group -O-alkyl, including from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl oxy, and cyclohexyloxy. In appropriate circumstances, the term “alkoxy” refers to a group as mentioned above which is bivalent.

[0084] The term “cycloalkyl”, unless otherwise specified, denotes a non-aromatic mono or multi cyclic ring system of about 3 to 12 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include perhydronaphthyl, adamantyl and norbomyl groups, bridged cyclic groups, and sprirobicyclic groups, e.g., sprio (4,4) non-2-yl. The term “C3-6cycloalkyl” refers to a cycloalkyl group as defined above having up to 6 carbon atoms.

[0085] The term “cycloalkylalkyl”, unless otherwise specified, refers to a cyclic ringcontaining radical containing in the range of about 3 up to 8 carbon atoms directly attached to an alkyl group which is then attached to the main structure at any carbon from the alkyl group, such as cyclopropylmethyl, cyclobutyl ethyl, and cyclopentylethyl.

[0086] The term “cycloalkenyl”, unless otherwise specified, refers to cyclic ringcontaining radicals containing in the range of about 3 up to 8 carbon atoms with at least one carbon-carbon double bond such as cyclopropenyl, cyclobutenyl, and cyclopentenyl. The term“cycloalkenylalkyl” refers to a cycloalkenyl group directly attached to an alkyl group which is then attached to the main structure at any carbon from the alkyl group.[871 The term “aryl”, unless otherwise specified, refers to aromatic radicals having in the range of 6 up to 20 carbon atoms such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl.

[0088] The term “arylalkyl”, unless otherwise specified, refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH2C6H5 and -C2H5C6H5.

[0089] The term “heterocyclic ring”, unless otherwise specified, refers to a non-aromatic 3 to 15 member ring radical which consists of carbon atoms and at least one heteroatom selected from nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclic ring radical may be a mono-, bi-, tri- or tetracyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quatemized. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom.

[0090] The term “heterocyclyl”, unless otherwise specified, refers to a heterocylic ring radical as defined above. The heterocylcyl ring radical may be attached to the main structure at any heteroatom or carbon atom.

[0091] The term “heterocyclylalkyl”, unless otherwise specified, refers to a heterocylic ring radical as defined above directly bonded to an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group. Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

[0092] The term “heteroaryl”, unless otherwise specified, refers to an optionally substituted 5 to 14 member aromatic ring having one or more heteroatoms selected from N, O, and S as ring atoms. The heteroaryl may be a mono-, bi- or tricyclic ring system. Examples of such “heterocyclic ring” or “heteroaryl” radicals include, but are not limited to, oxazolyl,thiazolyl, imidazolyl, pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolyl, isoquinolyl, azetidinyl, acridinyl, benzodi oxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyrrolidinyl, pyridazinyl, oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl, chromanyl, and isochromanyl. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom. The term “substituted heteroaryl” also includes ring systems substituted with one or more oxide (-O-) substituents, such as pyridinyl N-oxides.

[0093] The term “heteroarylalkyl”, unless otherwise specified, refers to a heteroaryl ring radical as defined above directly bonded to an alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom from alkyl group.

[0094] The term “cyclic ring” refers to a cyclic ring containing 3 to 10 carbon atoms.

[0095] The term “substituted” unless otherwise specified, refers to substitution with any one or any combination of the following substituents which may be the same or different and are independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, substituted or unsubstituted guanidine, -COORX, -C(O)RX, -C(S)RX, - C(O)NRxRy, -C(O)0NRxRy, -NRyRz,-NRxCONRyRz, -N(Rx)SORy, -N(Rx)SO2Ry, -(=N- N(Rx)Ry), - NRxC(O)ORy, -NRxRy, -NRxC(O)Ry-, -NRxC(S)Ry-NRxC(S)NRyRz, -SONRxRy-,-SO2NRxRy-, -ORX, -ORxC(O)NRyRz, -ORxC(O)ORy-, -OC(O)RX, -OC(O)NRxRy, - RxNRyC(O)Rz, -RxORy, -RxC(O)ORy, -RxC(O)NRyRz, -RXC(O)RX, -RxOC(O)Ry, -SRX, -SORX, -SO2RX, and -ONO2, wherein Rx, Ryand Rzin each of the above groups can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl alkyl, substituted or unsubstituted heterocyclic ring, or substituted heterocyclylalkyl ring, or any two of Rx, Ryand Rzmay be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NRx(e.g., Rxcan be hydrogen or C1-6 alkyl) or S. Substitution or the combinations of substituents envisioned by this invention are preferably those that result in the formation of a stable or chemically feasible compound. The term stable as used herein refers to the compounds or the structure that are not substantially altered when subjected to conditions to allow for their production, detection and preferably their recovery, purification and incorporation into a pharmaceutical composition. The substituents in the aforementioned "substituted" groups cannot be further substituted. For example, when the substituent on "substituted alkyl" is "substituted aryl", the substituent on "substituted aryl" cannot be "substituted alkenyl".

[0096] The term "halo", "halide", or, alternatively, "halogen" means fluoro, chloro, bromo or iodo.

[0097] The terms "haloalkyl," "haloalkenyl," "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.

[0098] The term "protecting group" or "PG" refers to a substituent that is employed to block or protect a particular functionality. Other functional groups on the compound may remain reactive. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino- protecting groups include, but are not limited to, acetyl, trifluoroacetyl, tert-butoxycarbonyl(BOC), benzyl oxycarbonyl (CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable hydroxy-protecting groups include, but are not limited to, acetyl and silyl. A "carboxy-protecting group" refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Suitable carboxy-protecting groups include, but are not limited to, -CFECFESO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2- (trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- (diphenylphosphino)-ethyl, and nitroethyl. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0099] Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Non-limiting examples of intermediate mixtures include a mixture of isomers in a ratio of 10:90, 13:87, 17:83, 20:80, or 22:78. Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0100] The term "tautomers" refers to compounds, which are characterized by relatively easy interconversion of isomeric forms in equilibrium. These isomers are intended to be covered by this invention. "Tautomers" are structurally distinct isomers that interconvert by tautomerization. "Tautomerization" is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. "Prototropic tautomerization" or "proton-shift tautomerization" involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible (e.g. in solution), a chemical equilibrium of tautomers can be reached. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2, 4-dione and4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers.

[0101] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0102] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a3C-or14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. For example, in the case of variable R, the (C1-C4) alkyl or the -O-(Ci-C4) alkyl can be suitably deuterated (e.g., -CDs, - OCDs).

[0103] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0104] The term "stereoisomers" is a general term for all isomers of an individual molecule that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers), geometric (cis / trans) isomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).

[0105] “Electrophile” or “electrophilic moiety” is any moiety capable of reacting with a nucleophile (e.g., a moiety having a lone pair of electrons, a negative charge, a partial negative charge and / or an excess of electrons, for example a — SH group). Electrophiles typically areelectron poor or comprise atoms which are electron poor. Tn certain embodiments an electrophile contains a positive charge or partial positive charge, has a resonance structure which contains a positive charge or partial positive charge or is a moiety in which delocalization or polarization of electrons results in one or more atom which contains a positive charge or partial positive charge. In some embodiments, the electrophiles comprise conjugated double bonds, for example an α, β-unsaturated carbonyl or α, β-unsaturated thiocarbonyl compound.

[0106] A "leaving group or atom" (Lg or 1g) is any group or atom that will, under the reaction conditions, cleave from the starting material, thus promoting reaction at a specified site. Suitable examples of such groups unless otherwise specified are halogen atoms and mesyloxy, p-nitrobenzensulphonyloxy and tosyloxy groups.

[0107] “Prodrug” is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein (e.g., compound of structure (I), (IA), (IA-I), (IA-II), (IA-III), (IA-IV), (IA-V), or (IA-VI)). Thus, the term “prodrug” refers to a precursor of a biologically active compound that is pharmaceutically acceptable. In some aspects, a prodrug is inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A C S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergam on Press, 1987, Prodrug design is discussed generally in Hardma, et al. (Eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed., pp. 11-16 (1996) all of which are incorporated in full by reference herein. The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, are typically prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to amammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of a hydroxy functional group, or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.

[0108] In some embodiments, prodrugs include compounds of structure (I), (IA), (IA-I), (IA-II), (IA-III), (IA-IV), (IA-V), or (IA-VI), having a phosphate, phosphoalkoxy, ester or boronic ester substituent. Without being bound by theory, it is believed that such substituents are converted to a hydroxyl group under physiological conditions. Accordingly, embodiments include any of the compounds disclosed herein, wherein a hydroxyl group has been replaced with a phosphate, phosphoalkoxy, ester or boronic ester group, for example a phosphate or phosphoalkoxy group. For example, in some embodiments a hydroxyl group on the R1moiety is replaced with a phosphate, phosphoalkoxy, ester or boronic ester group, for example a phosphate or alkoxy phosphate group.

[0109] The term "ester" refers to a compound, which is formed by reaction between an acid and an alcohol with elimination of water. An ester can be represented by the general formula RCOOR'.

[0110] These prodrugs and esters are intended to be covered within the scope of this invention.

[0111] Additionally, the instant invention also includes the compounds which differ only in the presence of one or more isotopically enriched atoms for example replacement of hydrogen with deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon.

[0112] When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and sub combinations of ranges and specific embodiments therein are intended to be included.

[0113] The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary from, for example, between 1% and 15% of the stated number or numerical range.

[0114] The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") includes those embodiments, for example, an embodiment of anycomposition of matter, composition, method, or process, or the like, that "consist of’ or "consist essentially of’ the described features.

[0115] The following abbreviations and terms have the indicated meanings throughout; Abbreviations used herein have their conventional meaning within the chemical and biological arts.

[0116] The term "cell proliferation" refers to a phenomenon by which the cell number has changed as a result of division. This term also encompasses cell growth by which the cell morphology has changed (e.g., increased in size) consistent with a proliferative signal.

[0117] The term "co-administration," "administered in combination with," and their grammatical equivalents, as used herein, encompasses administration of two or more agents to an animal so that both agents and / or their metabolites are present in the animal at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0118] The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g. reduction of platelet adhesion and / or cell migration. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried. In one embodiment, the amount of compound administered ranges from about 0.1 mg to 5 g, from about 1 mg to 2.0 g, from about 100 mg to 1.5 g, from about 200 mg to 1.5 g, from about 400 mg to 1.5 g, and from about 400 mg to 1.0 g.

[0119] As used herein, "treatment," "treating," or "ameliorating" refers to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and / or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of theunderlying disorder being treated. In addition a therapeutic benefit is also achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. These terms are used interchangeably.

[0120] A "therapeutic effect," as that term is used herein, encompasses a therapeutic benefit and / or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0121] As used herein, an amount of a compound effective to treat a disorder, or a "therapeutically effective amount" refers to an amount of the compound which is effective, upon single or multiple dose administration to a subject or a cell, in curing, alleviating, relieving or improving one or more symptoms of a disorder.

[0122] As used herein, an amount of a compound effective to prevent a disorder, or a "prophylactically effective amount" of the compound refers to an amount effective, upon single- or multiple-dose administration to the subject, in preventing or delaying the onset or recurrence of a disorder or one or more symptoms of the disorder.

[0123] As used herein, the term "subject" or “patient” is intended to include human and non-human animals. Exemplary human subjects include a human patient having a disorder, e.g., a disorder described herein or a normal subject. The term "non-human animals" of the invention includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and / or agriculturally useful animals, e.g., sheep, cow, pig, etc., and companion animals (dog, cat, horse, etc.).

[0124] The methods described herein can be useful in both human therapeutics and veterinary applications (e.g., dogs, cats, cows, sheep, pigs, horses, goats, chickens, turkeys, ducks, and geese).

[0125] In some embodiments, the patient is a mammal, and in some embodiments, the patient is human.

[0126] "Radiation therapy" means exposing a patient, using routine methods and compositions known to the practitioner, to radiation emitters such as alpha-particle emitting radionuclides (e.g., actinium and thorium radionuclides), low linear energy transfer (LET) radiation emitters (i.e. beta emitters), conversion electron emitters (e.g. strontium-89 and samarium- 153-EDTMP), or high-energy radiation, including without limitation x-rays, gamma rays, and neutrons.

[0127] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes, but is not limited to, any and all, a non-toxic solvent, dispersant, excipient, adjuvant, fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled release matrices, colorants / flavoring, carriers, buffers, stabilizers, solubilizers, or other material and combinations thereof which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of being administered to a patient. One example of such a carrier is pharmaceutically acceptable oil typically used for parenteral administration. Pharmaceutically acceptable carriers are well known in the art.

[0128] It is understood that substituents and substitution patterns on the compounds of the invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below. In general, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted group" can have a suitable substituent at each substitutable position of the group and, when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. Alternatively, an "optionally substituted group" can be unsubstituted.

[0129] Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. If a substituent is itself substituted with more than one group, it is understood that these multiple groups can be on the same carbon atom or on different carbon atoms, as long as a stable structure results. The term "stable," as used herein, refers to compounds that are not substantially altered when subjectedto conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.[1301 As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, the relevant teachings of which are incorporated herein by reference in their entirety. Pharmaceutically acceptable salts of the compounds of this invention include salts derived from suitable inorganic and organic acids and bases that are compatible with the treatment of patients.

[0131] Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable acid addition salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0132] In some embodiments, exemplary inorganic acids which form suitable salts include, but are not limited thereto, hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Ilustrative organic acids which form suitable salts include the mono-, di- and tricarboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic,succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2 phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Either the mono- or di-acid salts can be formed, or such salts can exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.

[0133] In some embodiments, acid addition salts of the compounds of formula A are most suitably formed from pharmaceutically acceptable acids, and include, for example, those formed with inorganic acids, e.g., hydrochloric, sulfuric or phosphoric acids and organic acids e.g. succinic, maleic, acetic or fumaric acid.

