Compounds useful as inhibitors of werner syndrome RECQ helicase (WRN)

Abstract

The present invention is directed compounds, pharmaceutical compositions containing them and their use in the treatment of diseases or disorders mediated by or modulated by inhibition of WRN.

Description

[0001]PRD4322WOPCT1 5 COMPOUNDS USEFUL AS INHIBITORS OF WERNER SYNDROME RECQ HELICASE (WRN) CROSS-REFERENCE TO RELATED APPLICATIONS 10 This application claims priority from United States Provisional Applications Serial No.63 / 757871 filed 13 February 2025 and United States Provisional Applications Serial No.63 / 678120 filed on 01 August 2024 the contents of each of which are hereby incorporated by reference in their entirety. 15 Field of the Invention The present invention is directed to compounds, pharmaceutical compositions containing them and their use in the treatment of diseases or disorders mediated by or modulated by inhibition of WRN. More particularly, the present invention is directed to oxazolo[4,5-b]pyridine and 4,5-dihydrooxazolo[5,4-c]pyridine derivatives, 20 pharmaceutical compositions containing them and their use in the treatment of diseases or disorders mediated by or modulated by inhibition of WRN. More particularly, the compounds of the present invention are useful in the treatment of microsatellite instability (MSI-H) cancers or mismatch repair deficient (dMMR) cancers. 25 Background of the Invention DNA mismatch repair (MMR) is an evolutionarily conserved pathway that functions to resolve base substitution and insertion-deletion mismatches that occur during DNA replication (Kunkel T, et al., Annual Review of Biochemistry, 2005, pp, 30 681-710, 74). MMR deficiency (dMMR), which is caused by loss-of-function alterations or hypermethylation of genes encoding MMR proteins (Muzny, D et al., Nature, 2012, pp 330-337, 487(7407)), is a prevalent early driver event in tumors where failure to repair DNA mismatches in neoplastic cells drives hypermutation characterized by insertion / deletion alterations within repetitive DNA sequences. The 1 PRD4322WOPCT1 5 latter phenotype, known as microsatellite instability (MSI), is observed in approximately 4% of all cancers, with a high burden of microsatellite instability (MSI- high; MSI-H) reported in 30% of endometrial carcinoma and 20% of colorectal carcinoma (Bonneville, R et al., JCO Precision Oncology, 2017, 2017). Moreover, the presence of deleterious germline alterations in MMR pathway genes (particularly 10 MLH1, MSH2, and MSH6) is pathognomonic for hereditary nonpolyposis colorectal cancer (Leach, F et al., Cell, 1993, pp 1215-1225, 75(6); Fishel, R et al., Cell, 1993, pp 1027-1038, 75(5); Bronner, C et al., Nature, 1994, pp 258-261, 368(6468)) (HNPCC; also known as Lynch syndrome), an autosomal-dominant disorder associated with predisposition to early onset MSI-H colorectal, endometrial, ovarian, 15 urothelial, gastric, and other cancers (Bonadona, V et al., Journal of the American Medical Association, 2011, pp 2304-2310, 305(22). While recent clinical trials have demonstrated that anti-PD-1 monoclonal antibodies (alone or in combination with anti- CTLA-4 therapy) are efficacious for advanced MSI-H / dMMR colorectal, endometrial, and other cancers,(Overman, M et al., Lancet Oncology, 2017, pp 1182-1191, 18(9); 20 Overman, M et al., Journal of Clinical Oncology, 2018, pp 773-779, 36(8); Marabelle, A et al., Journal of Clinical Oncology, 2020, pp 1-14, 38(1); Andre, T et al., New England Journal of Medicine, 2020, pp 2207-2218, 383(23); Le, D et al., Journal of Clinical Oncology, 2020, pp 11-19, 38(1); Lenz, H et al., Journal of Clinical Oncology, 2022, pp 161-170, 40(2); O’Malley, D et al., Journal of Clinical Oncology, 2022, pp 25 752-761, 40(7))leading to regulatory approvals for pembrolizumab, nivolumab and ipilimumab for such indications, there is an ongoing need to identify new therapies to treat and prevent dMMR / MSI-H cancer. Recent functional genomic studies have identified the Werner syndrome helicase WRN as a synthetic lethal dependency in preclinical models of MSI cancer 30 (Chan, E et al., Nature, 2019, pp 551-556, 568(67753); Kategaya, L et al., iScience, 2019, pp 488-497, 13; Lieb, S et al., eLife, 2019, 4333, 8; Behan, F et al., Nature, 2019, pp 511-516, 568(7753)) Genetic depletion of WRN, which is an ATP-dependent DNA helicase of the RecQ family (Hickson, I, Nature Reviews Cancer, 2003, pp 169- 178, 3(3)), resulted in the selective induction of DNA double-strand breaks (DSBs) in 2 PRD4322WOPCT1 5 MSI cancer cells, with