DNA polymerase theta inhibitors, compositions thereof, compositions further comprising a DNA dependent protein kinase, and uses of both in gene editing

Abstract

The present disclosure is directed to compositions comprising POLQ inhibitor Compounds of Formula (I), methods of preparing the forgoing, combinations of the forgoing with DNA PK inhibitors as well as methods of use for said compositions.

Description

Docket No.: 14928-WO-PCTDNA POLYMERASE THETA INHIBITORS, COMPOSITIONS THEREOF, COMPOSITIONS FURTHER COMPRISING A DNA DEPENDENT PROTEIN KINASE, AND USES OF BOTH IN GENE EDITINGCROSS-REFERENCE TO RELATED APPLICATIONSThis application claims priority to US Provisional Application No. 63 / 742,562, filed on January 7, 2025, the disclosure of which is incorporated herein by reference in its entirety for any purpose.FIELD

[0001] The present disclosure relates generally to compounds, compositions, methods, and kits for increasing genome editing efficiency by administering an inhibitor of DNA polymerase theta (PolQ, Pol0) of general formula (I), and a genome editing system to a eukaryotic cell(s). The present disclosure further relates to compositions including the PolQ inhibitor of general formula (I), and DNA-PK inhibitors of general formulas SI and BI, methods of inserting a polynucleotide of interest into the genome of a eukaryotic cell, and kits for inserting a gene of interest into the genome of a eukaryotic cell. The methods and kits can improve the efficiency of CRISPR / Cas-mediated polynucleotide insertion in cells, in particular in CRISPR-engineered CAR-T cells.INCORPORATION BY REFERENCEThis application contains subject matter related to applications PCT / US2024 / 043438 (WO 2025 / 049247), PCT / US2024 / 043441 (WO 2025 / 049250), and PCT / US2024 / 043446 (WO 2025 / 049253). These references are hereby incorporated by reference in their entirety.BACKGROUND

[0002] The development of cost-efficient and reliable methods for precise targeted alterations to the genome of living cells has been a long-standing goal. Genome editing has the potential to eliminate genes responsible for a particular disorder (i.e., a gene “knock-out”), or alternatively, provide a means for gene manipulation or insertion to correct a geneticDocket No.: 14928-WO-PCTdeficiency or enhance a biological process via a gene “knock-in.” Genome editing can be applied for treatment of a multitude of disorders, including treatment of inherited disorders, hematological disorders and cancer, and in methods of immunotherapy. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR associated (Cas) systems are prokaryotic immune systems (Ishino et al., Journal of Bacteriology 169:5429-5433 (1987)), which provide immunity against viruses and plasmids by targeting the nucleic acids of the viruses and plasmids in a sequence-specific manner (Soret et al., Nature Reviews Microbiology 6:181-186 (2008)). Since its original discovery, multiple groups have performed extensive research around potential applications of the CRISPR system in genetic engineering, including gene editing (Jinek et al., Science 337(6096):816-821 (2012); Cong et al, Science 339(6121): 819-823 (2013); and Mali et al., Science 339(6121):823-826 (2013)). The CRISPR-Cas9 gene editing system has been used successfully in a wide range of organisms and cell lines.

[0003] The Cas9 endonuclease generates a double-stranded DNA break at the target sequence, upstream of a protospacer adjacent motif (PAM). The target sequence can then be removed, or a sequence of interest can be inserted into the target sequence using an endogenous repair pathway of the cell. Endogenous DNA repair pathways include the Nonhomology Mediated End-Joining (NHEJ) pathway, Microhomology Mediated End-Joining (MMEJ) pathway, and the Homology Directed Repair (HDR) pathway.

[0004] NHEJ, MMEJ, and HDR pathways repair double-stranded DNA breaks, but repair of such double-stranded DNA breaks may result in insertions or deletions at the double stranded break site. In NHEJ, a homologous template is not required for repairing breaks in the DNA. NHEJ repair can be error-prone, although errors are decreased when the DNA break includes compatible overhangs. NHEJ and MMEJ are mechanistically distinct DNA repair pathways with different subsets of DNA repair enzymes involved in each of them. Unlike NHEJ, which can be precise in some cases, or error-prone in some cases, MMEJ is always error-prone and results in both deletion and insertions at the site under repair. MMEJ-associated deletions are due to the micro-homologies (2-10 base pairs) at both sides of a double-strand break. In contrast, HDR requires a homologous template to direct repair, but HDR repairs are typically high-fidelity and less error prone. HDR-driven repair of double-stranded DNA breaks is therefore preferable to NHEJ- or MMEJ-mediated repair; however, in many cell types HDRDocket No.: 14928-WO-PCTis limited by the activity of NHEJ at all cell cycle stages, and HDR is primarily utilized in the S / G2 phase of cell growth (Mao et al., Cell Cycle, 7:2902-2906 (2008)).

[0005] The ability to modify the genome of any cell at a precise location has improved with the recent discovery and implementation of CRISPR / Cas9 editing technology. However, the capacity to introduce specific directed changes at given loci is hindered by the fact that the major cellular repair pathway that occurs following Cas9-mediated DNA cleavage is the erroneous non-homologous end joining (NHEJ) pathway. Homology-directed recombination (HDR) is less efficient than NHEJ, reducing editing efficiencies in eukaryotic cells. While the achievement of insertion or deletions (indels) from NHEJ is up to 70% effective in some reports, the efficiency of HDR remains challenging, with rates at less than 1%. Accordingly, there is a need for increasing genome editing efficiency, in particular, HDR efficiency.

[0006] Studies have shown that reduced NHEJ activity in vivo results in increases in HDR activity, and this phenomenon can be exploited to increase the efficiency of HDR-mediated CRISPR / Cas9 precision genome engineering (Pierce et al. Genes Dev., 15, 3237-3242 (2001); Ma et al. RNA Biol., 13, 605-612 (2016); Maruyama, et al. Nat. Biotechnol., 33, 538-542 (2015); Robert et al. Genome Med., 7, 93 (2015)).

[0007] DNA-dependent protein kinase (DNA-PK) is a nuclear serine / threonine kinase that has been shown to be essential in DNA double stranded break repair machinery. In mammals, the predominant pathway for repair of double stranded DNA breaks is the non-homologous end joining (NHEJ) pathway which is functional regardless of the phase of the cell cycle and acts by removing non-ligatable ends and ligating ends of double strand breaks.

[0008] Although DNA-PKis result in increased HDR levels and reduction of NHEJ-associated InDeis, MH-dependent deletions are still present and occasionally elevated upon DNA-PK inhibition. Various reports have shown that knockout or knock-down of Pol 6 partially reduces MH-associated deletions and minimizes Cas9-related unwanted on-target effects, such as translocations and large deletions (Hussain et al. Nucleic Acids Res. 49, e74 (2021); Mateos-Gomez et al. Nature 518, 254-257 (2015); Kosicki et al. Nat. Commun. 13, 3422 (2022); Taheri-Ghahfarokhi et al. Nucleic Acids Res. 46, 8417-8434 (2018); Wyatt et al. Mol. Cell 63, 662-673 (2016); Schimmel et al. EMBO J. 36, 3634-3649 (2017)).Therefore, these studies suggest that inhibition of Pol 6 might contribute to improved gene targeting efficiencies and mitigate undesired on- and off-target effects, especially whenDocket No.: 14928-WO-PCTcombined with inhibition of DNA-PK activity. The hypothesis has been supported by recent publications (Schimme et al. Cell Reports 42, 112019 (2023); Nature Commun. 14, 4761 (2023)).

[0009] DNA polymerase theta (Pol0, PolQ) is the primary mediator of MMEJ in most eukaryotic cells. Therefore, MMEJ through Pol0 is also referred to as Pol0-mediated end joining (TMEJ). The helicase domain of Pol0 promotes the annealing of resected 3' overhangs utilizing microhomologies, while the polymerase domain extends annealed sequences. Resolution involves flap removal through endonucleases, such as Flap endonuclease 1 (FEN1), gap filling, and, finally, joining of ends by DNA ligase 1 (LIG1) or DNA ligase 3 (LIG3).

[0010] Human Pol0 (PolQ) is a unique, large (290 kDa) multifunctional A-family DNA polymerase that is required for DSB repair through the MMEJ pathway. Unique among eukaryotic polymerases, the N-terminal domain contains adenosinetriphosphatase (ATPase) activity that displaces RPA from single-stranded DNA. The C-terminal domain contains a DNA polymerase activity that is responsible for filling in the gap after annealing of resected DNA ends.

[0011] There is a need for potent and selective DNA-PK inhibitors in combination of DNA PolO (PolQ) inhibitors that transiently and simultaneously block the NHEJ and MMEJ pathways to promote DNA repair via the desirable HDR pathway, therefore, further improve the efficiency of CRISPR / Cas-mediated polynucleotide insertion in cells, such as CRISPR CAR-T cells compared with using either DNA-PKi or POLQi alone.

[0012] SUMMARYOne aspect of the present disclosure relates to compositions comprising a PolO (POLQ)inhibitor of Formula (I): (I), R1is C1-C4 alkyl, halo- C1-C4 alkyl, nitrile, CONH2, or halo; R2is C1-C4 alkyl, halo- C1-C4 alkyl, or C3-C8 cycloalkyl; R3is C1-C4 alkyl, C1-C4 alkyl-NH2, C1-C4 alkyl-N(Ci-C4 alkyl)2, C1-C4 alkyl-OH,Docket No.: 14928-WO-PCTnitrile, C3-C8 cycloalkyl, or azetidinyl; R4is H, C1-C4 alkyl, -CH(R”)O-P(O)(OR’)(OR’), -CH(R”)-0C(0)-CI-6alkyl-O-P(O)(OR’)(OR’), -CH(R”)-0C(0)-CI-6 alkyl-C(O)OH - CH(R”)-0C(0)-CI-6 alkyl-P(O)(OR’)(OR’), -CH(R”)-OC(O)- C1-6 alkyl-NR’R’, -CH(R”)- OC(O)-Ci-6 alkyl-C(O)O-Ci-6 alkyl, or -CH(R”)-0C(0)-CI-6 alkyl-heterocyclyl, wherein R’ and R” are, independently, selected from H or C1-C4 alkyl; R5is H, halo, C1-C4 alkyl, C1-C4 alkyl-OH, C2-C4 alkenyl, C1-C4 haloalkyl, -S-C1-C4 alkyl, C(O)H, optionally substituted C3-Cs cycloalkyl, halo, optionally substituted 4-10-membered heterocyclyl, optionally substituted C1-C4 alkyl-4- 10-membered heterocyclyl, optionally substituted -C(O)-4-10-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C(O)O-Ci-C4 alkyl, C(O)O-C3-C7 cycloalkyl, -C1-C4 alkyl-N(R6)-C(O)O-Ci-C4alkyl, C(O)O-Ci-C4alkyl, -C1-C4 alkyl-O-Ci-C4alkyl, -C1-C4 alkyl-O-Ci-C4alkyl-N(R6)2, -C1-C4 alkyl-O-Ci-C4alkyl= -C1-C4 alkyl-O-Ci-C4alkyl- N(R6)2, optionally substituted C(O)O-C3-Cs cycloalkyl, optionally substituted CO(O)-C4-C10 heterocyclyl, optionally substituted C2-C4 alkynyl-Ci-C4 alkyl, C2-C4 alkynyl-C3-C8 cycloalkyl, C2-C4 alkynyl-C4-Cio heterocyclyl, -N(R6)2, - C1-C4 alkyl-N(R6)2, -C(O)N(R6)2, -P(O)(R6)2, -P(O)(OR6)2, SO(=NR6), SR6(O)(=NR6), SO2R6, -N=S(O)(R6)2, wherein the optionally substituted C3-C8 cycloalkyl, heterocyclyl, -C(O)-heterocyclyl, aryl, heteroaryl, C2-C4 alkynyl-C1-C4 alkyl, C(O)O-C1-C4 alkyl, C(O)O-C3-C8 cycloalkyl and CO(O)-C4-C10heterocyclyl, is optionally substituted with one or more hydroxyl, C1-C4 alkyl, halo, cyano, hydroxy-Ci-C4alkyl, -C(O)-Ci-C4alkyl, -CO2H, -CO2-C1-C4 alkyl, -SO2-C1-C4 alkyl, -SO2-C3-C7 cycloalkyl; and each R6is, independently, H, Ci-C4alkyl, Ci-C4alkoxyl, C3-C8 cycloalkyl, or alternatively, two R6groups together with the nitrogen or the carbon atom to which they are bound form C4-C10 cycloalkyl or heterocyclyl, wherein the C4-C10 cycloalkyl or heterocyclyl is optionally substituted with one of more hydroxyl, C1-C4 alkyl, halo, cyano, hydroxy-Ci-C4 alkyl; -C(O)-Ci-C4 alkyl, -C(O)-OCi-C4 alkyl, or a pharmaceutically acceptable salt thereof.Docket No.: 14928-WO-PCT

[0013] Another aspect of the present disclosure relates to compositions comprising a a Pol0N R1T J “kN(PolQ) inhibitor of formula (I):3(I R1is C1-C4 alkyl, halo-Ci-C4 alkyl, nitrile, CONH2, or halo; R2is C1-C4 alkyl, halo- C1-C4 alkyl, or C3-C8 cycloalkyl; R3is C1-C4 alkyl, C1-C4 alkyl-NH2, C1-C4 alkyl-N(Ci-C4 alkyl)2, C1-C4 alkyl-OH, nitrile, C3-C8 cycloalkyl, or azetidinyl; R4is H, C1-C4 alkyl, -CH(R”)O-P(O)(OR’)(OR’), -CH(R”)-OC(O)-CI-6alkyl-O-P(O)(OR’)(OR’), -CH(R”)-OC(O)-CI-6 alkyl-C(O)OH -CH(R”)-OC(O)-CI-6 alkyl-P(O)(OR’)(OR’), -CH(R”)-OC(O)- C1-6 alkyl-NR’R’, -CH(R”)-OC(O)-Ci-6 alkyl-C(O)O-Ci-6 alkyl, or -CH(R”)-OC(O)-CI-6 alkyl -heterocyclyl, wherein R’ and R” are, independently, selected from H or C1-C4 alkyl; R5is H, halo, C1-C4 alkyl, C1-C4 alkyl-OH, C2-C4 alkenyl, C1-C4 haloalkyl, -S-C1-C4 alkyl, C(O)H, optionally substituted C3-08 cycloalkyl, halo, optionally substituted 4-10-membered heterocyclyl, optionally substituted C1-C4 alkyl-4- 10-membered heterocyclyl, optionally substituted -C(O)-4-10-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C(O)O-Ci-C4 alkyl, C(O)O-C3-C7 cycloalkyl, -C1-C4 alkyl-N(R6)-C(O)O-Ci-C4alkyl, C(O)O-Ci-C4alkyl, -C1-C4 alkyl-O-Ci-C4alkyl, -C1-C4 alkyl-O-Ci-C4alkyl-N(R6)2, -C1-C4 alkyl-O-Ci-C4alkyl= -C1-C4 alkyl-O-Ci-C4alkyl- N(R6)2, optionally substituted C(O)O-C3-Cs cycloalkyl, optionally substituted CO(O)-C4-C10 heterocyclyl, optionally substituted C2-C4 alkynyl-Ci-C4 alkyl, C2-C4 alkynyl-C3-C8 cycloalkyl, C2-C4 alkynyl-C4-Cio heterocyclyl, -N(R6)2, - C1-C4 alkyl-N(R6)2, -C(O)N(R6)2, -P(O)(R6)2, -P(O)(OR6)2, SO(=NR6), SR6(O)(=NR6), SO2R6, -N=S(O)(R6)2, wherein the optionally substituted C3-C8 cycloalkyl, heterocyclyl, -C(O)-heterocyclyl, aryl, heteroaryl, C2-C4 alkynyl-C1-C4 alkyl, C(O)O-C1-C4 alkyl, C(O)O-C3-C8 cycloalkyl and CO(O)-C4-C10heterocyclyl, is optionally substituted with one or more hydroxyl, C1-C4 alkyl, halo, cyano, hydroxy-Ci-C4alkyl, -C(O)-Ci-C4alkyl, -CO2H, -CO2-C1-C4 alkyl, -SO2-C1-C4 alkyl, -SO2-C3-C7 cycloalkyl; and each R6is, independently, H, Ci-C4alkyl, Ci-C4alkoxyl, C3-C8 cycloalkyl, or alternatively, two R6groups together with the nitrogen or the carbon atom toDocket No.: 14928-WO-PCTwhich they are bound form C4-C10 cycloalkyl or heterocyclyl, wherein the C4-C10 cycloalkyl or heterocyclyl is optionally substituted with one of more hydroxyl, C1-C4 alkyl, halo, cyano, hydroxy-Ci-C4 alkyl; -C(O)-Ci-C4 alkyl, -C(O)-OCi-C4 alkyl, or a pharmaceuticallyHN'acceptable salt thereof; and a DNAPK inhibitor of Formula (SI):v / n(SI), or a pharmaceutically acceptable salt thereof, wherein: Asis a 5-membered or 6-membered heteroaryl or heterocycloalkyl group containing at least one heteroatom selected from the group consisting of N, O, and S, wherein the heteroaryl or heterocycloalkyl is optionally substituted with one or more RS5; RS1is an aryl or heteroaryl containing at least one heteroatom selected from the group consisting of N, O, S, and Se, wherein the aryl or heteroaryl is optionally substituted with one or more RS6; RS2is H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, CN, OH, CH2OH, NH2, or CH2NH2; RS3and RS4are each independently selected from the group consisting of -OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylaryl, and aryl; each RS5is independently selected from the group consisting of halogen, oxo, thioxo, C1-C4 alkyl, CD3, CD2CD3, C1-C4 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, and aryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is optionally substituted with one or more RS7; or two geminal RS5, together with the intervening geminal carbon atom, form a C3-C6 cycloalkyl; each RS6is independently selected from the group consisting of halogen, oxo, NH2, OH, -CN, C(O)NHRS7, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, CD3, CD2CD3, Ci-Ce alkoxy, Ci-Ce haloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl and aryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is optionally substituted with one or more RS7; each RS7is independently selected from the group consisting of halogen, OH, oxo, NH2, CHO, C1-C4 alkyl, and C1-C6 alkoxy; and n is an integer from 1 to 3.Docket No.: 14928-WO-PCT

[0014] Another aspect of the present disclosure relates to compositions comprising a a Pol0(POLQ) inhibitor of formula (I): R1is C1-C4 alkyl, halo-Ci-C4 alkyl, nitrile, CONH2, or halo; R2is C1-C4 alkyl, halo- C1-C4 alkyl, or C3-C8 cycloalkyl; R3is C1-C4 alkyl, C1-C4 alkyl-NH2, C1-C4 alkyl-N(Ci-C4 alkyl)2, C1-C4 alkyl-OH, nitrile, C3-C8 cycloalkyl, or azetidinyl; R4is H, C1-C4 alkyl, -CH(R”)O-P(O)(OR’)(OR’), - CH(R”)-OC(O)-CI-6alkyl-O-P(O)(OR’)(OR’), -CH(R”)-OC(O)-CI-6 alkyl-C(O)OH -CH(R”)-OC(O)-CI-6 alkyl-P(O)(OR’)(OR’), -CH(R”)-OC(O)- C1-6 alkyl-NR’R’, -CH(R”)-OC(O)-Ci-6 alkyl-C(O)O-Ci-6 alkyl, or -CH(R”)-OC(O)-CI-6 alkyl -heterocyclyl, wherein R’ and R” are, independently, selected from H or C1-C4 alkyl; R5is H, halo, C1-C4 alkyl, C1-C4 alkyl-OH, C2-C4 alkenyl, C1-C4 haloalkyl, -S-C1-C4 alkyl, C(O)H, optionally substituted C3-08 cycloalkyl, halo, optionally substituted 4-10-membered heterocyclyl, optionally substituted C1-C4 alkyl-4- 10-membered heterocyclyl, optionally substituted -C(O)-4-10-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C(O)O-Ci-C4 alkyl, C(O)O-C3-C7 cycloalkyl, -C1-C4 alkyl-N(R6)-C(O)O-Ci-C4alkyl, C(O)O-Ci-C4alkyl, -C1-C4 alkyl-O-Ci-C4alkyl, -C1-C4 alkyl-O-Ci-C4alkyl-N(R6)2, -C1-C4 alkyl-O-Ci-C4alkyl= -C1-C4 alkyl-O-Ci-C4alkyl- N(R6)2, optionally substituted C(O)O-C3-Cs cycloalkyl, optionally substituted CO(O)-C4-C10 heterocyclyl, optionally substituted C2-C4 alkynyl-Ci-C4 alkyl, C2-C4 alkynyl-C3-C8 cycloalkyl, C2-C4 alkynyl-C4-Cio heterocyclyl, -N(R6)2, - C1-C4 alkyl-N(R6)2, -C(O)N(R6)2, -P(O)(R6)2, -P(O)(OR6)2, SO(=NR6), SR6(O)(=NR6), SO2R6, -N=S(O)(R6)2, wherein the optionally substituted C3-C8 cycloalkyl, heterocyclyl, -C(O)-heterocyclyl, aryl, heteroaryl, C2-C4 alkynyl-C1-C4 alkyl, C(O)O-C1-C4 alkyl, C(O)O-C3-C8 cycloalkyl and CO(O)-C4-C10heterocyclyl, is optionally substituted with one or more hydroxyl, C1-C4 alkyl, halo, cyano, hydroxy-Ci-C4alkyl, -C(O)-Ci-C4alkyl, -CO2H, -CO2-C1-C4 alkyl, -SO2-C1-C4 alkyl, -SO2-C3-C7 cycloalkyl; and each R6is, independently, H, Ci-C4alkyl, Ci-C4alkoxyl, C3-C8 cycloalkyl, or alternatively, two R6groups together with the nitrogen or the carbon atom toDocket No.: 14928-WO-PCTwhich they are bound form C4-C10 cycloalkyl or heterocyclyl, wherein the C4-C10 cycloalkyl or heterocyclyl is optionally substituted with one of more hydroxyl, C1-C4 alkyl, halo, cyano, hydroxy-Ci-C4 alkyl; -C(O)-Ci-C4 alkyl, -C(O)-OCi-C4 alkyl, or a pharmaceuticallyacceptable salt thereof; and a DNAPK inhibitor of Formula (BI): (BI), or a pharmaceutically acceptable salt thereof, wherein: ABis a 5- or 6-membered heteroaryl or heterocycloalkyl group containing at least one heteroatom selected from the group consisting of N, O, and S, wherein the heteroaryl or heterocycloalkyl is optionally substituted with one or more R4B; R1Bis an aryl or heteroaryl containing at least one heteroatom selected from the group consisting of N, O, S, and Se, wherein the aryl or heteroaryl is optionally substituted with one or more R5B; R2Bis H, halogen, -(CH2)nB-CN, -OH, -(CH2)nB-O-Ci-C4 alkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C(0)NH2; R3Bis selected from the group consisting of H, F, C2-C4 alkenyl, C2-C4 alkynyl, CN, OH, CH2OH, NH2, CH2NH2, and C1-C4 alkyl; each R4Bis independently selected from the group consisting of halogen, oxo, thioxo, C1-C4 alkyl, C1-C4 alkoxy, CD3, CD2CD3, and Ci-Ce haloalkyl; or two geminal R4Btogether with the intervening geminal carbon atom, form a C3-C6 cycloalkyl; each R5Bis independently selected from the group consisting of halogen, NH2, OH, -CN, C(0)NH2, C(O)NHR7B, C1-C4 alkyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, CD3, CD2CD3, Ci-Ce alkoxy, Ci-Ce haloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, and aryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is optionally substituted with one or more R6B; each R6Bis independently selected from the group consisting of halogen, OH, oxo, NH2, CHO, C1-C4 alkyl, and Ci-Ce alkoxy; each R7Bis independently selected from H and C1-C4 alkyl; each nB is independently an integer from 0-4; rBis an integer from 0 to 2; sBis an integer from 0 to 2; and tBis an integer from 1 to 2.Docket No.: 14928-WO-PCTAnother aspect of the present disclosure is directed to pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0015] Another aspect of the present disclosure is directed to pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and the DNAPK inhibitor (SI) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0016] Another aspect of the present disclosure is directed to pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and the DNAPK inhibitor (BI) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0017] Another aspect of the present disclosure is directed to a composition comprising (a) POLQ inhibitor I, (b) a DNA protein kinase inhibitor (DNA-PKI) (SI) or (BI), (c) a DNA cutting agent. In some embodiments, the DNA-PKI is a compound of (SI) or a pharmaceutically acceptable salt thereof. In other embodiments, the DNA-PKI is a compound of (BI) or a pharmaceutically acceptable salt thereof.

[0018] Another aspect of the present disclosure is directed to a method for targeted genome editing in a cell, comprising contacting the cell with a DNA cutting agent, POLQi compound of Formula I, and a DNA-PKI, wherein the DNA-PKI is a compound of (SI) or (BI) or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

[0019] Another aspect of the present disclosure is directed to a method for repairing a double stranded DNA break in the genome of a cell, comprising contacting the cell with a DNA cutting agent, POLQi compound of Formula I, and a DNA-PKI, wherein the DNA-PKI is a compound of Formula (SI) or (BI), or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

[0020] Another aspect of the present disclosure is directed to a method for simultaneously inhibiting or suppressing repair of a DNA break in a cell via both nonhomologous end joining (NHEJ) pathway and Microhomology Mediated End-Joining (MMEJ) pathway, comprising contacting the cell with a DNA cutting agent, a DNA-PKI, wherein the DNA-PKI is aDocket No.: 14928-WO-PCTcompound of Formula (SI) or (BI), or a pharmaceutically acceptable salt, hydrate, solvate or prodrug, thereof, and POLQi Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

[0021] Another aspect of the present disclosure is directed to a method for targeted insertion of a donor DNA into the genome of a cell, comprising contacting the cell with a DNA cutting agent, the donor DNA, POLQi compound of Formula I, and a DNA-PKI, wherein the DNA-PKI is a compound of Formula (SI) or (BI), or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

[0022] Another aspect of the present disclosure relates to compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for cell therapy in combination of POLQi Compound of Formula (I).

[0023] Another aspect of the present disclosure relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or pharmaceutical composition thereof, in the treatment of a cell in combination of DNAPK Inhibitor compound of Formula (SI) or (BI).

[0024] Other features and advantages of the disclosure will be apparent from the following detailed description and claims.BRIEF DESCRIPTION OF DRAWINGS

[0025] FIG. 1 shows the effect of DNA-PK inhibitor B-l alone and in combination with DNA POLQ inhibitor Q-2 or Q-6, respectively, on cell viability 5 days after electroporation. Concentration of DNA-PK inhibitor was 0.5pM for all conditions and the concentration of DNA POLQ inhibitor is as indicated (2.5pM or 5pM). Live cells are shown as a percentage of total cells.

[0026] FIG. 2 shows the effect of DNA-PK inhibitor B-l alone and in combination with DNA POLQ inhibitor Q-2 or Q-6, respectively, on T cell proliferation 5 days after electroporation. Concentration of DNA-PK inhibitor was 0.5pM for all conditions and the concentration of DNA POLQ inhibitor is as indicated (2.5pM or 5pM). Total live cell counts (x10e6) are shown.Docket No.: 14928-WO-PCT

[0027] FIG. 3 shows the effect of DNA-PK inhibitor B-l alone and in combination with DNA POLQ inhibitor Q-2 or Q-6, respectively, on CAR insertion into the TRAC locus 5 days after electroporation. Concentration of DNA-PK inhibitor was 0.5pM for all conditions and the concentration of DNA POLQ inhibitor is as indicated (2.5pM or 5pM). Frequency of CAR+ T cells is shown as a percentage of total live cells.

[0028] FIG. 4 shows the effect of DNA-PK inhibitor B-l alone and in combination with DNA POLQ inhibitor Q-2 or Q-6, respectively, on CAR insertion into the TRAC locus 5 days after electroporation. Concentration of DNA-PK inhibitor was 0.5pM for all conditions and the concentration of DNA POLQ inhibitor is as indicated (2.5pM or 5pM). KI efficiency is shown as a fold change over the untreated control condition (calculated by dividing the %CAR+ of DNA-PK or DNA PolQ inhibitor treated by untreated).

[0029] FIG. 5 shows the effect of DNA-PK inhibitor B-l alone and in combination with DNA POLQ inhibitor Q-2 or Q-6, respectively, on total CAR+ cell yields 5 days after electroporation. Concentration of DNA-PK inhibitor was 0.5pM for all conditions and the concentration of DNA POLQ inhibitor is as indicated (2.5pM or 5pM). Relative CAR+ yield is shown as a fold change over the untreated control condition (calculated by dividing the total number of CAR+ cells in DNA-PK or DNA PolQ inhibitor treated conditions by untreated).

[0030] FIG. 6 shows the effect of DNA-PK inhibitor (B-66, B-72, or S-35) in combination of DNA POLQ inhibitor Q-6 on cell viability 5 days after electroporation. Concentration of DNA-PK inhibitor was 0.5pM for all conditions and the concentration of DNA POLQ inhibitor was 5pM for all conditions. Live cells are shown as a percentage of total cells.

[0031] FIG. 7 shows the effect of DNA-PK inhibitor (B-66, B-72, or S-35) in combination of DNA POLQ inhibitor Q-6 on T cell proliferation 5 days after electroporation. Concentration of DNA-PK inhibitor was 0.5pM for all conditions and the concentration of DNA POLQ inhibitor was 5pM for all conditions. Total live cell counts (xl0e6) are shown.

[0032] FIG. 8 shows the effect of DNA-PK inhibitor (B-66, B-72, or S-35) in combination of DNA POLQ inhibitor Q-6 on CAR insertion into the TRAC locus 5 days after electroporation. Concentration of DNA-PK inhibitor was 0.5pM for all conditions and the concentration of DNA POLQ inhibitor was 5pM for all conditions. Frequency of CAR+ T cells is shown as a percentage of total live cells.Docket No.: 14928-WO-PCT

[0033] FIG. 9 shows the effect of DNA-PK inhibitor (B-66, B-72, or S-35) in combination of DNA POLQ inhibitor on CAR insertion into the TRAC locus 5 days after electroporation. Concentration of DNA-PK inhibitor was 0.5pM for all conditions and the concentration of DNA POLQ inhibitor was 5pM for all conditions. KI efficiency is shown as a fold change over the untreated control condition (calculated by dividing the %CAR+ of inhibitor treated by untreated).

[0034] FIG. 10 shows the effect of DNA-PK inhibitor (B-66, B-72, or S-35) in combination of DNA POLQ inhibitor Q-6 on total CAR+ cell yields 5 days after electroporation.Concentration of DNA-PK inhibitor was 0.5pM for all conditions and the concentration of DNA POLQ inhibitor was 5pM for all conditions. Relative CAR+ yield is shown as a fold change over the untreated control condition (calculated by dividing the total number of CAR+ cells in inhibitor treated conditions by untreated).DETAILED DESCRIPTIONDefinitions

[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed present disclosure. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.

[0036] The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.Docket No.: 14928-WO-PCT

[0037] The term "and / or" is used in this disclosure to mean either "and" or "or" unless indicated otherwise.

[0038] The term “optionally substituted” is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups but does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, -OH, -CN, -COOH, -CH2CN, -O-(Ci-Ce) alkyl, (Ci-Ce) alkyl, (Ci-Ce) alkoxy, (Ci-Ce) haloalkyl, (Ci-Ce) haloalkoxy, -O-(C2-Ce) alkenyl, -O-(C2-C6) alkynyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -OH, -OP(O)(OH)2, -OC(O)(Ci-C6) alkyl, -C(O)(Ci-C6) alkyl, -OC(O)O(Ci-C6) alkyl, -NH2, -NH((CI-C6) alkyl), -N((CI-C6) alkyl)2, -NHC(O)(CI-C6) alkyl, -C(O)NH(CI-C6) alkyl, -S(O)2(Ci-C6) alkyl, -S(O)NH(Ci-Ce) alkyl, and S(O)N((Ci-Ce) alkyl)2. The substituents can themselves be optionally substituted. “Optionally substituted” as used herein also refers to substituted or unsubstituted whose meaning is described below.

[0039] As used herein, the term “substituted,” means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =0), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a RM, and formulation into an efficacious therapeutic agent. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.Docket No.: 14928-WO-PCT

[0040] As used herein, the term “unsubstituted” means that the specified group bears no substituents.

[0041] As used herein, “Alkyl” refers to optionally substituted, straight and branched chain aliphatic groups having from 1 to 30 carbon atoms. “Cl, C2, C3, C4, C5 or C6 alkyl” or “Cl-C6 alkyl” is intended to include Cl, C2, C3, C4, C5 or C6 straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5 or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intends to include Cl, C2, C3, C4, C5 and C6 alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C1-C6 for straight chain, C3-C6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms. The term “heteroalkyl” as used herein contemplates an alkyl with one or more heteroatoms.

[0042] As used herein, the term “optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0043] “Alkoxy” refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, i.e., -O(alkyl). Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0044] As used herein, the term “alkenyl” includes unsaturated or partially unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above,Docket No.: 14928-WO-PCTbut that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-6 for straight chain, C3-6 for branched chain). The term “C2-6” includes alkenyl groups containing two to six carbon atoms. The term “C3-6” includes alkenyl groups containing three to six carbon atoms.

[0045] As used herein, the term “optionally substituted alkenyl” refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0046] As used herein, the term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-6 for straight chain, C3-6 for branched chain). The term “C2-6” includes alkynyl groups containing two to six carbon atoms. The term “C3-6” includes alkynyl groups containing three to six carbon atoms.

[0047] As used herein, the term “optionally substituted alkynyl” refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,Docket No.: 14928-WO-PCTalkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0048] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-l,2,3,6-tetrahydropyridinyl.

[0049] As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro) system having 3 to 30 carbon atoms (e.g., C3-12, C3-10, C3-8, or C3-6). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be nonaromatic.

[0050] As used herein, the term “heterocycloalkyl” refers to a saturated or partially unsaturated 3-8 membered monocyclic or bicyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1, 2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl,Docket No.: 14928-WO-PCT2,5-diazabicyclo[2.2. l]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, l,4-dioxa-8-azaspiro[4.5]decanyl, l,4-dioxaspiro[4.5]decanyl, l-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-l,l'-isobenzofurran]-yl, 7'H-spiro[cyclohexane-l,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-l,l'-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3,4]octanyl, 2-oxa-azaspiro[3,4]octan-6-yl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, and the like. In the case of multicyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be non-aromatic (e.g., 1,3-dihydrobenzo[c]isoxazol-3-yl).

[0051] As used herein, the term “optionally substituted heterocycloalkyl” refers to unsubstituted heterocycloalkyl having designated substituents replacing one or more hydrogen atoms on one or more carbon or heteroatom. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0052] Unless otherwise specifically defined, the term “aryl” refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but areDocket No.: 14928-WO-PCTnot limited to, — H, -halogen. — O — (Ci-e) alkyl, (Ci-e) alkyl, — O — (C2-6) alkenyl, — O — (C2-6) alkynyl, (C2-6) alkenyl, (C2-6) alkynyl, —OH, — 0P(0)(0H)2, — OC(O)(Ci-6) alkyl, — C(O)(Ci-6) alkyl, — OC(O)O(Ci-6) alkyl, — NH2, NH((CI-6) alkyl), N((CI-6) alkyl)2, — S(O)2 — (Ci-e) alkyl, — S(O)NH(Ci-e) alkyl, and — S(O)N((Ci-e) alkyl)2. The substituents can themselves be optionally substituted. Furthermore, when containing two or more fused rings, the aryl groups herein defined may have a saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannul enyl, 10,1 l-dihydro-5H-dibenzo[a,d][7]annulenyl, and the like. Furthermore, when containing two or more fused rings, the aryl groups herein defined may have a saturated or partially unsaturated heterocyclic ring fused with a fully unsaturated aromatic ring. Exemplary ring systems of these aryl groups include, but are not limited to, benzo[d][l,3]dioxol-5-yl, 2,3-dihydrobenzo[b][l,4]dioxin-6-yl, benzo[d]isoxazol-3(2H)-on-6-yl, benzo[d]oxazol-2(3H)-on-6-yl, and benzo[d]oxazol-2(3H)-on-5-yl.

[0053] Unless otherwise specifically defined, “heteroaryl” means a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, Se, or B, the remaining ring atoms being C. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, S, P, Se, or B. Heteroaryl as herein defined also means a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, Se, or B. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[l,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[l,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl,Docket No.: 14928-WO-PCTbenzo[de]isoquinolinyl, pyrido[4,3-b][l,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolof l,5-a]pyridinyl, [l,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[l,2-a]pyrimidinyl, tetrahydro pyrrolo[l,2-a]pyrimidinyl, 3,4-dihydro-2H-112-pyrrolo[2,l-b]pyrimidine, dibenzo[b,d] thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, lH-pyrido[3,4-b][l,4] thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [l,2,4]triazolo[l,5-a]pyridinyl, benzo [l,2,3]triazolyl, imidazo[l,2-a]pyrimidinyl, [l,2,4]triazolo[4,3-b]pyridazinyl, benzofc] [1, 2, 5]thiadiazolyl, benzo[c][l,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo [l,5-b][l,2]oxazinyl, 4, 5,6,7-tetrahydropyrazolo[l,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,l-b][l,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof.Furthermore, when containing two or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring, e.g., a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O, S, P, Se, or B, or a 6-membered heteroaromatic ring containing 1 to 3 nitrogens, wherein the saturated or partially unsaturated ring includes 0 to 4 heteroatoms selected from N, O, S, P, Se, or B, and is optionally substituted with one or more oxo. In heteroaryl ring systems containing more than two fused rings, a saturated or partially unsaturated ring may further be fused with a saturated or partially unsaturated ring described herein. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-l IH-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, l,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, 8H-pyrido[3,2-b]pyrrolizinyl, l,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizine, pyrazolo[l,5-a]pyrimidin-7(4H)-only, 3,4-dihydropyrazino[l,2-a]indol-l(2H)-onyl, or benzo[c][l,2]oxaborol-l(3H)-olyl.

[0054] The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl,Docket No.: 14928-WO-PCTalkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][l,3]dioxole-5-yl).

[0055] As used herein, the term “hydroxy” or “hydroxyl” includes groups with an — OH or — O—.

[0056] As used herein, the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

[0057] The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

[0058] As used herein, the term “cyano” refers to a nitrile radical (e.g., — CN).

[0059] As used herein, the term “optionally substituted haloalkyl” refers to unsubstituted haloalkyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,Docket No.: 14928-WO-PCTtrifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0060] As used herein, the term “alkoxy” or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moi eties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.

[0061] As used herein, the term “solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O.

[0062] As described herein, isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemicDocket No.: 14928-WO-PCTmixture.” The compounds of Formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.

[0063] As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerizations is called tautomerism. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs.

[0064] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others.

[0065] The present disclosure also contemplates isotopically labelled compounds of Formula I (e.g., those labeled with D,2H, or14C). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). Isotopically labelled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or in the Examples herein below, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.

[0066] The disclosure also includes pharmaceutical compositions comprising an effective amount of a disclosed compound and a pharmaceutically acceptable carrier.

[0067] As used herein, the term “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts ofDocket No.: 14928-WO-PCTthe parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxy ethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

[0068] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt.

[0069] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-l -carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton presents in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3.

[0070] It is to be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.

[0071] A "patient" or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus.Docket No.: 14928-WO-PCT

[0072] An "effective amount" when used in connection with a compound is an amount effective for use in a cell therapy.

[0073] The term "carrier" as used in this disclosure, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.

[0074] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0075] The term "administer", "administering", or "administration" as used in this disclosure refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.

[0076] The term "prodrug" as used in this disclosure, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound.

[0077] The present disclosure relates to compounds and compositions that are capable of inhibiting DNA-dependent protein kinase (DNA-PK) in combination with POLQi compound of Formula I in a subject or in a biological sample.

[0078] In a first aspect of the present disclosure, the composition described herein comprisesa RPOLQi33(I), R1is Ci-C4alkyl, halo-Ci-C4alkyl, nitrile, CONH2, or halo; R2is C1-C4 alkyl, halo- C1-C4 alkyl, or C3-C8 cycloalkyl; R3is C1-C4 alkyl, C1-C4 alkyl-NH2, C1-C4 alkyl-N(Ci-C4alkyl)2, C1-C4 alkyl-OH, nitrile, C3-C8 cycloalkyl, or azetidinyl; R4is H, C1-C4 alkyl, -CH(R”)O-P(O)(OR’)(OR’), -CH(R”)-OC(O)-Ci-6 alkyl-O-P(O)(OR’)(OR’), -CH(R”)-OC(O)-CI-6 alkyl-C(O)OH -CH(R”)-OC(O)-Docket No.: 14928-WO-PCTCi-6 alkyl-P(O)(OR’)(OR’), -CH(R”)-OC(O)- Ci-6 alkyl-NR’R’, -CH(R”)-0C(0)-CI-6 alkyl- C(0)0-Ci-6 alkyl, or -CH( ”)-0C(0)-CI-6 alkyl-heterocyclyl, wherein R’ and R” are, independently, selected from H or C1-C4 alkyl; R5is H, halo, C1-C4 alkyl, C1-C4 alkyl-OH, C2-C4 alkenyl, C1-C4 haloalkyl, -S-C1-C4 alkyl, C(O)H, optionally substituted C3-C8 cycloalkyl, halo, optionally substituted 4-10-membered heterocyclyl, optionally substituted C1-C4 alkyl-4-10-membered heterocyclyl, optionally substituted -C(O)-4-10-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C(O)O-Ci-C4alkyl, C(O)O-C3-C7 cycloalkyl, -C1-C4 alkyl-N(R6)- C(O)O-Ci-C4alkyl, C(O)O-Ci-C4alkyl, -C1-C4 alkyl-O-Ci-C4alkyl, -C1-C4 alkyl-O-Ci-C4alkyl-N(R6)2, -C1-C4 alkyl-O-Ci-C4 alkyl= -C1-C4 alkyl-O-Ci-C4 alkyl- N(R6)2, optionally substituted C(O)O-C3-Cs cycloalkyl, optionally substituted CO(O)-C4-C10 heterocyclyl, optionally substituted C2-C4 alkynyl-Ci-C4 alkyl, C2-C4 alkynyl-C3-C8 cycloalkyl, C2-C4 alkynyl-C4-Cio heterocyclyl, -N(R6)2, - C1-C4 alkyl-N(R6)2, -C(O)N(R6)2, -P(O)(R6)2, -P(O)(OR6)2, SO(=NR6), SR6(O)(=NR6), SO2R6, -N=S(O)(R6)2, wherein the optionally substituted C3-C8 cycloalkyl, heterocyclyl, -C(O)-heterocyclyl, aryl, heteroaryl, C2-C4 alkynyl-Ci-C4 alkyl, C(O)O-Ci-C4 alkyl, C(O)O-C3-Cs cycloalkyl and C0(0)-C4-Cio heterocyclyl, is optionally substituted with one of more hydroxyl, C1-C4 alkyl, halo, cyano, hydroxy-Ci-C4 alkyl, -C(O)- C1-C4 alkyl, -CO2H, -CO2-C1-C4 alkyl, -SO2-C1-C4 alkyl, -SO2-C3-C7 cycloalkyl; and each R6is, independently, H, Ci-C4alkyl, Ci-C4alkoxyl, C3-C8 cycloalkyl, or alternatively, two R6groups together with the nitrogen or the carbon atom to which they are bound form C4-C10 cycloalkyl or heterocyclyl, wherein the C4-C10 cycloalkyl or heterocyclyl is optionally substituted with one of more hydroxyl, C1-C4 alkyl, halo, cyano, hydroxy-Ci-C4 alkyl; -C(O)- C1-C4 alkyl, -C(O)-OCi-C4 alkyl, or a pharmaceutically acceptable salt thereof.

[0079] In another aspect of the present disclosure, the composition described hereincomprises aPOLQi (I), wherein R1is C1-C4 alkyl, halo-Ci-C4 alkyl, nitrile, CONH2, or halo; R2is C1-C4 alkyl, halo- C1-C4 alkyl, or Cs-CsDocket No.: 14928-WO-PCTcycloalkyl; R3is C1-C4 alkyl, nitrile, C3-C8 cycloalkyl, or azetidinyl; R4is H, CI-C4 alkyl, -CH(R”)O-P(O)(OR’)(OR’), -CH(R”)-0C(0)-CI-6 alkyl-O-P(O)(OR’)(OR’), -CH(R”)-OC(O)-Ci-6alkyl-P(O)(OR’)(OR’), -CH(R”)-OC(O)- C1-6 alkyl-NR’R’, or -CH(R”)-OC(O)-C1-6 alkyl-heterocyclyl, wherein R’ and R” are, independently, selected from H or C1-C4 alkyl; R5is C1-C4 alkyl, C3-C8 cycloalkyl, halo, optionally substituted 5-10-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C(O)O-Ci-C4 alkyl, optionally substituted C(O)O-C3-Cs cycloalkyl, optionally substituted CO(O)-C4-C10 heterocyclyl, optionally substituted C2-C4 alkynyl-Ci-C4 alkyl, C2-C4 alkynyl-C3-C8 cycloalkyl, C2-C4 alkynyl-C4-Cio heterocyclyl, -N(R6)2, -C(O)N(R6)2, -P(O)(R6)2, -P(O)(OR6)2, SO(=NR6), SO2R6, wherein the optionally substituted heterocyclyl, aryl, heteroaryl, C2-C4 alkynyl-Ci-C4 alkyl, C(O)O-Ci-C4 alkyl, C(O)O-C3-Cs cycloalkyl and C0(0)-C4-Cio heterocyclyl, is optionally substituted with one of more hydroxyl, C1-C4 alkyl, halo, cyano, hydroxy-Ci-C4 alkyl; -C(O)-Ci-C4 alkyl; and each R6is, independently, H, Ci-C4alkyl, or alternatively, two R6groups together with the nitrogen or the carbon atom to which they are bound form C4-C10 cycloalkyl or heterocyclyl, wherein the C4-C10 cycloalkyl or heterocyclyl is optionally substituted with one of more hydroxyl, C1-C4 alkyl, halo, cyano, hydroxy-Ci-C4 alkyl; -C(O)-Ci-C4 alkyl, -C(O)-OCi-C4 alkyl, or a pharmaceutically acceptable salt thereof.

[0080] In another aspect, the invention is a compound of Formula (IA):N R-jjT N^^Rs1 JI k(IA), or a pharmaceutically acceptable salt thereof.Docket No.: 14928-WO-PCT

[0081] In another aspect, the invention is a compound of Formula (IB):(IB), or a pharmaceutically acceptable salt thereof.

[0082] In another embodiment, the invention is a compound according to any of the preceding embodiments, wherein R1is chloro.

[0083] In yet another embodiment, the invention is a compound according to any of the preceding embodiments, wherein R2and R3are methyl.In another embodiment, the invention is a compound according to any of the preceding embodiments, wherein R4is H.In one embodiment, the invention is as compound according to any of the preceding embodiments, wherein R5is selected from -H, -Br, -Cl, -CHF2, -CH=CH2, -CH2N(CH3)2, -CH2OH, -CH2OCH3, -CH2CH2OCH2CH2NH2, -CH2CH2OCH2CH2NHCOO / BU, CH2CH2OCH2CH2NHCOOCH2CH3, -CH(CH2OH)2, -CO2H, -CO2CH2CH3, -CO2CH(CH3)2, -CCh-cyclopropyl, -CO2CH2CH2COOH,-N(CH3)2, -N(CH3)COOCH2CH3, -C(O)NHCH3,OCH2C(O)OCH2CH3, -SCH(CH3)2, -SO2CH3, -SO2CH2CH3, -SO2CH(CH3)2, -SO2-Docket No.: 14928-WO-PCTor a pharmaceutically acceptable salt thereof.In another embodiment, the invention is a compound according to any of the preceding embodiments, wherein R5is selected from: -Br, -Cl, -CO2H, -CO2CH2CH3, -N(CH3)2,Docket No.: 14928-WO-PCT,or a pharmaceutically acceptable salt thereof.In one aspect, the invention is a compound selected from the group consisting of 2'-chloro-N-(5-(4-chlorophenyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-(5-phenylthiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3 -carboxamide; 2'-Chloro-N-(5-(4-cyanophenyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(cyclopropylethynyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(5-chloropyridin-2-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-(difluoromethyl)-5'-methoxy-6-methyl-N-(5-phenylthiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(3,6-dihydro-2H-pyran-4-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3 -carboxamide; 2'-chloro-N-(5-(3-hydroxyprop-l-yn-l-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(2,5-dihydro-lH-pyrrol-3-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(5,6-dihydro-l,4-dioxin-2-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-(5-(l,2,3,6-tetrahydropyridin-4-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide; N-(5-bromothiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-(5-morpholinothiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(dimethylamino)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(3,3-difluoroazetidin-l-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; N-(5-(2,6-diazaspiro[3.3]heptan-2-yl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; N-(5-(3,3-bis(hydroxymethyl)azetidin-l-yl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-(5-(2-methylpiperazin-l-yl)-3a,6a-dihydrothiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(4-hydroxy-2-methylpiperidin-l-yl)-3a,6a-dihydrothiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-Docket No.: 14928-WO-PCTmethyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(dimethylphosphoryl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; dimethyl (5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)phosphonate; N-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(3-hydroxybut-l-yn-l-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(2,5-dihydrofuran-3-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; N-(5-(l-acetyl-2,5-dihydro-lH-pyrrol-3-yl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-(5-(l-methyl-2,5-dihydro-lH-pyrrol-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide; ethyl 5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazole-2-carboxylate; 5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)-N, N-dimethylthiazolo[5,4-d]thiazole-2-carboxamide;5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)-N-methylthiazolo[5,4-d]thiazole-2-carboxamide; di-tert-butyl ((2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methyl) phosphate; (2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methyl dihydrogen phosphate; tert-butyl ((2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methyl) succinate; (E)-tert-butyl ((2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-5-cyclopropylthiazolo[5,4-d]thiazol-3(2H)-yl)methyl) succinate; 4-((2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methoxy)-4-oxobutanoic acid (3x); (E)-4-((2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-5-cyclopropylthiazolo[5,4-d]thiazol-3(2H)-yl)methoxy)-4-oxobutanoic acid (3x’); 5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazole-2-carboxylic acid; 2'-chloro-N-(5-(ethylsulfonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-(5-(pyrrolidin-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide; ethyl 2-(5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)cyclopropane-l-carboxylate; 2'-chloro-5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4, d'Docket No.: 14928-WO-PCTbipyridine]-3 -carboxamide; ethyl 2-((5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)oxy)acetate; 2'-chloro-N-(5-(difluoromethyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(isopropylthio)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-((dimethylamino)methyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3 -carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-(5-(oxetan-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-N-(5-(methoxymethyl)thiazolo[5,4-d]thiazol-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide; N-(5-(2-(2-aminoethoxy)ethyl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3 -carboxamide; N-(5-(azetidin-3-yl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-(5-(propan-2-ylsulfonimidoyl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-(5-(S-methylsulfonimidoyl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3 -carboxamide; 2'-chloro-N-(5-((cyclopropyl(methyl)(oxo)-16-sulfaneylidene)amino)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-6-(hydroxymethyl)-5'-methoxy-[4,4'-bipyridine]-3-carboxamide; methyl 4-(5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate; 2'-chloro-N-(5-(3-hydroxyazetidine-l-carbonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(3-cyanoazetidin-l-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; diethyl (5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)phosphonate; methyl 3-(5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)-2,5-dihydro-lH-pyrrole-l -carboxylate; ethyl 3-(5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)-2, 5-dihydro-lH-pyrrole-l -carboxylate; methyl 3-(5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)pyrrolidine-l-carboxylate; 2'-chloro-5'-methoxy-6-methyl-N-(5-vinylthiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(3-cyanoazetidine-l-carbonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; N-(5-(l-acetylpyrrolidin-3-yl)thiazolo[5,4-d]thiazol-Docket No.: 14928-WO-PCT2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; isopropyl 5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazole-2-carboxylate; cyclopropyl 5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazole-2-carboxylate; 3-((5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazole-2-carbonyl)oxy)propanoic acid; 2'-chloro-N-(5-(3,3-difluoroazetidine-l-carbonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3 -carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-(5-(l-methylpyrrolidin-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-(5-(l-(methylsulfonyl)pyrrolidin-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3 -carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-(5-(l-(methylsulfonyl)-2,5-dihydro-lH-pyrrol-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(l-(ethylsulfonyl)-2,5-dihydro-lH-pyrrol-3-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(cyclopropylsulfonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(l-(ethylsulfonyl)pyrrolidin-3-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(l-(cyclopropylsulfonyl)-2,5-dihydro-lH-pyrrol-3-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3 -carboxamide; 2'-chloro-N-(5-(l-(isopropylsulfonyl)-2,5-dihydro-lH-pyrrol-3-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2-(5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)cyclopropane-l -carboxylic acid; 2'-chloro-N-(5-(l-(isopropylsulfonyl)pyrrolidin-3-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(l-(cyclopropylsulfonyl)pyrrolidin-3-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(2-(hydroxymethyl)cyclopropyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3 -carboxamide; 2'-chloro-N-(5-chlorothiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-(5-(methylsulfonyl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-formylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-((3-hydroxyazetidin-l-yl)methyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-(thiazolo[5,4-Docket No.: 14928-WO-PCTd]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(hydroxymethyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(isopropylsulfonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; ethyl (2-(2-(5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)ethoxy)ethyl)carbamate; ethyl 3-(5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)azetidine-l-carboxylate; 2'-chloro-N-(5-(1,3-dihydroxypropan-2-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-(5-(l-(methylsulfonyl)azetidin-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide; tert-butyl (2-(2-(5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)ethoxy)ethyl)carbamate; 2'-chloro-5'-methoxy-6-methyl-N-(5-(1-methylazetidin-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide; 5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)-N-(2-hydroxyethyl)-N-methylthiazolo[5,4-d]thiazole-2-carboxamide; 2'-chloro-N-(5-(ethylsulfonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridine]-4-carboxamide; dimethyl (5-(2'-chloro-5'-methoxy-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridine]-4-carboxamido)thiazolo[5,4-d]thiazol-2-yl)phosphonate; N-(5-bromothiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridine]-4-carboxamide; 2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-1-(2-(dimethylamino)ethyl)-5'-methoxy-6-oxo-1,6-dihydro-[3,4'-bipyridine]-4-carboxamide; 1-(2-aminoethyl)-2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-oxo-1,6-dihydro-[3,4'-bipyridine]-4-carboxamide; tert-butyl ((2'-chloro-N-(5-(ethoxycarbonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methyl) succinate; (E)-tert-butyl ((2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-5-(ethoxycarbonyl)thiazolo[5,4-d]thiazol-3(2H)-yl)methyl) succinate; 4-((2'-chloro-N-(5-(ethoxycarbonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methoxy)-4-oxobutanoic acid; (E)-4-((2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-5-(ethoxycarbonyl)thiazolo[5,4-d]thiazol-3(2H)-yl)methoxy)-4-oxobutanoic acid; ethyl (E)-5-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-6-(((di-tert-butoxyphosphoryl)oxy)methyl)-5,6-dihydrothiazolo[5,4-d]thiazole-2-carboxylate; ethyl 5-(2'-chloro-5'-methoxy-6-methyl-N-Docket No.: 14928-WO-PCT((phosphonooxy)methyl)-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazole-2-carboxylate; ethyl (E)-5-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-6-((phosphonooxy)methyl)-5,6-dihydrothiazolo[5,4-d]thiazole-2-carboxylate; (E)-4-((2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)- 5-cyclopropylthiazolo[5,4-d]thiazol-3(2H)-yl)methoxy)-4-oxobutanoic acid; 2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-6-(2-(dimethylamino)ethoxy)-5'-methoxy-[4,4'-bipyridine]-3 -carboxamide; 2'-chloro-N-(5-(3-hydroxycyclopentyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; ethyl 3-(5-(2'-chloro-5'-methoxy- 6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)bicyclo[l.1. l]pentane-1 -carboxylate; 2'-chloro-N-(5-(2,2-difluorocyclopropyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(3-(hydroxymethyl)bicyclo[l.1. l]pentan-l-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-(5-(methyl(pyrrolidin-l-yl)phosphoryl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-((3,3-difluoroazetidin-l-yl)(methyl)phosphoryl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-(5-(1-(S-methylsulfonimidoyl)cyclopropyl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide; (E)-5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)-N-ethoxythiazolo[5,4-d]thiazole-2-carbimidoyl cyanide; N-(5-(3-oxabicyclo[3.1.0]hexan-l-yl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; ethyl 2-((5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)ethynyl)cyclopropane-1-carboxylate; 2'-chloro-5'-methoxy-6-methyl-N-(5-((oxetan-3-yloxy)methyl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3 -carboxamide; 5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl propionate; N-(5-(2-(aminomethyl)cyclopropyl)-3a,6a-dihydrothiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; andethyl l-(5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylat or a pharmaceutically acceptable salt thereof.Docket No.: 14928-WO-PCTIn another aspect, the invention is a compound selected from the group consisting of: 2'-chloro-N-(5-(4-chlorophenyl)thiazolo[5,4-d]thiazol-2-yl)-5’-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-(5-phenylthiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide; 2'-Chloro-N-(5-(4-cyanophenyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(cyclopropylethynyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(5-chloropyridin-2-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-(difluoromethyl)-5'-methoxy-6-methyl-N-(5-phenylthiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(3,6-dihydro-2H-pyran-4-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(3-hydroxyprop-l-yn-l-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(2,5-dihydro-lH-pyrrol-3-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(5,6-dihydro-l,4-dioxin-2-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-(5-(l,2,3,6-tetrahydropyridin-4-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide; N-(5-bromothiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-5'-methoxy-6-methyl-N-(5-morpholinothiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(dimethylamino)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(3,3-difluoroazetidin-l-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; N-(5-(2,6-diazaspiro[3.3]heptan-2-yl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; N-(5-(3,3-bis(hydroxymethyl)azetidin-l-yl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-(5-(2-methylpiperazin-l-yl)-3a,6a-dihydrothiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3 -carboxamide; 2'-chloro-N-(5-(4-hydroxy-2-methylpiperidin-l-yl)-3a,6a-dihydrothiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(dimethylphosphoryl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3 -carboxamide; dimethyl (5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-Docket No.: 14928-WO-PCTcarboxamido)thiazolo[5,4-d]thiazol-2-yl)phosphonate; N-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(3-hydroxybut-l-yn-l-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-N-(5-(2,5-dihydrofuran-3-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; N-(5-(l-acetyl-2,5-dihydro-lH-pyrrol-3-yl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; 2'-chloro-5'-methoxy-6-methyl-N-(5-(l-methyl-2,5-dihydro-lH-pyrrol-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide; ethyl 5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazole-2-carboxylate; 5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)-N, N-dimethylthiazolo[5,4-d]thiazole-2-carboxamide; 5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)-N-methylthiazolo[5,4-d]thiazole-2-carboxamide; di-tert-butyl ((2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methyl) phosphate; (2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methyl dihydrogen phosphate; tert-butyl ((2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methyl) succinate; (E)-tert-butyl ((2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-5-cyclopropylthiazolo[5,4-d]thiazol-3(2H)-yl)methyl) succinate; 4-((2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methoxy)-4-oxobutanoic acid (3x); (E)-4-((2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-5-cyclopropylthiazolo[5,4-d]thiazol-3(2H)-yl)methoxy)-4-oxobutanoic acid (3x’); and 5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazole-2-carboxylic acid, or a pharmaceutically acceptable salt thereof.In one aspect, the invention is a composition comprising: a Pol0 (PolQ) inhibitor of formula(I) (I), wherein R1is C1-C4 alkyl, halo-Ci-C4 alkyl,Docket No.: 14928-WO-PCTnitrile, CONH2, or halo; R2is C1-C4 alkyl, halo- C1-C4 alkyl, or C3-C8 cycloalkyl; R3is C1-C4 alkyl, nitrile, C3-C8 cycloalkyl, or azetidinyl; R4is H, Ci-C4 alkyl, -CH(R”)O-P(O)(OR’)(OR’), -CH(R”)-0C(0)-CI-6 alkyl-O-P(O)(OR’)(OR’), -CH(R”)-0C(0)-CI-6 alkyl-P(O)(OR’)(OR’), -CH(R”)-OC(O)- C1-6 alkyl-NR’R’, or -CH(R”)-0C(0)-CI-6 alkyl-heterocyclyl, wherein R’ and R” are, independently, selected from H or C1-C4 alkyl; R5is C1-C4 alkyl, C3-C8 cycloalkyl, halo, optionally substituted 5-10-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C(O)O-C1-C4 alkyl, optionally substituted C(O)O-C3-Cs cycloalkyl, optionally substituted CO(O)-C4-C10 heterocyclyl, optionally substituted C2-C4 alkynyl-Ci-C4 alkyl, C2-C4 alkynyl-C3-C8 cycloalkyl, C2-C4 alkynyl-C4-Cio heterocyclyl, -N(R6)2, -C(O)N(R6)2, -P(O)(R6)2, -P(O)(OR6)2, SO(=NR6), SO2R6, wherein the optionally substituted heterocyclyl, aryl, heteroaryl, C2-C4 alkynyl-Ci-C4 alkyl, C(O)O-Ci-C4 alkyl, C(O)O-C3-Cs cycloalkyl and C0(0)-C4-Cio heterocyclyl, is optionally substituted with one of more hydroxyl, C1-C4 alkyl, halo, cyano, hydroxy-Ci-C4 alkyl; -C(O)-Ci-C4 alkyl; and each R6is, independently, H, Ci-C4alkyl, or alternatively, two R6groups together with the nitrogen or the carbon atom to which they are bound form C4-C10 cycloalkyl or heterocyclyl, wherein the C4-C10 cycloalkyl or heterocyclyl is optionally substituted with one of more hydroxyl, C1-C4 alkyl, halo, cyano, hydroxy-Ci-C4 alkyl; -C(O)-Ci-C4 alkyl, -C(O)-OCi-C4 alkyl, or a pharmaceuticallyacceptable salt thereof,; and a DNAPK inhibitor of Formula (SI): (SI), or a pharmaceutically acceptable salt thereof, wherein: Asis a 5-membered or 6-membered heteroaryl or heterocycloalkyl group containing at least one heteroatom selected from the group consisting of N, O, and S, wherein the heteroaryl or heterocycloalkyl is optionally substituted with one or more RS5; RS1is an aryl or heteroaryl containing at least one heteroatom selected from the group consisting of N, O, S, and Se, wherein the aryl or heteroaryl is optionally substituted with one or more RS6; RS2is H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, CN, OH, CH2OH, NH2, or CH2NH2; RS3and RS4are each independently selected from the group consisting of -OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4Docket No.: 14928-WO-PCThaloalkyl, C1-C4 alkylaryl, and aryl; each RS5is independently selected from the group consisting of halogen, oxo, thioxo, C1-C4 alkyl, CD3, CD2CD3, C1-C4 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, and aryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is optionally substituted with one or more RS7; or two geminal RS5, together with the intervening geminal carbon atom, form a C3-C6 cycloalkyl; each RS6is independently selected from the group consisting of halogen, oxo, NH2, OH, -CN, C(O)NHRS7, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, CD3, CD2CD3, Ci-Ce alkoxy, Ci-Ce haloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl and aryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is optionally substituted with one or more RS7; each RS7is independently selected from the group consisting of halogen, OH, oxo, NH2, CHO, C1-C4 alkyl, and C1-C6 alkoxy; and n is an integer from 1 to 3.In yet another aspect, the invention is a composition comprising: a Pol0 (PolQ) inhibitor offormula (I) (I), wherein R1is C1-C4 alkyl, halo-Ci- C4 alkyl, nitrile, CONH2, or halo; R2is C1-C4 alkyl, halo- C1-C4 alkyl, or C3-C8 cycloalkyl; R3is C1-C4 alkyl, nitrile, C3-C8 cycloalkyl, or azetidinyl; R4is H, Ci-C4 alkyl, -CH(R”)O- P(O)(OR’)(OR’), -CH(R”)-OC(O)-C 1-6 alky 1-O-P(O)(OR’)(OR’), -CH(R”)-0C(0)-CI-6 alkyl-P(O)(OR’)(OR’), -CH(R”)-OC(O)- C1-6 alkyl-NR’R’, or -CH(R”)-0C(0)-CI-6 alkyl-heterocyclyl, wherein R’ and R” are, independently, selected from H or C1-C4 alkyl; R5is C1-C4 alkyl, C3-C8 cycloalkyl, halo, optionally substituted 5-10-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C(O)O-C1-C4 alkyl, optionally substituted C(O)O-C3-C8 cycloalkyl, optionally substituted CO(O)-C4-C10 heterocyclyl, optionally substituted C2-C4 alkynyl-Ci-C4 alkyl, C2-C4 alkynyl-C3-C8 cycloalkyl, C2-C4 alkynyl-C4-Cio heterocyclyl, -N(R6)2, -C(O)N(R6)2, -P(O)(R6)2, -P(O)(OR6)2, SO(=NR6), SO2R6, wherein the optionally substituted heterocyclyl, aryl, heteroaryl, C2-C4 alkynyl-Ci-C4 alkyl, C(O)O-Ci-C4 alkyl, C(O)O-C3-C8 cycloalkyl andDocket No.: 14928-WO-PCTC0(0)-C4-Cio heterocyclyl, is optionally substituted with one of more hydroxyl, C1-C4 alkyl, halo, cyano, hydroxy-Ci-C4 alkyl; -C(O)-Ci-C4 alkyl; and each R6is, independently, H, Ci-C4alkyl, or alternatively, two R6groups together with the nitrogen or the carbon atom to which they are bound form C4-C10 cycloalkyl or heterocyclyl, wherein the C4-C10 cycloalkyl or heterocyclyl is optionally substituted with one of more hydroxyl, C1-C4 alkyl, halo, cyano, hydroxy-Ci-C4 alkyl; -C(O)-Ci-C4 alkyl, -C(O)-OCi-C4 alkyl, or a pharmaceuticallyacceptable salt thereof; and a DNAPK inhibitor of Formula (SI): (SI), or a pharmaceutically acceptable salt thereof, wherein: Asis a 5-membered or 6-membered heteroaryl or heterocycloalkyl group containing at least one heteroatom selected from the group consisting of N, O, and S, wherein the heteroaryl or heterocycloalkyl is optionally substituted with one or more RS5; RS1is an aryl or heteroaryl containing at least one heteroatom selected from the group consisting of N, O, S, and Se, wherein the aryl or heteroaryl is optionally substituted with one or more RS6; RS2is H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, CN, OH, CH2OH, NH2, or CH2NH2; RS3and RS4are each independently selected from the group consisting of -OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylaryl, and aryl; each RS5is independently selected from the group consisting of halogen, oxo, thioxo, C1-C4 alkyl, CD3, CD2CD3, C1-C4 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, and aryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is optionally substituted with one or more RS7; or two geminal RS5, together with the intervening geminal carbon atom, form a C3-C6 cycloalkyl; each RS6is independently selected from the group consisting of halogen, oxo, NH2, OH, -CN, C(O)NHRS7, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, CD3, CD2CD3, Ci-Ce alkoxy, Ci-Ce haloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl and aryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is optionally substituted with one or more RS7; each RS7is independently selected from the group consisting of halogen, OH, oxo, NH2, CHO, C1-C4 alkyl, and C1-C6 alkoxy; and n is an integer from 1 to 3.Docket No.: 14928-WO-PCTIn another aspect, the invention is a composition of the preceding aspect, wherein a DNAPK inhibitor of Formula (SI) is selected from the group consisting of:Docket No.: 14928-WO-PCTDocket No.: 14928-WO-PCT oDocket No.: 14928-WO-PCTDocket No.: 14928-WO-PCTDocket No.: 14928-WO-PCTDocket No.: 14928-WO-PCTDocket No.: 14928-WO-PCTDocket No.: 14928-WO-PCTDocket No.: 14928-WO-PCT; or a pharmaceutically acceptable salt thereof.Docket No.: 14928-WO-PCTIn another aspect, the invention is a pharmaceutical composition comprising the compound of any one of preceding aspects, and a pharmaceutically acceptable excipient, diluent, or carrier. In one aspect, the invention is a composition comprising: a Pol0 (PolQ) inhibitor of formula N R1Iu A NMn 'v(I):3(I), wherein R1is C1-C4 alkyl, halo-Ci-C4 alkyl, nitrile, CONH2, or halo; R2is C1-C4 alkyl, halo- C1-C4 alkyl, or C3-C8 cycloalkyl; R3is C1-C4 alkyl, nitrile, C3-C8 cycloalkyl, or azetidinyl; R4is H, CI-C4 alkyl, -CH(R”)O-P(O)(OR’)(OR’), -CH(R”)-0C(0)-CI-6 alkyl-O-P(O)(OR’)(OR’), -CH(R”)-0C(0)-CI-6 alkyl-P(O)(OR’)(OR’), -CH(R”)-OC(O)- C1-6 alkyl-NR’R’, or -CH(R”)-OC(O)-CI-6 alkyl-heterocyclyl, wherein R’ and R” are, independently, selected from H or C1-C4 alkyl; R5is C1-C4 alkyl, C3-C8 cycloalkyl, halo, optionally substituted 5-10-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C(O)O-C1-C4 alkyl, optionally substituted C(O)O-C3-Cs cycloalkyl, optionally substituted CO(O)- C4-C10 heterocyclyl, optionally substituted C2-C4 alkynyl-Ci-C4 alkyl, C2-C4 alkynyl-C3-C8 cycloalkyl, C2-C4 alkynyl-C4-Cio heterocyclyl, -N(R6)2, -C(O)N(R6)2, -P(O)(R6)2, -P(O)(OR6)2, SO(=NR6), SO2R6, wherein the optionally substituted heterocyclyl, aryl, heteroaryl, C2-C4 alkynyl-Ci-C4 alkyl, C(O)O-Ci-C4 alkyl, C(O)O-C3-Cs cycloalkyl and C0(0)-C4-Cio heterocyclyl, is optionally substituted with one of more hydroxyl, C1-C4 alkyl, halo, cyano, hydroxy-Ci-C4 alkyl; -C(O)-Ci-C4 alkyl; and each R6is, independently, H, Ci-C4alkyl, or alternatively, two R6groups together with the nitrogen or the carbon atom to which they are bound form C4-C10 cycloalkyl or heterocyclyl, wherein the C4-C10 cycloalkyl or heterocyclyl is optionally substituted with one of more hydroxyl, C1-C4 alkyl, halo, cyano, hydroxy-Ci-C4 alkyl; -C(O)-Ci-C4 alkyl, -C(O)-OCi-C4 alkyl, or a pharmaceuticallyDocket No.: 14928-WO-PCTR1BHISTI II rB x _R2Bacceptable salt thereof; and a DNAPK inhibitor of Formula (BI): (BI), or a pharmaceutically acceptable salt thereof, wherein: ABis a 5- or 6-membered heteroaryl or heterocycloalkyl group containing at least one heteroatom selected from the group consisting of N, O, and S, wherein the heteroaryl or heterocycloalkyl is optionally substituted with one or more R4B; R1Bis an aryl or heteroaryl containing at least one heteroatom selected from the group consisting of N, O, S, and Se, wherein the aryl or heteroaryl is optionally substituted with one or more R5B; R2Bis H, halogen, -(CH2)nB-CN, -OH, -(CH2)nB-O-Ci-C4 alkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C(0)NH2; R3Bis selected from the group consisting of H, F, C2-C4 alkenyl, C2-C4 alkynyl, CN, OH, CH2OH, NH2, CH2NH2, and C1-C4 alkyl; each R4Bis independently selected from the group consisting of halogen, oxo, thioxo, C1-C4 alkyl, C1-C4 alkoxy, CD3, CD2CD3, and Ci-Ce haloalkyl; or two geminal R4Btogether with the intervening geminal carbon atom, form a C3-C6 cycloalkyl; each R5Bis independently selected from the group consisting of halogen, NH2, OH, -CN, C(0)NH2, C(O)NHR7B, C1-C4 alkyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, CD3, CD2CD3, Ci-Ce alkoxy, Ci-Ce haloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, and aryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is optionally substituted with one or more R6B; each R6Bis independently selected from the group consisting of halogen, OH, oxo, NH2, CHO, C1-C4 alkyl, and Ci-Ce alkoxy; each R7Bis independently selected from H and C1-C4 alkyl; each nB is independently an integer from 0-4; rBis an integer from 0 to 2; sBis an integer from 0 to 2; and tBis an integer from 1 to 2.Docket No.: 14928-WO-PCTIn yet another aspect, the invention is a composition comprising: a Pol0 (PolQ) inhibitor offormula (I): (I), wherein R1is C1-C4 alkyl, halo-Ci- C4 alkyl, nitrile, CONH2, or halo; R2is C1-C4 alkyl, halo- C1-C4 alkyl, or C3-C8 cycloalkyl; R3is C1-C4 alkyl, nitrile, C3-C8 cycloalkyl, or azetidinyl; R4is H, CI-C4 alkyl, -CH(R”)O- P(O)(OR’)(OR’), -CII(R”)-OC(O)-CI-6 alkyl-O-P(O)(OR’)(OR’), -CII(R”)-OC(O)-CI-6 alkyl-P(O)(OR’)(OR’), -CH(R”)-OC(O)- C1-6 alkyl-NR’R’, or -CH(R”)-0C(0)-CI-6 alkyl-heterocyclyl, wherein R’ and R” are, independently, selected from II or C1-C4 alkyl; R5is C1-C4 alkyl, C3-C8 cycloalkyl, halo, optionally substituted 5-10-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C(O)O-C1-C4 alkyl, optionally substituted C(O)O-C3-Cs cycloalkyl, optionally substituted CO(O)-C4-C10 heterocyclyl, optionally substituted C2-C4 alkynyl-Ci-C4 alkyl, C2-C4 alkynyl-C3-C8 cycloalkyl, C2-C4 alkynyl-C4-Cio heterocyclyl, -N(R6)2, -C(O)N(R6)2, -P(O)(R6)2, -P(O)(OR6)2, SO(=NR6), SO2R6, wherein the optionally substituted heterocyclyl, aryl, heteroaryl, C2-C4 alkynyl-Ci-C4 alkyl, C(O)O-Ci-C4 alkyl, C(O)O-C3-Cs cycloalkyl and C0(0)-C4-Cio heterocyclyl, is optionally substituted with one of more hydroxyl, C1-C4 alkyl, halo, cyano, hydroxy-Ci-C4 alkyl; -C(O)-Ci-C4 alkyl; and each R6is, independently, H, Ci-C4alkyl, or alternatively, two R6groups together with the nitrogen or the carbon atom to which they are bound form C4-C10 cycloalkyl or heterocyclyl, wherein the C4-C10 cycloalkyl or heterocyclyl is optionally substituted with one of more hydroxyl, C1-C4 alkyl, halo, cyano, hydroxy-Ci-C4 alkyl; -C(O)-Ci-C4 alkyl, -C(O)-OCi-C4 alkyl, or a pharmaceuticallyR1BHNXacceptable salt thereof; and a DNAPK inhibitor of Formula (BI):Docket No.: 14928-WO-PCT(BI), or a pharmaceutically acceptable salt thereof, wherein: ABis a 5- or 6-membered heteroaryl or heterocycloalkyl group containing at least one heteroatom selected from the group consisting of N, O, and S, wherein the heteroaryl or heterocycloalkyl is optionally substituted with one or more R4B; R1Bis an aryl or heteroaryl containing at least one heteroatom selected from the group consisting of N, O, S, and Se, wherein the aryl or heteroaryl is optionally substituted with one or more R5B; R2Bis H, halogen, -(CH2)nB-CN, -OH, -(CH2)nB-O-Ci-C4 alkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C(0)NH2; R3Bis selected from the group consisting of H, F, C2-C4 alkenyl, C2-C4 alkynyl, CN, OH, CH2OH, NH2, CH2NH2, and C1-C4 alkyl; each R4Bis independently selected from the group consisting of halogen, oxo, thioxo, C1-C4 alkyl, C1-C4 alkoxy, CD3, CD2CD3, and Ci-Ce haloalkyl; or two geminal R4Btogether with the intervening geminal carbon atom, form a C3-C6 cycloalkyl; each R5Bis independently selected from the group consisting of halogen, NH2, OH, -CN, C(0)NH2, C(O)NHR7B, C1-C4 alkyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, CD3, CD2CD3, Ci-Ce alkoxy, Ci-Ce haloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, and aryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is optionally substituted with one or more R6B; each R6Bis independently selected from the group consisting of halogen, OH, oxo, NH2, CHO, C1-C4 alkyl, and Ci-Ce alkoxy; each R7Bis independently selected from H and C1-C4 alkyl; each nB is independently an integer from 0-4; rBis an integer from 0 to 2; sBis an integer from 0 to 2; and tBis an integer from 1 to 2.In another aspect, the invention is the composition according to any of the preceding aspects, wherein a DNAPK inhibitor of Formula (BI) is selected from the group consisting of:Docket No.: 14928-WO-PCTDocket No.: 14928-WO-PCTDocket No.: 14928-WO-PCTDocket No.: 14928-WO-PCTDocket No.: 14928-WO-PCTDocket No.: 14928-WO-PCTDocket No.: 14928-WO-PCT, or a pharmaceutically acceptable salt thereof.In one aspect, the invention is a pharmaceutical composition comprising the compound of any of the preceding aspects, and a pharmaceutically acceptable excipient, diluent, or carrier. In one aspect, the invention is a composition according to any one of the preceding aspects further comprising a DNA cutting agent;In one aspect, the invention is a composition according to any one of the preceding aspects, further comprising a cell.In one aspect, the invention is a composition according to any one of the preceding aspects further comprising a donor DNA.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the concentration of the DNA-PKI in the composition is about 10 pM or less and the concentration of the POLQi Compound II in the composition is about 15 pM or less.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the concentration of the DNA-PKI in the composition is from about 0.05-10 pM and the concentration of the POLQi Compound II in the composition is about 15 pM or less. In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the concentration of the DNA-PKI in the composition is from about 0.05-5 pM and the concentration of the POLQi Compound II in the composition is about 15 pM or less.Docket No.: 14928-WO-PCTIn one aspect, the invention is a composition according to any one of the preceding aspects, wherein the cell is a eukaryotic cell.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the cell is useful in adoptive cell therapy (ACT).In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the cell is a stem cell.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the stem cell is a hematopoietic stem cell (HSC) or an induced pluripotent stem cell (iPSC).In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the cell is an immune cell.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the immune cell is a leukocyte or a lymphocyte.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the immune cell is a lymphocyte.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the lymphocyte is a T cell, a B cell, or an NK cell.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the lymphocyte is a T cell.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein T cell is a primary T cell.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein T cell is a regulatory T cell.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the lymphocyte is an activated T cell.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the lymphocyte is a non-activated T cell.Docket No.: 14928-WO-PCTIn one aspect, the invention is a composition according to any one of the preceding aspects, wherein the cell is a human cell.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the DNA cutting agent comprises a CRISPR / Cas nuclease component and optionally a guide RNA component.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the DNA cutting agent comprises a CRISPR / Cas nuclease that generates a double strand DNA break or single strand DNA break.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the DNA cutting agent is selected from a zinc finger nuclease, a TALE effector domain nuclease (TALEN), a CRISPR / Cas nuclease component, and combinations thereof. In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the DNA cutting agent is a CRISPR / Cas nuclease component and a guide RNA component.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the CRISPR / Cas nuclease component comprises a Cas nuclease or an mRNA encoding the Cas nuclease.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the CRISPR / Cas nuclease component comprises the Cas nuclease.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the Cas nuclease is a Class 2, Type II Cas nuclease.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the Cas nuclease is a Cas9 nuclease.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the Cas nuclease is a S. pyogenes Cas9 nuclease.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the Cas nuclease is a Class 2, Type V Cas nuclease.Docket No.: 14928-WO-PCTIn one aspect, the invention is a composition according to any one of the preceding aspects, wherein the Cas nuclease is a Cas12a nuclease.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the Cas nuclease is a Acidaminococcus sp. Cas12a nuclease.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the Cas nuclease generates a single strand DNA break.In one aspect, the invention is a composition according to any one of the preceding aspects, comprising a modified RNA.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the guide RNA component is a guide RNA nucleic acid.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the guide RNA nucleic acid is a guide RNA (gRNA).In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the guide RNA nucleic acid is or encodes a dual-guide RNA (dgRNA) composed of a crRNA and tracrRNA.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the guide RNA nucleic acid is or encodes a single-guide (sgRNA).In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the gRNA is a modified gRNA.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the cutting agent is Cas9 and the modified gRNA comprises a modification at one or more of the first five nucleotides at the 5’ end.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the cutting agent is Casl2a and the modified gRNA comprises a DNA / RNA hybrid molecule.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the modified gRNA comprises a modification at one or more of the last five nucleotides at the 3’ end.Docket No.: 14928-WO-PCTIn one aspect, the invention is a composition according to any one of the preceding aspects, wherein the composition comprises a guide RNA nucleic acid and a Class 2, Type II or Class 2, Type V Cas nuclease; and the molar ratio of the guide RNA to Cas nuclease is from about 4:1 to 1:4.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the donor DNA comprises a template comprising a sequence encoding a protein, a regulatory sequence, or a sequence encoding structural RNA.In one aspect, the invention is a composition according to any one of the preceding aspects further comprising a vector.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the vector encodes the donor DNA.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the vector is a viral vector.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the vector is a non-viral vector.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the vector is an AAV.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the cell is not a cancer cell.In another aspect, the invention is a method of targeted insertion of a donor DNA into the genome of a cell, comprising contacting the cell with a DNA cutting agent, the donor DNA, POLQi Compound I, and a DNA-PKI, wherein the POLQi and DNA-PKI is a compound according to any one of the preceding aspects.In one aspect, the invention is a method according to any one of the preceding aspects, comprising growing the cell in a cell medium free of the DNA-PKI and POLQi Compound I, and adding the DNA-PKI POLQi Compound I, to the cell medium.Docket No.: 14928-WO-PCTIn one aspect, the invention is a method according to any one of the preceding aspects, comprising contacting the cell with the DNA cutting agent before contacting the cell with the DNA-PKI and POLQi Compound I.In one aspect, the invention is a method according to any one of the preceding aspects, comprising contacting the cell with the DNA-PKI within about six hours of contacting the cell with the DNA cutting agent.In one aspect, the invention is a method according to any one of the preceding aspects, comprising contacting the cell with the DNA-PKI and POLQi Compound I within about three hours of contacting the cell with the DNA cutting agent.In one aspect, the invention is a method according to any one of the preceding aspects, comprising contacting the cell with the DNA cutting agent simultaneously with the DNA-PKI and POLQi Compound I.In one aspect, the invention is a method according to any one of the preceding aspects, comprising contacting the cell with the DNA cutting agent after contacting the cell with the DNA-PKI and POLQi Compound I.In one aspect, the invention is a method according to any one of the preceding aspects, wherein contacting the cell with the DNA cutting agent comprises electroporation.In one aspect, the invention is a method according to any one of the preceding aspect,, comprising contacting the cell with the DNA cutting agent within about three hours of contacting the cell with the DNA-PKI and POLQi Compound I.In one aspect, the invention is a method according to any one of the preceding aspects, comprising growing the cell in a cell medium comprising the DNA-PKI and POLQi Compound I.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the cell is contacted with the DNA cutting agent and the DNA-PKI and POLQi Compound I for at least about one day.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the cell is contacted with the DNA cutting agent and the DNA-PKI and POLQi Compound I for about one day to about two weeks.Docket No.: 14928-WO-PCTIn one aspect, the invention is a method according to any one of the preceding aspects, wherein the cell is contacted with the DNA cutting agent and the DNA-PKI and POLQi Compound I for about two weeks.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the cell is contacted with the DNA-PKI in a cell medium, wherein the concentration of the DNA-PKI in the cell medium is about 10 pM or less and the concentration of the POLQi Compound I in the cell medium is about 15 pM or less.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the cell is contacted with the DNA-PKI in a cell medium, wherein the concentration of the DNA-PKI in the cell medium is from about 0.05-10 pM and the concentration of the POLQi Compound I in the cell medium is about 15 pM or less.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the concentration of the DNA-PKI in the cell medium is from about 0.025-5 pM and the concentration of the POLQi Compound I in the cell medium is about 15 pM or less. In one aspect, the invention is a method according to any one of the preceding aspects, wherein the cell is a eukaryotic cell.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the cell is for use in adoptive cell therapy (ACT).In one aspect, the invention is a method according to any one of the preceding aspects, wherein the cell is for use in autologous cell therapy.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the cell is for use in allogeneic cell therapy.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the cell is a stem cell.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the stem cell is a hematopoietic stem cell (HSC).In one aspect, the invention is a method according to any one of the preceding aspects, wherein the cell is an induced pluripotent stem cell (iPSC).Docket No.: 14928-WO-PCTIn one aspect, the invention is a method according to any one of the preceding aspects, wherein the cell is an immune cell.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the immune cell is a leukocyte or a lymphocyte.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the immune cell is a lymphocyte.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the lymphocyte is a T cell, a B cell, or an NK cell.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the lymphocyte is a T cell.In one aspect, the invention is a method according to any one of the preceding aspects, wherein T cell is a primary T cell.In one aspect, the invention is a method according to any one of the preceding aspects, wherein T cell is a regulatory T cell.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the lymphocyte is an activated T cell.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the lymphocyte is a non-activated T cell.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the cell is a human cell.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the DNA cutting agent is selected from a zinc finger nuclease, a TALE effector domain nuclease (TALEN), a CRISPR / Cas nuclease component, and combinations thereof. In one aspect, the invention is a method according to any one of the preceding aspects, wherein the DNA cutting agent is a CRISPR / Cas nuclease component.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the CRISPR / Cas nuclease component comprises a Cas nuclease or an mRNA encoding the Cas nuclease.Docket No.: 14928-WO-PCTIn one aspect, the invention is a method according to any one of the preceding aspects, wherein the CRISPR / Cas nuclease component comprises an mRNA encoding the Cas nuclease.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the Cas nuclease is a Class 2, Type II Cas nuclease.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the Cas nuclease is a Class 2, Type V Cas nuclease.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the Cas nuclease is a Cas9 nuclease.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the Cas nuclease is a S. pyogenes Cas9 nuclease.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the Cas nuclease is a Casl2a nuclease.In one aspect, the invention is a method according to any one of the preceding aspects, further comprising contacting the cell with a modified RNA.In one aspect, the invention is a method according to any one of the preceding aspects, further comprising contacting the cell with a guide RNA nucleic acid.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the guide RNA nucleic acid is a gRNA.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the guide RNA nucleic acid is or encodes a dual-guide RNA (dgRNA).In one aspect, the invention is a method according to any one of the preceding aspects, wherein the guide RNA nucleic acid is or encodes a single-guide (sgRNA).In one aspect, the invention is a method according to any one of the preceding aspects, wherein the gRNA is a modified gRNA.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the modified gRNA comprises a modification at one or more of the first five nucleotides at the 5’ end.Docket No.: 14928-WO-PCTIn one aspect, the invention is a method according to any one of the preceding aspects, wherein the modified gRNA comprises a modification at one or more of the last five nucleotides at the 3’ end.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the DNA cutting agent is a Class 2, Type II Cas nuclease or Class 2, Type V Cas nuclease mRNA; and the ratio of the guide RNA nucleic acid to Cas nuclease is from about 4: 1 to 1:4 by molar ratio.In one aspect, the invention is a method according to any one of the preceding aspects, further comprising contacting the cell with a donor DNA.In one aspect, the invention is a method according to any one of the preceding aspects, comprising contacting the cell with a vector comprising the donor DNA.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the donor DNA comprises a template comprising a sequence encoding a protein, a regulatory sequence, or a sequence encoding structural RNA.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the template sequence is integrated into the genome of the cell via homology directed repair (HDR).In one aspect, the invention is a method according to any one of the preceding aspects, further comprising contacting the cell with a vector.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the vector encodes the DNA cutting agent.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the vector encodes a donor DNA.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the vector is a viral vector.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the vector is a non-viral vector.Docket No.: 14928-WO-PCTIn one aspect, the invention is a method according to any one of the preceding aspects, wherein the vector is an AAV.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the DNA cutting agent interacts with a target sequence within the genome of the cell, resulting in a double stranded DNA break (DSB).In one aspect, the invention is a method according to any one of the preceding aspects, wherein the method results in a gene knockout.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the method results in a gene correction.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the method results in a gene insertion.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the donor DNA comprises a template comprising an exogenous nucleic acid encoding a protein.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the protein is selected from the group consisting of a cytokine, an immunosuppressor, an antibody, a receptor, and an enzyme.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the protein is a receptor.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the receptor is selected from the group consisting of an immunological receptor, a T-cell receptor (TCR), and a chimeric antigen receptor.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the receptor is an immunological receptor.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the receptor is a TCR.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the exogenous nucleic acid encodes a TCR alpha chain and / or a TCR beta chain.Docket No.: 14928-WO-PCTIn one aspect, the invention is a method according to any one of the preceding aspects, wherein the receptor a chimeric antigen receptor.In one aspect, the invention is a method according to any one of the preceding aspects, wherein the DNA cutting agent interacts with a target sequence within the TRAC gene of the T-cell.In one aspect, the invention is a method according to any one of the preceding aspects, comprising contacting the cell with at least two different DNA cutting agents that target different loci.In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the template comprises a first homology arm and a second homology arm that are complementary to sequences located upstream and downstream.It should be understood that all isomeric forms are included within the present disclosure, including mixtures thereof. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans configuration. All tautomeric forms are also intended to be included.