[0134] Other non-pharmaceutically acceptable salts, e g., oxalates can be used, for example, in the isolation of compounds of formula (I), (IA), (IA-I), (IA-II), (IA-III), (IA-IV), (IA-V), or (IA-VI), for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt. Also included within the scope of the invention are base addition salts (such as sodium, potassium and ammonium salts), solvates and hydrates of compounds of the invention. The conversion of a given compound salt to a desired compound salt is achieved by applying standard techniques, well known to one skilled in the art.

[0135] An “anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent” refers to any agent useful in the treatment of a neoplastic condition. One class of anti-cancer agents comprises chemotherapeutic agents. “Chemotherapy” means the administration of one or more chemotherapeutic drugs and / or other agents to a cancer patient by various methods, including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal, or inhalation or in the form of a suppository The term “cell proliferation” refers to a phenomenon by which the cell number has changed as a result of division. This term also encompasses cell growth by which the cell morphology has changed (e.g., increased in size) consistent with a proliferative signal.

[0136] The term “selective inhibition” or “selectively inhibit” refers to a biologically active agent refers to the agent's ability to preferentially reduce the target signalling activity as compared to off-target signalling activity, via direct or indirect interaction with the target.

[0137] “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted aryl” means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

[0138] A “pharmaceutical composition” refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients thereof.

[0139] When introducing elements disclosed herein, the articles "a," "an," "the," and "said" are intended to mean that there are one or more of the elements. The terms "comprising," "having" and "including" are intended to be open-ended and mean that there may be additional elements other than the listed elements.

[0140] For example, provided herein are methods of treating various cancers in mammals (including humans and non-humans), comprising administering to a patient in need thereof a compound of the invention, or a pharmaceutically acceptable salt thereof. Such cancers include hematologic malignancies (leukemias, lymphomas, myelomas, myelodysplastic and myeloproliferative syndromes) and solid tumors (carcinomas such as oral, gall bladder, prostate, breast, lung, colon, pancreatic, renal, ovarian as well as soft tissue and osteo sarcomas, and stromal tumors).PHARMACEUTICAL COMPOSITIONS

[0141] The invention provides a pharmaceutical composition comprising one or more compounds of the present invention. The pharmaceutical composition may include one or more additional active ingredients as described herein. The pharmaceutical composition may be administered for any of the disorders described herein.

[0142] The subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a compound of the present invention as the active ingredient. Where desired, the pharmaceutical compositions contain a compound of the present invention as the active ingredient and one or more pharmaceutically acceptable carriers or excipients, such as inert solid diluents and fders, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.

[0143] The pharmaceutical compositions can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions. Where desired, the subject compounds and other agent(s) may be mixed into a preparation or both components may be formulated into separate preparations to use them in combination separately or at the same time.

[0144] Methods include administration of a compound of the present invention by itself, or in combination as described herein, and in each case optionally including one or more suitable diluents, fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled release matrices, colorants / flavouring, carriers, excipients, buffers, stabilizers, solubilizers, and combinations thereof.

[0145] Preparations of various pharmaceutical compositions are known in the art., e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999), all of which are incorporated by reference herein in their entirety.

[0146] The compounds or pharmaceutical composition of the present invention can be administered by any route that enables delivery of the compounds to the site of action, such as oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical administration (e g. transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. The compounds can also be administered intraadiposally or intrathecally.

[0147] The compositions can be administered in solid, semi-solid, liquid or gaseous form, or may be in dried powder, such as lyophilized form. The pharmaceutical compositions can be packaged in forms convenient for delivery, including, for example, solid dosage forms such as capsules, sachets, cachets, gelatins, papers, tablets, capsules, suppositories, pellets, pills, troches, and lozenges. The type of packaging will generally depend on the desired route ofadministration. Implantable sustained release formulations are also contemplated, as are transdermal formulations.METHOD OF TREATMENT

[0148] In further aspects, the present invention provides a use of a compound of the invention, of a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer. In some embodiments, the present invention provides a use of a compound of the invention in the manufacture of a medicament for the treatment of any of cancer and / or neoplastic disorders.

[0149] A compound or composition described herein can be used to treat a neoplastic disorder. A "neoplastic disorder" is a disease or disorder characterized by cells that have the capacity for autonomous growth or replication, e g., an abnormal state or condition characterized by proliferative cell growth. Exemplary neoplastic disorders include but are not limited to : carcinoma, sarcoma, metastatic disorders, Solid tumor such as oral, gall bladder, prostate, breast, lung, colon, pancreatic, renal, ovarian as well as soft tissue and osteo sarcomas, and stromal tumors for e.g., tumors arising from prostate, brain, bone, colon, pancreas, lung, breast, ovarian, and liver origin, hematopoietic neoplastic disorders, e.g., leukemias, lymphomas, myelomas, myelodysplastic , myeloproliferative syndromes and other malignant plasma cell disorders, and metastatic tumors. Prevalent cancers include but not limited to: breast, prostate, colon, lung, liver, and pancreatic cancers. Treatment with the compound can be in an amount effective to ameliorate at least one symptom of the neoplastic disorder, e.g., reduced cell proliferation, reduced tumor mass, etc.

[0150] In another embodiment, a patient or population of patients to be treated with a pharmaceutical composition of the present disclosure have a solid tumor. In some embodiments, a solid tumor is a melanoma, renal cell carcinoma, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gall bladder cancer, laryngeal cancer, liver cancer, thyroid cancer, stomach cancer, salivary gland cancer, prostate cancer, pancreatic cancer, or Merkel cell carcinoma. In some embodiments, a patient or population of patients to be treated with a pharmaceutical composition of the present disclosure have a hematological cancer. In some embodiments, the patient has a hematological cancer such as Diffuse large B cell lymphoma (“DLBCL”), Hodgkin’s lymphoma (“HL”), Non-Hodgkin’s lymphoma (“NHL”), Follicular lymphoma (“FL”), acute myeloid leukemia (“AML”), or Multiple myeloma(“MM”). In some embodiments, a patient or population of patients to be treated having the cancer selected from the group consisting of ovarian cancer, lung cancer and melanoma.[1511 Exemplary cancers including but not limited to tumors such as, the following: renal cancer, kidney cancer, glioblastoma multiforme, metastatic breast cancer; breast carcinoma; breast sarcoma; neurofibroma; neurofibromatosis; pediatric tumors; neuroblastoma; malignant melanoma; carcinomas of the epidermis; leukemias such as but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplastic syndrome, chronic leukemias such as but not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, hairy cell leukemia; polycythemia vera; lymphomas such as but not limited to Hodgkin’s disease, non-Hodgkin’s disease; multiple myelomas such as but not limited to smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma and extramedullary plasmacytoma; Waldenstrom’s macroglobulinemia; monoclonal gammopathy of undetermined significance; benign monoclonal gammopathy; heavy chain disease; bone cancer and connective tissue sarcomas such as but not limited to bone sarcoma, myeloma bone disease, multiple myeloma, cholesteatoma-induced bone osteosarcoma, Paget’s disease of bone, osteosarcoma, chondrosarcoma, Ewing’s sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissue sarcomas, angiosarcoma (hemangiosarcoma) , fibrosarcoma, Kaposi’s sarcoma, leiomyosarcoma, liposarcoma, lymphangio sarcoma, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma; brain tumors such as but not limited to, glioma, astrocytoma, brain stem glioma, ependymoma, oligodendroglioma, nonglial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, and primary brain lymphoma; breast cancer including but not limited to adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, Paget’s disease (including juvenile Paget’s disease) and inflammatory breast cancer; adrenal cancer such as but not limited to pheochromocytom and adrenocortical carcinoma; thyroid cancer such as but not limited to papillary or follicular thyroid cancer, medullary thyroid cancer and anaplastic thyroid cancer; pancreatic cancer such as but not limited to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor;pituitary cancers such as but limited to Cushing’s disease, prolactin-secreting tumor, acromegaly, and diabetes insipius; eye cancers such as but not limited to ocular melanoma such as iris melanoma, choroidal melanoma, and cilliary body melanoma, and retinoblastoma; vaginal cancers such as squamous cell carcinoma, adenocarcinoma, and melanoma; vulvar cancer such as squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget’s disease; cervical cancers such as but not limited to, squamous cell carcinoma, and adenocarcinoma; uterine cancers such as but not limited to endometrial carcinoma and uterine sarcoma; ovarian cancers such as but not limited to, ovarian epithelial carcinoma, borderline tumor, germ cell tumor, and stromal tumor; cervical carcinoma; esophageal cancers such as but not limited to, squamous cancer, adenocarcinoma, adenoid cyctic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; stomach cancers such as but not limited to, adenocarcinoma, fungating (polypoid) , ulcerating, superficial spreading, diffusely spreading, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; colon cancers; colorectal cancer, KRAS mutated colorectal cancer; colon carcinoma; rectal cancers; liver cancers such as but not limited to hepatocellular carcinoma and hepatoblastoma, gallbladder cancers such as adenocarcinoma; cholangiocarcinomas such as but not limited to pappillary, nodular, and diffuse; lung cancers such as KRAS-mutated nonsmall cell lung cancer, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma) , adenocarcinoma, large-cell carcinoma and small-cell lung cancer; lung carcinoma; testicular cancers such as but not limited to germinal tumor, seminoma, anaplastic, classic (typical) , spermatocytic, nonseminoma, embryonal carcinoma, teratoma carcinoma, choriocarcinoma (yolk-sac tumor) , prostate cancers such as but not limited to, androgenindependent prostate cancer, androgen-dependent prostate cancer, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; penal cancers; oral cancers such as but not limited to squamous cell carcinoma; basal cancers; salivary gland cancers such as but not limited to adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma; pharynx cancers such as but not limited to squamous cell cancer, and verrucous; skin cancers such as but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, acrallentiginous melanoma; kidney cancers such as but not limited to renal cell cancer, adenocarcinoma, hypernephroma,fibrosarcoma, transitional cell cancer (renal pelvis and / or uterer) ; renal carcinoma; Wilms’ tumor; bladder cancers such as but not limited to transitional cell carcinoma, squamous cell cancer, adenocarcinoma, carcinosarcoma. In addition, cancers include myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma and papillary adenocarcinomas.

[0152] In another embodiment, the disclosure provides a method of treating cancer in a subject, comprising administering to the subject in need thereof an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of described herein. In some embodiments, the cancer can comprise cancer cells with elevated levels of RAD 18 mRNA expression. In some embodiments, elevated levels of RAD 18 are elevated levels of RAD 18 protein. In some embodiments, RAD 18 levels can be detected using quantitative methods like microarray, RNA-Seq, or reverse transcriptase polymerase chain reaction (RT-PCR). In some embodiments, the levels of RAD 18 in a cancer cell can be detected prior to administration of the compounds described herein. In some embodiments, RAD 18 levels can be detected in a cancer sample obtained from a subject. In some embodiments, if a subject has elevated levels of RAD 18, the subject can be treated with the compounds described herein. In some embodiments, elevated levels of RAD 18 in cancer cells indicate that a subject administered the compounds or pharmaceutical compositions described herein is responsive to treatment using the compounds or pharmaceutical compositions described herein. In some embodiments, the compounds described herein are not administered to a subject with elevated levels of RAD 18.

[0153] In another embodiments, the cancer is a DNA damage repair pathway deficient cancer. In some embodiments, the cancer is a PARP inhibitor resistant or refractory BRCA1 or BRCA2-mutant cancer. In some embodiments, the cancer comprises cells with elevated levels of RAD 18, where the elevated levels of RAD 18 are at least as high as the RAD 18 mRNA and / or protein levels in ES2 cells or HEP3B217 cells.

[0154] In another embodiments, the cancer is a BRCA1 mutant cancer and / or a BRCA2 mutant cancer. In some embodiments, the cancer is a BRCA1 or BRCA2 wildtype cancer. Insome embodiments, the cancer is a BRCA1 -deficient cancer. In some embodiments, the cancer is a BRCA2-deficient cancer. In some embodiments, the cancer that comprises cancer cells with a mutation in a gene that encodes BRCA1 and / or BRCA2. In some embodiments, the cancer is a BRCA1 mutant cancer and BRCA2 deficient cancer. In some embodiments, the cancer is a BRCA1 deficient cancer and BRCA2 mutant cancer. In some embodiments, the cancer comprises cells with elevated levels of RAD 18, where the elevated levels of RAD 18 are at least as high as the RAD 18 mRNA and / or protein levels in ES2 cells or HEP3B217 cells.

[0155] Further preferred, the invention provides for methods for inhibiting USP activity in a cell, comprising contacting the cell in which inhibition of USP1 activity is desired with an effective amount of a compound of formula (I), (IA), (IA-I), (IA-II), (IA-III), (IA-IV), (IA- V), and (IA-VI), pharmaceutically acceptable salts thereof or pharmaceutical compositions containing the compound or pharmaceutically acceptable salt thereof.

[0156] In one embodiment, a cell in which inhibition of USP1 activity is desired is contacted with an effective amount of a compound of formula (I), (IA), (IA-I), (IA-II), (IA- III), (IA-IV), (IA-V), and (IA-VI), to negatively modulate the activity of USP 1.

[0157] Further preferred, a therapeutically effective amount of pharmaceutically acceptable salt or pharmaceutical compositions containing a compound of formula (I), (IA), (IA-I), (IA-II), (IA-III), (IA-IV), (IA-V), and (IA-VI), may be used

[0158] By negatively modulating the activity of USP1, the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced USP1 activity within the cell. The cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of USP1.

[0159] Further preferred, methods of treating cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of formula (I), (IA), (IA-I), (IA-II), (IA-III), (IA-IV), (IA-V), and (IA-VI), pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the compound or pharmaceutically acceptable salts thereof are provided.

[0160] The compositions and methods provided herein may be used for the treatment of a USP1 associated cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of formula (I), (IA), (IA-I), (IA-II), (IA-III), (IA-IV), (IA-V), and (IA-VI), pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the compound or pharmaceutically acceptable salts thereof are provided. In one embodiment, the USP1 -associated cancer is breast cancer or ovarian cancer.

[0161] Further preferred, the cancer is Breast cancer, ovarian cancer, prostate cancer, lung cancer, colorectal cancer or pancreatic cancer.

[0162] Further preferred, the cancer is prostate cancer or pancreatic cancer.

[0163] Further preferred, the cancer is lung cancer or colorectal cancer

[0164] Further preferred, the cancer is Breast cancer or ovarian cancer.

[0165] The concentration and route of administration to the patient will vary depending on the cancer to be treated. The compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be coadministered with other anti-neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as in combination with other targeted agents or radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.

[0166] The invention further provides herein a compound of formula (I), (IA), (IA-I), (IA- II), (IA-III), (IA-IV), (IA-V), and (IA-VI), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein for use in therapy.

[0167] The invention further provides herein a compound of formula (I), (IA), (IA-I), (IA- II), (IA-III), (IA-IV), (IA-V), and (IA-VI), or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein for use in the treatment of cancer.

[0168] The invention further provides herein is a compound of formula (I), (IA), (IA-I), (IA-II), (IA-III), (IA-IV), (IA-V), and (IA-VI), or a pharmaceutically acceptable salt or solvate thereof for use in the inhibition of USP1.

[0169] The invention further provides herein is a compound of formula (I), (IA), (IA-I), (IA-II), (IA-III), (IA-IV), (IA-V), and (IA-VI), or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof as defined herein, for use in the treatment of a USP1 associated disease or disorder.

[0170] The invention further provides herein is the use of a compound of formula (I), (IA), (IA-I), (IA-II), (IA-III), (IA-IV), (IA-V), and (IA-VI), or a pharmaceutically acceptable saltor solvate thereof, as defined herein in the manufacture of a medicament for the treatment of cancer.[1711 The invention further provides herein is a use of a compound of formula (I), (IA), (IA-I), (IA-II), (IA-III), (IA-IV), (IA-V), and (IA-VI), or a pharmaceutically acceptable salt or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of activity of USP1.

[0172] The invention further provides herein is the use of a compound of formula (I), (IA), (IA-I), (IA-II), (IA-III), (IA-IV), (IA-V), and (IA-VI), or a pharmaceutically acceptable salt or solvate thereof, as defined herein, in the manufacture of a medicament for the treatment of a USP1 associated disease or disorder.

[0173] The invention further provides herein is a method for treating cancer in a patient in need thereof, the method comprising (a) determining that cancer is associated with a USP1 (e g., a USP1 -associated cancer) (e.g., as determined using a assay or kit); and (b) administering to the patient a therapeutically effective amount of a compound of formula (I), (IA), (IA-I), (IA-II), (IA-III), (IA-IV), (IA-V), and (IA-VI), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0174] Metastases of the aforementioned cancers can also be treated or prevented in accordance with the methods described herein.COMBINATION THERAPIES

[0175] In some embodiments, a compound described herein is administered together with an additional "second" therapeutic agent or treatment. The choice of second therapeutic agent may be made from any agent that is typically used in a monotherapy to treat the indicated disease or condition. As used herein, the term "administered together" and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of any of the formulas described herein, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0176] The compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co-administered with otheranti -neoplastic compounds, e g., chemotherapy, or used in combination with other treatments, such as in combination with other targeted agents or radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.

[0177] The compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds comprising the step of administering simultaneously or sequentially to a subject in need thereof at least one other anti-cancer agent, anti-inflammatory agent, immunosuppressive agent, steroid, non-steroidal anti-inflammatory agent, antihistamine, analgesic, or a mixture thereof.PROCESS FOR PREPARATION OF THE COMPOUND OF THE INVENTION

[0178] The instant compounds of the present invention may be prepared by the following general process. The process provided herein can similarly be applied to synthesize all possible variation of the compound of the invention, and in particular compounds of formulas (I), (IA), (IA-I), (IA-II), (IA-III), (IA-IV), (IA-V), and (IA-VI), as provided herein above with all intended modification or without any modification. Unless otherwise indicated, the variables such as R, Cy, Cy1, Cy2, L, L1, L2and Cy2used here in various intermediates or compounds of formulas are to be constructed to be the variables defined herein above in relation to compound of the invention and in particular to the compound of (I), (IA), (IA-I), (IA-II), (IA-III), (IA- IV), (IA-V), or (IA-VI).Synthetic Scheme I: This schematic representation of scheme aims to provide a possible route for the preparation of a compound of formula (I), (IA), (IA-I), (IA-II), (IA-III), (IA-IV), (IA-V), or (IA-VI).

[0179] A compound of formula (a) can be coupled with a compound of formula (b) wherein Lg is leaving group such as halogen, in presence of a suitable base such as NH4OHand NaOAc to form a compound of formula (c). A compound of formula (c) is reacted with ReI, wherein Reis substituted or unsubstituted alkyl, in presence of a suitable base such as NaH to form a compound of formula (d). A compound of formula (d) can be converted as a compound of formula (e). A compound of formula (e) can be coupled with a compound of formula (f) wherein Lg is leaving group such as halogen to form a compound of formula (g). A compound of formula (g) can be cyclized to form a desired compound of formula (I) wherein L, L1and L2are absent, and R is Hydrogen or Halogen.Illustration-1:Synthetic Scheme IA: This schematic representation of scheme aims to provide a possible route for the preparation of a compound of formula (I), (IA), (IA-I), (IA-II), (IA-III), (IA-IV),(IA-V), or (IA-VI).

[0180] A compound of formula (e) can be coupled with a compound of formula (fl) wherein Lg is leaving group such as halogen to form a compound of formula (gl). A compound of formula (gl) can be cyclized to form a compound of formula (h) wherein L1and L2are absent. A compound of formula (h) (wherein Lg is Br or I) can be reacted with a compound offormula (i) under Suzuki reaction conditions in presence of suitable palladium catalyst and a suitable base to form a desired compound of formula (I) wherein L1and L2are absent. Alternatively, A compound of formula (h) (wherein Lg is F) can be reacted with a suitable amine (e.g. piperidine, R-NH2, RR-NH or cyclic amine with free NH group) in presence of a suitable base to form a desired compound of formula (I) wherein L1and L2are absentIllustration-2:Synthetic Scheme IB: This schematic representation of scheme aims to provide a possible route for the preparation of a compound of formula (I), (IA), (IA-I), (IA-II), (IA-III), (IA-IV),(IA-V), or (IA-VI).

[0181] A compound of formula (fl) wherein Lg is leaving group such as halogen, can be coupled with a compound of formula (i) under Suzuki reaction conditions in presence of suitable palladium catalyst and a suitable base to form a compound of formula (jl). A compound of formula (jl) can be coupled with a compound of formula (e) in presence of suitable reagent such as HATU and a suitable base such as DIPEA to form a compound offormula (g). A compound of formula (g) can be cyclized in presence of suitable base such as DBU to form a desired compound of formula (I) wherein L1and L2are absent.Illustration-3:Synthetic Scheme II: This schematic representation of scheme aims to provide a possible route for the preparation of a compound of formula (I), (IA), (IA-I), (IA-II), (IA-III), (IA-IV),(IA-V), or (IA-VI).

[0182] A compound of formula (1) can be converted as a compound of formula (m) which can then be . reacted with a compound of formula (k) in presence of suitable reagent such asHATU and a suitable base such as DIPEA to form a compound of formula (n). A compound of formula (n) can be cyclized in presence of suitable base such as DBU to form a desired compound of formula (I), wherein L, L1and L2are absent.Illustration-4:Synthetic Scheme IIA: This schematic representation of scheme aims to provide a possible route for the preparation of a compound of formula (I), (IA), (IA-I), (IA-II), (IA-III), (IA-IV), (IA-V), or (IA-VI).

[0183] A compound of formula (11) wherein Lg is leaving group such as halogen, can be converted as a compound of formula (ml). A compound of formula (k) can be coupled with a compound of formula (ml) in presence of suitable reagent such as HATU and a suitable base such as DIPEA to form a compound of formula (nl). A compound of formula (nl) can be cyclized in presence of suitable base such as DBU to form a compound of formula (hl). A compound of formula (hl) can be coupled with a compound of formula (i) under Suzuki reaction conditions in presence of suitable palladium catalyst and a suitable base such as CS2CO3to form a desired compound of formula (I) wherein L1and L2are absent.Illustration-5:Synthetic Scheme IIA: This schematic representation of scheme aims to provide a possible route for the preparation of a compound of formula (I), (IA), (IA-I), (IA-II), (IA-III), (IA-IV), (IA-V), or (IA-VI).SCHEME IIA

[0184] A compound of formula (1) can be coupled with a compound of formula (i) underSuzuki reaction conditions in presence of suitable palladium catalyst and a suitable base such as CS2CO3to form a compound of formula (o). A compound of formula (o) can be converted as a compound of formula (p). A compound of formula (p) can be coupled with a compound of formula (k) in presence of suitable reagent such as HATU and a suitable base such as DIPEA to form a compound of formula (q). A compound of formula (q) can be cyclized in presence of suitable base such as DBU to form a desired compound of formula (I) wherein L1and L2are absent.Illustration-6:EXPERIMENTAL DETAILS

[0185] The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations. In the following examples molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Those molecules with two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereomers. Single enantiomers / diastereomers may be obtained by methods known to those skilled in the art.Table-3Intermediate 1A: 4-(4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile.•

[0186] To a solution of 3,3-dibromo-l,l,l-trifluoropropan-2-one (3.0 g, 1.0 eq) in water (3 ml, 2 vol) was added NaOAc (0.93 gm, 1.0 eq) (3 ml, 2 vol). Reaction mixture was heated at 100 °C for 1 hr. Cool the reaction mixture to RT. 4-formylbenzonitrile (1.5 gm, 1 eq)dissolved in MeOH (15 ml. 10 vol) was added to reaction mixture followed by addition of NH4OH (10 ml, 6 vol). Stirred the reaction mixture at RT for 2hr. Upon completion of reaction, the reaction mixture was poured in water and extracted with (3 X ) EtOAc. Combined the organic layer and dried over Na2SO4, evaporated under vacuum. Crude mixture was purified by column chromatography, eluted at 15-20 % EtOAc- n-Hexane to get 4-(4-(trifluoromethyl)- lH-imidazol-2-yl)benzonitrile( 0.5 gm). 1H NMR, CDC13(400 MHz): 10.1(bs, 1H), 7.99-7.97 (m, 2H), 7.77-7.7- (m, 2H), 7.44(s, 1H). Mass: 238.1[M+1],Intermediate IB: 2-methyl-4-(4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile:

[0187] 3,3 -dibromo- l,l,l-trifluoropropan-2-one (1.0 eq) and NaOAc (1.0 eq) was dissolved in water (2 vol). Reaction mixture was heated at 100 °C for 1 hr. Cooled the reaction mixture to RT. 4-formyl-2-methylbenzonitrile (1 eq) was dissolved in MeOH (10 vol) and added to reaction mixture followed by addition of NH4OH (10 ml, 6 vol). Stirred the reaction mixture at RT for 2hr. Reaction mixture was poured in water and extracted with (3 X) EtOAc. Combined the organic layer and dried over Na2SO4, evaporated under vacuum. Crude was purified by column chromatography, eluted at 15-20 % EtOAc- n-Hexane to get 2-methyl-4- (4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile ( 0.8 gm). Mass: 252.4 [M+l],Intermediate 2A: 4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile;

[0188] 4-(4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile (0.3 gm , 1.0 eq) was dissolved in THF( 3 ml, 10 vol). Solution was was cooled at 0 °C, to it NaH (0.04 g, 1.3 eq) was added portion wise at same temp. lodomethane (0.23 g, 1.3 eq) was added and reaction mixture was stirred at RT for 3 hr. Reaction mixture was poured into water and extracted in EtOAc(3x), Combined the organic layer and dried over Na2SO4, evaporated under vacuum. Crude was purified by column chromatography, eluted at 10-25 % EtOAc- n-Hexane to get 4- (l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile ( 0.25 gm). 1H NMR, CDC13(400 MHz): 7.81-7.72 (m, 4H), 7.37(s, 1H), 3.83(s, 3H). Mass: 252.0 [M+l],Intermediate 2B: 2-methyl-4-(l-methyI-4-(trifluoromethyl)-lH-imidazol-2-yI)benzonitrile.’