[0084] Compounds of the present disclosure, and pharmaceutically acceptable salts, hydrates, solvates, stereoisomers and prodrugs thereof may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present disclosure.

[0085] The compounds of the present disclosure may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present disclosure as well as mixtures thereof, including racemic mixtures, form part of the present disclosure. In addition, the present disclosure embraces all geometric and positional isomers. For example, if a compound of the present disclosure incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the present disclosure. Each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound. The compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry. The assay results may reflect the data collected for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry.Docket No.: 14928-WO-PCT

[0086] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of the present disclosure may be atropisomers (e.g., substituted biaryls) and are considered as part of this present disclosure. Enantiomers can also be separated by use of a chiral HPLC column.

[0087] It is also possible that the compounds of the present disclosure may exist in different tautomeric forms, and all such forms are embraced within the scope of the present disclosure. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the present disclosure.

[0088] All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this present disclosure, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and transforms, as well as mixtures, are embraced within the scope of the present disclosure. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the present disclosure). Individual stereoisomers of the compounds of the present disclosure may, for example, be substantially free of other stereoisomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present disclosure can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”, “solvate”, “ester,” “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.Docket No.: 14928-WO-PCT

[0089] The compounds of Formula I may form salts which are also within the scope of this present disclosure. Reference to a compound of the Formula herein is understood to include reference to salts thereof, unless otherwise indicated.

[0090] The present disclosure is directed to compounds as described herein and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, and pharmaceutical compositions comprising one or more compounds as described herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof.Method of Synthesizing the Compounds

[0091] The compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March’s Advanced Organic Chemistry': Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; Greene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCFI Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed. Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognised reference textbooks of organic synthesis known to those in the art.

[0092] During the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups. One of ordinary skill in the art will recognize that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how toDocket No.: 14928-WO-PCTintroduce and remove these groups can be found in Greene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd edition. John Wiley & Sons. New York, 1999.

[0093] It is to be understood that the synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.

[0094] In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers, however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer.Compositions Comprising Compounds of the Disclosure

[0095] Another aspect of the present disclosure relates to compositions comprising a (a) a DNA Polymerase theta (PolQ) inhibitor Compound I (b) a DNA protein kinase inhibitor (DNA-PKI) of formula (SI) or (BI) and (c) a DNA cutting agent, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. In some embodiments, the composition further comprises a cell. In some embodiments, the composition further comprises a donor DNA. In some embodiments, the composition further comprises a cell and a donor DNA.

[0096] In some embodiments, the cell is a eukaryotic cell. In some embodiments, the cell is useful in adoptive cell therapy (ACT). In some embodiments, the cell is a stem cell. In some embodiments, the cell is a hematopoietic stem cell (HSC) or an induced pluripotent stem cell (iPSC). In some embodiments, the cell is an immune cell. In some embodiments, the immune cell is a leukocyte, or a lymphocyte (e.g., a T cell, a B cell, or an NK cell). In some embodiments, the immune cell is a lymphocyte. In some embodiments, the lymphocyte is a T cell. In some embodiments, the lymphocyte is a primary T cell. In some embodiments, the lymphocyte is a regulatory T cell. In some embodiments, the lymphocyte is an activated TDocket No.: 14928-WO-PCTcell. In some embodiments, the lymphocyte is a non-activated T cell. In some embodiments, the cell is a human cell. In some embodiments, the cell is not a cancer cell.

[0097] In some embodiments, the donor DNA comprises a template comprising a sequence encoding a protein, a regulatory sequence, or a sequence encoding structural RNA.

[0098] In some embodiments, the DNA cutting agent is selected from a zinc finger nuclease, a TALE effector domain nuclease (TALEN), a CRISPR / Cas nuclease component, and combinations thereof.

[0099] In some embodiments, the DNA cutting agent comprises a CRISPR / Cas nuclease component and optionally a guide RNA component. In some embodiments, the CRISPR / Cas nuclease component comprises a Cas nuclease or an mRNA encoding the Cas nuclease. In some embodiments, the CRISPR / Cas nuclease component comprises or encodes a CRISPR / Cas nuclease that generates a double strand DNA break or single strand DNA break. In some embodiments, the CRISPR / Cas nuclease component comprises or encodes a CRISPR / Cas nuclease that generates a single strand DNA break.

[0100] In some embodiments, the DNA cutting agent is a CRISPR / Cas nuclease component and a guide RNA component. In some embodiments, the CRISPR / Cas nuclease component comprises a Cas nuclease or an mRNA encoding the Cas nuclease. In some embodiments, the Cas nuclease is a Class 2, Type II Cas nuclease. In some embodiments, the Cas nuclease is a Cas9 nuclease (e.g., a S. pyogenes Cas9 nuclease). In some embodiments, the Cas nuclease is a Class 2, Type V Cas nuclease. In some embodiments, the Cas nuclease is a Casl2a nuclease (e.g., a Acidaminococcus sp. Casl2a nuclease).

[0101] In some embodiments, the composition comprises a modified RNA.

[0102] In some embodiments, the guide RNA component is a guide RNA nucleic acid. In some embodiments, the guide RNA component is a guide RNA (gRNA). In some embodiments, the guide RNA nucleic acid is or encodes a dual-guide RNA (dgRNA). In some embodiments, the dual-guide RNA is composed of a crRNA and tracrRNA. In some embodiments, the guide RNA nucleic acid is or encodes a single-guide (sgRNA). In some embodiments, the gRNA is a modified gRNA.

[0103] In some embodiments, the DNA cutting agent is Cas9 or an mRNA encoding Cas9, and a modified gRNA comprising a modification at one or more of the first five nucleotides at the 5’ end. In some embodiments, the cutting agent is Casl2a or an mRNA encodingDocket No.: 14928-WO-PCTCasl2a, and a modified gRNA comprising a DNA / RNA hybrid molecule. In some embodiments, the modified gRNA comprises a modification at one or more of the last five nucleotides at the 3’ end.

[0104] In some embodiments, the DNA cutting agent is a Class 2, Type II or Class 2, Type V Cas nuclease and a guide RNA nucleic acid; and the molar ratio of the guide RNA to Cas nuclease is from about 4:1 to 1:4.

[0105] In some embodiments, the composition further comprises a vector. In some embodiments, the vector encodes the donor DNA. In some embodiments, the vector is a viral vector (e.g., an AAV). In some embodiments, the vector is a non-viral vector. In some embodiments, the vector is a non-viral vector comprising donor DNA having a linear, close end, circular, single strand, double strand format. In some embodiments, the composition further comprises a vector. In some embodiments, the vector encodes the donor DNA. In some embodiments, the vector is a viral vector (e.g., an AAV). In some embodiments, the vector is a non-viral vector. In some embodiments, the vector is a non-viral vector comprising donor DNA having a linear, close end, circular, single strand, double strand format.

[0106] In some embodiments, the concentration of the DNA-PKI in the composition is about 10 pM or less and the concentration of the POLQi compound of Formula II is about 20 uM or less. In some embodiments, the concentration of the DNA-PKI in the composition is from about 0.1 pM to about 10 pM and the concentration of the POLQi compound of Formula II is about 15 uM or less. In some embodiments, the concentration of the DNA-PKI in the composition is from about 0.25 pM to about 5 pM and the concentration of the POLQi compound of Formula II is about 15 uM or less. In some embodiments, the concentration of the DNA-PKI in the composition is from about 0.25 pM to about 10 pM and the concentration of the POLQi compound of Formula II is about 15 uM or less. In some embodiments, the concentration of the DNA-PKI in the composition is from about 0.1 pM to about 5 pM and the concentration of the POLQi compound of Formula II is about 15 uM or less. In some embodiments, the concentration of the DNA-PKI in the composition is from about 0.1 pM to about 2.5 pM and the concentration of the POLQi compound of Formula II is about 15 uM or less.Docket No.: 14928-WO-PCTMethods of Using the Disclosed Compounds

[0107] Another aspect of the present disclosure is directed to a method for targeted genome editing in a cell, comprising contacting the cell with a DNA cutting agent, a POLQi Compound of Formula I, and a DNA-PKI, wherein the DNA-PKI is a compound of Formula (SI) or (BI), or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

[0108] Another aspect of the present disclosure is directed to a method for repairing a double stranded DNA break in the genome of a cell, comprising contacting the cell with a DNA cutting agent, POLQi compound of Formula I, and a DNA-PKI, wherein the DNA-PKI is a compound of Formula (SI) or (BI), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the double stranded DNA break is a blunt end break. In some embodiments, the double stranded DNA break comprises paired single strand breaks (e.g., made by a combination of nickase nucleases).

[0109] Another aspect of the present disclosure is directed to a method for simultaneously inhibiting or suppressing repair of a DNA break in a cell via both nonhomologous end joining (NHEJ) pathway and Microhomology Mediated End-Joining (MMEJ) pathway, comprising contacting the cell with a DNA cutting agent, and a DNA-PKI, wherein the DNA-PKI is a compound of Formula (SI) or (BI), or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof and POLQi compound of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

[0110] Another aspect of the present disclosure is directed to a method for targeted insertion of a donor DNA into the genome of a cell, comprising contacting the cell with a DNA cutting agent, the donor DNA, POLQi compound of Formula I, and a DNA-PKI, wherein the DNA-PKI is a compound of Formula (SI) or (BI), or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

[0111] In some embodiments of the methods disclosed herein, the method comprises growing the cell in a cell medium free of the DNA-PKI and a POLQi compound of Formula I, and adding the DNA-PKI and POLQi compound of Formula I to the cell medium.

[0112] In some embodiments of the methods disclosed herein, the method comprises contacting the cell with the DNA cutting agent before contacting the cell with the DNA-PKI and a POLQi compound of Formula I. In some embodiments, the method comprises contacting the cell with the DNA-PKI and a POLQi compound of Formula I within about sixDocket No.: 14928-WO-PCThours of contacting the cell with the DNA cutting agent. In some embodiments, the methods comprise contacting the cell with the DNA-PKI and a POLQi compound of Formula I within about three hours of contacting the cell with the DNA cutting agent. In some embodiments, the methods comprise contacting the cell with the DNA-PKI and a POLQi compound of Formula I within about two hours of contacting the cell with the DNA cutting agent. In some embodiments, the methods comprise contacting the cell with the DNA-PKI and a POLQi compound of Formula I between about 15 minutes and about 45 minutes of contacting the cell with the DNA cutting agent. In some embodiments, the methods comprise contacting the cell with the DNA-PKI and a POLQi compound of Formula I about 30 minutes of contacting the cell with the DNA cutting agent.

[0113] In some embodiments, the methods comprise contacting the cell with the DNA cutting agent simultaneously with the DNA-PKI and a POLQi compound of Formula I.

[0114] In some embodiments of the methods disclosed herein, the method comprises growing the cell in a cell medium comprising the DNA-PKI and a POLQi compound of Formula I.

[0115] In some embodiments, the methods comprise contacting the cell with the DNA cutting agent after contacting the cell with the DNA-PKI and a POLQi compound of Formula I. In some embodiments, the methods comprise contacting the cell with the DNA cutting agent within about three hours of contacting the cell with the DNA-PKI and a POLQi compound of Formula I.

[0116] In some embodiments, contacting the cell with the DNA cutting agent comprises electroporating the cell to allow the DNA cutting agent to enter the cell. In some embodiments, contacting the cell with the DNA cutting agent comprises delivering the DNA cutting agent to the cell using other methods, e.g., microinjection or via a lipid nanoparticle, liposome, exosome, or gold nanoparticle. In some embodiments, the methods comprise contacting the cell with the DNA cutting agent and the donor DNA simultaneously.

[0117] In some embodiments of the methods disclosed herein, the method comprises contacting the cell with the DNA cutting agent and the DNA-PKI and a POLQi compound of Formula I for at least about one day. In some embodiments, the method comprises contacting the cell with the DNA cutting agent and the DNA-PKI and a POLQi compound of Formula I for about one day. In some embodiments, the method comprises contacting the cell with the DNA cutting agent and the DNA-PKI and a POLQi compound of Formula I for betweenDocket No.: 14928-WO-PCTabout one day and about two weeks. In some embodiments, the method comprises contacting the cell with the DNA cutting agent and the DNA-PKI and a POLQi compound of Formula I for about two weeks.

[0118] In some embodiments of the methods disclosed herein, the method comprises contacting the cell with the DNA-PKI and POLQi compound of Formula I in a cell medium, wherein the concentration of the DNA-PKI in the cell medium is about 10 pM or less and the concentration of the POLQi compound of Formula I in the cell medium is about 15 pM or less. In some embodiments, the method comprises contacting the cell with the DNA-PKI and POLQi compound of Formula I in a cell medium, wherein the concentration of the DNA-PKI and POLQi compound of Formula I in the cell medium is between about 0.1 pM and about 10 pM the concentration of the POLQi compound of Formula II in the cell medium is about 15 pM or less. In some embodiments, the method comprises contacting the cell with the DNA-PKI and POLQi compound of Formula I in a cell medium, wherein the concentration of the DNA-PKI in the cell medium is between about 0.25 pM and about 5 pM and the concentration of the POLQi compound of Formula I in the cell medium is about 15 pM or less.

[0119] In some embodiments of the methods disclosed herein, the cell is a eukaryotic cell. In some embodiments, the cell is for use in adoptive cell therapy (ACT). In some embodiments, the cell is for use in autologous cell therapy. In some embodiments, the cell is for use in allogenic cell therapy. In some embodiments, the cell is a stem cell. In some embodiments, the cell is a hematopoietic stem cell (HSC) or an induced pluripotent stem cell (iPSC). In some embodiments, the cell is an immune cell. In some embodiments, the immune cell is a leukocyte, or a lymphocyte (e.g., a T cell, a B cell, or an NK cell). In some embodiments, the immune cell is a lymphocyte. In some embodiments, the lymphocyte is a T cell. In some embodiments, the lymphocyte is a primary T cell. In some embodiments, the lymphocyte is a regulatory T cell. In some embodiments, the lymphocyte is an activated T cell. In some embodiments, the lymphocyte is a non-activated T cell. In some embodiments, the cell is a human cell. In some embodiments, the cell is not a cancer cell.

[0120] In some embodiments of the methods disclosed herein, the DNA cutting agent is selected from a zinc finger nuclease, a TALE effector domain nuclease (TALEN), a CRISPR / Cas nuclease component, and combinations thereof.Docket No.: 14928-WO-PCT

[0121] In some embodiments of the methods disclosed herein, the DNA cutting agent comprises a CRISPR / Cas nuclease component and optionally a guide RNA component. In some embodiments, the CRISPR / Cas nuclease component comprises a Cas nuclease or an mRNA encoding the Cas nuclease. In some embodiments, the CRISPR / Cas nuclease component comprises or encodes a CRISPR / Cas nuclease that generates a double strand DNA break or single strand DNA break. In some embodiments, the CRISPR / Cas nuclease component comprises or encodes a CRISPR / Cas nuclease that generates a single strand DNA break.

[0122] In some embodiments of the methods disclosed herein, the DNA cutting agent is a CRISPR / Cas nuclease component and a guide RNA component. In some embodiments, the CRISPR / Cas nuclease component comprises a Cas nuclease or an mRNA encoding the Cas nuclease. In some embodiments, the Cas nuclease is a Class 2, Type II Cas nuclease. In some embodiments, the Cas nuclease is a Cas9 nuclease (e.g., a S. pyogenes Cas9 nuclease). In some embodiments, the Cas nuclease is a Class 2, Type V Cas nuclease. In some embodiments, the Cas nuclease is a Casl2a nuclease (e.g., a Acidaminococcus sp. Casl2a nuclease).

[0123] In some embodiments of the methods disclosed herein, the methods further comprise contacting the cell with a modified RNA.

[0124] In some embodiments of the methods disclosed herein, the methods further comprise contacting the cell with a guide RNA component. In some embodiments, the guide RNA component is a guide RNA nucleic acid. In some embodiments, the guide RNA component is a guide RNA (gRNA). In some embodiments, the guide RNA nucleic acid is or encodes a dual-guide RNA (dgRNA). In some embodiments, the guide RNA nucleic acid is or encodes a single-guide (sgRNA). In some embodiments, the gRNA is a modified gRNA.

[0125] In some embodiments of the methods disclosed herein, the DNA cutting agent is Cas9 or an mRNA encoding Cas9, and a modified gRNA comprising a modification at one or more of the first five nucleotides at the 5’ end. In some embodiments, the cutting agent is Casl2a or an mRNA encoding Casl2a, and a modified gRNA comprising a DNA / RNA hybrid molecule. In some embodiments, the modified gRNA comprises a modification at one or more of the last five nucleotides at the 3’ end.Docket No.: 14928-WO-PCT

[0126] In some embodiments of the methods disclosed herein, the DNA cutting agent is a Class 2, Type II or Class 2, Type V Cas nuclease and a guide RNA nucleic acid; and the molar ratio of the guide RNA to Cas nuclease is from about 4: 1 to 1:4.

[0127] In some embodiments of the methods disclosed herein, the DNA cutting agent interacts with a target sequence within the TRAC gene of a T cell.

[0128] In some embodiments of the methods disclosed herein, the methods comprise contacting the cell with at least two different DNA cutting agents targeting different loci.

[0129] In some embodiments, the methods comprise contacting the cell with a vector encoding the DNA cutting agent. In some embodiments, the vector encodes the DNA cutting agent and the donor DNA. In some embodiments, the methods comprise contacting the cell with a vector encoding the DNA cutting agent, and a second vector encoding the donor DNA.

[0130] In some embodiments, the vector is a viral vector (e.g., an AAV). In some embodiments, the vector is a non-viral vector. In some embodiments, the vector is a non-viral vector comprising donor DNA having a linear, close end, circular, single strand, double strand format.

[0131] In some embodiments of the methods disclosed herein, the DNA cutting agent interacts with a target sequence within the genome of the cell, resulting in a double stranded DNA break (DSB).

[0132] In some embodiments of the methods disclosed herein, the methods further comprise contacting the cell with a donor DNA. In some embodiments, the methods comprise contacting the cell with a vector comprising the donor DNA. In some embodiments, the vector encodes the donor DNA. In some embodiments, the donor DNA comprises a template comprising a sequence encoding a protein, a regulatory sequence, or a sequence encoding structural RNA. In some embodiments, the donor DNA comprises a template comprising an exogenous nucleic acid encoding a protein. In some embodiments, the protein is selected from a cytokine, an immunosuppressor, an antibody, a receptor, and an enzyme. In some embodiments, the protein is a receptor. In some embodiments, the receptor is selected from an immunological receptor, a T-cell receptor (TCR), and a chimeric antigen receptor. In some embodiments, the exogenous nucleic acid encodes a TCR chain of a TCR, e.g. a TCR alpha, beta, delta, or gamma chain, or any combination thereof. In some embodiments, the exogenous nucleic acid encodes a TCR alpha and / or TCR beta chain. In some embodiments,Docket No.: 14928-WO-PCTthe template comprises a first homology arm and a second homology arm that are complementary to sequences located upstream and downstream of the cleavage site, respectively.

[0133] In some embodiments of the methods disclosed herein, the method results in a gene knockout. In some embodiments of the methods disclosed herein, the method results in a gene correction. In some embodiments of the methods disclosed herein, the method results in a gene insertion.

[0134] Another aspect of the present disclosure relates to the use of Compound I in combination with a compound of Formula (SI) or (BI), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or pharmaceutical composition thereof, in the treatment of a cell.

[0135] In one embodiment, the subject is a mammal.

[0136] In one embodiment, the mammal is a human.

[0137] Administration of the disclosed compounds may also be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes.

[0138] Depending on the intended mode of administration, the disclosed compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts.

[0139] Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a compound of the present disclosure and a pharmaceutically acceptable carrier, such as a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodiumDocket No.: 14928-WO-PCTbenzoate, sodium acetate, sodium chloride and / or polyethylene glycol; for tablets also; c) a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthan gum, algic acid or its sodium salt, or effervescent mixtures; e) absorbent, colorant, flavorant and sweetener; f) an emulsifier or dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier; and / or g) an agent that enhances absorption of the compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200.

[0140] Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.

[0141] The disclosed compounds may be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.

[0142] The disclosed compounds may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines. In some embodiments, a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in U. S. Pat. No. 5,262,564 which is hereby incorporated by reference in its entirety.

[0143] Disclosed compounds may also be delivered by the use of monoclonal antibodies as individual carriers to which the disclosed compounds are coupled. The disclosed compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted withDocket No.: 14928-WO-PCTpalmitoyl residues. Furthermore, the Disclosed compounds can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. In one embodiment, disclosed compounds are not covalently bound to a polymer, e.g., a polycarboxylic acid polymer, or a polyacrylate.

[0144] Parenteral injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.

[0145] Another aspect of the present disclosure is directed to pharmaceutical compositions comprising a compound of Formula (SI) of (BI), Compound I, and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. In some embodiments, the pharmaceutical composition can further comprise an additional pharmaceutically active agent.

[0146] In one embodiment, the pharmaceutical acceptable carrier further comprises an excipient, diluent, surfactant, or any combination thereof.

[0147] In one embodiment, the pharmaceutical composition further comprises at least one additional therapeutic agent.

[0148] Another aspect of the present disclosure is directed to pharmaceutical compositions for use in cell therapy comprising Compound I and a compound of Formula (SI) or (BI), or a pharmaceutically acceptable salt thereof.EXAMPLES

[0149] The disclosure is further illustrated by the following examples and synthesis schemes, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in theDocket No.: 14928-WO-PCTart without departing from the spirit of the present disclosure and / or scope of the appended claims.

[0150] The compounds of the present disclosure may be prepared by use of known chemical reactions and procedures. Nevertheless, the following general preparative methods are presented to aid the reader in synthesizing the compounds with specific details provided below in the experimental section to illustrate working examples.

[0151] All variable groups of these methods are as described in the generic description if they are not specifically defined below.

[0152] It is recognized that compounds of the disclosure with each claimed optional functional group may not be prepared by each of the below-listed methods. Within the scope of each method, optional substituents may appear on reagents or intermediates which may act as protecting or otherwise non-participating groups. Utilizing methods well known to those skilled in the art, these groups are introduced and / or removed during the course of the synthetic schemes which provide the compounds of the present disclosure.Acronyms and Abbreviations

[0153] Table 1 provides a list of acronyms and abbreviations used in this specification, along with their meanings.Table 1ACRONYM OR ABBREVIATION MEANING OR DEFINITIONAc AcetylACN, MeCN AcetonitrileAq. AqueousBoc t-ButyloxycarbonylBrettphos Pd G3 [(2-Di-cyclohexylphosphino-3,6-dimethoxy- 2', 4', 6'- triisopropyl- l,r-biphenyl)-2-(2'-amino- 1,1' -biphenyl)]palladium(II) methanesulfonate methanesulfonateDCM DichloromethaneDIPEA, DIEA N, N-diisopropylethylamine, also known as Hunig’s baseDMA N,N-DimethylacetamideDMAP 4-(Dimethylamino)pyridineDocket No.: 14928-WO-PCTDMF N, N-dimethylformamideDMSO Dimethyl sulfoxideEA, EtOAc Ethyl acetateh HourHC1 Hydrochloric acidHPLC High pressure liquid chromatography Hunig’s base See DIPEA, DIEALCMS, LC-MS, LC / MS Liquid chromatography-mass spectrometry min MinuteMS Mass spectrometryMTBE Methyl tert-butyl etherNMR Nuclear magnetic resonancePE Petroleum etherPrep PreparativeRT (in context of liquid Retention time, in minchromatography)rt or RT (in the context of reaction Room (ambient) temperature, circa 25 °C conditions)Sat. SaturatedSoln SolutionTEA Tri ethyl amineTFA Trifluoroacetic acidTHF TetrahydrofuranTLC Thin layer chromatographyAnalytical ProceduresNMR

[0154] The following conditions were used for obtaining proton nuclear magnetic resonance (NMR) spectra: NMR spectra were taken in either 400 MHz or 500 MHz. Bruker instrument using either DMSO-de or CDCh as solvent and internal standard. The crude NMR data was analyzed by using either ACD Spectrus version 2015-01 by ADC Labs or MestReNova software.Docket No.: 14928-WO-PCT

[0155] Chemical shifts are reported in parts per million (ppm) downfield from internal tetramethylsilane (TMS) or from the position of TMS inferred by the deuterated NMR solvent. Apparent multiplicities are reported as: singlet-s, doublet-d, triplet-t, quartet-q, or multiplet-m. Peaks that exhibit broadening are further denoted as br. Integrations are approximate. It should be noted that integration intensities, peak shapes, chemical shifts and coupling constants can be dependent on solvent, concentration, temperature, pH, and other factors. Further, peaks that overlap with or exchange with water or solvent peaks in the NMR spectrum may not provide reliable integration intensities. In some cases, NMR spectra may be obtained using water peak suppression, which may result in overlapping peaks not being visible or having altered shape and / or integration.

[0156] Liquid chromatographyThe following preparative and / or analytical (LC / MS) liquid chromatography methods were used.Method A: Column: XBridge Cl 8, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: ACN H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Temperature: 50 °C; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -).Method B: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Temperature: 50 °C; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -).Method C: Column: Acquity BEH C18, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN H2O (95:5) with 10 mM AA; Temperature: 50 °C; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm and 254 nm) and MS (ESI + / -).Method D: Column: Kinetex XB- C18 (75x3mm) 2.6 pm; Mobile phase A: 0.1% TFA in H2O; Mobile phase B: 0.1% TFA in ACN; Flow Rate:1.0 mL / min; Time (min) / Grad (%B): 0 / 05, 2.5 / 95, 2.51 / 95, 4.5 / 95, 4.51 / 05, 5.5 / 05.Method E: Column: Kinetex XB - C18 (75 x 3.0) mm, 2.6pm; Mobile Phase A: 5mm Ammonium formate pH 3.3: ACN (98:02); Mobile Phase B: ACN: Buffer (98:02); Flow: 1.0Docket No.: 14928-WO-PCTmL / min; Time (min) / Grad (%B): 0 / 20, 4.0 / 100, 4.1 / 100 (1.5 ml / min), 4.6 / 100 (1,5 ml / min), 4.7 / 20, 5.0 / 20.Method F: Column: XSELECT CSH Cl 8(50x4.6mm) 3.5 m, Mobile phase A:10mm AA in H2O: ACN (95:5), Mobile phase B: 10mm AA in H2O: ACN (5:95), Time / Grad (%B): 0 / 05, 2.5 / 95, 4.0 / 95, 4.3 / 05, 5.0 / 05.Analytical HPLC A: Column: Kinetex Biphenyl (100X4.6) mm, 2.6pm, Mobile phase: A: 0.05% TFA in WATER: ACN; Mobile phase: B: 0.05% TFA in ACN: water; Flow: 1.0 mL / min; Time / Gradient (%B): 0 / 10, 9 / 60, 11 / 100, 11.1 / 100 (1.5 mL / min), 12.5 / 100 (1.5 mL / min), 13 / 10, 15 / 10.Analytical HPLC B: Column: Kinetex EVO C18 (100x4.6) mm, 2.6 pm, Mobile phase: A: 0.05% TFA in water: ACN (95:5), Mobile phase: B: ACN: 0.05%TFA in water (95:5); Flow: 1.0 mL / min; Time (min) / Grad (%B): 0 / 10, 1 / 30, 9 / 80, 11 / 100, 11.1 / 100 (1.5 mL / min), 12.5 / 100 (1.5 mL / min), 13 / 10, 15 / 10.Analytical HPLC C: Column: Waters BEH XP C18, 2.1 mm x 50 mm, 2.5 pm particles; Mobile Phase A: ACN / H2O (5:95) with 0.1 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.1 % TFA; Temperature: 50.0 °C; Flow: 1.100 mL / min; Detection: UV (220.0 nm) and UV (254.0 nm) and MS (MM + / -); Gradient: 0-100 %B (0-3.00 min), 100 %B (3.00-3.50 min), 100-0 %B (3.50-3.51 min), 0 %B (3.51-4.25 min).Analytical HPLC D: Column: Waters BEH XP Cl 8, 2.1 mm x 50 mm, 2.5 pm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Temperature: 50.0 °C; Flow: 1.100 mL / min; Detection: UV (220.0 nm) and UV (254.0 nm) and MS (MM + / -). Gradient: 0-100 %B (0-3.00 min), 100 %B (3.00-3.50 min), 100-0 %B (3.50-3.51 min), 0 %B (3.51-4.25 min).POLQ INHIBITORSExample Q-1: 2'-chloro-N-(5-(4-chlorophenyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamideDocket No.: 14928-WO-PCTNa2CO3Pd(PPh3)4 Dioxane, H2O 80 °C, 16 hTFATrifilic acid0°C - RT, 2 hStep 1. 5-Bromo-N-(4-methoxybenzyl)thiazolo[5,4-d]thiazol-2-amine: To a stirred solution of 2,5-dibromothiazolo[5,4-d]thiazole (800 mg, 2.67 mmol) in NMP (8 mL) were added DIPEA (1.164 mL, 6.67 mmol) and (4-methoxyphenyl)methanamine (366 mg, 2.67 mmol) at ambient temperature. Then, it was stirred at 100 °C for 4h. The reaction mixture was concentrated under reduced pressure. The crude product was diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic fraction was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product. The concentrated product was purified by silica gel (230-400 mesh) column chromatography eluted in 30-35% EtOAc in petroleum ether to obtained 5-bromo-N-(4-methoxybenzyl)thiazolo[5,4-d]thiazol-2-amine (800 mg, 2.021 mmol, 76 % yield) as an-off white solid. LCMS ESI m / z: 356.2, 358.2 [M, M+2]+, RT = 2.93 min (Method E).Step 2. 5-(4-Chlorophenyl)-N-(4-methoxybenzyl)thiazolo[5,4-d]thiazol-2-amine: To a stirred solution of 5-bromo-N-(4-methoxybenzyl)thiazolo[5,4-d]thiazol-2-amine (150 mg, 0.421 mmol) and (4-chlorophenyl)boronic acid (72.4 mg, 0.463 mmol) in dioxane (3 mL) wereDocket No.: 14928-WO-PCTadded sodium carbonate (112 mg, 1.053 mmol) at ambient temperature. The reaction mixture was degassed for 5 min. Tetrakis(triphenylphosphine)palladium (0) (73.0 mg, 0.063 mmol) was added to the reaction mixture. The reaction mixture was degassed for 5 min. It was heated at 70 °C for 5 h, cooled, filtered through celite bed under reduced pressure, and washed with ethyl acetate (2 x 40 mL). The crude was concentrated under reduced pressure and then purified by trituration with 5%EtOAc in petroleum ether to obtain the desired product, 5-(4-chlorophenyl)-N-(4-methoxybenzyl)thiazolo[5,4-d]thiazol-2-amine (80 mg, 0.144 mmol, 34.3 % yield) as an off-white solid. LCMS m / z [M, M+H]+;389.2; RT 3.1 min (Method D).Step 3. 5-(4-Chlorophenyl)thiazolo[5,4-d]thiazol-2-amine: To a stirred solution of 5-(4-chlorophenyl)-N-(4-methoxybenzyl)thiazolo[5,4-d]thiazol-2-amine (80 mg, 0.103 mmol) in TFA (3 mL) were added trifluoromethanesulfonic acid (15.48 mg, 0.103 mmol) at 25 °C. Then, it was stirred at ambient temperature for 2 h. The reaction mixture was concentrated under reduced pressure and quenched with sodium bicarbonate solution (20 mL, pH 9). The crude product was extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was washed with 5%EtOAc in n-pentane to obtain 5-(4-chlorophenyl)thiazolo[5,4-d]thiazol-2-amine (30 mg, 0.020 mmol, 19.56 % yield) as a brown solid. LCMS m / z [M, M+H]+267.2, 268.2 RT=2.69 (Method D).Step 4. 2'-Chloro-N-(5-(4-chlorophenyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide: To a stirred solution of 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (30 mg, 0.108 mmol) in DMF (3 mL) were added 5-(4-chlorophenyl)thiazolo[5,4-d]thiazol-2-amine (23.06 mg, 0.086 mmol) and 1 -methylimidazole (8.95 mg, 0.108 mmol) followed by DIPEA (0.019 mL, 0.108 mmol) and Chloro-N, N, N', N'-tetramethylformamidinium hexafluorophosphate (30.2 mg, 0.108 mmol) at 25 °C. Then, it was stirred at ambient temperature for 16 h. The reaction was monitored by TLC and LCMS. he progress of reaction was monitored by LCMS. After completion of starting material, the reaction mixture concentrated under reduced pressure. The crude product was diluted with water (40 ml) and extracted with ethyl acetate (2 x 50ml). The combined organic fraction was washed with brine, dried over sodium sulphate, filtered, and concentrated under reduced pressure to afford the crude product. The concentrated product was purified by RP-prepDocket No.: 14928-WO-PCTpurification in 5 mM ammonium formate in water and ACN to obtained 2'-chloro-N-(5-(4-chlorophenyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (2 mg, 3.60 pmol, 3.35 % yield) as an off-white solid. Prep method: Diluent: water: THF: ACN (10:60:30); Column: X-Bridge C18 (150 xl9)mm, 5micron; Temperature: Ambient; Mobile phase A: 5Mm ammonium formate in water; Mobile phase B: acetonitrile; Flow:13mL / min; Time / Grad: 0 / 40,15 / 90,16 / 90. LCMS m / z 530.2, [M+H]+, RT = 2.80 (Method D); HPLC: 96.99%, RT = 9.31 min (Analytical HPLC Method A) and 96.99%; RT = 6.89 min (Analytical HPLC Method B); 1H-NMR (400 MHz, DMSO-d6): 8 13.20 (s, 1H), 8.87 (s, 1H), 8.18 (s, 1H), 8.00 (d, J = 8.8 Hz, 2H), 7.58-7.61 (m, 3H), 7.46 (s, 1H), 3.63 (s, 3H), 2.61 (s, 3H).Example Q-2. 2'-chloro-5'-methoxy-6-methyl-N-(5-phenylthiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3 -carboxamideExamples Q-2 was obtained using procedures similar to example Q-l. LCMS m / z 494.2, [M+H]+, RT = 2.62 (Method D); HPLC purity: 96.3%, RT = 7.90 min (Analytical HPLC MethodA).1HNMR(400 MHz, DMSO-de): 613.17 (s, 1H), 8.86 (s, lH), 8.19 (s, 1H), 7.99 (dd, J= 1.8, 7.8 Hz, 2H), 7.46 - 7.61 (m, 5H), 3.63 (s, 3H), 2.62 (s, 3H)Example Q-3: 2'-Chloro-N-(5-(4-cyanophenyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamideCNDocket No.: 14928-WO-PCTCNPd(PPh3)4 Dioxane, H2O 80 °C, 16 hStep 1: 4-(5-((4-methoxybenzyl)amino)thiazolo[5,4-d]thiazol-2-yl)benzonitrile: To a stirred solution of 5-bromo-N-(4-methoxybenzyl)thiazolo[5,4-d]thiazol-2-amine (150 mg, 0.421 mmol) and 4-cyanophenylboronic acid (74.2 mg, 0.505 mmol) in Dioxane (3 mL) and water (1 mL) were added K2CO3 (145 mg, 1.053 mmol) at the ambient temperature. The reaction mixture was degassed for 5 min. PdC12(dppf)-CH2C12 adduct (68.8 mg, 0.084 mmol) to the reaction mixture. It was degassed for another 5 min. The reaction mixture was heated at 100 °C for 5 h. It was filtered through celite bed under reduced pressure and washed with ethyl acetate (2 x 30 mL). The crude was concentrated under reduced pressure and then purified by silica gel (230-400 mesh) column chromatography eluted in 30-33% EtOAc in petroleum ether to obtain 4-(5-((4-methoxybenzyl)amino)thiazolo[5,4-d]thiazol-2-yl)benzonitrile (30 mg, 0.048 mmol, 11.30 % yield) as an off-white solid. LCMS m / z [M+H]+380.2; RT = 2.87 min (Method D).Step 2: 2'-chloro-N-(5-(4-cyanophenyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide: To a stirred solution of 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (20.08 mg, 0.072 mmol) in DMF (3 mL) were added 4-(5-((4-methoxybenzyl)amino)thiazolo[5,4-d]thiazol-2-yl)benzonitrile (30 mg, 0.079 mmol) and 1 -methylimidazole (8.98 mg, 0.108 mmol) followed by DIPEA (0.019 mL, 0.108 mmol) and chloro-N, N, N', N' -tetramethylformamidinium hexafluorophosphate (30.3 mg, 0.108 mmol) at 25 °C. Then, it was stirred at ambient temperature for 16 h. The reaction mixture was diluted with water (30 mL). The crudeDocket No.: 14928-WO-PCTproduct was extracted with ethyl acetate (2 x 50 mL), The combined organic layer was washed with brine, dried with anhydrous sodium sulphate, and concentrated under reduced pressure. LCMS m / z [M+H]+; 641.2; RT=3.51 min (Method E).Step 3. 2'-chloro-N-(5-(4-cyanophenyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide: To a stirred solution of 2'-chloro-N-(5-(4-cyanophenyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3 -carboxamide (40 mg, 0.063 mmol) in TFA (3 mL) was added trifluoromethanesulfonic acid (4.70 mg, 0.031 mmol) at 0 °C. The reaction mixture was stirred for Ih at ambient temperature. The reaction was monitored by LCMS. After its completion, the reaction mixture was concentrated in below 30 °C. The crude product was washed with n-hexane (2 xl5 mL) and dried. The concentrated product was purified by RP-prep purification in 0.1% formic acid in water in ACN to obtain 2'-chloro-N-(5-(4-cyanophenyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (8.26 mg, 0.016 mmol, 25.1 % yield) as a pale yellow solid. Purification conditions: Diluent: THF:water: ACN (30:30:40); Column: XBridge Prep C8 (19x250mm) 5p; Temperature: Ambient; Mobile phase A:0.1%Formic Acid in Water; Mobile phase B: Acetonitrile; Flow:15mL / min; Time / Grad: 0 / 40,7 / 80,12 / 80. LCMS ESI m / z 519.0 [M+H]+, RT = 2.92 min (Method E). HPLC purity: 98.8%, RT = 8.818 min (Analytical HPLC Method A); 98.8%, RT = 5.606 min (Analytical HPLC Method B). 'H NMR (400 MHz, DMSO-d6): 8 8.86 (s, IH), 8.16-8.19 (m, 3H), 8.00 (d, J = 8.80 Hz, 2H), 7.60 (s, IH), 7.48 (s, IH), 3.63 (s, 3H), 2.62 (s, 3H).Examples Q-4 to Q-13 below were obtained using procedures similar to example Q-3 above.Docket No.: 14928-WO-PCTExample Structure and name Analytical ‘HNMR# LCMSESI-MS(+)m / z / RT (min) / Purity / (Method)Q-4 4821H NMR (400 N Cl [M+H]+ / 2.57 MHz, DMSO-d6):min (Method 6 13.21 (s, 1H), C' X / YT 0 N J-<\ r ki D) / 95.71% / 8.84 (s, 1H), 8.16 I 1 A X / 7.68 min (s, 1H), 7.55 (s, II J H (Analytical 1H), 7.44 (s, 1H),HPLC Method 3.60 (s, 3 H), 2.60 A) (s, 3H), 1.67-1.74 2'-chloro-N-(5- (m, 1H), 0.98-1.03 (cyclopropylethynyl)thiazolo[5,4- (m, 2H), 0.70-0.89 d]thiazol-2-yl)-5'-methoxy-6-methyl- (m, 2H).|'4,4'-bipyridine]-3-carboxamideQ-5Cl5301H NMR (400 N Cl \ if [M+H]+ / 2.67 MHz, DMSO-d6) £ j min (Method 6 = 13.23 (s, 1H), S x r D) / 98.63% / 8.86 (s, 1H), 8.72 II J H 9.33 min (dd, J = 0.8, 2.4 (Analytical Hz, 1H), 8.21 - HPLC Method 8.10 (m, 3H), 7.60 2'-chloro-N-(5-(5-chloropyridin-2- A) (s, 1H), 7.48 (s, yl)thiazolo[5,4-d]thiazol-2-yl)-5'- 1H), 3.63 (s, 3H), methoxy-6-methyl-[4,4'-bipyridine]-3- 2.62 (s, 3H) carboxamideQ-6 N Cl A 4581H NMR (400 jf j [M+H]+ / 2.54 MHz, DMSO-d6) min (Method 6 = 12.98 (s, 1H), AAA5E) / 98.84% / 8.82 (s, 1H), 8.17 II d H 4.97 min (s, 1H), 7.57 (s, / ■" Ixr (Analytical 1H), 7.46 (s, 1H),HPLC Method 3.60 (s, 3 H), 2.60 2'-chloro-N-(5-cyclopropylthiazolo[5,4- B) (s, 3H), 1.19 - 1.15 d]thiazol-2-yl)-5'-methoxy-6-methyl- (m, 2H), 1.08 - [4,4'-bipyridine]-3-carboxamide 1.04 (m, 2H) One proton is merged with thesolventDocket No.: 14928-WO-PCTExample Structure and name Analytical ‘HNMR# LCMSESI-MS(+)m / z / RT (min) / Purity / (Method)Q-7 F 510.1 [M+H]+ / 1H NMR (400 jf J s^ Z L^jZ 2.58 min MHz, DMSO-de) 6(Method D) / = 13.20 (s, 1H), O" Y J J rAAA899.67% / 7.22 8.86 (s, 1H), 8.48 JI J H min (s, 1H), 8.02 - 7.96(Analytical (m, 2H), 7.74 (s, HPLC Method1H), 7.57 - 7.51 2'-(difluoromethyl)-5'-methoxy-6- A)methyl-N-(5-phenylthiazolo[5,4- (m, 3H), 7.48 (s, d]thiazol-2-yl)-[4,4'-bipyridine]-3- 1H), 7.00 (t, J = 56 carb oxami de Hz, 1H), 3.71 (s,3H), 2.63 (s, 3H)Q-8 Z^o 500 [M+H]+ / 1H NMR (400 N ci n i2.32 minjf J MHz, DMSO-de) 6(Method D) / = 13.11 (s, 1H), ° JL 2 T r 98.07% / 9.68 8.84 (s, 1H), 8.18 minJI J H (s, 1H), 7.58 (s, (Analytical 1H), 7.47 (s, 1H), HPLC Method6.74 - 6.70 (m, 2'-chloro-N-(5-(3,6-dihydro-2H-pyran- A)1H), 4.28 (d, J= 4-yl)thiazolo[5,4-d]thiazol-2-yl)-5'- 2.9 Hz, 2H), 3.84 methoxy-6-methyl-[4,4'-bipyridine]-3- (t, J = 5.4 Hz, 2H), carb oxami de3.61 (s, 3H), 2.61 (s, 5H)Q-9 N.. Cl 472.1 [M+H]+ / 1H NMR (400 Il 1C / j o ft 2.07 min MHz, DMSO-de) 61AANA / (Method D) / = 13.27 (s, 1H), II J H 95.32% / 6.33 8.85 (s, 1H), 8.17 min (s, 1H), 7.58 (s, (Analytical2'-chloro-N-(5-(3 -hydroxyprop- 1 -yn- 1 - 1H), 7.47 (s, 1H),HPLC Methodyl)thiazolo[5,4-d]thiazol-2-yl)-5'- 5.59 (t, J = 6.1 Hz,A)methoxy-6-methyl-[4,4'-bipyridine]-3- 1H), 4.42 (d, J = carboxamide 6.1 Hz, 2H), 3.61(s, 3H), 2.61 (s,3H)Docket No.: 14928-WO-PCTExample Structure and name Analytical ‘HNMR# LCMSESI-MS(+)m / z / RT (min) / Purity / (Method)Q-10 / '"'NHN Cl ft | 485 [M+H]+ / 1H NMR (4001.27 min MHz, DMSO-de) 6 (Method E) / = 8.98 (s, 1H), ° / IU SSUs 97.71% / 6.19 8.16 (s, 1H), 8.14 JI THmin (s, 1H), 7.40 (s, (Analytical 1H), 7.25 (s, 1H), 2'-chloro-N-(5-(2,5-dihydro-lH-pyrrol- HPLC Method 6.51 (s, 1H), 4.26 3-yl)thiazolo[5,4-d]thiazol-2-yl)-5'- A) (d, J = 2.1 Hz, methoxy-6-methyl-[4,4'-bipyridine]-3- 2H), 4.04 (d, J= carb oxami de 2.6 Hz, 2H), 3.62(s, 3H), 2.55 (s, 3H). one -NH protons is not visible on ¹H NMR spectra.Q-ll 501.8 [M+H]+ / 1H NMR (400N Cln J 2.59 min MHz, DMSO-de) 6 JU J'II (Method E) / = 13.05 (s, 1H),97.99% / 7.44 8.83 (s, 1H), 8.181 smin (s, 1H), 7.56 (s, II J H (Analytical 1H), 7.46 (s, 1H),HPLC Method 7.28 (s, 1H), 4.33 - 2'-chloro-N-(5-(5,6-dihydro-l,4-dioxin- A) 4.26 (m, 2H), 4.26 2-yl)thiazolo[5,4-d]thiazol-2-yl)-5'- - 4.20 (m, 2H), methoxy-6-methyl-[4,4'-bipyridine]-3- 3.61 (s, 3H), 2.60 carb oxami de (s, 3H) Q-12 499 [M+H]+ / 1H NMR (4001.79 min MHz, DMSO-de) 6 N Cl ft 1(Method D) / = 13.17 (s, 1H), 99.53% / 4.50 8.84 (s, 1H), 8.18 min (s, 1H), 7.58 (s, (Analytical 1H), 7.48 (s, 1H), II J H^^l\T HPLC Method 6.65 (br s, 1H), B) 3.86 (br s, 2H), 2'-chloro-5'-methoxy-6-methyl-N-(5- 3.61 (s, 3H), 3.35 - (l,2,3,6-tetrahydropyridin-4- 3.3 (m, 2H), 2.85 -Docket No.: 14928-WO-PCTExample Structure and name Analytical ‘HNMR# LCMSESI-MS(+)m / z / RT (min) / Purity / (Method)yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'- 2.8 (m, 2H), 2.61 bipyridine]-3-carboxamide (s, 3H). NH proton was not visible Q-13 N Cl 497.9 [M+H]+ / 1H NMR (4002.44 min MHz, DMSO-d6): oV o (Method D) / 8 13.20 (s, 1H),199.16% / 7.19 8.838 (s, 1H), 8.17 JI J H min (s, 1H), 7.57 (s, (Analytical 1H), 7.46 (s, 1H), HPLC Method 3.60 (s, 3 H), 2.60 N-(5-bromothiazolo[5,4-d]thiazol-2-yl)- A) (s, 3H), 2'-chloro-5'-methoxy-6-methyl-[4,4'- bipyridine]-3-carboxamideExample Q-14. 2'-chloro-5'-methoxy-6-methyl-N-(5-morpholinothiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamideDocket No.: 14928-WO-PCTH120 °C, 16 hThe titled compound was obtained similarly according to the procedures of Example Q-3, but using morpholine and tri ethylamine heating in acetonitrile at 120 C in step 1 of Example Q-3. LCMS ESI m / z 503 [M+H]+ / 2.12 min (Method E); HPLC Purity: 98.68%, RT = 4.37 min (Analytical HPLC Method B); 'HNMR (400 MHz, DMSO-d6) 8 = 12.77 (s, 1H), 8.80 (s, 1H), 8.17 (s, 1H), 7.55 (s, 1H), 7.46 (s, 1H), 3.80 - 3.66 (m, 4H), 3.6 (s, 3H), 3.48 - 3.40 (m, 4H), 2.60 (s, 3H).Examples Q-15 to Q-16 below were obtained using procedure similar to example Q-14 above.Q-15Docket No.: 14928-WO-PCTPMBHN- DIPEA, NMP 120 °C, 16 hQ-16N S. F PMBHN^ JQ DIPEA, NMP 120 °C, 16 hDocket No.: 14928-WO-PCTExample Structure and name Analytical LCMS 'H NMR#ESI-MS(+) m / z / RT (min) / Purity / (Method)Q-15 N Cl | 461 [M+H]+ / 2.141H NMR (400 MHz,< Y Q Y min (Method D) / DMSO-d6) 8 = 12.6899.58% / 6.1 min (s, 1H), 8.78 (s, 1H), ° ° (Analytical HPLC 8.16 (s, 1H), 7.54 (s,Method B) 1H), 7.43 (s, 1H), 3.60 JI 1 H / ^Ixr (s, 3H), 3.08 (s, 6H),2.59 (s, 3H)2'-chloro-N-(5- (dimethylamino)thiazolo[5,4- d]thiazol-2-yl)-5'-methoxy-6- methyl-[4,4'-bipyridine]-3- carboxamideQ-16F\ F 508.8[M+H]+ / 2.651H NMR (400 MHz,N ci r~ i min (Method E) / DMSO-de) 6 = 12.83 < Y q N-J 98.54 % / 7.26 (s, 1H), 8.80 (s, 1H), min (Analytical 8.17 (s, 1H), 7.55 (s, ° JL A HPLC Method B) 1H), 7.44 (s, 1H), 4.57 JI J H (t, J= 12.3 Hz, 4H),3.60 (s, 3H), 2.59 (s, 3H)2'-chloro-N-(5-(3,3- difluoroazetidin- 1 - yl)thiazolo[5,4-d]thiazol-2-yl)- 5'-methoxy-6-methyl-[4,4'- bipyridine]-3-carboxamideExample Q-17. N-(5-(2,6-diazaspiro[3.3]heptan-2-yl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamideDocket No.: 14928-WO-PCTN ClBocStep 1: N-(5-Bromothiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide: To a stirred solution of 2'-chloro~5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (40 mg, 0.144 mmol) in DMF (3 mL) were added 5-bromo-N-(4-methoxybenzyl)thiazolo[5,4-d]thiazol-2-amine (51.1 mg, 0.144 mmol) and 1-methylimidazole (11.93 mg, 0.144 mmol) followed by DIPEA (0.025 mL, 0.144 mmol) and chi oro-N, N, N', N' -tetramethylformamidinium hexafluorophosphate (60.4 mg, 0.215 mmol) at 25 °C. Then, it was stirred at ambient temperature for 16 h. The reaction mixture was quenched with water (40 mL). The crude product was extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine, dried with anhydrous sodium sulphate and concentrated under reduced pressure. The concentrated crude was purified by silica gel (230-400 mesh) column chromatography eluted in 25% EtOAc in petroleum ether to obtain N-(5-bromothiazolo[5,4-d]thiazol-2-yl)-2!-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (80 mg, 0.124 mmol, 87 % yield) as an off-white solid. LCMS ESI m / z [M+H]+618.2, 620.2, RT = 3.46 min (Method E).Step 2. tert-butyl 6-(5-(2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate: To a stirred solution of N-(5-bromothiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (50 mg, 0.081 mmol) in N-methyl-2-pyrrolidinone (1 mL) were added tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (38.0 mg, 0.162 mmol) and DIPEA (0.057 mL, 0.324 mmol) at ambientDocket No.: 14928-WO-PCTtemperature. The reaction mixture was heating at 100 °C for 16 h. The reaction was concentrated under reduced pressure. The crude product was diluted with water (40 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic fraction was washed with brine, dried over sodium sulphate, filtered, and concentrated under reduced pressure to afford the crude product. The crude product was washed with 5% EtOAc in petroleum ether to obtain tert-butyl 6-(5-(2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (50 mg, 0.054 mmol, 67.2 % yield) as an off-white solid. LCMS m / z [M+H]+734.2 RT = 3.58 min (Method E).Step 3. N-(5-(2,6-diazaspiro[3.3]heptan-2-yl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide: To a stirred solution of tert-butyl 6-(5-(2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (50 mg, 0.068 mmol) in TFA (3 mL) were added Trifluoromethanesulfonic acid (5.11 mg, 0.034 mmol) at 0 °C. Then, it was stirred at ambient temperature for 2 h. The crude product was concentrated under reduced pressure and was purified by RP-prep purification in 5mM Ammonium formate in water and ACN to obtain the titled compound as an-off white solid. LCMS ESI m / z 508.8 [M+H]+, RT = 2.65 min (Method E). HPLC purity: 98.54 %, RT = 7.26 min (Analytical HPLC Method B). ¹H NMR (400 MHz, DMSO-de) 6 = 8.87 (s, 1H), 8.15 (s, 1H), 7.45 (s, 1H), 7.31 (s, 1H), 4.19 (s, 4H), 3.97 (s, 4H), 3.61 (s, 3H), 2.56 (s, 3H), two -NH protons are not visible in the1H NMR spectra.Examples Q-18 to Q-20 below were obtained using procedures similar to Example Q-17 above.Docket No.: 14928-WO-PCTExample Structure and name Analytical ‘HNMR# LCMSESI-MS(+) m / z / RT (min) / Purity / (Method)Q-18 pOH 5331HNMR(400MHz, jf Y s^zN- / 6H [M+H]+ / 1.49 DMSO-de) 6 = 12.6 min (Method E) (s, 1H), 8.81 (s, 1H), ° 1 1 JLV / 99.51% / 5.11 8.16 (s, 1H), 7.53 (s, II J H min (Analytical 1H), 7.41 (s, 1H), HPLC Method 4.92 (t, J = 5.2 Hz, A) 2H), 3.80 (s, 4H), N-(5-(3,3- 3.61 (s, 3H), 3.54 (d, bis(hydroxymethyl)azetidin- 1 - J= 5.0 Hz, 4H), yl)thiazolo[5,4-d]thiazol-2-yl)-2'- 2.59 (s, 3H) chloro-5'-methoxy-6-methyl-[4,4'- bipyridine]-3-carboxamideQ-19 516.11HNMR(400MHz,N Cl 7 i [M+H]+ / 1.85 DMSO-d6) 6 = 8.80 if " Y sN-Ymin (Method D) (s, 1H), 8.17 (s, 1H), / 98.08 % / 3.64 7.53 (s, 1H), 7.42 (s,? jf ° min (Analytical 1H), 4.05 - 3.99 (m, JI J H HPLC Method 1H), 3.8 - 3.7 (m, B). 1H), 3.61 (s, 3H),3.54 (d, J = 10.6 Hz, 2'-chloro-5'-methoxy-6-methyl-N-(5- 1H), 3.17 (dt, J = (2-methylpiperazin- 1 -y 1 )- 3 a, 6a- 3.3, 12.4 Hz, 1H), dihydrothiazolo[5,4-d]thiazol-2-yl)- 2.96 (d, J = 10.0 Hz, [4,4'-bipyridine]-3-carboxamide 1H), 2.89 - 2.72 (m,2H), 2.65 -2.6 (m,Q-20 OH 5311HNMR(400MHz,N Cl \ [M+H]+ / 2.08 DMSO-de) 6 = 12.70 rT Y 9 Y / I J / Y min (Method D) (br s, 1H), 8.80 (s, / 98.08 % / 3.64 1H), 8.17 (s, 1H),1Y XY AY ASZ min (Analytical 7.53 (s, 1H), 7.42 (s, JI J H HPLC MethodY""lY 1H), 4.77 (d, J = 4.8A). Hz, 1H), 4.37 - 4.27 2'-chloro-N-(5-(4-hydroxy-2- (m, 1H), 3.91 - 3.77 methylpiperidin- 1 -yl)-3a,6a- (m, 2H), 3.61 (s, dihydrothiazolo[5,4-d]thiazol-2-yl)- 3H), 3.23 -3.17 (m,1H), 2.59 (s, 3H),1.94 - 1.89 (m, 1H),Docket No.: 14928-WO-PCTExample Structure and name Analytical ¹H NMR# LCMSESI-MS(+) m / z / RT (min) / Purity / (Method)5'-methoxy-6-methyl-[4,4'- 1.83 (d, J= 13.1 Hz, bipyridine]-3-carboxamide 1H), 1.55 - 1.47 (m,1H), 1.41 - 1.27 (m, 1H), 1.21 (d, J= 6.9 Hz, 3H)Example Q-21. 2'-chloro-N-(5-(dimethylphosphoryl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamidePd(PPh3)4DMF, 100°C, 6 hTo a stirred solution of N-(5-bromothiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (20 mg, 0.040 mmol) and dimethylphosphine oxide (9.43 mg, 0.121 mmol) in DMF (4 mL) were added potassium phosphate tribasic (21.36 mg, 0.101 mmol) at ambient temperature. The reaction mixture was degassed for 5 min.Palladium (II) acetate (1.808 mg, 8.05 pmol) and xantphos (4.66 mg, 8.05 pmol) were added to the reaction mixture. It was degassed for 5 min. The reaction mixture was heated at 70 °C for 3 h. It was filtered through celite bed under reduced pressure and washed with ethyl acetate (2 x 20 mL). The filtrate was concentrated under reduced pressure and was thenDocket No.: 14928-WO-PCTpurified by RP-prep purification in 5 mM ammonium formate in water and ACN to obtain 2'-chloro-N-(5-(dimethylphosphoryl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3 -carboxamide (1.5 mg, 2.83 pmol, 7.03 % yield) as an off-white solid. LCMS ESI m / z 494 [M+H]+, RT = 1.96 min (Method D). HPLC purity: 93.3%, RT = 5.61 min (Analytical HPLC Method A). 'H NMR (400 MHz, METHANOL-d4) 8 = 8.84 (s, 1H), 8.09 (s, 1H), 7.54 (s, 1H), 7.47 (s, 1H), 3.7 (s, 3H), 2.7 (s, 3H), 1.98 (s, 3H), 1.95 (s, 3H). NH proton is not visible on 1H NMR spectra.Example Q-22: dimethyl (5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)phosphonateTo a stirred solution of N-(5-bromothiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (50 mg, 0.101 mmol) in dioxane (4 mL) were added tripotassium phosphate (64.1 mg, 0.302 mmol) at ambient temperature. The reaction mixture was degassed for 5 minutes, dimethyl phosphonate (111 mg, 1.006 mmol) and PdC12(dppf)-CH2C12adduct (16.44 mg, 0.020 mmol) followed by dimethyl phosphonate (111 mg, 1.006 mmol) to the reaction mixture. It was heated at 100 °C for 1 h. The reaction mixture was filtered through celite bed under reduced pressure and washed with ethyl acetate (2 x 60 mL). The crude was concentrated under reduced pressure and purified by RP HPLC to give (5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)phosphonate (9 mg, 0.016 mmol, 16.15 % yield) as an off-white solid. HPLC purity 95%,Docket No.: 14928-WO-PCTm / z 525.8, RT = 1.29 min (Method B); HPLC purity 95.1%, m / z 525.9, RT = 1.4 min (Method A). ‘HNMR (400 MHz, DMSO-d6) 5 = 13.36 (br s, 1H), 8.86 (s, 1H), 8.17 (s, 1H), 7.59 (s, 1H), 7.48 (s, 1H), 3.82 (d, J = 11.5 Hz, 6H), 3.61 (s, 3H), 2.61 (s, 3H).Example Q-23: N-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamideStep 1: To a stirred solution of N-(5-bromothiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (100 mg, 0.162 mmol) in TFA (3 mL) were added trifluoromethanesulfonic acid (12.16 mg, 0.081 mmol) at 0 °C.Then, it was stirred at ambient temperature for 2 h. It was concentrated under reduced pressure to afford the crude product, which was purified by trituration with 3% EtOAc in petroleum ether to obtain N-(5-bromothiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (70 mg, 0.141 mmol, 87 % yield) as an off-white solid. LCMS ESI m / z: 497.2, 499.2 [M, M+2]+, RT = 2.80 min (Method E).Step 2: To a stirred solution of N-(5-bromothiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (30 mg, 0.060 mmol) inNMP (1 mL) were added DIPEA (0.032 mL, 0.181 mmol) and 2-oxa-6-azaspiro[3.3]heptane (8.98 mg, 0.091 mmol) at 0 °C. Then, it was stirred at 100 °C for 4 h. The reaction mixture was filtered through celite bed under reduced pressure and washed with ethyl acetate (2 x 40 mL). The crude product was concentrated under reduced pressure and was purified by RP-prep purification in 5mM ammonium formate in water and ACN to obtain N-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-Docket No.: 14928-WO-PCTcarboxamide (16 mg, 0.026 mmol, 42.8 % yield) as an off white solid. LCMS ESI m / z 515.0 [M+H]+, RT=1.49 min (Method E). 'HNMR (400 MHz, DMSO-de) 6 = 12.75 (s, 1H), 8.79 (s, 1H), 8.16 (s, 1H), 7.54 (s, 1H), 7.45 (s, 1H), 4.73 (s, 4H), 4.25 (s, 4H), 3.59 (s, 3H), 2.59 (s, 3H).Examples Q-24 to Q-25 below were obtained using procedures similar to Example Q-23 above.Example Structure and name Analytical ‘HNMR# LCMSESI-MS(+) m / z / RT (min) / Purity / (Method)Q-24 N Cl 486.01H NMR (400f J [M+H]+ / 2.06 MHz, DMSO-d6) 8 oA^0NA N 1 min (Method = 13.25 (s, 1H),1A A A / D) / 93.11% / 8.85 (s, 1H), 8.176.11 min (s, 1H), 7.56 (s, II 1 H (Analytical 1H), 7.45 (br s, HPLC Method 1H), 5.74 (d, J= B). 5.6 Hz, 1H), 4.73 - 2'-chloro-N-(5-(3 -hydroxybut- 1 -yn- 1 - 4.65 (m, 1H), 3.61 yl)thiazolo[5,4-d]thiazol-2-yl)-5'- (s, 3H), 2.60 (s, methoxy-6-methyl-[4,4'-bipyridine]-3- 3H), 1.42 (d, J= carboxamide6.6 Hz, 3H)Q-25 486.0 [M+H]+ / 1H NMR (400N Cl j2.26 min MHz, DMSO-de) 6 I T (Method D) / = 13.17 (s, 1H),1A A AA 97.44% / 5.75 8.84 (s, 1H), 8.17 (s, 1H), 7.58 (s, II J H min (AnalyticalHPLC Method 1H), 7.47 (s, 1H), A). 6.81 (s, 1H), 4.98 2'-chloro-N-(5-(2,5-dihydrofuran-3- (td, J = 2.5, 4.7 Hz, yl)thiazolo[5,4-d]thiazol-2-yl)-5'- 2H), 4.80 (td, J= methoxy-6-methyl-[4,4'-bipyridine]-3- 2.3, 4.8 Hz, 2H), carboxamide 3.61 (s, 3H), 2.61(s, 3H)Docket No.: 14928-WO-PCTExample Q-26. N-(5-(l-acetyl-2,5-dihydro-lH-pyrrol-3-yl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamideoThe titled compound (6 mg, 10.25 pmol, 16.56 % yield) was obtained as a pale-yellow solid by treating Example Q-10 with DIEA and acetic acid in THF. LCMS ESI m / z 527 [M+H]+, RT = 2.09 min (Method D). ¹H NMR (400 MHz, DMSO-de) 6 = 13.18 (s, 1H), 8.85 (s, 1H), 8.18 (d, J= 1.5 Hz, 1H), 7.58 (s, 1H), 7.47 (s, 1H), 6.71 - 6.69 (m, 1H), 4.82 - 4.73 (m, 1H), 4.52 (s, 2H), 4.35 - 4.27 (m, 1H), 3.61 (d, J= 2.4 Hz, 3H), 2.61 (s, 3H), 2.04 (d, J= 16.5 Hz, 3H).Example Q-27. 2'-chloro-5'-methoxy-6-methyl-N-(5-(l-methyl-2,5-dihydro-lH-pyrrol-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamideTo a stirred solution of 2'-chloro-N-(5-(2,5-dihydro-lH-pyrrol-3-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (30 mg, 0.062 mmol) in DMF (2 mL) were added paraformaldehyde (18.57 mg, 0.619 mmol) and acetic acid (10.62 pl, 0.186 mmol) followed by 2-Methylpyridine borane complex (16.54 mg, 0.155 mmol) at 25 °C. Then, it was stirred at 50 °C for 6 h. The reaction mixture was diluted with water (20 mL). The crude product was extracted with ethyl acetate (2 x 40 mL). The combined organic layer was washed with brine, dried with anhydrous sodium sulphate, and concentrated underDocket No.: 14928-WO-PCTreduced pressure. The concentrated product was purified by RP-prep purification in 5mM Ammonium formate in water and ACN to obtain 2'-chloro-5'-methoxy-6-methyl-N-(5-(l-methyl-2,5-dihydro-lH-pyrrol-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (1.9 mg, 3.46 pmol, 5.59 % yield) as a pale-yellow solid. LCMS ESI 499 [M+H]+, RT = 2.43 min (Method D). HPLC purity: 91%, RT = 7.02 min (Analytical HPLC Method B). ¹H NMR (400 MHz, MeOD-d4) 8 = 8.83 (s, 1H), 8.09 (s, 1H), 7.53 (s, 1H), 7.46 (s, 1H), 6.50 - 6.47 (m, 1H), 4.5 - 4.4 (m, 1H), 4.31 - 4.18 (m, 2H), 4.00 - 3.92 (m, 1H), 3.71 (s, 3H), 2.88 (s, 3H), 2.69 (m, 3H).Example Q-28. ethyl 5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazole-2-carboxylateStep 1. To a stirred solution of 5-bromo-N-(4-methoxybenzyl)thiazolo[5,4-d]thiazol-2-amine (400 mg, 1.123 mmol) in THF (10 mL) were added n-butyllithium (2.406 mL, 3.37 mmol) at -78 °C. The reaction mixture was stirred for 20 min at the same temperature. Dry ice was added to the reaction mixture at -78 °C. It was stirred for 1 h at -78 °C to room temperature.Docket No.: 14928-WO-PCTThe reaction mixture was quenched with water (10 mL) at -78 °C. The crude product was extracted with ethyl acetate (2 x 50 mL). The organic layer was concentrated under reduced pressure to give the crude product 5-((4-methoxybenzyl)amino)thiazolo[5,4-d]thiazole-2-carboxylic acid (500 mg, 0.467 mmol, 41.6 % yield) and it was used directly in the next step. LCMS m / z 323.2 [M+H]+, RT = 0.74-0.92 min (Method E).Step 2. ethyl 5-((4-methoxybenzyl)amino)thiazolo[5,4-d]thiazole-2-carboxylate: To a stirred solution of 5-((4-methoxybenzyl)amino)thiazolo[5,4-d]thiazole-2-carboxylic acid (500 mg, 1.556 mmol) in EtOH (9 mL) were added H2SO4 (0.415 mL, 7.78 mmol) at ambient temperature. The reaction mixture was stirred at 80 °C for 16 h. It was quenched with 10% sodium bicarbonate solution (10 mL) at 0 °C. The crude product was extracted with ethyl acetate (2 x 50 mL). The organic layer was concentrated under reduced pressure and purified by silica gel (230-400 mesh) column chromatography eluting in 40% EtOAc in petroleum ether to obtain ethyl 5-((4-methoxybenzyl)amino)thiazolo[5,4-d]thiazole-2-carboxylate (130 mg, 0.130 mmol, 8.37 % yield) as an off-white solid. LCMS m / z 350.2 [M+H]+, RT = 1.50 (Method E).Step 3. ethyl 5-(2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazole-2-carboxylate: To a stirred solution of 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (104 mg, 0.372 mmol) in DMF (8 mL) were added ethyl 5-((4-methoxybenzyl)amino)thiazolo[5,4-d]thiazole-2-carboxylate (130 mg, 0.372 mmol) and 1 -methylimidazole (124 mg, 1.488 mmol) followed by DIPEA (0.130 mL, 0.744 mmol) and chi oro-N, N, N', N' -tetramethylformamidinium hexafluorophosphate (313 mg, 1.116 mmol) at 25 °C. Then, it was stirred at ambient temperature for 16 h. The reaction mixture was diluted with water (20 mL). The crude product was extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine, dried with anhydrous sodium sulphate, and concentrated under reduced pressure to give the crude product which was used directly in the next step.Step 4. To a stirred solution of ethyl 5-(2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazole-2-carboxylate (100 mg, 0.164 mmol) in TFA (2 mL) were added trifluoromethanesulfonic acid (12.30 mg, 0.082 mmol) at 0 °C. Then, it was stirred at ambient temperature for 2 h. The crude product was concentratedDocket No.: 14928-WO-PCTunder reduced pressure and purified by RP-prep purification in 5 mM ammonium formate in water and ACN to obtain the titled product (25 mg, 30.2% yield) as an off-white solid. LCMS ESI m / z: 490.0 [M+H]+, RT = 2.49 min (Method E). HPLC (purity) = 97.1%, RT = 7.20 min (Analytical HPLC Method B); 'HNMR (400 MHz, DMSO-d6) 8 = 13.39 (s, 1H), 8.86 (s, 1H), 8.18 (s, 1H), 7.59 (s, 1H), 7.47 (s, 1H), 4.41 (q, J = 8 Hz, 2H), 3.61 (s, 3H), 2.6 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H).Example Q-29. 