[0189] 4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile (1.0 eq) was dissolved in THF(10 vol). Reaction mixture was cooled at 0 °C, to it NaH (1.3 eq) was added portion wise at same temp. lodomethane (1.3 eq) was added and reaction mixture was stirred at RT for 3 hr. Reaction mixture was poured into water and extracted in EtOAc(3x), Combined the organic layer and dried over Na2SO4, evaporated under vacuum. Crude was purified bycolumn chromatography, eluted at 10-25 % EtOAc- n-Hexane to get 2-m ethyl -4-( 1 -methyl -4- (trifluoromethyl)-lH-imidazol-2-yl)benzonitrile ( 0.8 gm) Mass: 266.49 [M+l],Intermediate 3A: N-hydroxy-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)benzimidamide:

[0190] To a solution of 4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile ( 0.5 gm , 1.0 eq) in EtOH( 5 ml, 10 vol) was added Na2CO3(0.1 g, 0.5 eq) and NH2OH. HC1 (0.13 g, 1.0 eq) , and reaction mixture was heated at 800C for 16 hr. Reaction mixture was evaporated under vacuum to dryness, Water (10 ml) was added and stirred at RT for 2 hr. Solid precipitated was filtered off and dried under vacuum to get N-hydroxy-4-(l-methyl-4- (trifluoromethyl)-lH-imidazol-2-yl)benzimidamide ( 0.38 gm). Crude was used for the next step without purification. Mass: 285.0 [M+l],Intermediate 3B: N-hydroxy-2-methyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazoI-2- yl)benzimidamide:

[0191] To a solution of 2-methyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)benzonitrile (1.0 eq) in EtOH( 10 vol) was added Na2COs (0.5 eq) and NH2OH. HC1 (1.0 eq) , and reaction mixture was heated at 800C for 16 hr. Reaction mixture was evaporated under vacuum to dryness, Water (10 ml) was added and stirred atRT for 2 hr. Solid precipitated was filtered off and dried under vacuum to get N-hydroxy-2-methyl-4-(l-methyl-4- (trifluoromethyl)-lH-imidazol-2-yl)benzimidamide ( 0.38 gm). Crude was used for the next step without purification Mass: 299.35 [M+l],Intermediate 3C: 4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzoic acid:

[0192] To a solution of 4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzonitrile ( 0.5 gm , 1.0 eq) in n-Butanol( 5 ml, 10 vol) was added t KOH (0.55 g, 5.0 eq) , and reaction mixture was heated at 1100C for 24 hr. Reaction mixture was poured into water, and pH adjusted (—4-5) using IN HC1 solution and extracted in EtOAc(3x), Combined the organic layer, and dried over Na2SO4, evaporated under vacuum. Crude was purified by column chromatography, eluted at 50-55 % EtOAc- n-Hexane to get 4-( 1 -methyl-4-(trifluoromethyl)- lH-imidazol-2-yl)benzoic acid ( 0.6 gm). Mass: 271.0 [M+l],Intermediate 4A: N-((5-bromo-2-fluorobenzoyl)oxy)-4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)benzimidamide:

[0193] Solution of N-hydroxy-4-(l -methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)benzimidamide ( 0.38 gm , 1.0 eq) and 5-bromo-2-fluorobenzoic acid (0.38 g, 1.3 eq) in DMF ( 5 ml, 10 vol), was cooled at 0 ° C. To it DIPEA (0.93 ml, 4.0 eq) was added stirred for 15 min . HATU(0.6 g, 1.3 eq) was added and reaction mixture was stirred at RT for 16 hr. Reaction mixture was poured into water and extracted in EtOAc(3x), Combined the organic layer and dried over Na2SO4, evaporated under vacuum. Crude was purified by column chromatography, eluted at 40-45 % EtOAc- n-Hexane to get N-((5-bromo-2- fluorobenzoyl)oxy)-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzimidamide ( 0.30 gm). Mass: 486.8 [M+l],Intermediate 4B: N-((2-fluoro-4-methoxybenzoyl)oxy)-4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)benzimidamide;

[0194] Was prepared using a similar condition as described above for Intermediate 4A using Intermediate 3 A and 2-fluoro-4-methoxybenzoic acid to give - 150 mg of title Intermediate 4B. Mass: 437.1 [M+l],Intermediate 4C: N-((2-bromo-4-fluorobenzoyl)oxy)-4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)benzimidamide.‘

[0195] Was prepared using a similar condition as described above for Intermediate 4A using Intermediate 3A and 2-bromo-4-fluorobenzoic acid a to give - 250 mg of title Intermediate 4C. Mass: 486.1 [M+l],Intermediate 4D: 5-bromo-2-fluoro-N-((4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)benzoyl)oxy)benzimidamide.'

[0196] Solution of 5-bromo-2-fluoro-N-hydroxybenzimidamide ( 0.3 gm , 1.0 eq) and 4- (l-methyl-4-(trifluorom ethyl)- lH-imidazol-2-yl)benzoic acid (0.41 g, 1.2 eq) in DMF ( 5 ml, 10 vol), was cooled at 0 ° C. To it DIPEA (0.7 ml, 3.0 eq) was added stirred for 15 min at same temp. HATU (0.73 g, 1.5 eq) was added and reaction mixture was stirred at RT for 16 hr. Reaction mixture was poured into water and extracted in EtOAc(3x), Combined the organic layer and dried over Na2SO4, evaporated under vacuum. Crude was purified by column chromatography, eluted at 40-45 % EtOAc- n-Hexane to get 5-bromo-2-fluoro-N-((4-(l- methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzoyl)oxy)benzimidamide ( 0.35 gm). Mass: 486.8[M+1],Intermediate 4E: 4-(l-methyl-4-(trifluoromethyl)-lFI-imidazol-2-yl)-N-((4-(l-methyl-4- (trifluoromethyl)-lH-imidazol-2-yl)benzoyl)oxy)benzimidamide:[1971 Was prepared using a similar condition as described above for Intermediate 4A using Intermediate 3A and Intermediate 3C to give ~ 300 mg of title Intermediate 4E Mass: 537.2 [M+l],Intermediate 4F: N-((2-fluoro-4-methoxybenzoyl)oxy)-2-methyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzimidamide:

[0198] Was prepared using a similar condition as described above for Intermediate 4A using Intermediate 3B and 2-fluoro-4-methoxybenzoic acid a to give ~ 150 mg of title Intermediate 4F Mass: 451.5 [M+l],Intermediate 4G: N-((2-bromo-4-fluorobenzoyl)oxy)-2-methyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzimidamide.•

[0199] Was prepared using a similar condition as described above for Intermediate 4A using Intermediate 3B and 2-bromo-4-fluorobenzoic acid a to give ~ 250 mg of title Intermediate 4C Mass: 500.28 [M+l],Intermediate 4H: N-((2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-4- carbonyl)oxy)-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzimidamide:

[0200] Solution of Intermediate 3A (0.25 gm, 1.0 eq) and (2-amino-3-cyano-4, 5,6,7- tetrahydrobenzo[b]thiophene-4-carboxylic acid) (0.25 g, 1.3 eq) in DMF (5 ml, 10 vol), was cooled to 0 °C . To it DIPEA (0.6 ml, 4.0 eq) was added stirred for 15 min on same temp. HATU (0.44 g, 1.3 eq) was added and reaction mixture was stirred at RT for 16 hr. Reaction mixture was poured into water and extracted in EtOAc(3x), Combined the organic layer and dried over Na2SO4, evaporated under vacuum. Crude was purified by column chromatography, eluted at 40-45 % EtOAc- n-Hexane to get N-((2-amino-3-cyano-4,5,6,7- tetrahydrobenzo[b]thiophene-4-carbonyl)oxy)-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol- 2-yl)benzimidamide ( 0.17 gm). Mass: 489.0 [M+l],Intermediate 41: N-((2-amino-3-cyano-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-4- carbonyl)oxy)-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzimidamide:

[0201] Solution of Intermediate 3A (0.4 gm, 1.0 eq) and (2-amino-3-cyano-4-methyl- 4,5,6,7-tetrahydrobenzo[b]thiophene-4-carboxylic acid) (0.37 g, 1.3 eq) in DMF (5 ml, 10 vol), was cooled at 0°C . To it DIPEA (0.6 ml, 4.0 eq) was added stirred for 15 min on sametemp. HATU (0.44 g, 1.3 eq) was added and reaction mixture was stirred at RT for 16 hr. Reaction mixture was poured into water and extracted in EtOAc(3x), Combined the organic layer and dried over Na2SO4, evaporated under vacuum. Crude was purified by column chromatography, eluted at 40-45 % EtOAc- n-Hexane to get N-((2-amino-3-cyano-4-methyl- 4, 5,6,7-tetrahydrobenzo[b]thiophene-4-carbonyl)oxy)-4-(l-methyl-4-(tri fluoromethyl)- 1EI- imidazol-2-yl)benzimidamide ( 0.17 gm). Mass: 503.1 [M+l],Intermediate 4 J: N-((2-amino-3-cyanobenzo[b]thiophene-4-carbonyl)oxy)-4-(l-methyl-4- (trifluoromethyl)-lH-imidazol-2-yl)benzimidamide:

[0202] Solution of Intermediate 3A (0.13 gm, 1.0 eq) and (2-amino-3- cyanobenzo[b]thiophene-4-carboxylic acid) (0.2 g, 1.3 eq) in DMF (5 ml, 10 vol), was cooled to 0°C. To it DIPEA (0.6 ml, 4.0 eq) was added stirred for 15 min on same temp. HATU (0.44 g, 1.3 eq) was added and reaction mixture was stirred at RT for 16 hr. Reaction mixture was poured into water and extracted in EtOAc(3x), Combined the organic layer and dried over Na2SO4, evaporated under vacuum. Crude was purified by column chromatography, eluted at 40-45 % EtOAc- n-Hexane to get N-((2-amino-3-cyanobenzo[b]thiophene-4-carbonyl)oxy)-4- (l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzimidamide ( 0.17 gm). Mass: 485.2 [M+l],Intermediate 4K: N-((l-naphthoyl)oxy)-4-(l-methyl-4-(trifluoromethyI)-lH-imidazol-2- yl)benzimidamide:

[0203] Solution of Intermediate 3 (0.3 gm, 1.0 eq) and (1-naphthoic acid) (0.24 g, 1.3 eq) in DMF (5 ml, 10 vol), was cooled at 0° C. To it DIPEA (0.73 ml, 4.0 eq) was added stirred for 15 min on same temp. HATU(0.5 g, 1.3 eq) was added and reaction mixture was stirred at RT for 16 hr. Reaction mixture was poured into water and extracted in EtOAc(3x), Combined the organic layer and dried over Na2SO4, evaporated under vacuum to get N-((l- naphthoyl)oxy)-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzimidamide ( 0.28 gm). Crude used for next step.Intermediate 5A: 3-(4-bromophenyl)-5-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)-l,2,4-oxadiazole;

[0204] Ssolution of Intermediate 3C (1.0 eq) and 4-bromo-N-hydroxybenzimidamide (0.38 g, 1.3 eq) in in 2-MeTHF (10 vol), was cooled at 00C. To it DIPEA (0.93 ml, 4.0 eq) was added and stirred for 15 min on same temp. T3P (1.3 eq) was added and reaction mixturewas stirred at 700C for 16 hr. Reaction mixture was poured into water and extracted in EtOAc(3x), Combined the organic layer and dried over Na2SO4, evaporated under vacuum. Crude was purified by column chromatography, eluted at 40-45 % EtOAc- n-Hexane to get 3- (4-bromophenyl)-5-(4-(l-methyl-4-(trifluoromethyI)-lH-imidazol-2-yl)phenyl)-l,2,4- oxadiazole ( 0.30 gm). Mass: 450.4 [M+l],Intermediate 5B: 5-(4-bromophenyl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)-l,2,4-oxadiazole:

[0205] Solution of Intermediate 3A (1.0 eq) and 4-bromobenzoic acid (1.3 eq) was dissolved in 2-MeTHF (10 vol), was cooled at 0 ° C. To it DIPEA (4.0 eq) was added stirred for 15 min on same temp. T3P (1.3 eq) was added and reaction mixture was stirred at 700C for 16 hr. Reaction mixture was poured into water and extracted in EtOAc(3x), Combined the organic layer and dried over Na2SO4, evaporated under vacuum. Crude was purified by column chromatography, eluted at 40-45 % EtOAc- n-Hexane to get 5-(4-bromophenyl)-3-(4-(l- methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole ( 0.35 gm). Mass: 450.4 [M+l],Intermediate 5C : 5-(2-chloropyrimidin-4-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)-l,2,4-oxadiazole;

[0206] Solution of Intermediate 3A (1.0 eq) and 2-chloropyrimidine-4-carboxyIic acid (1.3 eq) in 2-MeTHF (10 vol), was cooled to 0 ° C. To it DIPEA (4.0 eq) was added and stirred for 15 min on same temp. T3P (1.3 eq) was added and reaction mixture was stirred at 700C for 16 hr. Reaction mixture was poured into water and extracted in EtOAc(3x), Combined the organic layer and dried over Na2SO4, evaporated under vacuum. Crude was purified by column chromatography, eluted at 40-45 % EtOAc- n-Hexane to get 5-(2- chloropyrimidin-4-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)- 1,2,4-oxadiazole ( 0.15 gm). Mass: 450.4 [M+l],Intermediate 5D : 5-(2-chloropyrimidin-5-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)-l,2,4-oxadiazole:

[0207] Solution of Intermediate 3A (1.0 eq) and 2-chloropyrimidine-5-carboxylic acid (1.3 eq) in 2-MeTHF (10 vol), was cooled to 0 °C. To it DIPEA (4.0 eq) was added stirred for15 min on same temp. T3P (1.3 eq) was added and reaction mixture was stirred at 700C for16 hr. Reaction mixture was poured into water and extracted in EtOAc(3x), Combined theorganic layer and dried over Na2SO4, evaporated under vacuum. Crude was purified by column chromatography, eluted at 40-45 % EtOAc- n-Hexane to get 5-(2-chloropyrimidin-5-yl)-3- (4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole ( 0.12 gm). Mass: 450.4 [M+l],Intermediate 6A: 4-bromo-2-fluoro-N-hydroxybenzimidamide.'