5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)-N, N-dimethylthiazolo[5,4-d]thiazole-2-carboxamideThe titled compound was obtained similarly to Example Q-28, wherein diethyl amine was coupled in Step 2. LCMS ESI m / z 488.8 [M+H]+RT = 2.29 min (Method E). HPLC purity: 97.06%, RT = 5.09 min (Analytical HPLC Method A). 'H NMR (400 MHz, DMSO-d6) 6 13.30 (s, 1H), 8.86 (s, 1H), 8.17 (s, 1H), 7.58 (s, 1H), 7.46 (s, 1H), 3.61 (s, 3H), 3.57 (s, 3H), 3.08 (s, 3H), 2.6 (s, 3H).Example Q-30. 5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)-N-methylthiazolo[5,4-d]thiazole-2-carboxamideDocket No.: 14928-WO-PCTThe titled compound was obtained similarly to Example Q-28, wherein diethylamine was coupled in Step 2. LCMS ESI m / z 475 [M+H]+, RT = 1.91 min (Method E). HPLC purity: 86.8%, RT = 5.55 min (Analytical HPLC Method B). 'HNMR (400 MHz, DMSO-d6) 6 = 13.33 (s, 1H), 8.98 (d, J = 5.0 Hz, 1H), 8.86 (s, 1H), 8.17 (s, 1H), 7.58 (s, 1H), 7.46 (s, 1H), 3.61 (s, 3H), 2.82 (d, J = 4.8 Hz, 3H), 2.6 (s, 3H).Example Q-31. di-tert-butyl ((2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methyl) phosphate and Example Q-32.(2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methyl dihydrogen phosphateStepl. To a stirred solution of potassium di-tert-butyl phosphate (500 mg, 2.014 mmol) in DCM (6 mL) and H2O (6 mL) were added sodium bicarbonate (423 mg, 5.03 mmol) and tetrabutylammonium hydrogensulfate (342 mg, 1.007 mmol) at 0 °C. Then, it was stirred at 0 °C-25 °C for 30 min. Chloromethyl sulfurochloridate (365 mg, 2.215 mmol) was added to theDocket No.: 14928-WO-PCTreaction and stirred for 16 h at the ambient temperature. The crude product was diluted with water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic fraction was washed with brine, dried over sodium sulphate, filtered, and concentrated under reduced pressure to afford the crude product, which was washed with n-hexane and dried to afford desired di-tert-butyl (chloromethyl)phosphonate product. LCMS ESI m / z 356.2, 358.2 [M, M+2]+, RT = 2.79 min.Step 2. To a stirred solution of 2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (60 mg, 0.131 mmol) in DMF (0.2 mL) were added the above freshly made di-tert-butyl (chloromethyl) phosphate (136 mg, 0.524 mmol) and KI (21.75 mg, 0.131 mmol) followed by di-tert-butyl (chloromethyl) phosphate (136 mg, 0.524 mmol) at 25 °C. Then, it was stirred at 50 °C for 16 h. The reaction mixture was diluted with water (20 mL). The crude product was extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine, dried with anhydrous sodium sulphate, and concentrated under reduced pressure. The concentrated product was purified by RP-prep purification to obtain a mixture of tert-butyl ((2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methyl) hydrogen phosphate (LCMS ESI m / z 681.0 [M+H]+, RT = 3.36 min, Method E) and di-tert-butyl ((2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methyl) phosphate (Q-21, LCMS ESI m / z 624.0 [M+H]+, RT = 1.94 min, Method E) (total 14 mg) as a pale-yellow solid.Step 3. (2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methyl dihydrogen phosphate: To a stirred solution of the above di- and mono-tert-butyl analogs (10 mg, 0.016 mmol) in H2O (3 mL) were added formic acid (0.5 mL, 13.04 mmol) at 0 °C. Then, it was stirred at ambient temperature for 16 h. The reaction mixture was lyophilized and the solid obtained was triturated with diethyl ether to give the titled compound (7.5 mg, 78%) as a pale-yellow solid. LCMS ESI m / z 565.8 [M+H]+, RT = 1.41 min (Method E). HPLC purity: 95.36%, RT = 4.45 min (Analytical HPLC Method B). ¹H NMR (400 MHz, DMSO-de) 6 = 9.21 (s, 1H), 8.15 - 8.12 (m, 1H), 7.40 (s, 1H), 7.25 (s, 1H), 7.1 (br s, 1H), 6.98 (br s, 1H), 5.76 (d, J= 10.5 Hz, 2H), 3.63 (s, 3H), 2.56 (s, 3H), 2.42 - 2.4 (m, 1H), 1.18 - 1.13 (m, 2H), 1.04 - 1.01 (m, 2H).Docket No.: 14928-WO-PCTExample Q-33-I. tert-butyl ((2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methyl) succinateQ-33-IAnd Example Q-33-II. (E)-tert-butyl ((2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-5-cyclopropylthiazolo[5,4-d]thiazol-3(2H)-yl)methyl) succinateQ-33-IITo a stirred solution of 2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (60 mg, 0.131 mmol) in DMF (4 mL) were added K2CO3 (72.4 mg, 0.524 mmol) and KI (21.75 mg, 0.131 mmol) followed by tert-butyl (chloromethyl) succinate (117 mg, 0.524 mmol) at 25 °C. Then, it was stirred at 80 °C for 3h. The reaction mixture was diluted with water (30 mL). The crude product was extracted with ethyl acetate (2 x 50mL), The combined organic layer was washed with brine, dried withDocket No.: 14928-WO-PCTanhydrous sodium sulphate and concentrated under reduced pressure. The concentrated product was purified by RP-prep purification in 0.1 ammonium formate in ACN to obtained tert-butyl ((2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methyl) succinate (17 mg, 0.025 mmol, 19.46 % yield) and (E)-tert-butyl ((2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-5-cyclopropylthiazolo[5,4-d]thiazol-3(2H)-yl)methyl) succinate (8 mg, 0.012 mmol, 9.35 % yield) as an off white solid. Prep method: Diluent: THF(50): WATER(IO): ACN(40);Column: X-Select C18 (250x19) mm 5.0 p; Temperature: Ambient; Mobile phase A:5 mM Ammonium Formate in water9PH 3.3); Mobile phase B: Acetonitrile; Flow: 15 mL / min; Time / Gradient:0 / 65, 12 / 85, 15 / 85; Column: Kinetex XB- C18 (75x3 mm) 2.6 pm; Mobile phase A:0.1% TFA in FEO; Mobile phase B: 0.1% TFA in ACN; Flow Rate: 1.0 mL / min. Analytical data for Q-33-I: LCMS ESI m / z 643.9 [M+H]+, RT = 2.59 min (Method D).HPLC purity: 96.43%, RT = 5.44 min (Analytical HPLC Method B); 1HNMR (400 MHz, DMSO-d6) 6 = 9.19 (s, 1H), 8.16 (s, 1H), 7.46 (s, 1H), 7.29 (s, 1H), 6.00 (s, 2H), 3.64 (s, 3H), 2.63 - 2.58 (m, 5H), 1.27 (s, 9H), 1.18 - 1.15 (m, 2H), 1.05 - 1.03 (m, 2H). Three protons merged with solvent. Analytical data for Q-33-II: LCMS ESI m / z 643.9 [M+H]+, RT = 2.87 min (Method D). HPLC purity: 98.81%, RT = 4.73 min (Analytical HPLC Method B); ‘HNMR (400 MHz, DMSO-d6) 8 = 8.76 (s, 1H), 8.22 (s, 1H), 7.54 (s, 2H), 5.98 (s, 2H), 3.70 (s, 3H), 2.61 - 2.53 (m, 5H), 2.46 - 2.44 (m, 2H), 1.35 (s, 9H), 1.21 - 1.18 (m, 2H), 1.09 - 1.07 (m, 2H), one proton merged with solvent.Re-synthesis of tert-butyl ((2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methyl) succinate (Q-33-I) and (E)-tert-butyl ((2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-5-cyclopropylthiazolo [5,4-d]thiazol-3(2H)-yl)methyl) succinate (Q-33-H)Docket No.: 14928-WO-PCTQ-33-IITo a stirred solution of 2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (46 mg, 0.100 mmol) in DMF (2 mL) were added cesium carbonate (82 mg, 0.251 mmol) and potassium iodide (1.667 mg, 10.04 pmol). Then to the reaction mixture tert-butyl (chloromethyl) succinate (224 mg, 1.004 mmol) was added. The resulting reaction mixture was stirred at 50 °C for 16 h. It was purified by prep HPLC purification [Diluent: THF: ACN:water (20:50:30), Column: X-SELECT CSH C18 (250 xl9 mm, 5micron), Temperature: Ambient, Mobile phase A: 5 mM ammonium formate in water (pH=3.3), Mobile phase B: Acetonitrile, Flow: 15 mL / min, Time / Grad:0 / 60, 15 / 90] to afford tert-butyl ((2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methyl) succinate (Q-33-I, 14 mg, 21.59% yield) and (E)-tert-butyl ((2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-5-cyclopropylthiazolo[5,4-d]thiazol-3(2H)-yl)methyl) succinate (Q-33-II, 10 mg, 15.4% yield). Q-33-I: LCMS: ESI m / z 644.1 [M+H]+, RT=3.84 min (Method E). Analytical Method B: RT=6.18 min, HPLC purity = 99.77 %. 'H NMR (400MHz, DMSO-de): 6 = 8.75 (s, 1H), 8.22 (s, 1H), 7.54 (s, 2H), 5.98 (s, 2H), 3.69 (s, 3H), 2.6 (s, 3H), 2.58 - 2.55 (m, 2H), 2.46 -2.43 (m, 2H), 1.34 (s, 9H), 1.22 - 1.17 (m, 2H), 1.1 - 1.06 (m, 2H) One proton merged with solvent peak.Q-33-II: LCMS: ESI m / z 643.7 [M+H]+, RT=2.69 min (Method E). Analytical Method B: RT=6.18 min, HPLC purity = 99.63 %. 'H NMR (400 MHz, CDCh) 6 = 9.32 (s, 1H), 7.99 (s, 1H), 7.28 (s, 1H), 7.06 (s, 1H), 5.84 (s, 2H), 3.71 (s, 3H), 2.69 - 2.66 (m, 5H), 2.6 - 2.56 (m, 2H), 2.31 -2.27 (m, 1H), 1.41 (s, 9H), 1.22 - 1.14 (m, 4H).Example Q-34.4-((2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methoxy)-4-oxobutanoic acid (3x) and (E)-4-((2-Docket No.: 14928-WO-PCT((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-5-cyclopropylthiazolo[5,4-d]thiazol-3(2H)-yl)methoxy)-4-oxobutanoic acid (3x’)To a stirred solution of tert-butyl ((2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methyl) succinate (peakl) (16 mg, 0.025 mmol) in DCM (4 mL) were added TFA (0.019 mL, 0.248 mmol) at 0°C. Then, it was stirred at ambient temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The crude product was directly lyophilized and washed with diethyl ether and hexane to obtain the desired product, 4-((2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methoxy)-4-oxobutanoic acid (13 mg, 0.022 mmol, 87 % yield). LCMS ESI m / z 588 [M+H]+, RT = 2.45 min (Method D). HPLC purity: 97.41%, RT = 4.55 min (Analytical HPLC Method B); 1HNMR (400 MHz, DMSO-d6) 8 = 12.18 (s, 1H), 8.75 (s, 1H), 8.21 (s, 1H), 7.53 (s, 2H), 5.97 (s, 2H), 3.69 (s, 3H), 2.6 (s, 3H), 2.59 - 2.52 (m, 2H), 2.48 - 2.41 (m, 3H), 1.21 - 1.16 (m, 2H), 1.09 - 1.06 (m, 2H).Example Q-35. 5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazole-2-carboxylic acidDocket No.: 14928-WO-PCTThe titled compound was obtained by hydrolysis of the ethyl ester of Example Q-28. LCMS ESI m / z 461.9 [M+H]+, RT = 1.91 min (Method D). HPLC purity: 97.16%, RT = 6.70 min (Analytical HPLC Method A); 'HNMR (400 MHz, DMSO-de) 6 = 14.18 (s, 1H), 13.34 (s, 1H), 8.86 (s, 1H), 8.18 (s, 1H), 7.59 (s, 1H), 7.48 (s, 1H), 3.61 (s, 3H), 2.61 (s, 3H).Example Q-36. Synthesis of 2'-chloro-N-(5-(ethylsulfonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamideTFATrifilic acid0°C - RT, 20 minStep 2Step 1. Synthesis of 2'-chloro-N-(5-(ethylsulfonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide: To a stirred solution of N-(5-bromothiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (100 mg, 0.162 mmol) and sodium ethylsulfmate (75 mg, 0.648 mmol) in DMSO (6 mL) were added copper(I) iodide (6.17 mg, 0.032 mmol) and L-proline (3.73 mg, 0.032 mmol) at 25°C. The resulting reaction mixture was degassed with nitrogen over a period of 5 min and stirred at 100 °C for 16 h. TheDocket No.: 14928-WO-PCTreaction mixture was filtered through celite bed. The celite bed was washed with ethyl acetate (2 x 80 mL). The combined filtrate was concentrated under reduced pressure to afford the crude product 2'-chloro-N-(5-(ethylsulfonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (50 mg, 0.038 mmol, 23.50 % yield). The crude was taken as it is for next step. LCMS: ESI m / z 630.3 [M+H]+, RT=2.93 min (Method E).Step 2. Synthesis of 2'-chloro-N-(5-(ethylsulfonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide: To a stirred solution of 2'-chloro-N-(5-(ethylsulfonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (50 mg, 0.079 mmol) in TFA (3 mL) was added trifluoromethanesulfonic acid (5.95 mg, 0.040 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for 20 min. It was concentrated under reduced pressure to afford the crude product, which was purified by prep HPLC [Diluent: THF:water: ACN (40:20:40); Colum: X-select CSH Cl 8 (250 x 19 mm, 5micron); Temperature: ambient; Mobile phase A: l0 mM ammonium acetate in water (pH 4.5); Mobile phase B: Acetonitrile; Flow: 15 mL / min;Time / Grad: 0 / 30,12 / 70,14 / 70] to afford 2'-chloro-N-(5-(ethylsulfonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (7 mg, 0.014 mmol, 17.13 % yield) as an off-white solid. LCMS: ESI m / z 508 (M-H), RT=2.14 min (Method E).Analytical Method A: RT=8.19 min, HPLC Purity: 99.29 %.1H NMR (400 MHz, DMSO-de) 6 = 13.47 (s, 1H), 8.86 (s, 1H), 8.17 (s, 1H), 7.59 (s, 1H), 7.48 (s, 1H), 3.65 - 3.59 (m, 5H), 2.61 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H).Example Q-37. Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(5-(pyrrolidin-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamideDocket No.: 14928-WO-PCTTrifilic acid TFA, 25 °C, RTStep 2 Step 1. Synthesis of tert-butyl 3-(5-(2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)pyrrolidine-1-carboxylate:Reaction mixture A: To a stirred solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (91 mg, 0.486 mmol) in dioxane (1 mL) were added pyridine (0.5 mL) and 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate (154 mg, 0.389 mmol) at 25 °C. The resultant reaction mixture was stirred for 15 mins at 25 °C. The reaction mixture was filtered and assigned as reaction mixture A.Reaction mixture B: To a stirred solution of N-(5-bromothiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (200 mg, 0.324 mmol) in DMA (4 mL) were added 1-azabicyclo[2.2.2]octane (72.1 mg, 0.648 mmol)[Ir(dtbbpy)(ppy)2]PF6 (14.81 mg, 0.016 mmol) and (sp-4-2)-[4,4'-bis(l, 1 -dimethylethyl)-2,2'-bipyridine-kappaN1,kappaN1'] dibromo-nickel (7.89 mg, 0.016 mmol). To it then the reaction mixture A was added. The resultant reaction mixture was stirred at 25 °C for 16 h under blue-LED light (450 nm). The reaction mixture was filtered through celite bed. The celite bed was washed with ethyl acetate (2 x 50 mL). The filtrate was concentrated under reduced pressure to afford the crude product. The crude product was triturated with 2% EtOAc / petroleum ether to obtain tert-butyl 3-(5-(2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)pyrrolidine-1-carboxylate (200 mg, 0.068 mmol, 20.93 % yield) as a brown solid. LCMS: ESI m / z 707.2 [M+H]+, RT=3.59 min (Method E).Step 2. Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(5-(pyrrolidin-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide:To a stirred solution of tert-butyl 3-(5-(2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)pyrrolidine-1-carboxylate (200 mg, 0.283 mmol) in TFA (8 mL) was added trifluoromethanesulfonic acid (21.22 mg, 0.141 mmol) at 0 °C. The resulting reaction mixture was stirred at 25 °C for 20 min. The reaction mixture was concentrated under reduced pressure to afford the crude product. It was purified by preparative HPLC [Diluent: THF: ACN:water (20:50:30), Column: X-Select C18 (250 xl9 mm, 5 micron), Temperature: ambient, Mobile phase A: 5mM ammonium formate in water, Mobile phase B: acetonitrile, Flow: 15 mL / min, Time / Grad: 0 / 20,15 / 60] to afford 2'-chloro-5'-methoxy-6-methyl-N-(5-(pyrrolidin-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (18 mg, 0.035 mmol, 12.55 % yield) as an off-white solid. LCMS: ESI m / z 486.9 [M+H]+, RT=1.75 min (Method D). Analytical Method B: RT=6.98 min, HPLC purity = 96.01%. 'H NMR (400 MHz, DMSO-d6) 8 = 8.94 (s, 1H), 8.13 (s, 1H), 7.44 (s, 1H), 7.29 (s, 1H), 3.94 (quin, J= 7.3 Hz, 1H), 3.6 (s, 3H), 3.45 -3.43 (m, 2H), 3.25 - 3.2 (m, 2H), 2.56 (s, 3H), 2.45 - 2.35 (m, 1H), 2.21 - 2.14 (m, 1H). Two NH protons were not visible.Example Q-38. Synthesis of ethyl 2-(5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]- 3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)cyclopropane-l-carboxylateDocket No.: 14928-WO-PCTStep 4 Step 1. Synthesis of N-(4-methoxybenzyl)-5-vinylthiazolo[5,4-d]thiazol-2-amine:To a stirred solution of 5-bromo-N-(4-methoxybenzyl)thiazolo[5,4-d]thiazol-2-amine (500 mg, 1.403 mmol) in DMF (6 mL) was added tributyl(vinyl)stannane (890 mg, 2.81 mmol). Then to the reaction mixture, tetrakis(triphenylphosphine)palladium (162 mg, 0.140 mmol) was added. The resulting reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was diluted with ice-cold water (15 mL) and extracted with ethyl acetate (30 mL x 2). The combined ethyl acetate layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product. The crude was purified by silica gel flash column chromatography eluting with 0 - 60% ethyl acetate / petroleum ether to afford N-(4-methoxybenzyl)-5-vinylthiazolo[5,4-d]thiazol-2-amine (140 mg, 0.425 mmol, 30.2 % yield) as a yellow solid. LCMS: ESI m / z 304 [M+H]+, RT=1.45 min (Method C).Step 2. Synthesis of ethyl 2-(5-((4-methoxybenzyl)amino)thiazolo[5,4-d]thiazol-2-yl)cyclopropane-1-carboxylate: To a stirred solution of N-(4-methoxybenzyl)-5-vinylthiazolo[5,4-d]thiazol-2-amine (60 mg, 0.198 mmol) in Toluene (4 mL) was added 1-Methyl-lH-imidazole (3.29 mg, 0.040 mmol). Then to the reaction mixture, ethylDocket No.: 14928-WO-PCTdiazoacetate (1.681 mL, 1.978 mmol) and Cobalt(II) TPP (26.6 mg, 0.040 mmol) were added. The resulting reaction mixture was stirred at 80 °C for 3 h. The reaction mass was concentrated under reduced pressure to afford the crude product. The crude was purified by reverse phase purification [Column Type: ISCO Gold; Diluent: THF; Detection: PDA;Detection Quality: 220 nm;Mobile Phase A: Water; Mobile Phase B: Acetonitrile; Compound Elution: 50%ACN / 5 mM ammonium formate; Flow Rate: 80 mL / min] to afford ethyl 2-(5-((4-methoxybenzyl)amino)thiazolo[5,4-d]thiazol-2-yl)cyclopropane-l-carboxylate (45 mg, 0.094 mmol, 47.3 % yield). LCMS: ESI m / z 390 [M+H]+, RT=1.54 min (Method C).Step 3. Synthesis of ethyl 2-(5-(2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)cyclopropane-1-carboxylate:To a stirred solution of ethyl 2-(5-((4-methoxybenzyl)amino)thiazolo[5,4-d]thiazol-2-yl)cyclopropane-1-carboxylate (40 mg, 0.103 mmol) and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (28.6 mg, 0.103 mmol) in DMF (2.5 mL) were added DIPEA (0.036 mL, 0.205 mmol), 1-methyl-lH-imidazole (21.34 mg, 0.257 mmol) and N, N, N', N' -tetramethylchloroformamidinium hexafluorophosphate (86 mg, 0.308 mmol). The resulting reaction mixture was stirred at 25 °C for 16 h. It was concentrated under reduced pressure to afford the crude product ethyl 2-(5-(2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)cyclopropane-1-carboxylate (80 mg, 0.038 mmol, 37.1 % yield). LCMS: ESI m / z 650.2 [M+H]+, RT=1.73 min (Method C).Step 4. Synthesis of ethyl 2-(5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)cyclopropane-1-carboxylate: To a stirred solution of ethyl 2-(5-(2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)cyclopropane-1-carboxylate (80 mg, 0.123 mmol) in TFA (1.0 mL) was added trifluoromethanesulfonic acid (18.47 mg, 0.123 mmol) to 0 °C. The resulting reaction mixture was stirred at 0 °C for 10 min and then at 25 °C for 20 min. The reaction mixture was concentrated under reduced pressure to afford the crude, which was purified by SCP [Column: XBridge C18, 19 mm x 150 mm, 5 pm particles; Flow Rate: 20.00 mL / min; Column Temperature: 23 °C. Fraction collection was triggered by MS (MM + / -).Docket No.: 14928-WO-PCTFractions containing the desired product were combined and dried via centrifugal evaporation. Mobile Phase A (ACN / H2O (5:95) with 10 mM AA), Mobile Phase B (ACN / H2O (95:5) with 10 mM AA), Time / Grad (%A): 0 / 90, 12 / 45, 17 / 45, 17.1 / 0, 20 / 0, 20.1 / 95, 23 / 95] to afford ethyl 2-(5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)cyclopropane-1-carboxylate (18 mg, 0.034 mmol, 27.5 % yield). Analytical Method C: RT=1.73 min, m / z: 530 [M+H]+, LCMS purity = 99.7%; Analytical Method D: RT=1.83 min, m / z: 530 [M+H]+, LCMS purity =100%. ¹H NMR (400 MHz, DMSO-d6) 8 = 13.05 (s, 1H), 8.83 (s, 1H), 8.16 (s, 1H), 7.56 (s, 1H), 7.45 (s, 1H), 4.13 (q, J = 7.1 Hz, 2H), 3.59 (s, 3H), 3.03 - 2.94 (m, 1H), 2.60 (s, 3H), 2.32 - 2.26 (m, 1H), 1.73 -1.59 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H).Example Q-39. Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide;Docket No.: 14928-WO-PCTStep 1. Synthesis of 2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-N-(5-(tetrahydrofuran-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide: Reaction mixture A: To a stirred solution tetrahydrofuran-3-ol (10.71 mg, 0.122 mmol) in dioxane (1 mL) were added pyridine (0.5 mL) and 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate (40.3 mg, 0.162 mmol) at 25 °C. The resultant reaction mixture was stirred for 15 min at 25 °C. The reaction mixture was filtered and assigned as reaction mixture A.Reaction mixture B: To a stirred solution of N-(5-bromothiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (50 mg, 0.081 mmol) in DMA (2 mL) were added Azabicyclo[2.2.2]octane (9.01 mg, 0.081 mmol), [Ir(dtbbpy)(ppy)2]PF6 (3.70 mg, 4.05 pmol) and (SP-4-2)-[4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-kappaN1,kappaN1'] dibromo-nickel (1.973 mg, 4.05 pmol). To it then the reaction mixture A was added. The resultant reaction mixture was stirred at 25 °C for 16 h under blue-LED light (450 nm). The reaction mixture was filtered through celite bed. The celite bed was washed with ethyl acetate (2 x 50 mL). The filtrate was concentrated under reduced pressure to afford the crude product. The crude product was triturated with 2% EtOAc / petroleum ether to obtain the crude product 2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-N-(5-(tetrahydrofuran-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (50 mg, 0.012 mmol, 15.22 % yield) as a brown solid. It was taken as it is for next step. LCMS: ESI m / z 608.2 [M+H]+, RT=3.59 min (Method E).Step 2. Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide:To a stirred solution of 2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-N-(5-(tetrahydrofuran-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (40 mg, 0.066 mmol) was added trifluoromethanesulfonic acid (4.94 mg, 0.033 mmol) at 0 °C. The resulting reaction mixture was stirred at 25 °C for 2 h. It was concentrated under reduced pressure to afford the crude product, which was purified by preparative HPLC [Diluent: THF: ACN:water (50:30:20), Column: X- Bridge C18 (19x250 mm, 5micron), Temperature: ambient, Mobile phase A: 5 mM ammonium formate in water, Mobile phase B: ACN / MeOH, Flow: 15 mL / min, Time / Grad: 0 / 30,12 / 70] to afford 2'-chloro-5'-methoxy-6-methyl-N-(5-Docket No.: 14928-WO-PCT(tetrahydrofuran-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (7 mg, 0.014 mmol, 20.91 % yield) as an off-white solid. LCMS: ESI m / z 488 [M+H]+, RT=2.09 min (Method E). Analytical Method B: RT=7.41 min, HPLC purity = 95.88 %. ¹H NMR (400 MHz, DMSO-d6) 8 = 9.05 (s, 1H), 8.1 (s, 1H), 7.28 (s, 1H), 7.09 (s, 1H), 4.1 - 4.05 (m, 1H), 3.92 - 3.88 (m, 1H), 3.83 - 3.77 (m, 3H), 3.61 (s, 3H), 2.38 - 2.35 (m, 1H), 2.21 - 2.14 (m, 1H). Three methyl protons are merged with solvent peak.Example Q-40. Synthesis of ethyl 2-((5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)oxy)acetate:NTFA, Trifilic acid, 25 °C, 2 hStep 2Docket No.: 14928-WO-PCTStep 1. Synthesis of ethyl 2-((5-(2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)oxy)acetate:To a stirred solution of N-(5-bromothiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (50 mg, 0.081 mmol) in Acetonitrile (4 mL) were added ethyl 2-hydroxyacetate (8.44 mg, 0.081 mmol), TEMPO (12.66 mg, 0.081 mmol), [Ir(dtbbpy)(ppy)₂]PF₆ (3.70 mg, 4.05 pmol) and (SP-4-2)-[4,4'-bis(l,l-dimethylethyl)-2,2'-bipyridine-kappaN1,kappaN1'] dibromo-nickel (1.973 mg, 4.05 pmol). The reaction mixture was stirred at 25 °C in Blue-LED light (450 nm) for 16 h. The reaction mixture was filtered through celite bed. The celite bed was washed with ethyl acetate (2 x 50 mL). The ethyl acetate layer was concentrated under reduced pressure to afford the crude. The crude product was washed with 2% EtOAc / PE and dried under vacuum to afford ethyl 2-((5-(2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)oxy)acetate (50 mg, 0.062 mmol, 77 % yield). LCMS: m / z: 662.2 (M+22]+, RT= 3.2 min (Method E).Step 2. Synthesis of ethyl 2-((5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido) thiazolo [5,4-d]thiazol-2-yl)oxy)acetate:To a stirred solution of ethyl 2-((5-(2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)oxy)acetate (50 mg, 0.078 mmol) in TFA (2 mL) was added Trifluoromethanesulfonic acid (5.86 mg, 0.039 mmol) at 0 °C. The resulting reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford the crude. The crude product was purified by preparative HPLC [Diluent: THF: ACN:water (20:50:30); Column: X-SELECT CSHt C18(250 xl9)mm, 5micron; Temperature: Ambient; Mobile phase A: 5mM ammonium formate in water (pH 3.3); Mobile phase B: Acetonitrile; Flow: 15 mL / min; Time / Grad: 0 / 45,12 / 80,14 / 80], LCMS: ESI m / z 520 [M+H]+, RT=2.62 min (Method E). HPLC: RT: 7.76 min, HPLC purity = 95.09 % (Analytical Method B). 'H NMR (400 MHz, DMSO-d6) 6= 12.84 (s, 1H), 8.9 (s, 1H), 8.13 (s, 1H), 7.44 (s, 1H), 7.3 (s, 1H), 5.11 (s, 2H), 4.19 (q, J = 7.2 Hz, 2H), 3.6 (s, 3H), 2.56 (s, 3H), 1.21 (t, J= 4 Hz, 3H).Example Q-41. Synthesis of ethyl (5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido) thiazolo [5,4-d]thiazol-2-yl)(methyl)carbamate:Docket No.: 14928-WO-PCTmethyl amineNMP120 °C, 5 hStep 1Step 1. Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(5-(methylamino)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide: To a stirred solution of N-(5-bromothiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (70 mg, 0.141 mmol) in N-methyl-2-pyrrolidinone (1 mL) were added methanamine hydrochloride (47.6 mg, 0.705 mmol) and DIPEA (0.098 mL, 0.564 mmol) at 25 °C. The resulting reaction mixture was stirred at 120 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford the crude product 2'-chloro-5'-methoxy-6-methyl-N-(5-(methylamino)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (50 mg, 0.055 mmol, 38.9 % yield). The crude was used as it is for next step. LCMS: ESI m / z 447 [M+H]+, RT=1.00 min (Method C).Step 2. Synthesis of ethyl (5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)(methyl)carbamate: To a stirred solution of 2'-chloro-5'-methoxy-6-methyl-N-(5-(methylamino)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-Docket No.: 14928-WO-PCTbipyridine]-3 -carboxamide (50 mg, 0.112 mmol) in CH₂Cl₂ (5 mL)were added Triethylamine (34.0 mg, 0.336 mmol) and ethyl carbonochloridate (18.21 mg, 0.168 mmol) at 0 °C. The resulting reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with water (20 mL) and extracted with DCM (2 x 30 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford the crude product. The crude was purified by preparative HPLC [Diluent: THF:water: ACN (40:20:40); Column: X-select csh C18 (250 X 19 mm, 5micron); Temperature: ambient; Mobile phase A: 5 mM ammonium formate in water; Mobile phase B: Acetonitrile; Flow: 15 mL / min; Time / Grad: 0 / 40,12 / 75,15 / 75] to afford ethyl (5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)(methyl)carbamate (7.5 mg, 0.014 mmol, 12.63 % yield) as an off-white solid. LCMS: ESI m / z 519.0 (M+H), RT=3.75 min (Method C). HPLC: RT=9.31 min, HPLC purity = 97.75 % (Analytical Method A). ¹H NMR (400 MHz, DMSO-de) 6 = 9.06 (s, 1H), 8.1 (s, 1H), 7.26 (s, 1H), 7.06 (s, 1H), 4.27 (q, J= 7.2 Hz, 2H), 3.62 (s, 3H), 3.49 (s, 3H), 1.31 (t, J= 8 Hz, 3H) One Methyl group (merged with DMSO) and NH protons were not visible.Example Q-42. Synthesis of 2'-chloro-N-(5-(difluoromethyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide:Docket No.: 14928-WO-PCTN ClStep 1Step 3Step 1. Synthesis of ethyl 5-((4-methoxybenzyl)amino)thiazolo[5,4-d]thiazole-2-carboxylate: To a stirred solution of 5-bromo-N-(4-methoxybenzyl)thiazolo[5,4-d]thiazol-2-amine (300 mg, 0.842 mmol) in Ethanol (10 mL) was added and sodium acetate (207 mg, 2.53 mmol) at 25 °C. The reaction mixture was purged with nitrogen, then to the reaction mixture PdC12(dppf)-CH2C12 adduct (68.8 mg, 0.084 mmol) was added. The resulting reaction mixture was stirred at 90 °C under 10 kg pressure of carbon monoxide for 16 h. The reaction mixture was filtered through celite bed. The celite bed was washed with EtOAc (30 mL) and the combined filtrate was concentrated under reduced pressure. The concentrated reaction mixture was diluted with EtOAc (50 mL), washed with water (30 mL), brine (30 mL), dried over (Na₂SO₄), filtered and concentrated under reduced pressure to afford the crude. The crude was purified by silica-gel flash column purification eluting with 0-40%EA / PE to afford ethyl 5-((4-methoxybenzyl)amino)thiazolo[5,4-d]thiazole-2-carboxylate (193 mg, 0.529 mmol, 62.8 % yield) as a pale red solid. LCMS: RT=2.91 min, m / z: 350.01 (M+H)+(Method E).Docket No.: 14928-WO-PCTStep 2. Synthesis of ethyl 5-(2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazole-2-carboxylate: To a stirred solution of ethyl 5-((4-methoxybenzyl)amino)thiazolo[5,4-d]thiazole-2-carboxylate (180 mg, 0.515 mmol), 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (158 mg, 0.567 mmol) and N, N, N', N'-Tetramethylchloroformamidinium hexafluorophosphate (217 mg, 0.773 mmol) in DMF (5 mL) at 0 °C was added 1 -methylimidazole (0.125 mL, 1.545 mmol) followed by DIPEA (0.270 mL, 1.545 mmol). The resulting reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with EtOAc (20 mL). The ethyl acetate layer was washed with water (10 mL), brine (10 mL), dried over (Na₂SO₄), filtered and concentrated under reduced pressure to afford the crude. The crude was purified by silica gel flash column chromatography eluting with 0 - 30% EA / petroleum ether to yield desired product as ethyl 5-(2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazole-2-carboxylate (198 mg, 0.320 mmol, 62.0 % yield) as a yellow solid. LCMS: ESI m / z 610.0 [M+H]+, RT=2.774 min (Method E).Step 3. Synthesis of 2'-chloro-N-(5-formylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide: A stirred solution of ethyl 5-(2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazole-2-carboxylate (100 mg, 0.164 mmol) in THF (5 mL) was cooled to -78 °C. Then to the reaction mixture DIBAL-H (0.492 mL, 0.492 mmol) was added drop wise. The reaction mixture was allowed to stir at -78 °C for 1 h. To the reaction mixture 1.5N HC1 (5 mL) was added. The reaction mixture was extracted with EtOAc (2 x 10 mL). The combined ethyl acetate layer was washed with water (10 mL), brine (10 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to afford the crude. The crude product was purified by silica gel flash column chromatography eluting with 40%EA / PE to yield desired product as 2'-chloro-N-(5-formylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (55 mg, 0.066 mmol, 40.4 % yield) as a pale yellow solid. LCMS: ESI m / z 566.2 [M+H]+, RT= 3.101 min (Method E).Step 4. Synthesis of 2'-chloro-N-(5-(difluoromethyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide: To a stirred solution of 2'-chloro-N-(5-formylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-Docket No.: 14928-WO-PCTmethoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (50 mg, 0.088 mmol) in DCM (2 mL) was added Diethylaminosulfur trifluoride (35.6 mg, 0.221 mmol) at 0 °C. The resulting reaction mixture was stirred at same temperature for 3h. The resulting reaction mixture was diluted with DCM (5 mL). The DCM layer was washed with water (3 mL), brine (3 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to yield 2'-chloro-N-(5-(difluoromethyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (45 mg, 0.058 mmol, 65.8 % yield) as a brown gummy. LCMS: ESI m / z 588.0 [M+H]+, RT=1.733 min (Method C).Step 5. Synthesis of 2'-chloro-N-(5-(difluoromethyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide: To a stirred solution of 2'-chloro-N-(5-(difluoromethyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (40 mg, 0.068 mmol) in TFA (0.5 mL) at 0 °C was added triflic acid (0.604 μL, 6.80 μmol) was added. The resulting reaction mixture was allowed to stir at 25 °C for 1 h. After completion of the reaction, the volatiles were removed under reduced pressure. The resulting crude was purified by RP HPLC [Column: XBridge C18, 19 mm x 150 mm, 5 μm particles; Flow Rate: 20.00 mL / min; Column Temperature: 23 °C. Fraction collection was triggered by MS (MM + / -). Fractions containing the desired product were combined and dried via centrifugal evaporation Time / Grad (%A): 0 / 90, 10 / 50, 15 / 50, 15.1 / 0, 18 / 0, 18.1 / 90, 21 / 90] to afford desired product 2'-chloro-N-(5-(difluoromethyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (13.1 mg, 0.027 mmol, 40.0 % yield). Analytical Method C: RT=1.52 min, m / z: 467.9 [M+H]+, LCMS purity = 97.3 %; Analytical Method D: RT=1.63 min, m / z: 467.9 [M+H]+, LCMS purity = 97.4 %. ¹H NMR (400 MHz, DMSO-d6) 8 = 13.31 (s, 1H), 8.86 (s, 1H), 8.17 (s, 1H), 7.59 - 7.31 (m, 3H), 3.6 (s, 3H), 2.61 (s, 3H).Example Q-43. Synthesis of 2'-chloro-N-(5-(isopropylthio)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide:Docket No.: 14928-WO-PCT2) TFA Step 1. Synthesis of 5-(isopropylthio)-N-(4-methoxybenzyl)thiazolo[5,4-d]thiazol-2-amine: To a stirred solution of 5-bromo-N-(4-methoxybenzyl)thiazolo[5,4-d]thiazol-2-amine (300 mg, 0.842 mmol) in DMF (6.0 mL). Then to it 2-propanethiol (0.158 mL, 1.684 mmol), palladium(II) acetate (37.8 mg, 0.168 mmol), Xantphos (97 mg, 0.168 mmol) and potassium carbonate (291 mg, 2.105 mmol) were added. The resulting reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with 10 mL of water and extracted with ethylacetate (2x15 mL). The combined ethyl acetate layer was dried over sodium sulfate, filtered and concentrated under vacuum to afford the crude. The crude obtained purified by silica gel flash column chromatography eluting with 0 - 50 % ethyl acetate in pet ether to afford 5-(isopropylthio)-N-(4-methoxybenzyl)thiazolo[5,4-d]thiazol-2-amine (110 mg, 0.310 mmol, 36.8 % yield) as a yellow solid. LCMS: ESI m / z 352.3 [M+H]+, RT=3.18 min(Method D).Step 2. Synthesis of 2'-chloro-N-(5-(isopropylthio)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide: To a stirred solution of 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (25 mg, 0.090 mmol) and 5-(isopropylthio)-N-(4-methoxybenzyl)thiazolo[5,4-d]thiazol-2-amine (31.5 mg, 0.090 mmol) in DMF (2 mL)were added DIPEA (0.031 mL, 0.179 mmol), 1-Methylimidazole (0.018 mL, 0.224 mmol)and chi oro-N, N, N', N' -tetramethylformamidiniumDocket No.: 14928-WO-PCThexafluorophosphate (76 mg, 0.269 mmol). The resulting reaction mixture was stirred at 25 °Cfor 16 h. The reaction mixture was diluted with water (5 mL). Solid obtained was filtered through buchner funnel, washed with water (2 mL) and dried under reduced pressure to afford 2'-chloro-N-(5-(isopropylthio)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (30 mg, 0.038 mmol, 42.6 % yield) as a brown solid. The crude was taken as it is for next step. LCMS: ESI m / z 612 [M+H]+, RT=1.92 min (Method C). The desired final compound was obtained by removing the PMB protecting group using similar methods described in other examples. LCMS: ESI m / z 492 [M+H]+, RT=1.97 min (Method C). Analytical Method D: RT=1.89 min, HPLC purity = 99.1 %. ¹H NMR (400 MHz, DMSO-de) 5 = 13.11 (s, 1H), 8.83 (s, 1H), 8.17 (s, 1H), 7.57 (s, 1H), 7.46 (s, 1H), 3.80 (quin, J = 6.8 Hz, 1H), 3.61 (s, 3H), 2.61 (s, 3H), 1.39 (d, J = 6.8 Hz, 6H).Example Q-44. Synthesis of 2'-chloro-N-(5-((dimethylamino)methyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide:acetic acid N2-Methylpyridine I^MB borane complex DMF, 50 °C, 1 hStep 1 Step 1. Synthesis of 2'-chloro-N-(5-((dimethylamino)methyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide: To a stirred solution of 2'-chloro-N-(5-formylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (70 mg, 0.124 mmol) in DMF (1 mL) were added dimethylamine solution in THF (0.124 mL, 0.247 mmol), acetic acid (0.035 mL, 0.618 mmol)and 2-methylpyridine borane complex (54.0 mg, 0.495 mmol). TheDocket No.: 14928-WO-PCTresulting reaction mixture was stirred at 50 °Cfor 1 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic fraction was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product. The crude was purified by RP column purification (Column Type: ISCO Gold, Diluent: THF, Detection: UV, Detection Quality: 254 nm, Mobile Phase A: water; Mobile Phase B: acetonitrile; Compound Elution: 20% ACN in 5 mM ammonium formate in water, Flow Rate: 60 mL / min) to afford 2'-chloro-N-(5-((dimethylamino)methyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (25 mg, 0.034 mmol, 27.2 % yield) as a colorless semi solid. LCMS: ESI m / z 595 [M+H]+, RT=1.08 & 1.56 min (Method C).Step 2. Synthesis of 2'-chloro-N-(5-((dimethylamino)methyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide: To a stirred solution of 2'-chloro-N-(5-((dimethylamino)methyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (25 mg, 0.042 mmol)in TFA (1 mL)was added triflic acid (0.05 mL) at 0 °C. The resulting reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated by purging with nitrogen to afford the crude product. The crude product was purified by SCP [ Column: XBridge C18, 19 mm x 150 mm, 5 μm particles; Flow Rate: 20.00 mL / min; Column Temperature: 23 °C. Fraction collection was triggered by MS (MM + / -). Fractions containing the desired product were combined and dried via centrifugal evaporation; Mobile Phase A (ACN / H2O (5:95) with 10 mM AA);Mobile Phase B (ACN / H2O (95:5) with 10 mM AA) Time / Grad (%A): 0 / 95, 10 / 58, 15 / 58, 15.1 / 0, 18 / 0,18.1 / 95, 21 / 95] to afford 2'-chloro-N-(5-((dimethylamino)methyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (8.40 mg, 0.018 mmol, 41.8 % yield). Analytical Method D: RT=1.45 min, m / z: 475 [M+H]+, LCMS purity = 99.4 %; Analytical Method A: RT=0.99 min, m / z: 474.9 (M+H), LCMS purity = 99.4 %.JH NMR (400 MHz, DMSO-d6) 8 = 13.00 (br s, 1H), 8.83 (s, 1H), 8.17 (s, 1H), 7.57 (s, 1H), 7.46 (s, 1H), 3.85 (s, 2H), 3.61 (s, 3H), 2.61 (s, 3H), 2.32 (s, 6H).Example Q-45. Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(5-(oxetan-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide:Docket No.: 14928-WO-PCTStep 1Step 2Step 1. N-(4-methoxybenzyl)-5-(oxetan-3-yl)thiazolo[5,4-d]thiazol-2-amine: To a clean flask equipped with a stir bar, sulfonyl hydrazide (1.2 mmol, 1.5 equiv.), aryl bromide (0.75 mmol, 1.0 equiv.), Ni(dme)Br2 (46.2 mg, 0.15 mmol, 20 mol%), and dNbpy (27.9 mg, 0.15 mmol, 20 mol%) were added. The flask was capped with a septum, then evacuated and backfilled with argon gas three times. Dry DMF (5.0 mL) and Et₃N (0.5 mL) were added via syringe under an argon atmosphere. The reaction mixture was stirred at room temperature for 2 min. Then, the reaction flask was submerged in a pre-heated oil bath at 75 °C and stirred for 3 h, at which point TLC indicated complete consumption of the starting material. The reaction mixture was concentrated in vacuo to remove excess Et₃N. The residue in DMF solution was then purified by Cl 8 column (RediSep Rf reversed phase Cl 8 column, eluting with a gradient flow of 90: 10 A / B to 0: 100 A / B, 214 nm UV detection). Solvent A is H2O with 0.1% formic acid; solvent B is MeCN. The product came out at the solvent ratio is A: B = 50:50 and was isolated as a pale yellow solid. Then the product was further purified by flash column chromatography (silica gel, hexane / EtOAc 3:1 to 2:1) to afford the desired finalDocket No.: 14928-WO-PCTproduct (98.0 mg, 41%) as a white solid. 'H NMR (700 MHz, CDCh): 67.30 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 5.57 (t, J = 5.6 Hz, 1H), 5.05 (dd, J = 8.4, 6.1 Hz, 2H), 4.95 (t, J = 6.5 Hz, 2H), 4.56 (tt, J = 8.4, 6.8 Hz, 1H), 4.49 (d, J = 5.4 Hz, 2H), 3.81 (s, 3H) ppm.13C NMR (176 MHz, CDCh): 6 170.14, 164.38, 159.58, 146.68, 139.97, 129.33, 129.07, 114.40, 77.52, 55.47, 48.79, 39.68 ppm.Step 2. Synthesis of 2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-N-(5-(oxetan-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide: To a stirred solution of 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (20.06 mg, 0.072 mmol), N-(4-methoxybenzyl)-5-(oxetan-3-yl)thiazolo[5,4-d]thiazol-2-amine (20 mg, 0.060 mmol) and N, N, N', N' -tetramethylchloroformamidinium hexafluorophosphate (50.5 mg, 0.180 mmol) in DMF (0.5 mL) at 0 °C was added 1 -methylimidazole (14.96 mg, 0.180 mmol) followed by DIPEA (0.031 mL, 0.180 mmol). The resulting reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with EtOAc (5 mL). The ethyl acetate layer was washed with aq. sodium bicarbonate solution (3 mL), water (3 mL), brine (3 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to yield 2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-N-(5-(oxetan-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3 -carboxamide (40 mg, 0.050 mmol, 84 % yield) as a yellow gummy. LCMS: ESI m / z 594.0 [M+H]+, RT=1.484 min (Method C).Step 3. Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(5-(oxetan-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide: To a stirred solution of 2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-N-(5-(oxetan-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (40 mg, 0.067 mmol) in TFA (0.5 mL) at 0 °C was added triflic acid (0.598 μL, 6.73 μmol). The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove the volatiles to afford the crude. The crude was purified by SCP [Column: XBridge C18, 19 mm x 150 mm, 5 μm particles; Flow Rate: 20.00 mL / min; Column Temperature: 23 °C. Fraction collection was triggered by MS (MM + / -). Fractions containing the desired product were lyophilized.Mobile Phase A (ACN / H2O (5:95) with 10 mM AA); Mobile Phase B (ACN / H2O (95:5) with 10 mM AA); Time / Grad (%A): 0 / 95, 12 / 60, 17 / 60, 17.1 / 0, 20 / 0,20.1 / 95, 23 / 95] to afford the desired product 2'-chloro-5'-methoxy-6-methyl-N-(5-(oxetan-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (2.0 mg, 4.02 pmol, 5.97 % yield). LCMS: ESI m / zDocket No.: 14928-WO-PCT474.0 [M+H]+, RT=1.28 min (Method C). Analytical Method D: 474 [M+H]+, RT=1.38 min, HPLC purity = 98 %. 'H NMR (400 MHz, DMSO-d6) 6 = 13.08 (br s, 1H), 8.85 (s, 1H), 8.17 (s, 1H), 7.56 (s, 1H), 7.45 (s, 1H), 4.98 (dd, J = 5.9, 8.1 Hz, 2H), 4.84 - 4.78 (m, 2H),4.77 - 4.70 (m, 1H), 3.61 (s, 3H), 2.60 (s, 3H).Example Q-46. Synthesis of 2'-chloro-5'-methoxy-N-(5-(methoxymethyl)thiazolo[5,4-d]thiazol-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamideStep 1. Synthesis of 2'-chloro-N-(5-(hydroxymethyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide: A stirred solution of ethyl 5-(2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazole-2-carboxylate (100 mg, 0.164 mmol) in THF (5 mL) was cooled to -78 °C. Then to the reaction mixture DIBAL-H (0.492 mL, 0.492 mmol) was added drop wise. The reaction mixture was allowed to stir at 0 °C for 3 h. It was quenchedDocket No.: 14928-WO-PCTwith 1.5 N HC1 (5 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL). The combined ethyl acetate layer was washed with water (10 mL), brine (10 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure. The resulting crude was purified by silica gel flash column chromatography eluting with 80%EA / PE to afford 2'-chloro-N-(5-(hydroxymethyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (41 mg, 0.069 mmol, 42.3 % yield) as a paleyellow solid. LCMS: ESI m / z 568.0 [M+H]+, RT= 2.628 min (Method E).Step 2. 2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-N-(5-(methoxymethyl)thiazolo[5,4-d]thiazol-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide: To a stirred solution of 2'-chloro-N-(5-(hydroxymethyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (40 mg, 0.070 mmol) and silver oxide (82 mg, 0.352 mmol) in DCM (2 mL) was added Mel (0.022 mL, 0.352 mmol). The resulting reaction mixture was heated at 40 °C for 16 h. It was filtered through celite bed, washed with DCM (10 mL) and concentrated under reduced pressure to afford crude. The resulting crude was purified by using RP column purification [Column Type: ISCO Gold Column Size: 40g Purification Mode: Reverse Phase Loading Mode: Liquid TLC Composition: Diluent: THF Detection: PDA Detection Quality: 220 nm; Mobile Phase A: Water; Mobile Phase B:Acetonitrile; Compound Elution: 25% ACN in 10 mM ammonium formate in water; Flow Rate: 40 mL / min] to afford 2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-N-(5-(methoxymethyl)thiazolo[5,4-d]thiazol-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (16 mg, 0.018 mmol, 25.2 % yield) as a yellow gummy. LCMS: ESI m / z 582.1 [M+H]+, RT= 3.35 min (Method E).Step 3. 2'-chloro-5'-methoxy-N-(5-(methoxymethyl)thiazolo[5,4-d]thiazol-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide: To a stirred solution of 2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-N-(5-(methoxymethyl)thiazolo[5,4-d]thiazol-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (15 mg, 0.026 mmol) was added TFA (1 mL) was added triflic acid (0.229 μL, 2.58 μmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. It was concentrated under reduced pressure to afford the crude. The resulting crude was purified by SCP Column: XBridge C18, 19 mm x 150 mm, 5 pm particles; Flow Rate: 20.00 mL / min; Column Temperature: 23 °C. Fraction collection was triggered by MS (MM + / -). Fractions containing the desired product were combined and dried via centrifugal evaporationDocket No.: 14928-WO-PCTTime / Grad (%A): 0 / 95, 10 / 58, 18 / 58, 18.1 / 0, 21.0 / 0, 21.1 / 95, 23 / 95 ] to afford the desired product tert-butyl 2'-chloro-5'-methoxy-N-(5-(methoxymethyl)thiazolo[5,4-d]thiazol-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (3.1 mg, 6.59 pmol, 25.6 % yield). LCMS 1: RT: 1.5 min, ESI m / z: 462.0 [M+H]+, LCMS purity = 98.2 % (Analytical Method D). LCMS 2: RT: 1.38 min, ESI m / z: 462.0 [M+H]+, LCMS purity = 98.7 % (Analytical Method C). ¹H NMR (400 MHz, DMSO-de) 6 = 13.07 (br s, 1H), 8.84 (s, 1H), 8.17 (s, 1H), 7.57 (s, 1H), 7.45 (s, 1H), 4.79 (s, 2H), 3.61 (s, 3H), 3.42 (s, 3H), 2.60 (s, 3H).Example Q-47. Synthesis of N-(5-(2-(2-aminoethoxy)ethyl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide, TEAN ClStep 3 Step 1. tert-Butyl (2-(2-(5-((4-methoxybenzyl)amino)thiazolo[5,4-d]thiazol-2-yl)ethoxy)ethyl)carbamate. To a clean flask equipped with a stir bar, sulfonyl hydrazide (2.0 mmol, 2.5 equiv.), aryl bromide (0.8 mmol, 1.0 equiv.), Ni(dme)Br2 (61.6 mg, 0.2 mmol, 25 mol%), and dNH2-bpy (37.0 mg, 0.2 mmol, 25 mol%) were added. The flask was cappedDocket No.: 14928-WO-PCTwith a septum, then evacuated and backfilled with argon gas three times. Dry DMF (5 mL) and Et₃N (0.6 mL) were added via syringe under an argon atmosphere. The reaction mixture was stirred at room temperature for 2 min. Then, the reaction flask was submerged in a preheated oil bath at 75 °C and stirred for 4 h. The reaction mixtrue was concentrated in vacuo to remove excess Et3N. The residue in DMF solution was then purified by Cl 8 column (RediSep Rf reversed phase C18 column, eluting with a gradient flow of 75:25 A / B to 30:70 A / B, 214 nm UV detection). Solvent A is H2O with 0.1% formic acid; solvent B is MeCN. The product came out at the solvent ratio is A: B = 30:70 and was isolated as a brown oil. After concentration, the product was purified by flash column chromatography (silica gel, hexane / EtOAc = 3:2) to afford the product (92 mg, 25%) as a pale brown solid. 1HNMR Step 2. Synthesis of tert-butyl (2-(2-(5-(2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)ethoxy)ethyl)carbamate: To a stirred solution of tert-butyl (2-(2-(5-((4-methoxybenzyl)amino)thiazolo[5,4-d]thiazol-2-yl)ethoxy)ethyl)carbamate (27 mg, 0.058 mmol), 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (19.44 mg, 0.070 mmol) and N, N, N', N'-Tetramethylchloroformamidinium hexafluorophosphate (48.9 mg, 0.174 mmol) in DMF (1 mL)) at 0 °C was added 1 -methylimidazole (14.49 mg, 0.174 mmol) and DIPEA (0.030 mL, 0.174 mmol). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was purified by RP-Column Purification [Column Type: Column Type: ISCO Gold Column Size: 40g Purification Mode: Reverse Phase Loading Mode:Liquid TLC Composition: Diluent: THF, CAN Detection: PDA Detection Quality: 220 nm Mobile Phase A: Water, Mobile Phase B: Acetonitrile, Compound Elution: 60% ACN in 5 mM ammonium formate in water, Flow Rate: 50 mL / min] to yield tert-butyl (2-(2-(5-(2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2 yl)ethoxy)ethyl)carbamate (18 mg, 0.024 mmol, 41.8 % yield) as an off white solid. LCMS: ESI m / z 725.2 [M+H]+, RT=3.543 min (Method E).Step 3: Synthesis of N-(5-(2-(2-aminoethoxy)ethyl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide, TFA: To a stirred solution of tertbutyl (2-(2-(5-(2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)ethoxy)ethyl)carbamate (18 mg, 0.025 mmol) in TFA (0.3 mL) at 0 °C was added triflicacid (0.220 pl, 2.482 pmol). The reaction mixture wasDocket No.: 14928-WO-PCTstirred at 0 °C for 3 h. The reaction mixture was concentrated under reduced pressure to afford crude N-(5-(2-(2-aminoethoxy)ethyl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide, TFA (15 mg, 0.020 mmol, 82 % yield) as a brown gummy. LCMS: ESI m / z: 505.2 [M+H]+, RT=0.799 min (Method C). 'H NMR (400 MHz, DMSO-de) 6 = 9.00 (s, 1H), 8.12 (s, 1H), 7.35 (s, 1H), 7.19 (s, 1H), 3.83 (t, J = 6.4 Hz, 2H), 3.63 - 3.58 (m, 5H), 3.28 - 3.27 (m, 2H), 2.96 (t, J = 5.3 Hz, 2H), 2.54 (s, 3H). NH protons are not visible.Example Q-48. Synthesis of N-(5-(azetidin-3-yl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamideStep 2Step 3 Step 1. Synthesis of benzyl 3-(5-((4-methoxybenzyl)amino)thiazolo[5,4-d]thiazol-2-yl)azetidine-l-carboxylate: To a clean flask equipped with a stir bar, sulfonyl hydrazideDocket No.: 14928-WO-PCT(1.05 mmol, 1.5 equiv.), aryl bromide (250 mg, 0.7 mmol, 1.0 equiv.), Ni(dme)Br2 (43.1 mg, 0.14 mmol, 20 mol%) and dtbbpy (37.5 mg, 0.14 mmol, 20 mol%) were added. The flask was capped with a septum, then evacuated and backfilled with argon gas three times. Dry DMF (3.5 mL) and Et₃N (2.1 mmol, 0.3 mL) were added via syringe under an argon atmosphere. The reaction mixture was stirred at room temperature for 2 min. Then, the reaction flask was submerged in a pre-heated oil bath at 60 °C and stirred for 3 h, at which point TLC indicated complete consumption of the starting material. The reaction mixture was concentrated in vacuo to remove excess Et3N. The residue in DMF solution was then purified by Cl 8 column (RediSep Rf reversed phase C18 column, eluting with a gradient flow of 70:30 A / B to 30:70 A / B, 214 nm UV detection). Solvent A is H2O with 0.1% formic acid; solvent B is MeCN. The product came out at the solvent ratio is A: B = 30: 70 and was isolated as a brown solid. Then the product was purified by flash column chromatography (silica gel, hexane: ethyl acetate = 3: 1 to 2: 1) to afford the product (162.0 mg, 50%) as a pale yellow solid.JH NMR (600 MHz, CD3CN / CDCl3=1 / 1): δ 7.40 - 7.31 (m, 5H), 7.29 - 7.26 (m, 2H), 6.86 (dd, J = 8.7, 2.0 Hz, 2H), 6.65 (t, J = 5.7 Hz, 1H), 5.06 (d, J = 1.9 Hz, 2H), 4.45 (dd, J = 5.9, 1.9 Hz, 2H), 4.35 (br., 2H), 4.17 (br., 2H), 4.13 -4.08 (m, 1H), 3.75 (d, J = 1.9 Hz, 3H) ppm.13C NMR (151 MHz, CD3CN / CDCl3=1 / 1): δ 170.5, 164.7, 159.6, 156.9, 147.1, 139.8, 137.5, 130.6, 129.6, 129.1, 128.6, 128.4, 114.4, 67.0, 57.5 - 55.9 (m), 55.6, 48.0, 33.4 ppm.Step 2. Synthesis of benzyl 3-(5-(2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)azetidine-l-carboxylate: To a stirred solution of benzyl 3-(5-((4-methoxybenzyl)amino)thiazolo[5,4-d]thiazol-2-yl)azetidine-l -carboxylate (25 mg, 0.054 mmol) in DMF (1.5 mL) were added 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (29.9 mg, 0.107 mmol), DIPEA (0.00455 mL, 0.026 mmol), 1-methyl-lH-imidazole (13.36 mg, 0.161 mmol) and N, N, N', N'-tetramethylchloroformamidinium hexafluorophosphate (75 mg, 0.268 mmol). The resulting reaction mixture was stirred at 25 °C for 16 h. It was concentrated under vacuum to afford the crude. The crude was purified by RP column purification [Column Type: ISCO Gold;Diluent: THF; Detection: PDA, Detection Quality: 220 nm, Mobile Phase A: Water; Mobile Phase B: Acetonitrile; Compound Elution: 50% ACN in 5 mM ammonium formate in water; Flow Rate: 40 mL / min] to afford benzyl 3-(5-(2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-Docket No.: 14928-WO-PCTmethyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)azetidine-l-carboxylate (35 mg, 0.046 mmol, 86 % yield). LCMS: ESI m / z 727.2 [M+H]+, RT=1.66 min (Method C).Step 3. Synthesis of N-(5-(azetidin-3-yl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide: To a stirred solution of benzyl 3-(5-(2,-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)azetidine-l-carboxylate (35 mg, 0.048 mmol) in TFA (1.5 mL). The reaction mixture was cooled to 0 °C and to it trifluoromethanesulfonic acid (36.1 mg, 0.241 mmol) was added. The resulting reaction mixture was stirred at 0 °C over a period of 10 mins and then at 25 °C for 20 min. The reaction mixture was concentrated by purging with nitrogen to remove the organic solvent and then it was diluted with 5 mL of DCM and neutralized with sat. solution of sodium bicarbonate solution. The DCM layer was separated. The aqueous layer was re-extracted with 10% MeOH / DCM (5 x 2 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under vacuum at 30 °C. The crude product was purified by SCP [Column: XBridge C18, 19 mm x 150 mm, 5 pm particles; Flow Rate: 20.00 mL / min; Column Temperature: 23 °C. Fraction collection was triggered by MS (MM + / -). Mobile Phase A (ACN / H2O (5:95) with 10 mM AA). Mobile Phase B (ACN / H2O (95:5) with 10 mM AA) Time / Grad (%A): 0 / 95, 10 / 70, 15 / 70, 15.1 / 0, 18 / 0, 18.1 / 95, 21 / 95] to afford N-(5-(azetidin-3-yl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (4.69 mg, 20.21 % yield). Analytical Method C: RT=0.97 min, m / z: 472.9 [M+H]+, LCMS purity = 98.1 %; Analytical Method D: RT=1.04 min, m / z: 473 [M+H]+, LCMS purity = 98.8 %. ‘HNMR (400 MHz, DMSO-de) 8 = 9.00 (s, 1H), 8.13 (s, 1H), 7.37 (s, 1H), 7.20 (s, 1H), 4.42 - 4.32 (m, 1H), 4.20 - 4.15 (m, 2H), 4.13 - 4.08 (m, 2H), 3.61 (s, 3H), 2.54 (s, 3H) (NH protons were not visible).Example Q-49. Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(5-(propan-2-ylsulfonimidoyl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamideDocket No.: 14928-WO-PCT[bis(acetoxy) iodojbenzene TFA Ammonium Trifilic acid carbamate 0°C - RT, 1 h CH3OH Step 4 25 °CStep 3 Step 1. Synthesis of 2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-N-(5-(propan-2-ylsulfonimidoyl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide: To a stirred solution of 2'-chloro-N-(5-(isopropylthio)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (20 mg, 0.033 mmol) in MeOH (ImL) were added (di acetoxy iodo)benzene (42.1 mg, 0.131 mmol) and ammonium carbamate (10.20 mg, 0.131 mmol). The resulting reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to afford 30 mg of crude, which was taken as it is for next step. LCMS: ESI m / z 643 [M+H]+, RT=1.43 min (Method C).Step 2. Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(5-(propan-2-ylsulfonimidoyl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide: To a stirred solution of 2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-N-(5-(propan-2-ylsulfonimidoyl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (30 mg, 0.047 mmol) in Dichloromethane (1 mL) were added TFA (0.02 mL) and trifilic acid (0.001 mL) at 0 °C. The resulting reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated by purging with nitrogen to afford the crude product, which was then purified by SCP [Column: XBridge C18, 19 mm x 150 mm, 5 μm particles; Flow Rate: 20.00 mL / min; Column Temperature: 23 °C. Fraction collection was triggered by MS (MM + / -). Fractions containing the desired product were combined and dried via centrifugal evaporation. Mobile Phase A (ACN / H2O (5:95) with 10 mM AA), Mobile Phase BDocket No.: 14928-WO-PCT(ACN / H2O (95:5) with 10 mM AA), Time / Grad (%A): 0 / 95, 10 / 65, 15 / 65, 15.1 / 0, 18 / 0, 18.1 / 95, 21 / 95] to afford 2'-chloro-5'-methoxy-6-methyl-N-(5-(propan-2-ylsulfonimidoyl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (1.30 mg, 2.461 pmol, 31.7 % yield). Analytical Method C: RT=1.32 min, m / z: 523 [M+H]+, LCMS purity = 99%. Analytical Method D: RT=1.28 min, m / z: 523 [M+H]+, LCMS purity = 100 %. 'H NMR(400 MHz, DMSO-de) 6 = 13.37 (s, 1H), 8.86 (s, 1H), 8.18 (s, 1H), 7.59 (s, 1H), 7.48 (s, 1H), 5.16 (s, 1H), 3.61 (s, 3H), 3.58 - 3.51 (m, 1H), 2.61 (s, 3H), 1.29 (dd, J = 1.4, 6.8 Hz, 6H).Example Q-50. Synthesis of 2'-chloro-5’-methoxy-6-methyl-N-(5-(S-methylsulfonimidoyl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamidemethyl carbamimidoth ioate sulfate TCFH, NMI CS2CO3 DMF, 25 °C, 16 h DMSO80°C, 6 h Step 2 Step 1N Cl YNM-Z T [bis(acetoxy) l 9 iodo]benzene: - ► Il T 7 Ammonium PMB carbamate CH3OH 25 °C Step 4Step 3Docket No.: 14928-WO-PCTStep 1. Synthesis of N-(4-methoxybenzyl)-5-(methylthio)thiazolo[5,4-d]thiazol-2-amine:To a stirred solution of 5-bromo-N-(4-methoxybenzyl)thiazolo[5,4-d]thiazol-2-amine (150 mg, 0.421 mmol) in DMSO (3 mL) was added methyl carbamimidothioate sulfate (158 mg, 0.842 mmol) and cesium carbonate (549 mg, 1.684 mmol). The resulting reaction mixture was stirred at 80 °C for 6 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic fraction was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude. The crude obtained purified by silica gel flash column chromatography eluting with 10 - 15 % ethyl acetate in pet ether to afford N-(4-methoxybenzyl)-5-(methylthio)thiazolo[5,4-d]thiazol-2-amine (60 mg, 0.173 mmol, 41.0 % yield) as a yellow solid. LCMS: ESI m / z 324 [M+H]+, RT=3.05 min (Method E).Step 2. Synthesis of 2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-N-(5-(methylthio)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide: To a stirred solution of 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (50 mg, 0.179 mmol) in DMF (3 mL) were added N-(4-methoxybenzyl)-5-(methylthio)thiazolo[5,4-d]thiazol-2-amine (58.0 mg, 0.179 mmol) DIPEA (0.063 mL, 0.359 mmol) 1-methylimidazole (0.036 mL, 0.449 mmol) and chloro-N, N, N', N' -tetramethylformamidinium hexafluorophosphate (151 mg, 0.538 mmol)The resulting reaction mixture was stirred at 25 °C for 16 h. It was diluted with water (5 mL). The solid obtained was filtered through buchner funnel, washed with water (2 mL) and dried under vacuum to afford 2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-N-(5-(methylthio)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3 -carboxamide (80 mg, 0.126 mmol, 70.2 % yield) as an off-white solid. LCMS: ESI m / z 584 [M+H]+, RT=3.52 min, (Method E).Step 3. Synthesis of 2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-N-(5-(S-methylsulfonimidoyl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide: To a stirred solution of 2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-N-(5-(methylthio)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (60 mg, 0.103 mmol) in MeOH (2 mL) were added (diacetoxyiodo)benzene (132 mg, 0.411 mmol) and ammonium carbamate (32.1 mg, 0.411 mmol) The resulting reaction mixture was stirred at 25 °C for 2 h. the reaction mixture was concentrated to afford the crude product 2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-N-(5-(S-methylsulfonimidoyl)thiazolo[5,4-Docket No.: 14928-WO-PCTd]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (60 mg, 0.035 mmol, 34.2 % yield). The crude was taken as it is for next step. LCMS: ESI m / z 615 [M+H]+, RT=1.30 min (Method C).Step 4. Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(5-(S-methylsulfonimidoyl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide: To a stirred solution of 2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-N-(5-(S-methylsulfonimidoyl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (60 mg, 0.098 mmol) in dichloromethane (2 mL) were added TFA (0.1 mL) and trifilic acid (0.05 mL) at 0 °C. The resulting reaction mixture was stirred at 25 °C for Ih. The reaction mixture was concentrated under reduced pressure to afford the crude product. The crude compound was purified by SCP [Column: XBridge C18, 19 mm x 150 mm, 5 pm particles; Flow Rate: 20.00 mL / min; Column Temperature: 23 °C. Fraction collection was triggered by MS (MM + / -). Fractions containing the desired product were combined and dried via centrifugal evaporation. Mobile Phase A (ACN / H2O (5:95) with 10 mM AA) Mobile Phase B (ACN / H2O (95:5) with 10 mM AA) Time / Grad (%A): 0 / 95, 10 / 68, 15 / 68, 15.1 / 0, 18 / 0, 18.1 / 95, 21 / 95] to afford 2'-chloro-5'-methoxy-6-methyl-N-(5-(S-methylsulfonimidoyl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (16.1 mg, 0.032 mmol, 32.7 % yield). LCMS: ESI m / z 495 [M+H]+, RT=1.11 min (Method D).Analytical HPLC Method C: RT=1.11 min, HPLC purity = 98.8 %. 'H NMR (400 MHz, DMSO-de) 6 = 13.36 (br s, IH), 8.86 (s, IH), 8.17 (s, IH), 7.59 (s, IH), 7.48 (s, IH), 5.19 (br s, IH), 3.60 (s, 3H), 3.31 (s, 3H), 2.61 (s, 3H).Example Q-51. Synthesis of 2'-chloro-N-(5-((cyclopropyl(methyl)(oxo)-16-sulfaneylidene)amino)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide:Docket No.: 14928-WO-PCTHsxBrN S Pd2(dba)3, XantphosI^MB Cs2CO3, DMF, 80 °C, 4h Step 1Step 1. Synthesis of 2'-chloro-N-(5-((cyclopropyl(methyl)(oxo)-16-sulfaneylidene)amino)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide: To a stirred solution ofN-(5-bromothiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (50 mg, 0.081 mmol) in DMF (2 mL) was added cyclopropyl(imino)(methyl)-16-sulfanone (19.32 mg, 0.162 mmol). To it then CS2CO3 (79 mg, 0.243 mmol), xantphos (14.07 mg, 0.024 mmol) and tris(dibenzylideneacetone)dipalladium(0) (14.84 mg, 0.016 mmol) were added. The resulting reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude was purified by RP column purification [Column Type: ISCO Gold; Diluent: THF / water / ACN Detection: UV Detection Quality: 254 nm; Mobile Phase A: Water; Mobile Phase B:Acetonitrile; Compound Elution: 55%ACN / 5 mM ammonium in water; Flow Rate: 60 mL / min] to afford 2'-chloro-N-(5-((cyclopropyl(methyl)(oxo)-16-sulfaneylidene)amino)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-methoxybenzyl)-6-Docket No.: 14928-WO-PCTmethyl-[4,4'-bipyridine]-3-carboxamide (26 mg, 0.028 mmol, 34.8 % yield). LCMS: ESI m / z 655 [M+H]+, RT=1.41 min (Method C).Step 2. Synthesis of 2'-chloro-N-(5-((cyclopropyl(methyl)(oxo)-16-sulfaneylidene)amino)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide: To a stirred solution of 2'-chloro-N-(5-((cyclopropyl(methyl)(oxo)-16-sulfaneylidene)amino)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (20 mg, 0.031 mmol) in TFA (1.0 ml) was added trifluoromethanesulfonic acid (5.50 mg, 0.037 mmol) at 0 °C. The resulting reaction mixture was stirred at 0 °C for 10 min and 25 °C for 50 min. The reaction mixture was concentrated by purging with nitrogen to remove the organic solvent and crude product was obtained. The crude was purified by SCP [Column: XBridge C18, 19 mm x 150 mm, 5 μm particles; Flow Rate: 20.00 mL / min; Column Temperature: 23 °C. Fraction collection was triggered by MS (MM + / -). Fractions containing the desired product were combined and dried via centrifugal evaporation. Mobile Phase A (ACN / H2O (5:95) with 10 mM AA) Mobile Phase B (ACN / H2O (95:5) with 10 mM AA) Time / Grad (%A): 0 / 95, 10 / 60, 15 / 60, 15.1 / 0, 18 / 0, 18.1 / 95, 21 / 95] to afford 2'-chloro-N-(5-((cyclopropyl(methyl)(oxo)-16-sulfaneylidene)amino)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (10.59 mg, 0.020 mmol, 64.1 % yield) Analytical Method D: RT=1.42 min, m / z: 534.9 [M+H]+, LCMS purity = 98.9 %. Analytical Method C: RT=1.26 min, m / z: 534.9 [M+H]+, LCMS purity = 99 %. ¹H NMR (400 MHz, DMSO-d6) 8 = 12.81 (s, 1H), 8.80 (s, 1H), 8.17 (s, 1H), 7.55 (s, 1H), 7.44 (s, 1H), 3.61 (s, 3H), 3.53 (s, 3H), 3.15 - 3.03 (m, 1H), 2.60 (s, 3H), 1.37 - 1.08 (m, 4H).Synthesis of 2'-chloro-5'-methoxy-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridine]-4-carboxylic acidDocket No.: 14928-WO-PCTStep 3Step 1. Synthesis of methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate (2, A4EF5-050): To a stirred solution of methyl 5-bromo-2-hydroxyisonicotinate (2.0 g, 8.62 mmol) in MeCN (10 mL) was added cesium carbonate (3.37 g, 10.34 mmol). Then to the reaction mixture methyl iodide (0.593 mL, 9.48 mmol) was added. The resulting reaction mixture was stirred at 25 °C over a period of 4 h. It was filtered through buchner funnel and the filtrate obtained was concentrated under vacuum to afford the crude methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate (2.1 g, 7.97 mmol, 93 % yield). LCMS: ESI m / z 246 [M+H]+, RT=0.78 min (Method C). 'H NMR (400MHz, DMSO-de) 68.21 (s, 1H), 6.72 (s, 1H), 3.85 (s, 3H), 3.44 (s, 3H).Step 2. Synthesis of methyl 2'-chloro-5'-methoxy-l-methyl-6-oxo-l,6-dihydro-[3,4'-bipyridine]-4-carboxylate: To a stirred solution of methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate (1.5 g, 6.10 mmol) in dioxane (10.0 mL) and H2O (2.0 mL) were added (2-chloro-5-methoxypyridin-4-yl)boronic acid (1.257 g, 6.71 mmol) and cesium carbonate (2.383 g, 7.32 mmol). Then the reaction mixture [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.895 g, 1.219 mmol) was added. The resulting reaction mixture was stirred at 90 °C for 4 h. The reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (2 x 20 mL). The combined ethylDocket No.: 14928-WO-PCTacetate layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude. The crude was purified by silica gel flash column chromatography eluting with 0 - 80% ethyl acetate / petroleum ether to afford methyl 2'-chloro-5'-methoxy-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridine]-4-carboxylate (860 mg, 2.507 mmol, 41.1 % yield). LCMS: ESI m / z 309 [M+H]+, RT=0.90 min (Method C).1H NMR (400 MHz, DMSO-d6) 88.12 (s, 1H), 8.00 (s, 1H), 7.47 (s, 1H), 6.72 (s, 1H), 3.76 (s, 3H), 3.68 (s, 3H), 3.49 (m, 3H).Step 3. Synthesis of 2'-chloro-5'-methoxy-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridine]-4-carboxylic acid: To a solution of methyl 2'-chloro-5'-methoxy-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridine]-4-carboxylate (600 mg, 1.944 mmol) in H2O (1.0 mL) and THF (2.5 mL) was added Lithium hydroxide monohydrate (163 mg, 3.89 mmol). The resulting reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove the volatiles. Then to the reaction mixture 2 mL of water was added and acidified with 1.5 N HC1. Solid obtained was filtered through buchner funnel, washed with water (2 mL) and dried under vacuum to afford 2'-chloro-5'-methoxy-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridine]-4-carboxylic acid (550 mg, 1.753 mmol, 90 % yield). LCMS: ESI m / z 295 [M+H]+, RT=0.42 min (Method C). 