[0208] To a solution of 4-bromo-2-fluorobenzonitrile (1.0 eq) in EtOH( 10 vol) was added Na2CO3(0.5 eq) and NH2OH. HC1 (1.0 eq) and reaction mixture was heated at 800C for 16 hr. Reaction mixture was evaporated under vacuum to dryness, to it Water (10 ml) was added and stirred at RT for 2 hr. Solid precipitated was filtered off and dried under vacuum to get 4- bromo-2-fluoro-N-hydroxybenzimidamide ( 0.40 gm). Crude was used for the next step without purification Mass: 234.3 [M+l],Intermediate 6B: 2-(4-bromophenyl)-N-hydroxyacetimidamide;

[0209] To a solution of 2-(4-bromophenyl)acetonitrile (1.0 eq) in EtOH( 10 vol) was added Na2CO3(0.5 eq) and NH2OH. HC1 (1.0 eq) , and reaction mixture was heated at 800C for 16 hr. Reaction mixture was evaporated under vacuum to dryness, to it Water (10 ml) was added and stirred at RT for 2 hr. Solid precipitated was filtered off and dried under vacuum to get 2-(4-bromophenyl)-N-hydroxyacetimidamide (0.42 gm). Crude was used for the next step without purification. Mass: 230.4 [M+l],Intermediate 7A: N-((2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-4- carbonyl)oxy)-4-bromo-2-fluorobenzimidamide:

[0210] Solution of Intermediate 6A (1.0 eq) and (2-amino-3-cyano-4, 5,6,7- tetrahydrobenzo[b]thiophene-4-carboxylic acid) (1.3 eq) in DMF (5 ml, 10 vol), was cooled to 0°C . To it DIPEA (4.0 eq) was added and stirred for 15 min at same temp . HATU (1.3 eq) was added and reaction mixture was stirred at RT for 16 hr. Reaction mixture was poured into water and extracted in EtOAc(3x), Combined the organic layer and dried over Na2SO4, evaporated under vacuum. Crude was purified by column chromatography, eluted at 40-45 % EtOAc- n- Hexane to get N-((2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-4-carbonyl)oxy)-4- bromo-2-fluorobenzimidamide ( 0.24 gm). Mass: 438.13 [M+l],Intermediate 7B: N-((2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-4- carbonyl)oxy)-2-(4-bromophenyl)acetimidamide:

[0211] Solution of Intermediate 6B (1.0 eq) and (2-amino-3-cyano-4,5,6,7- tetrahydrobenzo[b]thiophene-4-carboxylic acid) (1.3 eq) in DMF (5 ml, 10 vol), was cooled to 0°C. To it DIPEA (4.0 eq) was added stirred for 15 min on same temp. HATU (1.3 eq) was added and reaction mixture was stirred at RT for 16 hr. Reaction mixture was poured into water and extracted in EtOAc(3x), Combined the organic layer and dried over Na2SO4, evaporated under vacuum. Crude was purified by column chromatography, eluted at 50-55 % EtOAc- n- Hexane to get N-((2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-4- carbonyl)oxy)-2-(4-bromophenyl)acetimidamide ( 026 gm). Mass: 434.18 [M+l],Intermediate 8A: 2-amino-4-(3-(4-bromo-2-fluorophenyl)-l,2,4-oxadiazol-5-yl)-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carbonitrile:

[0212] To a solution of Intermediate 7A (1.0 eq) in Dioxane (10 vol), was added DBU (2.5 eq) stirred and reaction mixture was heated at 110 °C for 16 hr. Reaction mixture was evaporated under vacuum. Crude was purified by column chromatography, eluted at 30-35 % EtOAc- n-Hexane to get 2-amino-4-(3-(4-bromo-2-fluorophenyl)-l,2,4-oxadiazol-5-yl)-4.5.6.7-tetrahydrobenzo[b]thiophene-3-carbonitrile( 0.15 gm). Mass: 420.4 [M+l],Intermediate 8B: 2-amino-4-((3-(4-bromophenyl)-l,2,4-oxadiazol-5-yl)methyl)-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carbonitrile;

[0213] To a solution of Intermediate 7B (1.0 eq) in Dioxane (10 vol) was added DBU (2.5 eq) and the reaction mixture was heated at 110 °C for 16 hr. Reaction mixture was evaporated under vacuum. Crude was purified by column chromatography, eluted at 30-35 % EtOAc- n-Hexane to get 2-amino-4-((3-(4-bromophenyl)-l,2,4-oxadiazol-5-yl)methyl)-4.5.6.7-tetrahydrobenzo[b]thiophene-3-carbonitrile ( 0.15 gm). Mass: 416.5 [M+l],Intermediate 9A: l-(4-(4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)ethan-l-one.•

[0214] Solution of 3, 3 -dibromo- 1,1,1 -trifluoropropan-2-one (1.0 eq) and NaOAc (1.0 eq) in water (2 vol) was heated at 100 °C for 1 hr. Cooled the reaction mixture to RT. 4- formylbenzonitrile (1 eq) was dissolved in MeOH (10 vol) and added to reaction mixture followed by addition of NH4OH (6 vol). Stirred the reaction mixture at RT for 2hr. Reaction mixture was poured in water and extracted with (3 X) EtOAc. Combined the organic layer and dried over Na2SO4, evaporated under vacuum. Crude was purified by column chromatography, eluted at 15-20 % EtOAc- n-Hexane to get l-(4-(4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)ethan-l-one ( 0.6 gm). Mass: 255.14[M+1],Intermediate 9B: 1 -(4- (1 -methyl-4-(trifluoromethyl)-l H-imidazol-2-yl)phenyl)ethan-1 -one:

[0215] To a solution of l-(4-(4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)ethan-l-one (1.0 eq) in THF(10 vol) was added NaH (1.3 eq) portion wise at at 0 °C . lodomethane (1.3 eq) was added and reaction mixture was stirred at RT for 3 hr. Reaction mixture was poured into water and extracted in EtOAc(3x), Combined the organic layer and dried over Na2SO4, evaporated under vacuum. Crude was purified by column chromatography, eluted at 10-25 % EtOAc- n-Hexane to get l-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)ethan- 1-one ( 0.4 gm). Mass: 279.27 [M+l],Intermediate 9C: 4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)benzohydrazide.•

[0216] To a solution of l-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)ethan-l-one (1.0 eq) in EtOH( 10 vol) was added NH2NH2OH (35 %)(1.0 eq) , and reaction mixture was heated at 800C for 16 hr. Reaction mixture was evaporated under vacuum to dryness, to it Water (10 ml) was added and stirred at RT for 2 hr. Solid precipitated was filtered off and dried under vacuum to get N-hydroxy-4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)benzimidamide ( 0.38 gm). Crude was used for the next step without purification. Mass: 285.12 [M+l],Example-1 5-(5-bromo-2-fluorophenyl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)- 1,2,4-oxadiazole:

[0217] To a solution of N-((5-bromo-2-fluorobenzoyl)oxy)-4-(l-methyl-4- (trifluoromethyl)-lH-imidazol-2-yl)benzimidamide ( 0.3 gm , 1.0 eq) in Dioxane ( 3 ml, 10 vol) was added DBU (0.23 ml, 2.5 eq) stirred and reaction mixture was heated at 110 °C for 16 hr. Reaction mixture was evaporated under vacuum. Crude was purified by column chromatography, eluted at 20-25 % EtOAc- n-Hexane to get 5-(5-bromo-2-fluorophenyl)-3- (4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole ( 0.16 gm). Mass: 466.9 [M+l],Example-2-(2-fluoro-4-methoxyphenyl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-1,2,4-oxadiazole:

[0218] Was prepared using a similar condition as described for Intermediate 5A using Intermediate 4B to give -180 mg of title as white solid Mass: 419.4 [M+l],Example-3 5-(2-bromo-4-fluorophenyl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)- 1,2,4-oxadiazole:

[0219] Was prepared using a similar condition as described for Intermediate 5A using Intermediate 4C to give -150 mg of title as off white solid Mass: 468.1 [M+l],Example-4 3-(5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-2-fluorophenyl)-5-(4-(l-methyl-4- (trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole:

[0220] To a solution of 3-(5-bromo-2-fluorophenyl)-5-(4-(l-methyl-4-(trifluoromethyl)- lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole (0.2 g, 1.0 eq) and 4-cyclopropyl-6-methoxy-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (0.17 g, 1.5 eq) in Dioxane (5 ml) was added CS2CO3(0.17 g, 3.0 eq) , N2gas was purged for 15 mins. tetrakis(triphenylphosphine)palladium (0) (0.05 g, 0.1 eq) were added and purged again for 5 mins. Reaction mixture was heated at 1100C for 16 h. Reaction mixture was poured into ice- cold water (20 ml) and extracted with EtOAc(3 X 50 ml), combined organic layer and dried over Na2SO4. Purified by column chromatography compound eluted at 60-70% EtOAc-n- Hexane to give 3-(5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-2-fluorophenyl)-5-(4-(l- methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole. Mass: 536.6 [M+l],Example-5 5-(4-fluoro-2'-isopropyl-[1,1'-biphenyl]-3-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl) phenyl)-l,2,4-oxadiazole

[0221] Was prepared using a similar Suzuki condition described above for Example 4 above using Example 1 and 2-iso propyl-phenyl boronic acid to give - 40 mg of title compound as off white solid. Mass: 507.5 [M+l],Example-65-(2'-isopropyl-4-(4-methylpiperazin-l-yl)-[1,1'-biphenyl]-3-yl)-3-(4-(l-methyl-4- (trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole

[0222] To a solution of example 5 (1 .0 eq) in DMF ( 2 ml, 10 vol) was added K2CO3 (3.0 eq) and 1 -methylpiperazine (5.0 eq) d and reaction mixture was heated at 100 °C for 16 hr. Reaction mixture was poured into ice cold water and extracted with (3X) EtOAc, combined organic layer dried over Na2SO4and evaporated under vacuum. Crude was purified by column chromatography, eluted at 2-3 % MeOH-DCM to get example 6 as off white solid. Mass: 587.2 [M+l],Example-7 5-(2-fluoro-4-methoxyphenyl)-3-(2-methyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)-l,2,4-oxadiazole;

[0223] Was prepared using a similar condition as described for Intermediate 5A using Intermediate 4F to give -150 mg of title as white solid Mass: 433.5 [M+l],Example-8 5-(2-bromo-4-fluorophenyl)-3-(2-methyl-4-(l-methyI-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)-l,2,4-oxadiazole;

[0224] Was prepared using a similar condition as described for Intermediate 5A using Intermediate 4G to give -180 mg of title as off white solid. Mass: 482.6 [M+l],General procedure for following exampleTo a solution of example 1 (1.0 eq) in DMF ( 2 ml, 10 vol) was added K2CO3(3.0 eq) and corresponding amine (5.0 eq) and reaction mixture was heated at 100 °C for 16 hr. Reaction mixture was poured into ice cold water and extracted with (3X) EtOAc, combined organic layer dried over Na2SO4and evaporated under vacuum. Crude was purified by column chromatography, eluted at 3-5 % MeOH-DCM to get examples 9 to 12General procedure for following example

[0225] To a solution of example 2 (1.0 eq) in DMF ( 2 ml, 10 vol) was added K2CO3 (3.0 eq) and corresponding amine (5.0 eq) reaction mixture was heated at 100 °C for 16 hr. Reaction mixture was poured into ice cold water and extracted with (3X) EtOAc, combined organic layer dried over Na2SO4 and evaporated under vacuum. Crude was purified by column chromatography, eluted at 3-5 % MeOH-DCM to get examples 13-18General procedure for following example

[0226] To a solution of Example 3 (1.0 eq) and Boronic Acid (1.5 eq) in Dioxane (5 ml) was added K2CO3(3.0 eq) , N2gas purged for 15 mins. tetrakis(triphenylphosphine)palladium (0) (0.05 eq) was added and purged again for 5 mins. Reaction mixture was heated at 1100C for 16 h. Reaction mixture was poured into ice-cold water (20 ml) and extracted with EtOAc (3 X 50 ml), combined organic layer and dried over Na2SO4. Compound was purified by column chromatography by elution at 60-70% EtOAc-n-Hexane to give examples 19-44 and 55.General procedure for following example

[0227] To a solution of example 7 (1.0 eq) in DMF ( 2 ml, 10 vol) was added K2CO3 (3.0 eq) and corresponding amine (5.0 eq) and reaction mixture was heated at 100 °C for 16 hr. Reaction mixture was poured into ice cold water and extracted with (3X) EtOAc, combined organic layer dried over Na2SO4and evaporated under vacuum. Crude was purified by column chromatography, ( 3-5 % MeOH-DCM) to get examples 45 to 49Example-505-(5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-2-fluorophenyl)-3-(4-(l-methyl-4- (trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole.-

[0228] Was prepared using a similar condition as described for Example 4 using Example 1 and 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine to give ~40 mg of title as off white solid. Mass: 537.5 [M+l],Example-51 -(5-bromo-2-fluorophenyl)-5-(4-(l-methyI-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)- 1,2,4-oxadiazole;

[0229] Was prepared using a similar condition as described for Intermediate 5A using Intermediate 3C and 4-bromo-2-fluoro-N-hydroxybenzimidamide to give -180 mg of title as off white solid. Mass: 468.15 [M+l],Example-523,5-bis(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole

[0230] Was prepared using a similar condition described above for Example 1 using Intermediate 4E to give - 90 mg of title compound as off white solid. Mass: 519.1 [M+l],rH NMR, DMSO(400 MHz): 8.35-8.33(m, 2H), 8.26-8.24(m, 2H), 8.08-7.99 (m, 6H), 3.90- 388(m, 6H).Example-53 3-(5-bromo-2-(4-methylpiperazin-l-yl)phenyl)-5-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)-l,2,4-oxadiazole

[0231] To a solution of 3-(5-bromo-2-fluorophenyl)-5-(4-(l-methyl-4- (trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole (1.0 eq) in DMF ( 2 ml, 10 vol) was added K2CO3(3.0 eq) and 1 -methylpiperazine (5.0 eq) and reaction mixture was heated at 100 °C for 16 hr. Reaction mixture was poured into ice cold water and extracted with (3X) EtOAc, combined organic layer dried over Na2SO4 and evaporated under vacuum. Crude was purified by column chromatography, eluted at 2-3 % MeOH-DCM to get 3-(5-bromo-2-fluorophenyl)-5-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4- oxadiazole as off white solid. Mass: 548.18 [M+l],Example-54 5-(2-(2-isopropylphenyl)pyrimidin-4-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)-l,2,4-oxadiazole:

[0232] Was prepared using a similar condition as described for Example 4 using Intermediate 5C and 2-iso propyl-phenyl boronic acid to give ~31 mg of title as off white solid. Mass: 491.5 [M+l],General procedure for Example 56 and 57

[0233] To a solution of Example 7 (1.0 eq) and Boronic Acid (1.5 eq) in Dioxane (5 ml) was added CS2CO3(3.0 eq) , N2gas purged for 15 mins. tetrakis(triphenylphosphine)palladium (0) (0.05 eq) was added and purged again for 5 mins. Reaction mixture was heated at 1100C for 16 h. Reaction mixture was poured into ice-cold water (20 ml) and extracted with EtOAc (3 X 50 ml), combined organic layer and dried over Na2SO4. Purified by column chromatography compound eluted at 60-70% EtOAc-n-Hexane to give examples 56 and 57Example- 58(S)-4-(5-fluoro-2-(3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4- oxadiazol-5-yl)phenyl)but-3-yn-2-ol:

[0234] Example 3 (1.0 eq) and (S)-but-3-yn-2-ol (1.2 eq) was dissolved in Et3N (5 ml), N2gas was purged for 15 mins. PdCl2(PPh3)2(0.1 eq), CuI (0.05 eq) were added and purged again for 5 mins. Reaction mixture was heated at 800C for 16 h. Reaction mixture was poured into Sat aqs NH4CI (20 ml) and extracted with EtOAc (3 X), combined organic layer and dried over Na2SO4. Purified by column chromatography compound eluted at 60-70% EtOAc-n-Hexane to give (S)-4-(5-fluoro-2-(3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)-l,2,4-oxadiazol-5-yl)phenyl)but-3-yn-2-ol. Mass: 457.34 [M+l],Example- 59 (S)-4-(5-fluoro-2-(3-(2-methyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-1.2.4-oxadiazol-5-yl)phenyl)but-3-yn-2-ol:

[0235] Example 7 (1.0 eq) and (S)-but-3-yn-2-ol (1.2 eq) was dissolved in Et3N (5 ml), N2gas was purged for 15 mins. PdCl2(PPh3)2(0.1 eq), Cui (0.05 eq) were added and purged again for 5 mins. Reaction mixture was heated at 800C for 16 h. Reaction mixture was poured into Sat aqs NH4Cl (20 ml) and extracted with EtOAc (3 X), combined organic layer and dried over Na2SO4. Purified by column chromatography compound eluted at 60-70% EtOAc-n- Hexane to get (S)-4-(5-fluoro-2-(3-(2-methyl-4-(l-methyl-4-(trifluoromethyl)-lEI-imidazol-2- yl)phenyl)-l,2,4-oxadiazol-5-yl)phenyl)but-3-yn-2-ol. Mass: 471.26 [M+l],Example-60 (R)-4-(5-fluoro-2-(3-(2-methyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-1.2.4-oxadiazol-5-yl)phenyl)but-3-yn-2-ol :

[0236] Example 7 (1.0 eq) and (R)-but-3-yn-2-ol (1.2 eq) was dissolved in Et3N (5 ml), N2gas was purged for 15 mins. PdCl2(PPh3)2(0.1 eq), Cui (0.05 eq) were added and purged again for 5 mins. Reaction mixture was heated at 800C for 16 h. Reaction mixture was poured into Sat aqs NH4Cl (20 ml) and extracted with EtOAc (3 X), combined organic layer and dried over Na2SO4. Purified by column chromatography compound eluted at 60-70% EtOAc-n- Hexane to get (R)-4-(5-fluoro-2-(3-(2-methyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol- 2-yl)phenyl)-l,2,4-oxadiazol-5-yl)phenyl)but-3-yn-2-ol. Mass: 471.26 [M+l],Example-615-(2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-4-methoxyphenyl)-3-(4-(l-methyl-4- (trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole

[0237] To a cooled (0 °C) solution of tert-butyl 3-(5-methoxy-2-(3-(4-(l-methyl-4- (tri fluoromethyl)- lH-imidazol-2-yl)phenyl)-l, 2, 4-oxadiazol-5-yl)phenyl)-3, 8- diazabicyclo[3.2.1]octane-8-carboxylate (1.0 eq) in DCM (2 ml) was added 4 M HC1 indioxane (2 ml) . Reaction mixture was stirred at RT for 1 h. concentrated under vacuum, crude was triturated with diethyl ether and dried under vacuum to get 5-(2-(3,8- diazabicyclo[3.2.1]octan-3-yl)-4-methoxyphenyl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)-l,2,4-oxadiazole. Mass: 548.18 [M+l],Example-625-(2'-isopropyl-[1,1'-biphenyl]-4-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)- 1 ,2,4-oxadiazole:

[0238] Was prepared using a similar condition as described for Example 4 using Intermediate 5B and 2-iso propyl-phenyl boronic acid to give ~28 mg of title as off white solid. Mass: 489.4 [M+l],Example-63 3-(2'-isopropyl-[1,1'-biphenyl]-4-yl)-5-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)-l,2,4-oxadiazole;

[0239] Was prepared using a similar condition as described for Example 4 using Intermediate 5A and 2-iso propyl-phenyl boronic acid to give ~45 mg of title as off white solid. Mass: 489.4 [M+l],Example-64 -(4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)phenyl)-3-(4-(l-methyl-4-(trifluoromethyl)- lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole.’

[0240] Was prepared using a similar condition as described for Example 4 using Intermediate 5B and 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrimidine to give ~21 mg of title as off white solid. Mass: 519.2 [M+l],Example-65 -(2-(2-isopropylphenyl)pyrimidin-5-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)-l,2,4-oxadiazole;

[0241] Was prepared using a similar condition as described for Example 4 using Intermediate 5D and 2-iso propyl-phenyl boronic acid to give ~25 mg of title as off white solid. Mass: 491.4 [M+l],Example-663,5-bis(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-lH-l,2,4-triazole;

[0242] To a solution of N-hydroxy-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)benzimidamide (1.0 eq) and 4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)benzonitrile (2.0 eq) in BuOH ( 2 vol) was added K2CO3(3.0 eq) and reaction mixture was heated at 150 °C for 16 hr. Reaction mixture was evaporated under vacuum. Crude was purified by column chromatography, eluted at 4-5 % MeOH-DCM to get 3,5-bis(4-(l-methyl-4- (trifluoromethyl)-lH-imidazol-2-yl)phenyl)-lH-l,2,4-triazole as off white solid (30 mg). 1H NMR, DMSO(400 MHz): 8.28-8.24(m, 4H), 8.01(s, 2H), 7.95-7.93(m, 4H) 3.87 (s, 6H), 3.83 (s, 2H). Mass: 519.2 [M+l],Example 67 2-amino-4-(3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4- oxadiazol-5-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile:

[0243] To a solution of Intermediate 4H (0.17 gm, 1.0 eq) in Dioxane (2 ml, 10 vol) was added DBU (0.12 ml, 2.5 eq) and reaction mixture was heated at 110 °C for 16 hr. Reaction mixture was evaporated under vacuum. Crude was purified by column chromatography, eluted at 20-25 % EtOAc- n-Heaxne to get desired title compound 2-amino-4-(3-(4-(l-methyl-4- (trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazol-5-yl)-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carbonitrile ( 0.06 gm). 1H NMR, DMSO (400 MHz): 8.13- 8.11(m, 2H), 8.00(s, 1H), 7.95-7.93(m, 2H), 7.12(bs, 2H), 3.85(s, 3H), 2.59-2.54(m, 2H), 2.17- 2.08(m, 2H), 1.86-1.84(m, 2H). Mass: 471.1 [M+l],Example 68 2-amino-4-methyl-4-(3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4- oxadiazol-5-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile:

[0244] To a solution of Intermediate 41 (0.17 gm, 1.0 eq) in Dioxane (2 ml, 10 vol) was added DBU (0.12 ml, 2.5 eq) and reaction mixture was heated at 110 °C for 16 hr. Reaction mixture was evaporated under vacuum. Crude was purified by column chromatography, eluted at 20-25 % EtOAc- n-Heaxne to get desired title compound 2-amino-4-methyl-4-(3-(4-(l- methyl-4-(tri fluoromethyl)- lH-imidazol-2-yl)phenyl)-l, 2, 4-oxadiazol-5-yl)-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carbonitrile ( 0.06 gm). Mass: 485.1 [M+l],Example 692-amino-4-(3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4- oxadiazol-5-yl)benzo[b]thiophene-3-carbonitrile:[2451 To a solution of Intermediate 4J (0.17 gm, 1.0 eq) in Dioxane (2 ml, 10 vol)was added DBU (0.12 ml, 2.5 eq) and reaction mixture was heated at 110 °C for 16 hr. Reaction mixture was evaporated under vacuum. Crude was purified by column chromatography, eluted at 20-25 % EtOAc- n-Heaxne to get desired title compound 2-amino-4-(3-(4-(l-methyl-4- (tri fluoromethyl)- lH-imidazol-2-yl)phenyl)-l, 2, 4-oxadiazol-5-yl)benzo[b]thiophene-3- carbonitrile ( 0.06 gm) Mass: 466.2 [M+l],Example 70 3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-5-(naphthalen-l-yl)-l,2,4- oxadiazole:

[0246] To a solution of Intermediate 4K ( 0.28 gm , 1.0 eq) in Dioxane ( 2 ml, 10 vol) was added DBU (0.2 ml, 2.5 eq) and reaction mixture was heated at 110 °C for 16 hr. Reaction mixture was evaporated under vacuum. Crude was purified by column chromatography, eluted at 20-25 % EtOAc- n-Hexane to get 3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)-5-(naphthalen-l-yl)-l,2,4-oxadiazole ( 0.08 gm) Mass: 421.2 [M+l],Example-71 -amino-5-(3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazol-5- yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile:

[0247] Was prepared using a similar condition as described for Intermediate 5A using Intermediate 3A and 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-5-carboxylic acid to give ~80 mg of title as off white solid. Mass: 471.4 [M+l],Example-72 2-amino-7-(3-(2-fluoro-4-(2-fluoropyridin-3-yl)phenyl)-l,2,4-oxadiazol-5-yl)-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carbonitrile:

[0248] To a solution of Intermediate 8A (1.0 eq) and (2-fluoropyri din-3 -yl)boronic acid (1.5 eq) in Dioxane: H2O (5: 1 ml) was added CS2CO3(3.0 eq) , N2gas purged for 15 mins. PdC12(dppf) (0.1 eq) was added and purged again for 5 mins. Reaction mixture was heated at 1100C for 16 h. Reaction mixture was poured into ice-cold water (20 ml) and extracted with EtOAc(3 X 50 ml), combined organic layer and dried over Na2SO4. Purified by column chromatography compound eluted at 60-70% EtOAc-n-Hexane to give 2-amino-7-(3-(2-fluoro-4-(2-fluoropyri din-3-yl)phenyl)- 1,2, 4-oxadiazol-5-yl)-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carbonitrile. Mass: 436.5 [M+l],Example-73 2-amino-7-(3-(4-(2-fluoropyridin-3-yl)benzyl)-l,2,4-oxadiazol-5-yl)-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carbonitrile:

[0249] To a solution of Intermediate 8B (1.0 eq) and (2-fluoropyridin-3-yl)boronic acid (1.5 eq) in Dioxane: H2O (5:1 ml) was added CS2CO3(3.0 eq) , N2gas purged for 15 mins. PdC12(dppf) (0.1 eq) was added and purged again for 5 mins. Reaction mixture was heated at 1100C for 16 h. Reaction mixture was poured into ice-cold water (20 ml) and extracted with EtOAc (3 X 50 ml), combined organic layer and dried over Na2SO4. Purified by column chromatography compound eluted at 60-65% EtOAc-n-Hexane to give 2-amino-7-(3-(4-(2- fluoropyridin-3-yl)benzyl)-l,2,4-oxadiazol-5-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carbonitrile. Mass: 436.5 [M+l],Example-74 -(isoquinolin-l-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4- oxadiazole:

[0250] Was prepared using a similar condition as described for Intermediate 5A using Intermediate 3A and isoquinoline-l-carboxylic acid to give ~32 mg of title as off white solid. Mass: 422.3 [M+l],Example-75 2-(3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazol-5- yl)naphthalen-l-ol.'

[0251] Was prepared using a similar condition as described for Intermediate 5A using Intermediate 3A and l-hydroxy-2-naphthoic acid to give ~45 mg of title as off white solid. Mass: 437.4 [M+l],Example-76 4-(3-bromo-4-(3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4- oxadiazol-5-yl)phenyl)morpholine

[0252] To a solution of example 3 (1.0 eq) in DMF ( 2 ml, 10 vol), was added K2CO3(3.0 eq) and morpholine (5.0 eq) and reaction mixture was heated at 100 °C for 16 hr. Reaction mixture was poured into ice cold water and extracted with (3X) EtOAc, combined organiclayer dried over Na2SO4and evaporated under vacuum. Crude was purified by column chromatography, eluted at 2-3 % MeOH-DCM to get 4-(3-bromo-4-(3-(4-(l-methyl-4- (trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazol-5-yl)phenyl)morpholine as off white solid. Mass: 535.24 [M+l],PART C: Biological Activity

[0253] The biological and / or pharmacological properties of the compounds of this invention may be confirmed by variety of assays. The biological and / or pharmacological assays which can be carried out with the compounds according to the invention and / or their pharmaceutically acceptable salts is exemplified below.Test-1: USPI / UAF 1 Assay:

[0254] Deubiquitinase activity of USPI / UAF 1 was monitored in a fluorometric assay using ubiquitin-rhodaminel 10 as substrate. Briefly, enzymatic reactions were conducted in an assay buffer composed of 50 mM HEPES, pH 7.8, 0.5 mM EDTA, 1, 1 mM DTT, 0.1 mg / mL BSA, and 0.01% Tween-20 that contained 0.1 nM USP1 / UAF1. Compounds were tested at desired concentrations. The plates were incubated for 15 min to attain equilibrium, and then the enzymatic reaction was initiated by dispensing 100 nM Ub-Rho solution. Fluorescence measurement was performed in a spectramax M2 , where kinetic measurements of rhodamine fluorescence were acquired using a 480 nm excitation / 540 nm emission filter set. The change in fluorescence intensity over a 30-minute reaction period was normalized against no-inhibitor and no-enzyme controls and the resulting percent inhibition data were fitted to a sigmoidal dose response using a four-parameter Hill equation. Data was be analysed and percent inhibition and / or IC50 for each test compound is calculated accordingly.Test-2: Cell Viability assay (MTT assay):Cell viability assay was carried out using 10% FBS supplemented media. Cells (HCT116, H358, A549 or AGS) were seeded at desired density in 96 well plate and incubated in a humidified CO2incubator. After 24hours of plating, test compounds at desired concentration range were added to the plates and incubated in the CO2incubator for 72hours. Post 72hrs treatment, 12.5μL of MTT was added to all wells including DMSO control. MTT treated plates were incubated further for 3 hours and MTT crystals were dissolved using 125 μL of DMSO. Absorbance was read on a BIORAD iMark Microplate plate reader at a wavelength of 570 nm. Data was be analysed and percent inhibition and / or IC50 for each test compound is calculated accordingly.Test-3: Cell Viability assay (MTT assay):