'H NMR (400MHz, DMSO-de) 6 13.31 (br s, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.43 (s, 1H), 6.70 (s, 1H), 3.77 (s, 3H), 3.48 (s, 3H).Example Q-52. Synthesis of 2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-6-(hydroxymethyl)-5'-methoxy-[4,4'-bipyridine]-3-carboxamideSNHDocket No.: 14928-WO-PCTStep 1Step 2Step 1. Synthesis of 2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-6-(hydroxymethyl)-5'-methoxy-N-(4-methoxybenzyl)-[4,4'-bipyridine]-3-carboxamide: To a stirred solution of 2'-chloro-6-(hydroxymethyl)-5'-methoxy-[4,4'-bipyridine]-3-carboxylic acid (70 mg, 0.238 mmol) and 5-cyclopropyl-N-(4-methoxybenzyl)thiazolo[5,4-d]thiazol-2-amine (35 mg, 0.110 mmol) in DMF (2 mL) were added DIPEA (0.124 mL, 0.713 mmol), 1-methyl-1H-imidazole (59.2 mg, 0.713 mmol) and N, N, N', N'-tetramethylchloroformamidinium hexafluorophosphate (333 mg, 1.188 mmol). The resulting reaction mixture was stirred at 25 °C for 6 h. The reaction mixture was diluted with 15 mL of ethyl acetate and ice water (20 mL). The ethyl acetate layer was separated, washed with brine (10 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get 2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-6-(hydroxymethyl)-5'-methoxy-N-(4-methoxybenzyl)-[4,4'-bipyridine]-3-carboxamide (80 mg, 0.048 mmol, 20.41 % yield). The crude was taken as it is for next step. LCMS: ESI m / z 594 [M+H]+, RT=1.71 min (Method C).Step 2. Synthesis of 2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-6-(hydroxymethyl)-5'-methoxy-[4,4'-bipyridine]-3-carboxamide: To a stirred solution of 2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-6-(hydroxymethyl)-5'-methoxy-N-(4-methoxybenzyl)-[4,4'-bipyridine]-3-carboxamide (79 mg, 0.133 mmol) in TFA (0.5 mL) wasDocket No.: 14928-WO-PCTadded Trifluoromethanesulfonic acid (39.9 mg, 0.266 mmol) at 0 °C. The resulting reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated by purging with nitrogen to afford the crude. The crude was purified by PREP-HPLC Purification [Diluent: THF: ACN:water (50:30:20) Column: X-Bridge C8 (250x19) mm 5.0 p, Temperature:Ambient Mobile phase A: 5mM ammonium formate in water (pH 3.3), Mobile phase B: ACN, Flow: 15 mL / min, Time / Grad: 0 / 20,12 / 60, 15 / 60] to afford 2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-6-(hydroxymethyl)-5'-methoxy-[4,4'-bipyridine]-3-carboxamide (6 mg, 0.012 mmol, 9.17 % yield)) as an off-white solid. LCMS: ESI m / z 474 [M+H]+, RT=2.00 min (Method E). Analytical Method B: RT=4.07 min, HPLC purity = 96.3 %. ‘H-NMR (400 MHz, DMSO-de): 6 13.02 (s, 1H), 8.88 (s, 1H), 8.19 (s, 1H), 7.54 (s, 2H), 5.61 (t, J = 6.00 Hz, 1H), 4.69 (d, J= 6.00 Hz, 2H), 3.62 (s, 3H), 2.48-2.45 (m, 1H), 1.20-1.15 (m, 2H), 1.08-1.04 (m, 2H).The following Examples were prepared in a methodology analogous to the previous examples using suitable reagents, precursors and starting materials.Example Structure and name Analytical# LCMSESI-MS(+)m / z / RT(min) / Purity / (Method)Q-53 556.81H NMR (400[M+H]+ / MHz, DMSO-de) 6 2.39 min = 13.11 (s, 1H), (Method D) 8.84 (s, 1H), 8.17 / 99.45% / (s, 1H), 7.57 (s, 4.71 min 1H), 7.46 (s, 1H), (Analytical 6.65 (s, 1H), 4.15 - HPLC 4.05 (m, 2H), 3.64 Method A). (s, 3H), 3.62 - 3.58(m, 5H), 2.75 - methyl 4-(5-(2'-chloro-5'-methoxy-6- 2.65 (m, 2H), 2.6 methyl-[4,4'-bipyridine]-3- carboxamido)thiazolo[5,4-d]thiazol-2-yl)- (s, 3H) 3,6-dihydropyridine- 1 (2H)-carboxylateDocket No.: 14928-WO-PCTExample Structure and name Analytical ‘HNMR# LCMSESI-MS(+)m / z / RT(min) / Purity / (Method)Q-54 HO 516.81H NMR (400[M+H]+ / MHz, DMSO-de) 6 1.92 min = 13.3 (s, 1H), 8.85 N ci 7 (Method D) (s, 1H), 8.17 (s, / 99.09% / 1H), 7.59 (s, 1H), X J / X5.86 min 7.48 (s, 1H), 5.82 l l 2 JL T (Analytical (br, 1H), 4.87 - HPLC 4.83 (m, 1H), 4.6 - J! J HMethod A). 4.5 (m, 1H), 4.35 - 4.31 (m, 2H), 3.87 -3.83 (m, 1H), 2'-chloro-N-(5-(3-hydroxyazetidine-l- carbonyl)thiazolo[5,4-d]thiazol-2-yl)-5'- 3.61 (s, 3H), 2.61 methoxy-6-methyl-[4,4'-bipyridine]-3- (s, 3H) carboxamideQ-55 CN 497.81H NMR (400N Cl pX [M+H]+ / 1.7 MHz, DMSO-d6) 8 J Y S N-Jmin (Method = 13.2 (s, 1H), 8.84 C) / 98.7% / (s, lH), 8.16 (s, T l 2 iTP1.65 min 1H), 7.56 (s, 1H), JI 1 H (Analytical 7.45 (s, 1H), 3.9 (s, / ^l\T HPLC 1H), 3.6 (s, 3H), 2.6Method C). (s, 3H)2'-chloro-N-(5-(3-cyanoazetidin-l- yl)thiazolo[5,4-d]thiazol-2-yl)-5'- methoxy-6-methyl-[4,4'-bipyridine]-3- carb oxami deQ-56 553.81H NMR (400N Cl 0 [M+H]+ / MHz, DMSO-de) 62.26 min = 13.34 (s, 1H), oY o (Method D) 8.86 (s, 1H), 8.181AZNY \ / 98.84% / (s, 1H), 7.59 (s, ( IH7.82 min 1H), 7.48 (s, 1H),(Analytical 4.26 - 4.12 (m, 4H), HPLC 3.61 (s, 3H), 2.61 diethyl (5-(2'-chloro-5'-methoxy-6- Method B). (s, 3H), 1.29 (t, J = methyl-[4,4'-bipyridine]-3- 8 Hz, 6H)Docket No.: 14928-WO-PCTExample Structure and name Analytical ‘HNMR# LCMSESI-MS(+)m / z / RT(min) / Purity / (Method) carboxamido)thiazolo[5,4-d]thiazol-2- yl)phosphonateQ-57 o 543 [M+H]+1H NMR (400 / 2.36 min MHz, DMSO-de) 6 N Cl fi j |jf j s_z (Method E) / = 13.18 (s, 1H),98.61% / 8.85 (s, 1H), 8.17 ° JL JL JlV 6.86 min (s, 1H), 7.58 (s, 1 JH(Analytical 1H), 7.47 (s, 1H),HPLC 6.68 (br d, J = 7.1 Method A). Hz, 1H), 4.55 (br d, methyl 3-(5-(2'-chloro-5'-methoxy-6- J= 5.1 Hz, 2H), methyl-[4,4'-bipyridine]-3- 4.35 (br s, 2H), 3.67 carboxamido)thiazolo[5,4-d]thiazol-2-yl)- (d, J = 2.4 Hz, 3H), 2,5-dihydro-lH-pyrrole-l-carboxylate 3.61 (s, 3H), 2.61(s, 3H)Q-58 0 557 [M+H]+1H NMR (400 / "-rAoN Cl n J 1 / 3.04 min MHz, DMSO-de) 6 / JS7 (Method E) / = 13.18 (s, 1H), ° 1 k 97.42% / 8.85 (s, 1H), 8.176.08 min (s, 1H), 7.57 (s, I JH(Analytical 1H), 7.46 (s, 1H), HPLC 6.67 (br d, J= 8.3 ethyl 3-(5-(2'-chloro-5'-methoxy-6- Method A). Hz, 1H), 4.55 (br d, methyl-[4,4'-bipyridine]-3- J = 12.0 Hz, 2H), carboxamido)thiazolo[5,4-d]thiazol-2-yl)- 4.33 (br s, 2H), 4.10 2,5-dihydro-lH-pyrrole-l-carboxylate (q, J = 7.1 Hz, 2H),3.61 (s, 3H), 2.62 (s, 3H), 1.3 - 1.18 (m, 3H)Docket No.: 14928-WO-PCTExample Structure and name Analytical ‘HNMR# LCMSESI-MS(+)m / z / RT(min) / Purity / (Method)Q-59 o 488 [M+H]+1H NMR (400N Cl t J 1 / 2.09 min MHz, DMSO-de) 6 if JS7 (Method E) / = 13.05 (br s, 1H),99.87% / 8.84 (s, 1H), 8.16 2 JLV5.12 min (s, 1H), 7.56 (s, 1 JH(Analytical 1H), 7.45 (s, 1H), HPLC 3.95 - 3.93 (m, methyl 3-(5-(2'-chloro-5'-methoxy-6- Method A). 1H), 3.80 (t, J = 9.2 methyl-[4,4'-bipyridine]-3- Hz, 1H), 3.60 (d, J carboxamido)thiazolo[5,4-d]thiazol-2- = 3.6 Hz, 7H), 3.53 yl)pyrrolidine- 1 -carboxylate - 3.4 (m, 2H), 2.6 (s, 3H), 2.4 - 2.35 (m, 1H), 2.24 - 2.1 (m, 1H)Q-60 N ci U 444 [M+H]+1H NMR (400XJ 0 N y-\ -r / 1.63 min MHz, DMSO-d6) 8 ft(Method C) / = 13.14 (s, 1H), I A JI A A A A / c / 98.9% / 1.53 8.84 (s, 1H), 8.18 II J Hmin (s, 1H), 7.57 (s, (Analytical 1H), 7.46 (s, 1H), 2'-chloro-5'-methoxy-6-methyl-N-(5- HPLC 7.01 (dd, J= 10.9, vinylthiazolo[5,4-d]thiazol-2-yl)-[4,4'- Method C). 17.4 Hz, 1H), 6.12 bipyridine]-3-carboxamide (d, J = 17.4 Hz,1H), 5.64 (d, J = 11.1 Hz, 1H), 3.61 (s, 3H), 2.61 (s, 3H) Q-61 N ci n 526 [M+H]+1H NMR (400 / 2.08 min MHz, DM SO-6 / r,) O X-^jJX o N / NA V^CN(Method E) / 3.61 (s, 3 H) 3.82 - 99.46% / 4.06 (m, 1 H) 4.2 - II J Hx^-N-^ 3.85 min 4.3 (m, 1 H) 4.3 - (Analytical 4.4 (m, 1 H) 4.7 - 2'-chloro-N-(5-(3-cyanoazetidine-l- HPLC 4.74 (s, 1 H) 4.81 - carbonyl)thiazolo[5,4-d]thiazol-2-yl)-5'- Method B). 4.95 (m, 1 H) 7.13 methoxy-6-methyl-[4,4'-bipyridine]-3- (s, 1 H) 7.31 (s, 1 carb oxami de H) 8.11 (s, 1 H),9.08 (s, 1 H). NH proton not visible.Three methylDocket No.: 14928-WO-PCTExample Structure and name Analytical ‘HNMR# LCMSESI-MS(+)m / z / RT(min) / Purity / (Method)proton merged with solvent peakQ-62 0 529 [M+H]+1H NMR (400 N Cl | J / 1.23 min MHz, DMSO-d6) 8(Method C) / = 13.06 (d, J = 2.5 XX o J3- / KiI 99.1% / 1.34 Hz, 1H), 8.83 (s, 1 JI JLymin lH), 8.16 (s, 1H), / 1'■fK JH(Analytical 7.58 (s, 1H), 7.47 HPLC (s, 1H), 4.05 - 3.79 N-(5-(l-acetylpyrrolidin-3- Method C). (m, 2H), 3.76 - 3.50 yl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro- (m, 6H), 2.61 (s, 5'-methoxy-6-methyl-[4,4'-bipyridine]-3- 3H), 2.48 - 2.35 (m, carb oxami de1H), 2.31 - 2.08 (m, 1H), 1.97 (d, J = 4.3 Hz, 3H)Q-63 N Cl O | 503.91H NMR (400 MHz,[M+H]+ / DMSO-d6) 5= 13.39 ° 1 S i / Xj 1.68 min (brs, 1H), 8.86 (s, II J H (Method C) / 1H), 8.18 (s, 1H),100% / 1.7 7.59 (s, 1H), 7.48 (s, min 1H), 5.25 - 5.19 (m, isopropyl 5-(2'-chloro-5'-methoxy-6- (Analytical 1H), 3.61 (s, 3H), methyl-[4,4'-bipyridine]-3- HPLC 2.61 (s, 3H), 1.36 (d, carboxamido)thiazolo[5,4-d]thiazole-2- Method C). J = 6.3 Hz, 6H) carboxylateQ-64 N ci0A 502 [M+H]+’HNMR (400 MHz,XX zSyX)X^ / 1.62 min DMSO-d6) 5 = 13.41(Method C) / (br s, 1H), 8.87 (s, I I 2 FMAAYs799.2% / 1.58 lH), 8.17(s, 1H), 7.58 min (s, 1H), 7.46 (s, 1H), (Analytical 4.46 - 4.34 (m, 1H), HPLC 3.61 (s, 3H), 2.61 (s, cyclopropyl 5-(2'-chloro-5'-methoxy-6- 3H), 0.93 - 0.77 (m, methyl-[4,4'-bipyridine]-3- Method C).4H). carboxamido)thiazolo[5,4-d]thiazole-2- carboxylateDocket No.: 14928-WO-PCTExample Structure and name Analytical ‘HNMR# LCMSESI-MS(+)m / z / RT(min) / Purity / (Method)Q-65 o 533.9 ’H NMR (400 MHz,[M+H]+ / DMSO-d6) 5 = 13.41 N Cl 91.01 min (br s, 1H), 12.48 (br (Method C) / s, 1H), 8.88 (s, 1H), i rv 96.4% / 8.17 (s, 1H), 7.57 (s, JI J H 1.23min 1H), 7.45 (s, 1H), (Analytical 4.54 (t, J = 6.1 Hz, HPLC 2H), 3.61 (s, 3H), 3-((5-(2'-chloro-5'-methoxy-6-methyl- Method C). 2.76 (t, J = 6.1 Hz, [4,4'-bipyridine]-3- 2H), 2.61 (s, 3H) carboxamido)thiazolo[5,4-d]thiazole-2- carbonyl)oxy)propanoic acidQ-66 N Cl O 536.9 ’H NMR (400 MHz,[M+H]+ / DMSO-d6) 5 = 13.37 A / ^N-^S71.66 min (br s, 1H), 8.87 (s, JI J H (Method C) / 1H), 8.17 (s, 1H),98.7% / 1.64 7.57 (s, 1H), 7.46 (s, min 1H), 5.07 (brt, J = 2'-chloro-N-(5-(3,3-difluoroazetidine-l- (Analytical 11.8 Hz, 2H), 4.58 carbonyl)thiazolo[5,4-d]thiazol-2-yl)-5'- HPLC (brt, J = 11.9 methoxy-6-methyl-[4,4'-bipyridine]-3- Method C). Hz,2H), 3.61 (s, 3H), carboxamide 2.61 (s, 3H)Q-67 N Cl f j 501 [M+H]+’H NMR (400 MHz, / 1.63 min METHANOL-d4) 5 = (Method C) / 8.82 (s, 1H), 8.08 (s, 87% / 1.71 1H), 7.52 (s, 1H), min 7.45 (s, 1H), 4.36 - (Analytical 4.19 (m, 1H), 3.70 (s, 2'-chloro-5'-methoxy-6-methyl-N-(5-(l- HPLC 3H), 3.63 (dd, J= methylpyrrolidin-3-yl)thiazolo[5,4- Method C). 8.4, 10.9 Hz, 1H), d]thiazol-2-yl)-[4,4'-bipyridine]-3- 3.39 - 3.34 (m, 1H), carboxamide 3.25 (dd, J= 9.1, 10.6Hz, 1H), 3.16 - 3.08 (m, 1H), 2.81 (s, 3H), 2.78 - 2.71 (m, 1H), 2.69 (s, 3H), 2.43 - 2.32 (m, 1H)Docket No.: 14928-WO-PCTExample Structure and name Analytical ‘HNMR# LCMSESI-MS(+)m / z / RT(min) / Purity / (Method)Q-68 N Cl 1 \|-SO2Me 564.9 ’H NMR (400 MHz,[M+H]+ / METHANOL-d4) 5 = J J S'- / "-71.47 min 8.82 (s, 1H), 8.08 (s,? jT 2 I T (Method C) / 1H), 7.52 (s, 1H),99.6% / 1.37 7.45 (s, 1H), 4.36 - 1 JHmin 4.19 (m, 1H), 3.70 (s, (Analytical 3H), 3.63 (dd, J = 8.4, 2'-chloro-5'-methoxy-6-methyl-N-(5-(l- HPLC 10.9 Hz, 1H), 3.39 - (methylsulfonyl)pyrrolidin-3- Method C). 3.34 (m, 1H), 3.25 yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'- (dd, J = 9.1, 10.6 Hz, bipyridine]-3-carboxamide 1H), 3.16 - 3.08 (m,1H), 2.81 (s, 3H), 2.78 -2.71 (m, 1H), 2.69 (s, 3H), 2.43 - 2.32 (m, 1H).Q-6900k- 563 [M+H]+1H NMR (400 MHz, Z^N' 'MeN Cl || J / 1.43 min DMSO-d6) 5= 13.19 IJ (Method C) / (brs, 1H), 8.84 (s, O Hl1H), 8.199.8% / 1.48 17 (s, 1H),Hmin 7.58 (s, 1H), 7.47 (s, X J(Analytical 1H), 6.70 - 6.64 (m, H 1H), 4.60 -4.55 (m, 2'-chloro-5'-methoxy-6-methyl-N-(5-(l- PLC2H), 4.39 - 4.32 (m, (methylsulfonyl)-2,5-dihydro-lH-pyrrol- Method C).2H), 3.61 (s, 3H), 3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'- 3.02 (s, 3H), 2.61 (s, bipyridine]-3-carboxamide3H)Q-70 ° o!£> 577 [M+H]+1H NMR (400 MHz, Z^N"N Cl (| j / 1.58 min DMSO-d6) 5= 13.19 if J (Method C) / (brs, 1H), 8.84 (s, ° JL 2 XV 100% / 1.53 1H), 8.17 (s, 1H), min 7.58 (s, 1H), 7.47 (s, XXH(Analytical 1H), 6.68 (t,.1= 2.0HPLC Hz, 1H), 4.60 (brt, J 2'-chloro-N-(5-(l-(ethylsulfonyl)-2,5- Method C). = 3.6 Hz, 2H), 4.45 - dihydro-lH-pyrrol-3-yl)thiazolo[5,4- 4.32 (m, 2H), 3.61 (s, d]thiazol-2-yl)-5'-methoxy-6-methyl- 3H), 3.23 (q, J = 7.3 [4,4'-bipyridine]-3-carboxamide Hz, 2H), 2.61 (s, 3H),Docket No.: 14928-WO-PCTExample Structure and name Analytical ‘HNMR# LCMSESI-MS(+)m / z / RT(min) / Purity / (Method)1.25 (t, J= 7.3 Hz, 3H)Q-71 522 [M+H]+XH NMR (400 N Cl / 1.43 min MHz, DMS0-d6) 8 oVo;<r (Method C) / = 13.47 (br s, 1H), AAA 99.5% / 1.52 8.87 (s, 1H), 8.17 JI J H min (s, 1H), 7.60 (s, (Analytical 1H), 7.48 (s, 1H), 2'-chloro-N-(5- HPLC 3.61 (s, 3H), 3.19 - (cyclopropylsulfonyl)thiazolo[5,4- Method C). 3.08 (m, 1H), 2.62 d]thiazol-2-yl)-5'-methoxy-6-methyl- (s, 3H), 1.39 - 1.14 [4,4'-bipyridine]-3-carboxamide (m, 4H)Q-72 N^.01[ N- SO2Et 579 [M+H]+1H NMR (400 / 1.56 min MHz, DMSO-d6) 6 I 1 JL JI A (Method C) / = 13.07 (s, 1H), I JH99.7% / 1.46 8.83 (s, 1H), 8.17 min (s, 1H), 7.58 (s, 2'-chloro-N-(5-(l- (Analytical 1H), 7.47 (s, 1H), (ethyl sulfonyl)pyrrolidin-3 - HPLC 4.01 (quin, J = 7.3 yl)thiazolo[5,4-d]thiazol-2-yl)-5'- Method C). Hz, 1H), 3.80 (dd, J methoxy-6-methyl-[4,4'-bipyridine]-3- = 7.4, 9.8 Hz,lH), carboxamide 3.6 (s, 3H), 3.57 - 3.41 (m, 3H), 3.16 (q, J = 7.4 Hz, 2H), 2.6 (s, 3H), 2.47 - 2.40 (m, 1H), 2.3 - 2.21 (m, 1H), 1.23 (t, J = 7.4 Hz, 3H).Q-73 0^0 589 [M+H]+’H NMR (400 MHz, N Cl U J V / 1.53 min DMSO-d6) 5= 13.19 IT (Method C) / (s, 1H), 8.84 (s, 1H), 0 ( |Z1 1 11 99.7% / 1.59 8.18 (s, 1H), 7.58 (s,Hmin 1H), 7.47 (s, 1H), -^ 1 IXT J(Analytical 6.70 (t, J = 2.0Hz, HPLC 1H), 4.61 (brd, J= 2'-chloro-N-(5-(l-(cyclopropylsulfonyl)- Method C). 3.0 Hz, 2H),4.45 - 2,5-dihydro-lH-pyrrol-3-yl)thiazolo[5,4-4.38 (m, 2H), 3.61 (s,Docket No.: 14928-WO-PCTExample Structure and name Analytical ‘HNMR# LCMSESI-MS(+)m / z / RT(min) / Purity / (Method)d]thiazol-2-yl)-5'-methoxy-6-methyl- 3H), 2.84 (tt, J= 5.1, [4,4'-bipyridine]-3-carboxamide 7.6 Hz, 1H), 2.61 (s,3H), 1.05 - 0.95 (m, 4H)Q-74 U 591 [M+H]+XH NMR (400 MHz,N Cl U J | / 1.7 min DMSO-de) 6 = 13.19 i x x-r0 0(Method C) / ^4 H (s, 1H), 8.84 (s, 1H),1 / XX® 99.7% / 1.658.17 (s, 1H), 7.58 (s, JHmin1H), 7.47 (s, 1H), (Analytical2'-chloro-N-(5 -( 1 -(isopropyl sulfonyl)-2, 5 - HPLC 6.70 (t, J= 2.1 Hz, dihydro-lH-pyrrol-3-yl)thiazolo[5,4- Method C). 1H), 4.62 (br d, J = d]thiazol-2-yl)-5'-methoxy-6-methyl- 3.4 Hz, 2H), 4.46 - [4,4'-bipyridine]-3-carboxamide 4.38 (m, 2H), 3.61(s, 3H), 3.60 - 3.54 (m, 1H), 2.61 (s, 3H), 1.28 (d, J= 6.9 Hz, 6H)Q-75 / V A OH 502 [M+H]+1H NMR (400ji J / 2.08 min MHz, DMSO-tL) 6 ° 1 JL Xv&(Method D) ppm 1.57 - 1.65 (m, XXH / 99.68% / 2 H) 2.14 - 2.19 (m,5.65 min 1 H), 2.59 (s, 3 H) 2-(5-(2'-chloro-5'-methoxy-6-methyl- (Analytical 2.87 - 2.92 (m, 1 H) [4,4'-bipyridine]-3- HPLC 3.60 (s, 3 H) 7.39 carboxamido)thiazolo[5,4-d]thiazol-2- Method B). (s, 1 H) 7.52 (s, 1 yl)cyclopropane- 1 -carboxylic acid H) 8.15 (s, 1 H)8.87 (s, 1 H) 12.65 (br s, 1 H). COOH peak not visible Q-76 N Cl [0593 [M+H]+1H NMR (400XX x ‘T ~ / d,x / 1.56 min MHz, DMSO-d6) 8 1 A 1 1 JL V (Method C) / = 13.07 (s, 1H), j JAN H5100% / 1.66 8.83 (s, 1H), 8.17 min (s, 1H), 7.58 (s, 2'-chloro-N-(5-(l- (Analytical1H), 7.47 (s, 1H),(i sopropyl sulfonyl)pyrrolidin-3 -Docket No.: 14928-WO-PCTExample Structure and name Analytical ‘HNMR# LCMSESI-MS(+)m / z / RT(min) / Purity / (Method)yl)thiazolo[5,4-d]thiazol-2-yl)-5'- HPLC 4.02 (quin, J = 7.1 methoxy-6-methyl-[4,4'-bipyridine]-3- Method C). Hz, 1H), 3.83 (dd, J carboxamide = 7.3, 9.6 Hz, 1H),3.60 (s, 3H), 3.59 - 3.38 (m, 4H), 2.61 (s, 3H), 2.48 - 2.41 (m, 1H), 2.33 - 2.22 (m, 1H), 1.25 (dd, J = 0.9, 6.8 Hz, 6H).0Q-77 591 [M+H]+XH NMR (400 MHz, N Cl r N- s' / 1.51 min DMSO-de) 6 = 13.06 (Method C) / XJ XT (br s, 1H), 8.83 (s, i 98.2% / 1.6A 1 A AN A^S / 1H), 8.17 (s, 1H), JO JHmin7.58 (s, 1H), 7.46 (s, (Analytical1H), 4.02 (quin, J = HPLC2'-chloro-N-(5-(l- 7.3 Hz, 1H), 3.83 Method C).(cyclopropylsulfonyl)pyrrolidin-3- (dd, J= 7.4, 10.0 yl)thiazolo[5,4-d]thiazol-2-yl)-5'- Hz, 1H), 3.62 - 3.42 methoxy-6-methyl-[4,4'-bipyridine]-3- (m, 6H), 2.79 - 2.70 carboxamide(m, 1H), 2.61 (s, 3H), 2.48 - 2.42 (m, 1H), 2.35 - 2.2 (m, 1H), 1.01 - 0.92 (m, 4H).A OH Q-78 488 [M+H]+1HNMR (4OO XX yy " / 1.23 min MHz, DMSO-d6) 8 □A 0 A NI 1 JI JA (Method C) / = 12.98 (br s, 1H), AA-N s H 1 H97.8% / 1.35 8.82 (s, 1H), 8.16 min (s, 1H), 7.56 (s, 2'-chloro-N-(5-(2- (Analytical 1H), 7.45 (s, 1H), (hydroxymethyl)cyclopropyl)thiazolo[5,4- HPLC4.75 (t, J = 5.7 Hz, d]thiazol-2-yl)-5'-methoxy-6-methyl- Method D).lH), 3.59 (s, 3H), [4,4'-bipyridine]-3-carboxamide3.58 - 3.47 (m, 2H), 2.60 (s, 3H), 2.40 -Docket No.: 14928-WO-PCTExample Structure and name Analytical ‘HNMR# LCMSESI-MS(+)m / z / RT(min) / Purity / (Method)2.31 (m, 1H), 1.73 - 1.62 (m, 1H), 1.24 - 1.19 (m, 1H), 1.66 - 1.13 (m, 1H)Q-79 N Cl 451.9XH NMR (400 MHz,I T [M+H]+ / DMSO-de) 6 = 13.23 O NAsvcl11.69 minA A A / (s, 1H), 8.84 (s, 1H),(Method C) / II J H 8.17 (s, 1H), 7.58 (s,97% / 1.61H), 7.47 (s, 1H), min(Analytical 3.60 (s, 3H), 2.61 2'-chloro-N-(5-chl orothi azol o [ 5, 4- (s, 3H) HPLCd]thiazol-2-yl)-5'-methoxy-6-methyl- Method C).[4,4'-bipyridine]-3-carboxamideQ-80 495.91H NMR (400 N Cl A*jf JSA^° [M+H]+ / MHz, DMSO-d6) 8 oA^ O NA 1.29 min = 13.49 (br s, 1H),1A A A A (Method C) / 8.86 (s, 1H), 8.17 AA^N S100% / 1.34 (s, 1H), 7.58 (s, JI J Hmin 1H), 7.46 (s, 1H), (Analytical 3.6 (s, 3H), 3.51 (s,3H), 2.61 (s, 3H) HPLC 2'-chloro-5'-methoxy-6-methyl-N-(5- Method C). (methylsulfonyl)thiazolo[5,4-d]thiazol-2- yl)-[4,4'-bipyridine]-3-carboxamideQ-81 445.91H NMR (400 N ci n[M+H]+ / MHz, DMSO-d6) 6 jf j sA1.43 min = 13.52 (br s, 1H),9.96 (s, 1H), 8.88 (Method C) / s A AANA 97.7% / 1.33 (s, 1H), 8.17 (s, II J H min 1H), 7.59 (s, 1H),7.48 (s, 1H), 3.62 (Analytical(s, 3H), 2.61 (s, 3H) HPLC 2'-chloro-N-(5-formylthiazolo[5,4- Method D). d]thiazol-2-yl)-5'-methoxy-6-methyl- [4,4'-bipyridine]-3-carboxamideDocket No.: 14928-WO-PCTExample Structure and name Analytical ‘HNMR# LCMSESI-MS(+)m / z / RT(min) / Purity / (Method)Q-82 N Cl ’H NMR (400 MHz,[f J 503 [M+H]+O^A OV"^OH / 1.2 min DMSO-d6) 5 = 12.97(Method C) / (brs, 1H), 8.83 (s, ' XAA^NASJI J H 94.7% / 0.97 1H), 8.16 (s, 1H), min 7.56 (s, 1H), 7.45 (s, (Analytical 1H), 5.41 (d, J = 6.5 2'-chloro-N-(5-((3-hydroxyazetidin-l- HPLC Hz, 1H), 4.31 -4.23 yl)methyl)thiazolo[5,4-d]thiazol-2-yl)-5'- Method C). (m, 1H), 3.98 (s, 2H), methoxy-6-methyl-[4,4'-bipyridine]-3- 3.69 - 3.65 (m, 2H), carboxamide 3.60 (s, 3H), 2.99 - 2.96 (m, 2H), 2.60 (s, 3H).Q-83 N Cl 417.9XH NMR (400 MHz,[M+H]+ / DMSO-de) 6 = 13.091XJ 71 1.24 minA A A / (s, 1H), 9.12 (s, 1H),(Method C) / JI J H 8.84 (s, 1H), 8.17 (s, / "l\r 98.9% / 1.351H), 7.57 (s, 1H), min(Analytical 7.46 (s, 1H), 3.6 (s, 2'-chloro-5'-methoxy-6-methyl-N- HPLC 3H), 2.6 (s, 3H) (thiazolo[5,4-d]thiazol-2-yl)-[4,4'- Method C).bipyridine]-3-carboxamideQ-84 N ClH° 448 [M+H]+1H NMR: (400 / 1.24 min MHz, DMSO-d6) 8 0 X^ '^X 0 JY Hl (Method C) / = 13.02 (s, 1H),1A A AA 99.3% / 1.11 8.83 (s, 1H), 8.17 J J H min (s, 1H), 7.57 (s, (Analytical 1H), 7.46 (s, 1H), HPLC 6.22 (t, J = 5.9 Hz, 2'-chloro-N-(5- Method C). 1H), 4.81 (d, J = 5.9 (hydroxymethyl)thiazolo[5,4-d]thiazol-2- Hz, 2H), 3.61 (s, yl)-5'-methoxy-6-methyl-[4,4'- 3H), 2.61 (s, 3H). bipyridine]-3-carboxamideDocket No.: 14928-WO-PCTExample Structure and name Analytical ‘HNMR# LCMSESI-MS(+)m / z / RT(min) / Purity / (Method)Q-85 524 [M+H]+1HNMR (4OO N Cl - — ( Oif YS--XS< H / 1.48 min MHz, DMSO-d6) 8(Method C) / = 13.48 (s, 1H), ° JL £ rPb100% / 1.58 8.86 (s, 1H), 8.18 JI J H min (s, 1H), 7.60 (s, (Analytical 1H), 7.49 (s, 1H), HPLC 3.81- 3.76 (m, 1H), 2'-chloro-N-(5- Method C). 3.62 (s, 3 H), 2.62 (isopropylsulfonyl)thiazolo[5,4-d]thiazol- (s, 3H), 1.32 (d, J = 2-yl)-5'-methoxy-6-methyl-[4,4'- 6.8 Hz, 6H) bipyridine]-3-carboxamideQ-86 N Cl O 577.11HNMR (400 MHz,[M+H]+ / DMSO-d6) 6 = ° I U li V*H1.55 min 13.01 (s, 1H), 8.83 JUH(Method C) / (s, 1H), 8.17 (s,99.5% / 1.45 1H), 7.57 (s, 1H), ethyl (2-(2-(5-(2'-chloro-5'-methoxy-6- min 7.46 (s, 1H), 7.05 methyl-[4,4'-bipyridine]-3- (Analytical (br t, J = 5.6 Hz, carboxamido)thiazolo[5,4-d]thiazol-2- HPLC 1H), 3.97 (q, J = 7.1 yl)ethoxy)ethyl)carbamate Method C). Hz,2H),3.78 (t, J = 6.1 Hz, 2H), 3.60 (s, 3H), 3.46 (t, J = 5.9 Hz, 2H), 3.32 - 3.28 (m, 2H), 3.15 (q, J = 5.9 Hz, 2H), 2.60 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H).Q-87 o 544.91H NMR (400 N Cl / -NAA [M+H]+ / MHz, DMSO-d6) 6 J Y 1.54 min = 13.07 (s, 1H),? A 1 A n (Method C) / NASZ8.83 (s, 1H), 8.17 J \ H 99.9% / 1.62 (s, 1H), 7.58 (s, -A"hA min1H), 7.46 (s, 1H), (Analytical4.44 - 4.23 (m, 3H), ethyl 3-(5-(2'-chloro-5'-methoxy-6- HPLCmethyl-[4,4'-bipyridine]-3- 4.13 (br s, 2H), 4.04Method C).(q, J = 7.0 Hz, 2H),3.60 (s, 3 H), 2.61Docket No.: 14928-WO-PCTExample Structure and name Analytical ‘HNMR# LCMSESI-MS(+)m / z / RT(min) / Purity / (Method) carboxamido)thiazolo[5,4-d]thiazol-2- (s, 3H), 1.18 (t, J = yl)azetidine-l -carboxylate 7.1 Hz, 3H)Q-88 OHN Cl < 492 [M+H]+1HNMR (400 MHz, if J S^ X^OH / 1.02 min DMSO-d6) 8 = (Method C) / 13.01 (s, 1H), 8.84 99.6% / 1.13II J H (s, 1H), 8.15 (s, min 1H), 7.55 (s, 1H), (Analytical7.42 (s, 1H), 4.91 2'-chloro-N-(5-(l,3-dihydroxypropan-2- HPLC(t, J = 8 Hz, 2H), yl)thiazolo[5,4-d]thiazol-2-yl)-5'- Method C).3.77 (t, J = 4 Hz, methoxy-6-methyl-[4,4'-bipyridine]-3- 4H), 3.60 (s, 3H), carb oxami de3.3 - 3.2 (m, 1H), 2.59 (s, 3H)Q-89 o 551 [M+H]+1H NMR (400N Cl / 1.3 min MHz, DMSO-d6) 6 f J (Method C) / = 13.09 (br s, 1H),? I J 1 / 99.6% / 1.41 8.83 (s, 1H), 8.17 II 1 H min (s, 1H), 7.58 (s, (Analytical1H), 7.47 (s, 1H), HPLC2'-chloro-5'-methoxy-6-methyl-N-(5-(l- 4.40 - 4.25 (m, 3H),Method C).(methylsulfonyl)azetidin-3- 4.19 - 4.12 (m, 2H), yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'- 3.60 (s, 3H), 3.08 bipyridine]-3-carboxamide (s, 3H), 2.61 (s, 3H) Q-90 N ci 605.01H NMR (400[M+H]+ / MHz, DMSO-d6) 6? I s six 1.77 min = 13.01 (br s, 1H), II J H (Method D) 8.82 (s, 1H), 8.16Ntert / 99.5% / (s, 1H), 7.57 (s, butyl (2-(2-(5-(2'-chloro-5'-methoxy-6- 1.67 min 1H), 7.45 (s, 1H), methyl-[4,4'-bipyridine]-3- (Analytical 6.75 (br t, J = 5.3 carboxamido)thiazolo[5,4-d]thiazol-2- HPLC Hz, 1H), 3.77 (t, J = yl)ethoxy)ethyl)carbamate Method C). 6.1 Hz, 2H),3.60 (s,3H), 3.46 - 3.42 (m, 2H), 3.30 (t, J = 6.1Hz, 2H), 3.10 (q, JDocket No.: 14928-WO-PCTExample Structure and name Analytical ‘HNMR# LCMSESI-MS(+)m / z / RT(min) / Purity / (Method)= 6.0 Hz, 2H), 2.60 (s, 3H), 1.37 (s, 9H).Q-91NCl r-N^ 487 [M+H]+1HNMR(4OO Jl J / 1.0 min MHz, DMSO-d6) 8? I H H (Method C) / = 8.85 (s, 1H), 8.16 JI J H 98.7% / 1.15 (s, 1H), 7.55 (s, / 'hr min 1H), 7.43 (s, 1H),(Analytical 4.08 - 3.99 (m, 1H), 2'-chloro-5'-methoxy-6-methyl-N-(5-(l- HPLC 3.74 (t, J = 7.6 Hz, methylazetidin-3-yl)thiazolo[5,4- Method C). 2H), 3.60 (s,3H), d]thiazol-2-yl)-[4,4'-bipyridine]-3- 3.45 - 3.43 (m, 2H), carboxamide 2.60 (s, 3H), 2.36 (s, 3H). -NH proton not visible.Q-92 xN<^clU 519 [M+H]+'HNMRdHNMR jf J OH / 1.24 min (400 MHz, DMSO- J JTV ' (Method C) / d6) 6 ppm 2.61 (s, 3 II J H 99.2% / 1.29 H) 3.09 (s, 2H) min 3.54 - 3.69 (m, 7 H) (Analytical 4.11 - 4.22 (m, 1 H) 5-(2'-chloro-5'-methoxy-6-methyl-[4,4'- HPLC 4.73 - 4.85 (m, 1 H) bipyridine]-3-carboxamido)-N-(2- Method D). 7.47 (s, 1 H) 7.58 hydroxyethyl)-N-methylthiazolo[5,4- (s, 1 H) 8.17 (s, 1 d]thiazole-2-carboxamide H) 8.86 (s, 1 H)13.29 (br s, 1 H).Q-93 N ClrT e sOnEt 525.91H NMR (400[M+H]+ / MHz, DM SO-6 / 6) 6 1.12 min ppm 1.26 (t, J=7.32 (Method C) / JHHz, 3 H) 3.54 (d,97.9% / 1.38 J=2.25 Hz, 6 H) min 3.62 (q, J=7.34 Hz, (Analytical2'-chloro-N-(5- 2 H) 6.84 (s, 1 H)HPLC(ethylsulfonyl)thiazolo[5,4-d]thiazol-2- 7.53 (s, 1 H) 8.05 Method C).yl)-5'-m ethoxy- 1 -methyl-6-oxo- 1,6- (d, J=4.25 Hz, 2 H) dihydro-[3,4'-bipyridine]-4-carboxamide 13.55 (br s, 1 H)Docket No.: 14928-WO-PCTExample Structure and name Analytical ‘HNMR# LCMSESI-MS(+)m / z / RT(min) / Purity / (Method)Q-94 N Cl 541.91H NMR (400f J / SV [M+H]+ / MHz, DMSO-t / 6) 8 u11.24 min ppm 3.54 (d, J=3.38 11H(Method C) / Hz, 6 H) 3.80 (s, 397.2% / 1.07 H) 3.83 (s, 3 H) min 6.82 (s, 1 H) 7.52 (Analyticaldimethyl (5-(2'-chloro-5'-m ethoxy- 1 - (s, 1 H) 8.04 (s, 2 HPLCmethyl-6-oxo-l,6-dihydro-[3,4'- H) 13.44 (br s, 1 H)Method C).bipyridine]-4-carboxamido)thiazolo[5,4- d]thiazol-2-yl)phosphonateQ-95 N Cl< C Br 511.81H NMR (400[M+H]+ / MHz, DMSO-d6) 6 O-V o N< J 1.43 min ppm 3.53 (s, 6 H) Ey-E-E' (Method C) / 6.80 (s, 1 H) 7.51100% / 1.57 (s, 1 H) 8.03 (d, " VHmin J=3.00 Hz, 2 H) (Analytical 13.28 (br s, 1 H) N-(5-bromothiazolo[5,4-d]thiazol-2-yl)- HPLC2'-chloro-5'-m ethoxy- 1 -methyl-6-oxo- 1,6- Method C).dihydro-[3,4'-bipyridine]-4-carboxamideQ-96 N ci A 530.91H NMR (400ff J [M+H]+ / MHz, DMSO-t / 6) 6 ° 1 u EV 1.32 min ppm 1.02 - 1.10 (m,(Method C) / 2H) 1.13 - 1.21 (m, 100% / 1.41 2 H) 2.22 (s, 6 H) 1 imin 2.45 - 2.48 (m, 1 H) (Analytical 2.60 (br t, J=5.69 2'-chloro-N-(5-cyclopropylthiazolo[5,4- HPLC Hz, 2 H) 3.53 (s, 3 d]thiazol-2-yl)- 1 -(2- Method D). H), 4.07 (br t, (dimethylamino)ethyl)-5'-methoxy-6-oxo- J=6.38 Hz, 2 H) l,6-dihydro-[3,4'-bipyridine]-4- 6.75 (s, 1 H) 7.47 carboxamide(s, 1 H) 7.95 (s, 1 H) 8.03 (s, 1 H) 12.96 (s, 1 H)Docket No.: 14928-WO-PCTExample Structure and name Analytical ¹H NMR# LCMSESI-MS(+)m / z / RT(min) / Purity / (Method)Q-97N ClA 503 [M+H]+1H-NMR (400 MHz, DMSO-d6): δ(Method D) 8.02 (s, 1H), 7.83 / 99.71% / (s, 1H), 7.50 (s, N JH5.39 min 1H), 6.81 (s, 1H),(Analytical 4.16 (t, J = 4.00 Hz, HPLC 2H), 3.51 (s, 3H), l-(2-aminoethyl)-2'-chloro-N-(5- Method B). 3.19 (t, J = 5.6 Hz, cyclopropylthiazolo[5,4-d]thiazol-2-yl)- 2H), 2.46 - 2.4 (m, 5'-methoxy-6-oxo-l,6-dihydro-[3,4'- 1H), 1.15 - 1.11 (m, bipyridine]-4-carboxamide 2H), 1.04- 1.01 (m, 2H)Example Q-98. Synthesis of tert-butyl ((2'-chloro-7V-(5-(ethoxycarbonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methyl) succinate (Q-98-I) and (£)-tert-butyl ((2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-5-(ethoxycarbonyl)thiazolo[5,4-J|thiazol-3(2Er)-yl)methyl) succinate (Q-98-II).Docket No.: 14928-WO-PCTtert-butyl (chloromethyl) TFA succinate Trifilic acid K2CO3, KI CH2Cl2DMF RT, 20 min 50 °C.36h Step 1 Step 2Step 1. Ethyl 5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-J|thiazole-2-carboxylate: To a stirred solution of ethyl 5-(2’-chloro-5'-methoxy-A-(4-methoxybenzyl)-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazole-2-carboxylate (300 mg, 0.492 mmol) in TFA (5 mL) were added Trifluoromethanesulfonic acid (36.9 mg, 0.246 mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by trituration with 2% EtOAc in petroleum ether to obtain ethyl 5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-J]thiazole-2-carboxylate (220 mg, 0.422 mmol, 86 % yield) as a pale-yellow solid. LCMS: ESI m / z 490.0 [M+H]+, RT = 1.348 min (Method C).Step 2. Synthesis of tert-butyl ((2'-chloro-7V-(5-(ethoxycarbonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methyl) succinate (Q-98-I) and (£)-tert-butyl ((2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-Docket No.: 14928-WO-PCTcarbonyl)imino)-5-(ethoxycarbonyl)thiazolo[5,4-J|thiazol-3(2 / r)-yl)methyl) succinate (Q-98-II). To a stirred solution of ethyl 5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazole-2-carboxylate (150 mg, 0.306 mmol) in DMF (5 mL) were added K2CO3 (169 mg, 1.225 mmol) and KI (50.8 mg, 0.306 mmol) followed by tert-butyl(chloromethyl) succinate (273 mg, 1.225 mmol) at 25 °C. The reaction mixture was warmed to 60 °C and stirred 16 h. The reaction mixture was diluted with water (30 mL). The crude product was extracted with ethyl acetate (2 x 50 mL). The combined organic layers was washed with brine (30 mL), dried over anhydrous sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to afford crude product which was purified by RP-PREP HPLC purification [Diluent: THF(50): WATER(IO): ACN(40); Column: X-Select C18 (250x19) mm 5. Op; Temperaure: Ambient; Mobile phase A: 5 mM ammonium formate in water (pH 3.3); Mobile phase B: Acetonitrile; Flow: 15 mL / min;Time / Gradient:0 / 65, 12 / 85, 15 / 85)] afford tert-butyl ((2'-chloro-A-(5-(ethoxycarbonyl)thiazolo[5,4-J]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methyl) succinate (25 mg, 0.035 mmol, 11.59 % yield) as a pale-yellow solid (Q-98-I) and (£)-tert-butyl ((2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-5-(ethoxycarbonyl)thiazolo[5,4-J]thiazol-3(2rt)-yl)methyl) succinate (25 mg, 0.036 mmol, 11.84 % yield) (Q-98-II) as an off-white solid.Q-98-I analysis: LCMS: ESI m / z 675.8 [M+H]+, RT=2.84 min (Method D); Analytical Method B: RT=5.76 min, HPLC purity = 98.22 %. ¹H NMR (400MHz, DMSO-de) 68.81 (s, 1H), 8.23 (s, 1H), 7.60 (s, 1H), 7.57 (s, 1H), 6.05 (br s, 2H), 4.43 (q, J=7.1 Hz, 2H), 3.71 (s, 3H), 2.63 (s, 3H), 2.59 - 2.55 (m, 2H), 2.49 - 2.47 (m, 2H), 1.39 - 1.35 (m, 12H).Q-98-II analysis: LCMS: ESI m / z 675.9 [M+H]+, RT=2.62 min (Method D). Analytical Method B: RT=6.45 min, HPLC purity = 98.99 %. ¹H NMR (400MHz, DMSO-de) 69.23 (s, 1H), 8.17 (s, 1H), 7.48 (s, 1H), 7.32 (s, 1H), 6.08 (s, 2H), 4.41 (q, J=6.8 Hz, 2H), 3.66 (s, 3H), 2.62 - 2.6 (m, 2H), 2.59 (s, 3H), 2.49 - 2.47 (m, 2H), 1.35 (t, J = 4 Hz, 3H), 1.26 (s, 9H).Example Q-99. Synthesis of 4-((2'-chloro- / V-(5-(ethoxycarbonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methoxy)-4-oxobutanoic acid.Docket No.: 14928-WO-PCTTFA CH2Cl20 °C-RT8 hterLButyl((2'-chloro-A-(5-(ethoxycarbonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methyl) succinate (10 mg, 0.015 mmol) was dissolved in TFA (2 mL) at 0 °C. The resulting reaction mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure to afford the crude product which was directly Lyophilized. The resulting solid was washed with diethyl ether and hexane to obtain 4-((2'-chloro-A-(5-(ethoxycarbonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido) methoxy)-4-oxobutanoic acid (7 mg, 11.00 pmol, 74.3% yield). LCMS: ESI m / z 622 [M+H]+, RT=2.53 min (Method E). Analytical Method A: RT=6.65 min, HPLC purity = 97.4 %. ¹H NMR (400MHz, DMSO-d6) δ 12.2 (br s, 1H), 8.82 (s, 1H), 8.23 (s, 1H), 7.60 (s, 1H), 7.57 (s, 1H), 6.03 (br s, 2H), 4.44 (q, J=7.1 Hz, 2H), 3.7 (s, 3H), 2.63 (s, 3H), 2.59 - 2.55 (m, 4H), 1.36 (t, J=7.1 Hz, 3H).Example Q-100. Synthesis of (£')-4-((2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-5-(ethoxycarbonyl)thiazolo[5,4- |thiazol-3(2Er)-yl)methoxy)-4-oxobutanoic acid.Docket No.: 14928-WO-PCT(E)-tert-Butyl ((2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-5-(ethoxycarbonyl) thiazolo[5,4-J]thiazol-3(2J7)-yl)methyl) succinate (8 mg, 0.012 mmol) was dissolved in TFA (2 mL) at 0 °C. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure to afford crude product which was directly Lyophilized. The resulting solid was washed with diethyl ether and hexane to obtain (E)-4-((2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-5-(ethoxycarbonyl)thiazolo[5,4-J]thiazol-3(2J7)-yl)methoxy)-4-oxobutanoic acid (2.2 mg, 3.41 pmol, 28.8% yield) as a pale-yellow solid. LCMS: ESI m / z 620 [M+H]+, RT=2.44 min (Method E). Analytical Method A: RT=7.76 min, HPLC purity = 95.76 %. ¹H NMR (400MHz, DMSO-d6) δ 12.2 (br s, 1H), 9.24 (s, 1H), 8.17 (s, 1H), 7.49 (s, 1H), 7.33 (s, 1H), 6.07 (s, 2H), 4.42 (q, J= 8 Hz, 2H), 3.66 (s, 3H), 2.67 - 2.6 (m, 7H), 1.36 (t, J=8 Hz, 3H).Example Q-101. Synthesis of ethyl (Zi)-5-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-6-(((di-tert-butoxyphosphoryl)oxy)methyl)-5,6-dihydrothiazolo[5,4-J|thiazole-2-carboxylateN Cl O' XISNDocket No.: 14928-WO-PCTO*BuO" 6'0'BU£ KI, Cs2CO3, DMFA 8-ml screw cap vial containing ethyl 5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazole-2-carboxylate (95 mg, 0.194 mmol), cesium carbonate (126 mg, 0.388 mmol) and KI (35.4 mg, 0.213 mmol) in DMF (4 mL) was added freshly prepared di-tert-butyl(chloromethyl) phosphate (251 mg, 0.969 mmol) at room temperature. The vial was capped under a stream of nitrogen gas. The reaction mixture was stirred at 40 °C for 16 h and cooled to room temperature followed by addition of di- / c / 7-butyl (chloromethyl) phosphate (100 mg, 0.388 mmol). The vial was capped under a stream of nitrogen gas. The resulting reaction mixture was stirred at 40 °C for 16 h. The reaction mixture was filtered through syringe filter, washed with DMF (0.2 mL) and the resulting filtrate was purified by RP-PREP HPLC purification: Diluent: THF (70): WATER (10): ACN (20); Column: X-Bridge C8 (250x19) mm 5. Op; Temperature: Ambient; Mobile phase A:5mM Ammonium formate in water (pH 3.3); Mobile phase B: Acetonitrile; Flow: 15mL / min; Time / Gradient:0 / 45, 12 / 80, 15 / 80. The purified fractions were collected under freezing condition and lyophilized to yield ethyl 5-(2'-chloro-A-(((di-ter / butoxyphosphoryl) oxy)methyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thi azole-2-carboxylate (5.5 mg, 8.38 pmol, 4.32% yield) as an off-white solid and ethyl (E)-5-((2'-Docket No.: 14928-WO-PCTchloro-5'-methoxy-6-methyl-[4,4'...

Claims

Docket No.: 14928-WO-PCTCLAIMS1. A compound of Formula (I),whereinR1is C1-C4 alkyl, halo-Ci-C4 alkyl, nitrile, CONH2, or halo;R2is C1-C4 alkyl, halo- C1-C4 alkyl, or C3-C8 cycloalkyl;R3is C1-C4 alkyl, C1-C4 alkyl-NH2, C1-C4 alkyl-N(Ci-C4 alkyl)2, C1-C4 alkyl-OH, nitrile, C3-Cs cycloalkyl, or azetidinyl;R4is H, C1-C4 alkyl, -CH(R”)O-P(O)(OR’)(OR’), -CH(R”)-0C(0)-CI-6 alkyl-O-P(O)(OR’)(OR’), -CH(R”)-0C(0)-CI-6 alkyl-C(O)OH -CH(R”)-0C(0)-C I-6 alkyl-P(O)(OR’)(OR’), -CH(R”)-OC(O)- C1-6 alkyl-NR’R’, -CH(R”)-0C(0)-CI-6 alkyl-C(O)O-Ci-6alkyl, or -CH(R”)-0C(0)-CI-6 alkyl-heterocyclyl, wherein R’ and R” are, independently, selected from H or C1-C4 alkyl;R5is H, halo, C1-C4 alkyl, C1-C4 alkyl-OH, C2-C4 alkenyl, C1-C4 haloalkyl, -S-C1-C4 alkyl, C(O)H, optionally substituted C3-C8 cycloalkyl, halo, optionally substituted 4-10-membered heterocyclyl, optionally substituted C1-C4 alkyl-4-10-membered heterocyclyl, optionally substituted -C(O)-4-10-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C(O)O-Ci-C4 alkyl, C(O)O-C3-C7 cycloalkyl, -C1-C4 alkyl-N(R6)- C(O)O-Ci-C4alkyl, C(O)O-Ci-C4alkyl, -C1-C4 alkyl-O-Ci-C4alkyl, -Ci-C4alkyl-O-Ci-C4alkyl-N(R6)2, -C1-C4 alkyl-O-Ci-C4alkyl= -C1-C4 alkyl-O-Ci-C4alkyl-N(R6)2, optionally substituted C(O)O-C3-Cs cycloalkyl, optionally substituted CO(O)-C4-C10 heterocyclyl, optionally substituted C2-C4 alkynyl-Ci-C4 alkyl, C2-C4 alkynyl-C3-C8 cycloalkyl, C2-C4 alkynyl-C4-Cio heterocyclyl, -N(R6)2, - C1-C4 alkyl-N(R6)2, -C(O)N(R6)2, -P(O)(R6)2, -P(O)(OR6)2, SO(=NR6), SR6(O)(=NR6), SO2R6, -N=S(O)(R6)2, wherein theDocket No.: 14928-WO-PCToptionally substituted C3-C8 cycloalkyl, heterocyclyl, -C(O)-heterocyclyl, aryl, heteroaryl, C2-C4 alkynyl-C1-C4 alkyl, C(O)O-C1-C4 alkyl, C(O)O-C3-C8 cycloalkyl and CO(O)-C4-C10heterocyclyl, is optionally substituted with one or more hydroxyl, Ci-C4alkyl, halo, cyano, hydroxy-Ci-C4alkyl, -C(O)-Ci-C4alkyl, -CO2H, -CO2-Ci-C4alkyl, -SO2-Ci-C4alkyl, -SO2-C3-C7 cycloalkyl;and each R6 is, independently, H, C1-C4 alkyl, C1-C4 alkoxyl, C3-C8 cycloalkyl, or alternatively, two R6groups together with the nitrogen or the carbon atom to which they are bound form C4-C10 cycloalkyl or heterocyclyl, wherein the C4-C10 cycloalkyl or heterocyclyl is optionally substituted with one of more hydroxyl, Ci-C4alkyl, halo, cyano, hydroxy-Ci-C4alkyl; -C(O)-Ci-C4alkyl, -C(O)-OCi-C4alkyl,or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein the compound is of Formula (IA):(IA),or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1, wherein the compound is of Formula (IB):or a pharmaceutically acceptable salt thereof.

4. A compound according to any one of the preceding claims, wherein R1is chloro.Docket No.: 14928-WO-PCT5. A compound according to any one of the preceding claims, wherein R2and R3are methyl.

6. A compound according to any one of the preceding claims, wherein R4is H.

7. A compound according to any one of the preceding claims, wherein R5is selected from: - H, -Br, -Cl, -CHF2, -CH=CH2, -CH2N(CH3)2, -CH2OH, -CH2OCH3, - CH2CH2OCH2CH2NH2, -CH2CH2OCH2CH2NHCOO / BU, CH2CH2OCH2CH2NHCOOCH2CH3, -CH(CH2OH)2, -CO2H, -CO2CH2CH3, - CO2CH(CH3)2, -CO2-cyclopropyl, -CO2CH2CH2COOH,-N(CH3)2, -<, NJ ■, NJ ■ H NCCHOCOOCJfcCJL, -C(O)NHCH3, C(O)N(CH3)2, °,0F f, OH CN F o JJ rO^F<, 0— Jo n b, J, J, J, J,, OCOCH2CH3, -OCH2COCH2CH3, -OCH2C(O)OCH2CH3, -SCH(CH3)2, -SO2CH3, -Docket No.: 14928-WO-PCT0or a pharmaceutically acceptable salt thereof.

8. A compound according to any one of the preceding claims, wherein the compound is selected from:2'-chloro-N-(5-(4-chlorophenyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3 -carboxamide;2'-chloro-5'-methoxy-6-methyl-N-(5-phenylthiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide;2'-Chloro-N-(5-(4-cyanophenyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3 -carboxamide;Docket No.: 14928-WO-PCT2'-chloro-N-(5-(cyclopropylethynyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3 -carboxamide;2'-chloro-N-(5-(5-chloropyridin-2-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3 -carboxamide;2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3 -carboxamide;2'-(difluoromethyl)-5'-methoxy-6-methyl-N-(5-phenylthiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3 -carboxamide;2'-chloro-N-(5-(3,6-dihydro-2H-pyran-4-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-N-(5-(3-hydroxyprop-l-yn-l-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-N-(5-(2,5-dihydro-lH-pyrrol-3-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-N-(5-(5,6-dihydro-l,4-dioxin-2-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-5'-methoxy-6-methyl-N-(5-(l,2,3,6-tetrahydropyridin-4-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide;N-(5-bromothiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-5'-methoxy-6-methyl-N-(5-morpholinothiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3 -carboxamide;2'-chloro-N-(5-(dimethylamino)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3 -carboxamide;2'-chloro-N-(5-(3,3-difluoroazetidin-l-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;N-(5-(2,6-diazaspiro[3.3]heptan-2-yl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;Docket No.: 14928-WO-PCTN-(5-(3,3-bis(hydroxymethyl)azetidin-l-yl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-5'-methoxy-6-methyl-N-(5-(2-methylpiperazin-l-yl)-3a,6a-dihydrothiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide;2'-chloro-N-(5-(4-hydroxy-2-methylpiperidin-l-yl)-3a,6a-dihydrothiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-N-(5-(dimethylphosphoryl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3 -carboxamide;dimethyl (5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)phosphonate;N-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-N-(5-(3-hydroxybut-l-yn-l-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-N-(5-(2,5-dihydrofuran-3-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;N-(5-(l-acetyl-2,5-dihydro-lH-pyrrol-3-yl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-5'-methoxy-6-methyl-N-(5-(l-methyl-2,5-dihydro-lH-pyrrol-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide;ethyl 5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazole-2-carboxylate;5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)-N, N-dimethylthiazolo[5,4-d]thiazole-2-carboxamide;5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)-N-methylthiazolo[5,4-d]thiazole-2-carboxamide;di-tert-butyl ((2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methyl) phosphate;Docket No.: 14928-WO-PCT(2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methyl dihydrogen phosphate;tert-butyl ((2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methyl) succinate;(E)-tert-butyl ((2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-5-cyclopropylthiazolo[5,4-d]thiazol-3(2H)-yl)methyl) succinate;4-((2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methoxy)-4-oxobutanoic acid (3x);(E)-4-((2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-5-cyclopropylthiazolo[5,4-d]thiazol-3(2H)-yl)methoxy)-4-oxobutanoic acid (3x’); and5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazole-2-carboxylic acid;2'-chloro-N-(5-(ethylsulfonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3 -carboxamide;2'-chloro-5'-methoxy-6-methyl-N-(5-(pyrrolidin-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3 -carboxamide;ethyl 2-(5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)cyclopropane- 1 -carboxylate;2'-chloro-5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3 -carboxamide;ethyl 2-((5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)oxy)acetate;2'-chloro-N-(5-(difluoromethyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3 -carboxamide;2'-chloro-N-(5-(isopropylthio)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-N-(4-methoxybenzyl)- 6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-N-(5-((dimethylamino)methyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;Docket No.: 14928-WO-PCT2'-chloro-5'-methoxy-6-methyl-N-(5-(oxetan-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3 -carboxamide;2'-chloro-5'-methoxy-N-(5-(methoxymethyl)thiazolo[5,4-d]thiazol-2-yl)-6-methyl-[4,4'-bipyridine]-3 -carboxamide;N-(5-(2-(2-aminoethoxy)ethyl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;N-(5-(azetidin-3-yl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3 -carboxamide;2'-chloro-5'-methoxy-6-methyl-N-(5-(propan-2-ylsulfonimidoyl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide;2'-chloro-5'-methoxy-6-methyl-N-(5-(S-methylsulfonimidoyl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide;2'-chloro-N-(5-((cyclopropyl(methyl)(oxo)-16-sulfaneylidene)amino)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-6-(hydroxymethyl)-5'-methoxy-[4,4'-bipyridine]-3 -carboxamide;methyl 4-(5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate;2'-chloro-N-(5-(3-hydroxyazetidine-l-carbonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-N-(5-(3-cyanoazetidin-l-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3 -carboxamide;diethyl (5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)phosphonate;methyl 3-(5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)-2,5-dihydro-lH-pyrrole-l -carboxylate;ethyl 3-(5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)-2,5-dihydro-lH-pyrrole-l-carboxylate;Docket No.: 14928-WO-PCTmethyl 3-(5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)pyrrolidine-1-carboxylate;2'-chloro-5'-methoxy-6-methyl-N-(5-vinylthiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide;2'-chloro-N-(5-(3-cyanoazetidine-l-carbonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;N-(5-(l-acetylpyrrolidin-3-yl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;isopropyl 5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazole-2-carboxylate;cyclopropyl 5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazole-2-carboxylate;3-((5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazole-2-carbonyl)oxy)propanoic acid;2'-chloro-N-(5-(3,3-difluoroazetidine-l-carbonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-5'-methoxy-6-methyl-N-(5-(l-methylpyrrolidin-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide;2'-chloro-5'-methoxy-6-methyl-N-(5-(l-(methylsulfonyl)pyrrolidin-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide;2'-chloro-5'-methoxy-6-methyl-N-(5-(l-(methylsulfonyl)-2,5-dihydro-lH-pyrrol-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide;2'-chloro-N-(5-(l-(ethylsulfonyl)-2,5-dihydro-lH-pyrrol-3-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-N-(5-(cyclopropylsulfonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3 -carboxamide;2'-chloro-N-(5-(l-(ethylsulfonyl)pyrrolidin-3-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;Docket No.: 14928-WO-PCT2'-chloro-N-(5-(l-(cyclopropylsulfonyl)-2,5-dihydro-lH-pyrrol-3-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-N-(5-(l-(isopropylsulfonyl)-2,5-dihydro-lH-pyrrol-3-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2-(5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol- 2-yl)cyclopropane- 1 -carboxylic acid;2'-chloro-N-(5-(l-(isopropylsulfonyl)pyrrolidin-3-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-N-(5-(l-(cyclopropylsulfonyl)pyrrolidin-3-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-N-(5-(2-(hydroxymethyl)cyclopropyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-N-(5-chlorothiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-5'-methoxy-6-methyl-N-(5-(methylsulfonyl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3 -carboxamide;2'-chloro-N-(5-formylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-N-(5-((3-hydroxyazetidin-l-yl)methyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-5'-methoxy-6-methyl-N-(thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide;2'-chloro-N-(5-(hydroxymethyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3 -carboxamide;2'-chloro-N-(5-(isopropylsulfonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3 -carboxamide;ethyl (2-(2-(5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)ethoxy)ethyl)carbamate;Docket No.: 14928-WO-PCTethyl 3-(5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)azetidine- 1 -carboxylate;2'-chloro-N-(5-(1,3-dihydroxypropan-2-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-5'-methoxy-6-methyl-N-(5-(l-(methylsulfonyl)azetidin-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide;tert-butyl (2-(2-(5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)ethoxy)ethyl)carbamate;2'-chloro-5'-methoxy-6-methyl-N-(5-(1-methylazetidin-3-yl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide;5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)-N-(2 -hydroxy ethyl)-N-methylthiazolo[5,4-d]thiazole-2-carboxamide;2'-chloro-N-(5-(ethylsulfonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridine]-4-carboxamide;dimethyl (5-(2'-chloro-5'-methoxy-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridine]-4-carboxamido)thiazolo[5,4-d]thiazol-2-yl)phosphonate;N-(5-bromothiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridine]-4-carboxamide;2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-1-(2-(dimethylamino)ethyl)-5'-methoxy-6-oxo-1,6-dihydro-[3,4'-bipyridine]-4-carboxamide;1-(2-aminoethyl)-2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-oxo-1,6-dihydro-[3,4'-bipyridine]-4-carboxamide;tert-butyl ((2'-chloro-N-(5-(ethoxycarbonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methyl) succinate;(E)-tert-butyl ((2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-5-(ethoxycarbonyl)thiazolo[5,4-d]thiazol-3(2H)-yl)methyl) succinate;4-((2'-chloro-N-(5-(ethoxycarbonyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)methoxy)-4-oxobutanoic acid;Docket No.: 14928-WO-PCT(E)-4-((2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-5-(ethoxycarbonyl)thiazolo[5,4-d]thiazol-3(2H)-yl)methoxy)-4-oxobutanoic acid;ethyl (E)-5-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-6-(((di-tert-butoxyphosphoryl)oxy)methyl)-5,6-dihydrothiazolo[5,4-d]thiazole-2-carboxylate; ethyl 5-(2'-chloro-5'-methoxy-6-methyl-N-((phosphonooxy)methyl)-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazole-2-carboxylate;ethyl (E)-5-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-6-((phosphonooxy)methyl)-5,6-dihydrothiazolo[5,4-d]thiazole-2-carboxylate;(E)-4-((2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-5-cyclopropylthiazolo[5,4-d]thiazol-3(2H)-yl)methoxy)-4-oxobutanoic acid;2'-chloro-N-(5-cyclopropylthiazolo[5,4-d]thiazol-2-yl)-6-(2-(dimethylamino)ethoxy)-5'-methoxy-[4,4'-bipyridine]-3-carboxamide;2'-chloro-N-(5-(3-hydroxycyclopentyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;ethyl 3-(5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)bicyclo[1.1.1]pentane-1-carboxylate;2'-chloro-N-(5-(2,2-difluorocyclopropyl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-N-(5-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-5'-methoxy-6-methyl-N-(5-(methyl(pyrrolidin-l-yl)phosphoryl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide;2'-chloro-N-(5-((3,3-difluoroazetidin-l-yl)(methyl)phosphoryl)thiazolo[5,4-d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;2'-chloro-5'-methoxy-6-methyl-N-(5-(1-(S-methylsulfonimidoyl)cyclopropyl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide;(E)-5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)-N-ethoxythiazolo[5,4-d]thiazole-2-carbimidoyl cyanide;Docket No.: 14928-WO-PCTN-(5-(3-oxabicyclo[3.1.0]hexan-l-yl)thiazolo[5,4-d]thiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide;ethyl 2-((5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)ethynyl)cyclopropane-1-carboxylate;2'-chloro-5'-methoxy-6-methyl-N-(5-((oxetan-3-yloxy)methyl)thiazolo[5,4-d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide;5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl propionate;N-(5-(2-(aminomethyl)cyclopropyl)-3a,6a-dihydrothiazolo[5,4-d]thiazol-2-yl)-2'-chl oro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide; andethyl 1-(5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazolo[5,4-d]thiazol-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising the compound of any one of claims 1-8, and a pharmaceutically acceptable excipient, diluent, or carrier.

10. A composition comprising:a Pole (PolQ) inhibitor of formula (I):WhereinR1is C1-C4 alkyl, halo-Ci-C4 alkyl, nitrile, CONH2, or halo;Docket No.: 14928-WO-PCTR2is C1-C4 alkyl, halo- C1-C4 alkyl, or C3-C8 cycloalkyl;R3is C1-C4 alkyl, C1-C4 alkyl-NH2, C1-C4 alkyl-N(Ci-C4 alkyl)2, C1-C4 alkyl-OH, nitrile, C3-Cs cycloalkyl, or azetidinyl;R4is H, C1-C4 alkyl, -CH(R”)O-P(O)(OR’)(OR’), -CH(R”)-0C(0)-CI-6 alkyl-O-P(O)(OR’)(OR’), -CH(R”)-0C(0)-CI-6 alkyl-C(O)OH -CH(R”)-0C(0)-CI-6 alkyl-P(O)(OR’)(OR’), -CH(R”)-OC(O)- C1-6 alkyl-NR’R’, -CH(R”)-0C(0)-CI-6 alkyl-C(O)O-Ci-6 alkyl, or -CH(R”)-0C(0)-CI-6 alkyl-heterocyclyl, wherein R’ and R” are, independently, selected from H or C1-C4 alkyl;R5is H, halo, C1-C4 alkyl, C1-C4 alkyl-OH, C2-C4 alkenyl, C1-C4 haloalkyl, -S-C1-C4 alkyl, C(O)H, optionally substituted C3-C8 cycloalkyl, halo, optionally substituted 4-10-membered heterocyclyl, optionally substituted C1-C4 alkyl-4-10-membered heterocyclyl, optionally substituted -C(O)-4-10-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C(O)O-Ci-C4 alkyl, C(O)O-C3-C7 cycloalkyl, -C1-C4 alkyl-N(R6)- C(O)O-Ci-C4alkyl, C(O)O-Ci-C4alkyl, -C1-C4 alkyl-O-Ci-C4alkyl, -Ci-C4alkyl-O-Ci-C4alkyl-N(R6)2, -C1-C4 alkyl-O-Ci-C4alkyl= -C1-C4 alkyl-O-Ci-C4alkyl-N(R6)2, optionally substituted C(O)O-C3-Cs cycloalkyl, optionally substituted CO(O)-C4-C10 heterocyclyl, optionally substituted C2-C4 alkynyl-Ci-C4 alkyl, C2-C4 alkynyl-C3-C8 cycloalkyl, C2-C4 alkynyl-C4-Cio heterocyclyl, -N(R6)2, - C1-C4 alkyl-N(R6)2, -C(O)N(R6)2, -P(O)(R6)2, -P(O)(OR6)2, SO(=NR6), SR6(O)(=NR6), SO2R6, -N=S(O)(R6)2, wherein the optionally substituted C3-C8 cycloalkyl, heterocyclyl, -C(O)-heterocyclyl, aryl, heteroaryl, C2-C4 alkynyl-C1-C4 alkyl, C(O)O-C1-C4 alkyl, C(O)O-C3-C8 cycloalkyl and CO(O)-C4-C10heterocyclyl, is optionally substituted with one or more hydroxyl, C1-C4 alkyl, halo, cyano, hydroxy-Ci-C4alkyl, -C(O)-Ci-C4alkyl, -CO2H, -CO2-C1-C4 alkyl, -SO2-C1-C4 alkyl, -SO2-C3-C7 cycloalkyl;and each R6is, independently, H, Ci-C4alkyl, Ci-C4alkoxyl, C3-C8 cycloalkyl, or alternatively, two R6groups together with the nitrogen or the carbon atom to which they are bound form C4-C10 cycloalkyl or heterocyclyl, wherein the C4-C10 cycloalkyl or heterocyclyl is optionally substituted with one of more hydroxyl, C1-C4 alkyl, halo, cyano, hydroxy-Ci-C4 alkyl; -C(O)-Ci-C4 alkyl, -C(O)-OCi-C4 alkyl, or a pharmaceutically acceptable salt thereof, andDocket No.: 14928-WO-PCTa DNAPK inhibitor of Formula (SI):RS1(SI),or a pharmaceutically acceptable salt thereof,wherein:Asis a 5-membered or 6-membered heteroaryl or heterocycloalkyl group containing at least one heteroatom selected from the group consisting of N, O, and S, wherein the heteroaryl or heterocycloalkyl is optionally substituted with one or more RS5;RS1is an aryl or heteroaryl containing at least one heteroatom selected from the group consisting of N, O, S, and Se, wherein the aryl or heteroaryl is optionally substituted with one or more RS6;RS2is H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, CN, OH, CH2OH, NH2, or CH2NH2; RS3and RS4are each independently selected from the group consisting of -OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylaryl, and aryl;each RS5is independently selected from the group consisting of halogen, oxo, thioxo, C1-C4 alkyl, CD3, CD2CD3, C1-C4 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, and aryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is optionally substituted with one or more RS7; ortwo geminal RS5, together with the intervening geminal carbon atom, form a C3-C6 cycloalkyl;each RS6is independently selected from the group consisting of halogen, oxo, NH2, OH, -CN, C(O)NHRS7, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, CD3, CD2CD3, C1-C6alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl and aryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is optionally substituted with one or more RS7;Docket No.: 14928-WO-PCTeach RS7is independently selected from the group consisting of halogen, OH, oxo, NH2, CHO, C1-C4 alkyl, and C1-C6 alkoxy; andn is an integer from 1 to 311. A composition comprising:a P0I6 (POLQ) inhibitor of formula (I):whereinR1is C1-C4 alkyl, halo-Ci-C4 alkyl, nitrile, CONH2, or halo;R2is C1-C4 alkyl, halo- C1-C4 alkyl, or C3-C8 cycloalkyl;R3is C1-C4 alkyl, C1-C4 alkyl-NH2, C1-C4 alkyl-N(Ci-C4 alkyl)2, C1-C4 alkyl-OH, nitrile, C3-Cs cycloalkyl, or azetidinyl;R4is H, C1-C4 alkyl, -CH(R”)O-P(O)(OR’)(OR’), -CH(R”)-OC(O)-CI-6 alkyl-O- P(O)(OR’)(OR’), -CH(R”)-OC(O)-CI-6alkyl-C(O)OH -CH(R”)-OC(O)-CI-6 alkyl-P(O)(OR’)(OR’), -CH(R”)-OC(O)- C1-6 alkyl-NR’R’, -CH(R”)-OC(O)-CI-6 alkyl-C(O)O-Ci-6 alkyl, or -CH(R”)-OC(O)-CI-6 alkyl-heterocyclyl, wherein R’ and R” are, independently, selected from H or C1-C4 alkyl;R5is H, halo, C1-C4 alkyl, C1-C4 alkyl-OH, C2-C4 alkenyl, C1-C4 haloalkyl, -S-C1-C4 alkyl, C(O)H, optionally substituted C3-C8 cycloalkyl, halo, optionally substituted 4-10-membered heterocyclyl, optionally substituted C1-C4 alkyl-4-10-membered heterocyclyl, optionally substituted -C(O)-4-10-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C(O)O-Ci-C4 alkyl, C(O)O-C3-C7 cycloalkyl, -C1-C4 alkyl-N(R6)- C(O)O-Ci-C4alkyl, C(O)O-Ci-C4alkyl, -C1-C4 alkyl-O-Ci-C4alkyl, -Ci-C4alkyl-O-Ci-C4alkyl-N(R6)2, -C1-C4 alkyl-O-Ci-C4alkyl= -C1-C4 alkyl-O-Ci-C4alkyl-Docket No.: 14928-WO-PCTN(R6)2, optionally substituted C(O)O-C3-Cs cycloalkyl, optionally substituted CO(O)-C4-C10 heterocyclyl, optionally substituted C2-C4 alkynyl-Ci-C4 alkyl, C2-C4 alkynyl-C3-C8 cycloalkyl, C2-C4 alkynyl-C4-Cio heterocyclyl, -N(R6)2, - C1-C4 alkyl-N(R6)2, -C(O)N(R6)2, -P(O)(R6)2, -P(O)(OR6)2, SO(=NR6), SR6(O)(=NR6), SO2R6, -N=S(O)(R6)2, wherein the optionally substituted C3-C8 cycloalkyl, heterocyclyl, -C(O)-heterocyclyl, aryl, heteroaryl, C2-C4 alkynyl-C1-C4 alkyl, C(O)O-C1-C4 alkyl, C(O)O-C3-C8 cycloalkyl and CO(O)-C4-C10heterocyclyl, is optionally substituted with one or more hydroxyl, C1-C4 alkyl, halo, cyano, hydroxy-Ci-C4alkyl, -C(O)-Ci-C4alkyl, -CO2H, -CO2-C1-C4 alkyl, -SO2-C1-C4 alkyl, -SO2-C3-C7 cycloalkyl;and each R6is, independently, H, Ci-C4alkyl, Ci-C4alkoxyl, C3-Cs cycloalkyl, or alternatively, two R6groups together with the nitrogen or the carbon atom to which they are bound form C4-C10 cycloalkyl or heterocyclyl, wherein the C4-C10 cycloalkyl or heterocyclyl is optionally substituted with one of more hydroxyl, C1-C4 alkyl, halo, cyano, hydroxy-Ci-C4 alkyl; -C(O)-Ci-C4 alkyl, -C(O)-OCi-C4 alkyl, or a pharmaceutically acceptable salt thereof; anda DNAPK inhibitor of Formula (SI):R1BHhKor a pharmaceutically acceptable salt thereof,wherein:ABis a 5- or 6-membered heteroaryl or heterocycloalkyl group containing at least one heteroatom selected from the group consisting of N, O, and S, wherein the heteroaryl or heterocycloalkyl is optionally substituted with one or more R4B;R1Bis an aryl or heteroaryl containing at least one heteroatom selected from the group consisting of N, O, S, and Se, wherein the aryl or heteroaryl is optionally substituted with one or more R5B;Docket No.: 14928-WO-PCTR2Bis H, halogen, -(CH2)nB-CN, -OH, -(CH2)nB-O-Ci-C4 alkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C(0)NH2;R3Bis selected from the group consisting of H, F, C2-C4 alkenyl, C2-C4 alkynyl, CN, OH, CH2OH, NH2, CH2NH2, and C1-C4 alkyl;each R4Bis independently selected from the group consisting of halogen, oxo, thioxo, C1-C4 alkyl, C1-C4 alkoxy, CD3, CD2CD3, and Ci-Ce haloalkyl; ortwo geminal R4Btogether with the intervening geminal carbon atom, form a C3-C6 cycloalkyl; each R5Bis independently selected from the group consisting of halogen, NH2, OH, -CN, C(O)NH2, C(O)NHR7B, C1-C4 alkyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, CD3, CD2CD3, Ci-Ce alkoxy, Ci-Ce haloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, and aryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is optionally substituted with one or more R6B;each R6Bis independently selected from the group consisting of halogen, OH, oxo, NH2, CHO, C1-C4 alkyl, and Ci-Ce alkoxy;each R7Bis independently selected from H and C1-C4 alkyl;each nB is independently an integer from 0-4;rBis an integer from 0 to 2;sBis an integer from 0 to 2; andtBis an integer from 1 to 2.

12. A composition according to any one of the preceding claims further comprising a DNA cutting agent.

13. A method of targeted insertion of a donor DNA into the genome of a cell, comprising contacting the cell with a DNA cutting agent, the donor DNA, POLQi Compound I, and a DNA-PKI, wherein the DNA-PKI is a compound according to any one of claims 10 or 11.

14. The method of claim 13, comprising growing the cell in a cell medium comprising a DNA-PKI compound and a POLQi Compound I.Docket No.: 14928-WO-PCT15. The composition of any one of the preceding claims, wherein the composition comprises a guide RNA nucleic acid and a Class 2, Type II or Class 2, Type V Cas nuclease; and the molar ratio of the guide RNA to Cas nuclease is from about 4: 1 to 1:4.

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