[0255] Cell viability assay was carried out using ~ 3 to 10% FBS supplemented media. Cells (H1792 or UWB1.289) were seeded at desired density in 96 well plate and incubated in a humidified CO2incubator. After 24hours of plating, test compounds at desired concentration range were added to the plates and incubated in the CO2incubator for 168 hours. Post 168 hrs treatment, 12.5 μL of MTT was added to all wells including DMSO control. MTT treated plates were incubated further for 3 hours and MTT crystals were dissolved using 125 μL of DMSO. Absorbance was read on a BIO-RAD iMark Microplate plate reader at a wavelength of 570 nm. Data was be analysed and percent inhibition and / or IC50 for each test compound is calculated accordingly.Test 5: Cell Viability assay (CTG assay):

[0256] Growth inhibition assays was carried out using 10% FBS supplemented media. Cells (MDA-MB-436) were seeded at a desired concentration of 1000-6,000 cells / well in a well plate with desired number of wells. Test compounds at a desired concentration range were added after 24 hours. Growth was assessed using the Cell Titer-Gio (CTG, Cell Signaling) for measuring reduction at 7th day after the addition of test compound chemiluminescence values were read by a plate reader. Data was analysed and percent inhibition and / or IC50 for each test compound is calculated accordingly.Test-6: Colony formation assay:

[0257] For the colony formation assay, cells were seeded at low density in 12 or 6-well plates and grown overnight in humidified incubator. The medium was replaced with growth medium containing different concentrations of the test compound. After 48hrs, media containing fresh compound was replenished and the plates were incubated for an additional 7- 8 days to allow for colony formation. Cells were then fixed with methanol and stained with 0.1% crystal. The number of colonies consisting of 50 or more cells was scored. Cells treated with equal volume of DMSO, and saline were used as a control and designated as 100%. Doseresponse curves were generated by using GraphPad Prism.Table-4

[0258] The present invention has been described above with the aid of functional building blocks illustrating the implementation of specified functions and relationships thereof. The boundaries of these functional building blocks have been arbitrarily defined herein for the convenience of the description. Alternate boundaries can be defined so long as the specified functions and relationships thereof are appropriately performed.

[0259] The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, by applying knowledge within the skill of the art, readily modify and / or adapt for various applications such specific embodiments, without undue experimentation, without departing from the general concept of the present invention. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology herein is for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance

Claims

What is Claimed is:

1. A compound of F ormul a (IA) :or a tautomer thereof, prodrug thereof, N-oxide thereof, a pharmaceutically acceptable ester thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, whereinR-Cy is selected fromX1is absent, O, S, CR1, NR1or N;X2is absent, O, S, CR2, NR2or N;X3is absent, O, S, CR3, NR3or N;X4is absent, O, S, CR4, NR4or N;X5is absent, O, S, CR6, NR6or N;With the proviso that each of X1, X2, X3, X4and X5are not absent at the same time; when one or more of X1, X2, X3, X4and X5is or are absent it will always form a stable ring.Cy1is selected fromwherein Cy1is optionally substituted with one or more Rb. each occurrence of L, L1and L2are independently absent or independently selected from substituted or unsubstituted C1-4alkyl, substituted or unsubstituted C2-4alkenyl, substituted or unsubstituted C2-4alkynyl, substituted or unsubstituted C3-10cycloalkyl, substituted or unsubstituted C3-10 heterocycloalkyl, -(CRbRc)n-. O, S, -S(=O)P-, -C(=O)- ,-NRx- , -S(=O)P-NH-, - NH-S(=O)P-, -CO-NRX- and -NRX-CO-; each occurrence of R1, R2, R3, R4, and R6are independently selected from hydrogen, hydroxy, halogen, CN (Cyano), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkenyl, substituted or unsubstituted haloalkynyl, substituted or unsubstituted haloalkoxy, -C(=O)ORb, -C(=O)Rb, -C(=S)Rb, - C(=O)NRbRc, -C(=O)ONRbRc, -NRbRc, -NRb-ORc, -NRbC(=O)NRbRc, -NRbS(=O)Rc, - NRbS(=O)2Rc, -NRb-ORc, =N-NRbRc, -NRbC(=O)ORc, -NRbC(=O)Rc, -NRbC(=S)Rc,-NRbC(=S)NRbRc, -SONRbRc, -SO2NRbRc, -ORb, -ORbC(=O)NRbRc, -ORbC(=O)ORc, - OC(=O)Rb, -OC(=O)NRbRc, -RbNRcC(=O)Rb, -RbORc, -RbC(=O)ORc, -RbC(=O)NRbRc, - RbC(=O)Rc, -RbOC(=O)Rc, -SRb, -SORC, -SO2Rb, -CRbRcC(=O)Rbor -CRbRcC(=S)Rz, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino or any two of Rband Rcmay be joined to a form a substituted or unsubstituted saturated or unsaturated 3-6 member ring, which may optionally include heteroatoms which may be same or different and are selected from O, NRaor S or ; optionally wherein any two variables of R1and R2or R2and R3or R3and R4or R4and R6together with the ring they attached can form a 5 to 8 membered optionally substituted ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NRXor S.Cy2is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl; each occurrence of R and R5are independently selected from hydrogen, hydroxy, halogen, CN (Cyano), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkenyl, substituted or unsubstituted haloalkynyl, substituted or unsubstituted haloalkoxy, -C(=O)ORb, -C(=O)Rb, -C(=S)Rb, -C(=O)NRbRc, -C(=O)ONRbRc, - NRbRc, -NRb-ORc, -NRbC(=O)NRbRc, -NRbS(=O)Rc, -NRbS(=O)2Rc, -NRb-ORc, =N-NRbRc, - NRbC(=O)ORc, -NRbC(=O)Rc, -NRbC(=S)Rc,-NRbC(=S)NRbRc, -SONRbRc, -SO2NRbRc, -ORb, - ORbC(=O)NRbRc, -ORbC(=O)ORc, -OC(=O)Rb, -OC(=O)NRbRc, -RbNRcC(=O)Rb, -RbORc, - RbC(=O)ORc, -RbC(=O)NRbRc, -RbC(=O)Rc, -RbOC(=O)Rc, -SRb, -SORC, -SO2Rb, - CRbRcC(=O)Rbor -CRbRcC(=S)Rz, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substitutedheterocyclylalkyl ring, or substituted or unsubstituted amino or any two Rband Rcmay be joined to a form a substituted or unsubstituted saturated or unsaturated 3-6 member ring, which may optionally include heteroatoms which may be same or different and are selected from O, NRaor S; each occurrence of Rdand Reare independently selected from hydrogen, hydroxy, halogen, CN (Cyano), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, -C(=O)ORb, - C(=O)Rb, -C(=S)Rb, -C(=O)NRbRc, -C(=O)ONRbRc, -NRbRc, -NRb-ORc, -NRbC(=O)NRbRc, - NRbS(=O)Rc, -NRbS(=O)2Rc, -NRb-ORc, =N-NRbRc, -NRbC(=O)ORc, -NRbC(=O)Rc, - NRbC(=S)Rc,-NRbC(=S)NRbRc, -SONRbRc, -SO2NRbRc, -ORb, -ORbC(=O)NRbRc, - ORbC(=O)ORc, -OC(=O)Rb, -OC(=O)NRbRc, -RbNRcC(=O)Rb, -RbORc, -RbC(=O)ORc, - RbC(=O)NRbRc, -RbC(=O)Rc, -RbOC(=O)Rc, -SRb, -SORc, -SO2Rb, -CRbRcC(=O)Rbor - CRbRcC(=S)Rz, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino or any two Rdand / or Remay be joined to a form a (i) a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NRXor S, or (ii)an oxo (=0), thio(=S) or imino(=NRx) group; each occurrence of Rband Rcis independently selected from hydrogen, hydroxy, halogen, CN (Cyano), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkenyl, substituted or unsubstituted haloalkynyl, substituted or unsubstituted haloalkoxy, -C(=O)ORf, -C(=O)Rf, -C(=S)Rf, -C(=O)NRfRg, -C(=O)ONRfRg, - NRfRg, -NRf-ORg, -NRfC(=0)NRfRg, -NRfS(=0)Rg, -NRfS(=O)2Rg, -NRf-ORg, =N-NRfRg, - NRfC(=0)ORg, -NRfC(=0)Rg, -NRfC(=S)Rg,-NRfC(=S)NRfRg, -SONRfRg, -SO2NRfRg, -ORf, - ORfC(=0)NRfRg, -ORfC(=0)ORg, -OC(=O)Rf, -0C(=0)NRfRg, -RfNRgC(-O)Rf, -RfORc, - RfC(=O)ORg, -RfC(=0)NRfRg, -RfC(=O)Rg, -RfOC(=O)Rg, -SRf, -SORg, -SO2Rg, - CRfRgC(=0)Rg, -CRfRgC(=S)Rz, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino or any two Rband / or Rcmay be joined to a form a (i) a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NRXor S, or (ii)an oxo (=0), thio(=S) or imino(=NRx) group; each occurrence of Rxand Rzare independently selected from hydrogen, hydroxy, cyano, halogen, -ORf, -COORf, -S(=O)q-Rf, -NRfRg, -C(=Z’)-Rf, substituted or unsubstituted alkyl group, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted Cycloalkyl; each occurrence of Rfand Rgis independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkenyl, substituted or unsubstituted haloalkynyl, substituted or unsubstituted haloalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or un substituted heterocyclic ring, substituted heterocyclylalkyl ring, or substituted or unsubstituted amino;Z’ is selected from O, S or =N; each occurrence of n is 0,1, 2, 3, 4, 5, 6, 7 or 8; and each occurrence of p and q are independently 0,1 or 2.

2. A compound of Formula (IA-I), (IA-II), (IA-III), (IA-1V) (IA-V) or (IA-VI):or a tautomer thereof, prodrug thereof, N-oxide thereof, a pharmaceutically acceptable ester thereof, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein and all the variables (X1, X2, X3, X4, X5, Y1, Y2, Y3, L, L1, L2, R, R5, Cy1and Cy2) are independently as defined in claim 1.

3. The compound of anyone of claims 1-2, wherein Cy2is selected from substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

4. The compound of anyone of claims 1-3, wherein Cy2is selected fromwherein Cy2is optionally substituted with one or more Rd.

5. The compound of anyone of claims 1-4, wherein R is selected from hydrogen, hydroxy, halogen, CN (Cyano), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl6. The compound of anyone of claims 1-5, wherein R is selected from hydrogen, halogen, substituted or unsubstituted alkyl,wherein R is optionally substituted with one or more Rd;7. The compound of anyone of claims 1-6, wherein Rdis selected from hydrogen, hydroxy, halogen, CN (Cyano), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, COOH, CONH2, - NRbRc, -ORb, -SRb, -SORcor -SO2Rbor any two Rdmay be joined to a form a (i) a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NRXor S, or (ii)an oxo (=0), thio(=S) or imino(=NRx) group8. The compound of anyone of claims 1-7, wherein Rdis selected from hydrogen, halogen, - NH2-, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy or substituted or unsubstituted cycloalkyl.

9. The compound of anyone of claims 1-8, wherein R is selected from hydrogen, methyl, ethyl, fluorine, chlorine, bromine,The compound of anyone of claims 1-9, wherein Cy is selected from11. The compound of anyone of claims 1-10, wherein R-Cy- is selected from12. The compound of anyone of claims 1-11, wherein R5is selected from substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

13. The compound of anyone of claims 1-12, wherein R5is substituted or unsubstituted heteroaryl.

14. The compound of anyone of claims 1-13, wherein R5is selected fromwherein R5is optionally substituted with one or more Rd.

15. The compound of anyone of claims 1-14, wherein R5is selected from16. The compound of anyone of claims 1-1 , whereinL is absent or selected from substituted or unsubstituted C1-4alkyl, O, S, -S(=O)Por NRX;L1is absent or selected from substituted or unsubstituted C1-4alkyl, O, S, -S(=O)Por NRx; orL2is absent or selected from substituted or unsubstituted C1-4alkyl, O, S, -S(=O)PorNRx.

17. The compound of anyone of claims 1-16, whereinL is absent or selected from substituted or unsubstituted C1-4alkyl;L1is absent or selected from substituted or unsubstituted C1-4alkyl; orL2is absent or selected from substituted or unsubstituted C1-4alkyl.

18. The compound of anyone of claims 1-17, whereinL is absent;L1is absent or methyl; orL2is absent or methyl.

19. A compound selected from5-(5-bromo-2-fluorophenyl)-3-(4-(l -methyl -4-(tri fluoromethyl)-lH-imidazol-2-yl)phenyl)-1,2,4-oxadiazole;5-(2-fluoro-4-methoxyphenyl)-3-(4-(l -methyl-4-(tri fluoromethyl)- lH-imidazol-2-yl)phenyl)-1,2,4-oxadiazole;5-(2-bromo-4-fluorophenyl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-1,2,4-oxadiazole;3-(5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-2-fluorophenyl)-5-(4-(l -methyl -4- (trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole;5-(4-fluoro-2'-isopropyl-[1,1'-biphenyl]-3-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl) phenyl)- 1 ,2,4-oxadiazole;5-(2'-isopropyl-4-(4-methylpiperazin-l-yl)-[1,1'-biphenyl]-3-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole;5-(2-fluoro-4-methoxyphenyl)-3-(2-methyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)- 1 ,2,4-oxadiazole;5-(2-bromo-4-fluorophenyl)-3-(2-methyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)-l,2,4-oxadiazole;4-(4-bromo-2-(3-(4-(l-methyl-4-(trifluoromethyl)- lH-imidazol-2-yl)phenyl)- 1,2,4- oxadiazol-5-yl)phenyl)morpholine;5-(5-bromo-2-(4-methylpiperazin-l-yl)phenyl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)-l,2,4-oxadiazole;5-(2-(azepan-l-yl)-5-bromophenyl)-3-(4-(l -methyl -4-(trifluorom ethyl)- lH-imidazol-2- yl)phenyl)- 1 ,2,4-oxadiazole;4-(4-bromo-2-(3-(4-(l -methyl-4-(tri fluoromethyl)- lH-imidazol-2-yl)phenyl)- 1,2,4- oxadiazol-5-yl)phenyl)-2,6-dimethylmorpholine;4-(5-methoxy-2-(3-(4-(l -methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)- 1,2,4- oxadiazol-5-yl)phenyl)-2,6-dimethylmorpholine;4-(5-methoxy-2-(3-(4-(l -methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)- 1,2,4- oxadiazol-5-yl)phenyl)morpholine;5-(4-methoxy-2-(4-methylpiperazin-l -yl)phenyl)-3-(4-(l -methyl-4-(tri fluoromethyl)- 1H- imidazol-2-yl)phenyl)-l,2,4-oxadiazole; tert-butyl 3-(5-methoxy-2-(3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)- l,2,4-oxadiazol-5-yl)phenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate;5-(2-(l,4-diazepan-l-yl)-4-methoxyphenyl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)- 1 ,2,4-oxadiazole;5-(4-methoxy-2-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)phenyl)-3-(4-(l -methyl- 4-(trifluoromethyl)- lH-imidazol-2-yl)phenyl)- 1 ,2,4-oxadiazole;5-(5-fluoro-[1 , 1'-biphenyl ]-2-yl)-3 -(4-( 1 -methyl -4-(trifluoromethyl)- 1 H-imidazol -2- yl)phenyl)-l,2,4-oxadiazole;5-(5-fluoro-3',5'-bis(trifluoromethyl)-[1 , 1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole;5-(2',5-difluoro-6'-methoxy-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)-l,2,4-oxadiazole;5-(5'-chloro-5-fluoro-2'-methoxy-[1 , 1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(tri fluoromethyl)- lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole;5-(3',5'-dichloro-5-fluoro-[1,1'-biphenyl]-2-yl)-3-(4-(l -methyl -4-(tri fluoromethyl)- 1H- imidazol-2-yl)phenyl)-l,2,4-oxadiazole;3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-5-(2',3',5-trifluoro-[1,1'- biphenyl]-2-yl)- 1 ,2,4-oxadiazole;5-(5'-chl oro-2', 5-difluoro-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(tri fluorom ethyl)- 1H- imidazol-2-yl)phenyl)-l,2,4-oxadiazole;3,5'-difluoro-2'-(3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4- oxadiazol-5-yl)-[ 1 , 1 '-biphenyl]-2-carbonitrile;5-(3'-chloro-2',5-difluoro-[1,1'-biphenyl]-2-yl)-3-(4-(l -methyl -4-(tri fluorom ethyl)- 1H- imidazol-2-yl)phenyl)- 1 ,2,4-oxadiazole;5'-fluoro-2'-(3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazol-5- yl)-[ 1 , 1 '-biphenyl]-4-carbonitrile;5-(4'-chl oro-2', 5-difluoro-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(tri fluorom ethyl)- 1H- imidazol-2-yl)phenyl)- 1 ,2,4-oxadiazole;5-(4'-ethoxy-5-fluoro-[1,1'-biphenyl]-2-yl)-3-(4-(l -methyl -4-(tri fluoromethyl)- IH-imidazol- 2-yl)phenyl)- 1 ,2,4-oxadiazole;5-(5-fluoro-3',5'-dimethyl-[l, l'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(tri fluoromethyl)- 1H- imidazol-2-yl)phenyl)-l,2,4-oxadiazole;5-(5-fluoro-3'-(trifluoromethoxy)-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-1 H-imi dazol -2-y l)pheny 1)- 1 ,2,4-oxadi azole;5-(2'-chloro-5-fluoro-4'-methoxy-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)- lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazole;5-(5-fluoro-2',4'-dimethoxy-[1,1'-biphenyl]-2-yl)-3-(4-(l -methyl-4-(tri fluoromethyl)-! H- imidazol-2-yl)phenyl)-l,2,4-oxadiazole;5-(4'-chloro-3',5-difluoro-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)-l,2,4-oxadiazole;5-(3',5-difluoro-4'-methoxy-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)-l,2,4-oxadiazole;5-(5-fluoro-3',4'-dimethoxy-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)-l,2,4-oxadiazole;5-(4'-chloro-5-fluoro-3'-methyl-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)-l,2,4-oxadiazole;5-(4',5-difluoro-3'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-1 H-imi dazol -2-yl)phenyl)- 1 ,2,4-oxadi azole;3-(4-(l-methyl-4-(tri fluoromethyl)- IH-imidazol -2 -yl)phenyl)-5-(3', 5, 5'-trifluoro-[ 1,1'- biphenyl]-2-yl)- 1 ,2,4-oxadi azole;5-(3',5-difluoro-4'-methoxy-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)-l,2,4-oxadiazole;5-(2',5'-dichloro-5-fluoro-[1,1'-biphenyl]-2-yl)-3-(4-(l -methyl -4-(tri fluoromethyl)- 1H- imidazol-2-yl)phenyl)- 1 ,2,4-oxadi azole;5-(2-(2,6-dimethoxypyridin-3-yl)-4-fluorophenyl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)-l,2,4-oxadiazole;5-(3'-chloro-5-fluoro-4'-methyl-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)- 1 ,2,4-oxadiazole;4-(5-methoxy-2-(3-(2-methyl-4-(l -methyl-4-(tri fluoromethyl)- lH-imidazol-2-yl)phenyl)-1.2.4-oxadiazol-5-yl)phenyl)-2,6-dimethylmorpholine;5-(4-methoxy-2-(4-methyl- 1 ,4-diazepan- 1 -yl)phenyl)-3 -(2-methyl-4-( 1 -methyl-4-(tri fluoromethyl)- lH-imidazol-2-yl)phenyl)-l, 2, 4-oxadiazole;5-(2-( 1 ,4-diazepan- 1 -yl)-4-methoxypheny l)-3 -(2-methyl-4-( 1 -methyl-4-(trifluoromethyl)-1 H-imi dazol -2-y l)pheny 1)- 1 ,2,4-oxadi azole;4-(5-methoxy-2-(3-(2-methyl-4-(l -methyl-4-(tri fluoromethyl)- lH-imidazol-2-yl)phenyl)-1.2.4-oxadiazol-5-yl)phenyl)morpholine;5-(4-methoxy-2-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)phenyl)-3-(2-methyl-4- (l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)- 1,2, 4-oxadiazole 5-(5-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-2-fluorophenyl)-3-(4-(l-methyl-4- (trifluoromethyl)- lH-imidazol-2-yl)phenyl)-l, 2, 4-oxadiazole;3-(5-bromo-2-fluorophenyl)-5-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-1.2.4-oxadiazole;3, 5-bis(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l, 2, 4-oxadiazole;3 -(5-bromo-2-(4-methylpiperazin- 1 -yl)phenyl)-5-(4-( 1 -methyl-4-(trifluoromethyl)- 1H- imidazol-2-yl)phenyl)- 1,2, 4-oxadiazole;5-(2-(2-isopropylphenyl)pyrimidin-4-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)- 1 ,2, 4-oxadiazole;5-(5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH- imidazol-2-yl)phenyl)- 1,2, 4-oxadiazole;5-(2',5-difluoro-6'-methoxy-[1,1'-biphenyl]-2-yl)-3-(2-methyl-4-(l-methyl-4- (trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l, 2, 4-oxadiazole;5-(4-fluoro-2-(l-methyl-lH-pyrazol-4-yl)phenyl)-3-(2-methyl-4-(l-methyl-4- (trifluoromethyl)- lH-imidazol-2-yl)phenyl)-l, 2, 4-oxadiazole;(R)-4-(5-fluoro-2-(3-(4-(l -methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)- 1,2,4- oxadiazol-5-yl)phenyl)but-3-yn-2-ol;(R)-4-(5-fluoro-2-(3-(2 -methyl -4-(l -methyl -4-(trifluorom ethyl)- 1 H-imidazol-2-yl)phenyl)-1.2.4-oxadiazol-5-yl)phenyl)but-3-yn-2-ol;(S)-4-(5-fluoro-2-(3-(2-methyl-4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)- l,2,4-oxadiazol-5-yl)phenyl)but-3-yn-2-ol;5-(2-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-methoxyphenyl)-3-(4-(l-methyl-4- (trifluorom ethyl)- lH-imidazol-2-yl)phenyl)- 1,2, 4-oxadiazole;5-(2'-isopropyl-[1,1'-biphenyl]-4-yl)-3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)- 1 ,2, 4-oxadiazole;3-(2'-isopropyl-[1,1'-biphenyl]-4-yl)-5-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2- yl)phenyl)- 1,2, 4-oxadiazole;5-(4-(4-cyclopropyl-6-methoxypyrimidin-5-yl)phenyl)-3-(4-(l-methyl-4-(trifluoromethyl)-1 H-imi dazol -2-yl)pheny 1)- 1 ,2,4-oxadi azole;5-(2-(2-isopropylphenyl)pyrimidin-5-yl)-3-(4-(l -m ethyl -4-(tri fluoromethyl)- IH-imidazol -2- yl)phenyl)-l,2,4-oxadiazole;3, 5-bis(4-(l-methyl-4-(tri fluoromethyl)- lH-imidazol-2-yl)phenyl)-lH-l, 2, 4-tri azole;2-amino-4-(3-(4-(l-methyl-4-(tri fluoromethyl)- lH-imidazol-2-yl)phenyl)-l, 2, 4-oxadiazol-5- yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile;2-amino-4-methyl-4-(3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4- oxadiazol-5-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile;2-amino-4-(3-(4-(l-methyl-4-(tri fluoromethyl)- lH-imidazol-2-yl)phenyl)-l, 2, 4-oxadiazol-5- yl)benzo[b]thiophene-3-carbonitrile;3-(4-(l -methyl-4-(tri fluoromethyl)- lH-imidazol-2-yl)phenyl)-5-(naphthalen-l-yl)- 1,2,4- oxadi azole;2-amino-5-(3-(4-(l-methyl-4-(tri fluoromethyl)- lH-imidazol-2-yl)phenyl)-l, 2, 4-oxadiazol-5- yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile;2-amino-7-(3-(2-fluoro-4-(2-fluoropyridin-3-yl)phenyl)-l,2,4-oxadiazol-5-yl)-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carbonitrile;2-amino-7-(3-(4-(2-fluoropyridin-3-yl)benzyl)- 1,2, 4-oxadiazol-5-yl)-4, 5,6,7- tetrahydrobenzo[b]thiophene-3-carbonitrile;5-(isoquinolin-l-yl)-3-(4-(l-methyl-4-(tri fluoromethyl)- lH-imidazol-2-yl)phenyl)- 1,2,4- oxadi azole;2-(3-(4-(l-methyl-4-(trifluoromethyl)-lH-imidazol-2-yl)phenyl)-l,2,4-oxadiazol-5- yl)naphthalen- 1 -ol;4-(3-bromo-4-(3-(4-(l -methyl-4-(tri fluoromethyl)- lH-imidazol-2-yl)phenyl)- 1,2,4- oxadiazol-5-yl)phenyl)morpholine; and pharmaceutically acceptable salts thereof.

20. A pharmaceutical composition comprising a compound of claim 1-19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

21. A method for treating cancer in a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1-19, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of claim 1-19, or a pharmaceutically acceptable salt thereof.

22. The method of claim 21, further comprising the step of administering simultaneously or sequentially to a subject in need thereof at least one other anti-cancer agent, anti-inflammatoryagent, immunosuppressive agent, steroid, non-steroidal anti-inflammatory agent, antihistamine, analgesic, or a mixture thereof.

23. A method of treating a USP mediated disorder in a subject in need thereof, in particular USP1 mediated disorder comprising administering to the subject in need thereof a therapeutically effective amount of a compound of claim 1-19, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of claim 1-19, or a pharmaceutically acceptable salt thereof.

24. Use of a compound of claim 1-19, for treating cancer or a USP-mediated disorder, in particular USP1 mediated cancer or disorder in a subject.

25. Use of a compound of claim 1-19 for the manufacture of a medicament for treating cancer or a USP mediated disorder, in particular USP1 mediated cancer or disorder in a subject.

26. A method of treating a variety of cancers, such as solid cancer and, more specifically, solid cancers with USP mutation wherein the method comprises of administering to a subject a Compounds of claim 1-19, or the pharmaceutically acceptable salts and / or compositions thereof.

27. The method of claim 21-26, wherein cancer is selected from Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma,cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.

28. The method of any of claim 21-27, wherein the cancer is lung cancer, non-small cell lung cancer (NSCLC), colon cancer, breast cancer, bladder cancer, triple negative breast cancer , osteosarcoma, ovarian cancer, skin cancer, prostate cancer, pancreatic cancer, sarcomas, Ewing’s sarcoma, hematological cancer such as Diffuse large B cell lymphoma (“DLBCL”), Hodgkin’s lymphoma (“HL”), Non-Hodgkin’s lymphoma (“NHL”), Follicular lymphoma (“FL”), acute myeloid leukemia (“AML”), and Multiple myeloma (“MM”).

29. The method of claim 28, wherein the cancer is (i) colon cancer, (ii) pancreatic cancer (iii) breast cancer (iv) triple negative breast cancer or (v) prostate cancer.

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