attendant activation of DNA damage response pathways, cell cycle arrest, chromosome fragmentation, apoptosis, loss of viability and clonogenicity, and inhibition of tumor growth. Synthetic lethal dependence upon WRN was independently demonstrated in 55 of 60 preclinical models of MSI colorectal cancer, including models resistant to standard-of-care chemotherapy, immunotherapy, and 10 molecularly targeted therapy (Picco, G et al., Cancer Discovery, 2021, pp 1923-1937, 11(8)). Interestingly, the ATP-dependent helicase activity of WRN was essential to the survival of MSI cancer cells, whereas its 3’-5’ exonuclease function was dispensable (Chan, E et al., Nature, 2019, pp 551-556, 568(67753); Kategaya, L et al., iScience, 2019, pp 488-497, 13; Lieb, S et al., eLife, 2019, 4333, 8; Behan, F et al., Nature, 15 2019, pp 511-516, 568(7753)). The dependence of MSI cancer cells on WRN was subsequently demonstrated to be mechanistically driven by prevalent expansion alterations in microsatellites characterized by a TA dinucleotide repeat motif, causing cruciform DNA structures that require WRN helicase activity for their resolution (van Wietmarschen, N et al., Nature, 2020, pp 292-298, 586(7828)). In the absence of 20 WRN, DNA cruciforms at expanded TA loci are enzymatically cleaved to generate cytotoxic DSBs. In vitro reconstitution of this system orthogonally demonstrated that WRN resolves DNA cruciform caused by TA microsatellite expansion (Mengoli, V et al., EMBO Journal, 2023, e111998, 42(3)). Collectively, these data demonstrate that pharmacological inhibition of WRN 25 helicase is a potential strategy for treating and intercepting MSI cancer. Thus, there remains a need for new treatments and therapies for the treatment of cancer, and in particular cancers characterized as microsatellite instability (MSI) or mismatch repair deficient (dMMR). 30 BORDAS, V., et al., in PCT Publication WO2022 / 249060 A1, published 01 December 2022 described some triazolo-pyrimidine analogues for treating diseases connected to the inhibition of Werner Syndrome RecQ Helicase (WRN). ZHU, H., et al., in PCT Publication WO2024 / 120378 A2, published 13 June 2024 describe triazole compounds useful as WRN inhibitors, preparation methods, 3 PRD4322WOPCT1 5 pharmaceutical compositions and pharmaceutical uses for the treatment of WRN- mediated diseases or disorders. Summary of the Invention The present invention is directed to compounds of formula (I) 10 (I) the core scaffold is ; (such that the core 15 scaffold ) 4 PRD4322WOPCT1 5 , 6- membered nitrogen containing heteroaryl; wherein the 6-membered N containing heteroaryl is substituted with -OH, and further optionally substituted with one or two 10 substituents independently selected from the group consisting of halogen, hydroxy, methyl, ethyl, -CF3, -CH2CF3, methoxy, ethoxy, -C(O)OH, -C(O)O-(C1-4alkyl), NRARB; wherein RAand RBare each independently selected from the group consisting of hydrogen and C1-4alkyl; and wherein R6is hydrogen or methyl; provided that whe ; (such that the 15 core scaffold ), then R1is selected from the group consisting of ; R3is chloro; R4is selected from the group consisting of hydroxy substituted C1-4alkyl, 1-20 hydroxy-cyclobut-1-yl, 1-hydroxy-cyclopent-1-yl, 1-hydroxy-cyclohex-1-yl, 3-hydroxy- tetrahydrofuran-3-yl and 4-hydroxy-tetrahydropyran-4-yl; 5 PRD4322WOPCT1 5 and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. The present invention is further directed to processes for the preparation of the compounds of formula (I). The present invention is further directed to a product 10 prepared according to any of processes described herein. Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the product prepared according to the process described herein. An illustration of the invention is a pharmaceutical composition made by mixing the product prepared according to the process described 15 herein and a pharmaceutically acceptable carrier. Illustrating the invention is a process for making a pharmaceutical composition comprising mixing the product prepared according to the process described herein and a pharmaceutically acceptable carrier. Exemplifying the invention are methods of treating a disorder mediated by or 20 modulated by inhibition of WRN, more particularly cancers characterized as microsatellite instability (MSI) or mismatch repair deficient (dMMR), selected from the group consisting of colonic, gastric, rectal, endometrial, adrenocortical, uterine, cervical, mesothelial, esophageal, breast, kidney, prostate, ovarian, pancreatic, germ cell, liver, lung, biliary tract / gallbladder, head / neck, thyroid, thymic, small bowel, 25 bladder, skin, prostate, brain, neuroendocrine, soft tissue, appendiceal, leukemia, lymphoma, and myeloma cancers comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. In an embodiment, the present invention is directed to a compound of formula 30 (I) for use as a medicament. In another embodiment, the present invention is directed to a compound of formula (I) for use in the treatment of a disorder mediated by or modulated by inhibition of WRN, more particularly cancers characterized as microsatellite instability (MSI) or mismatch repair deficient (dMMR), selected from the group consisting of colonic, gastric, rectal, endometrial, adrenocortical, uterine, 6 PRD4322WOPCT1 5 cervical, mesothelial, esophageal, breast, kidney, prostate, ovarian, pancreatic, germ cell, liver, lung, biliary tract / gallbladder, head / neck, thyroid, thymic, small bowel, bladder, skin, prostate, brain, neuroendocrine, soft tissue, appendiceal, leukemia, lymphoma, and myeloma cancers. In another embodiment, the present invention is directed to a composition 10 comprising a compound of formula (I) for the treatment of a disorder mediated by or modulated by inhibition of WRN, more particularly cancers characterized as microsatellite instability (MSI) or mismatch repair deficient (dMMR), selected from the group consisting of colonic, gastric, rectal, endometrial, adrenocortical, uterine, cervical, mesothelial, esophageal, breast, kidney, prostate, ovarian, pancreatic, germ 15 cell, liver, lung, biliary tract / gallbladder, head / neck, thyroid, thymic, small bowel, bladder, skin, prostate, brain, neuroendocrine, soft tissue, appendiceal, leukemia, lymphoma, and myeloma cancers. Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating: (a) a disorder mediated by or 20 modulated by inhibition of WRN, or (b) a cancer characterized as microsatellite instability (MSI) or mismatch repair deficient (dMMR), in a subject in need thereof. Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating: (a) colonic, (b) gastric, (c) rectal, (d) endometrial, (e) adrenocortical, (f) uterine, (g) cervical, (h) mesothelial, (i) 25 esophageal, (j) breast, (k) kidney, (l) prostate, (m) ovarian, (n) pancreatic, (o) germ cell, (p) liver, (q) lung, (r) biliary tract / gallbladder, (s) head / neck, (t) thyroid, (u) thymic, (v) small bowel, (w) bladder, (x) skin, (y) prostate, (z) brain, (aa) neuroendocrine, (ab) soft tissue, (ac) appendiceal, (ad) leukemia, (ae) lymphoma, or (af) myeloma cancers, in a subject in need thereof. 30 In another example, the present invention is directed to a compound as described herein for use in a method for treating a disorder mediated by or modulated by inhibition of WRN, more particularly cancers characterized as microsatellite instability (MSI) or mismatch repair deficient (dMMR), selected from the group consisting of colonic, gastric, rectal, endometrial, adrenocortical, uterine, cervical, 7 PRD4322WOPCT1 5 mesothelial, esophageal, breast, kidney, prostate, ovarian, pancreatic, germ cell, liver, lung, biliary tract / gallbladder, head / neck, thyroid, thymic, small bowel, bladder, skin, prostate, brain, neuroendocrine, soft tissue, appendiceal, leukemia, lymphoma, and myeloma cancers, in a subject in need thereof. In some embodiments, the present invention is directed to compositions 10 comprising (a) a compound of formula (I) and (b) one or more additional therapeutic agents, for the treatment of a disorder mediated by or modulated by inhibition of WRN. In further embodiments, the present invention is directed to compositions comprising (a) a compound of formula (I) and (b) one or more additional therapeutic agents, for use in the preparation of a medicament for the treatment of a disorder 15 mediated by or modulated by inhibition of WRN. In further embodiments, the present invention is directed to methods of treating a disorder mediated by or modulated by inhibition of WRN comprising administration of a composition comprising (a) a compound of formula (I) and (b) one or more additional therapeutic agents. In further embodiments, the present invention is directed to a composition comprising (a) a 20 compound of formula (I) and (b) one or more additional therapeutic agents use in a method for treating a disorder mediated by or modulated by inhibition of WRN. Detailed Description of the Invention The present invention is directed to compounds of formula (I) 25 (I) PRD4322WOPCT1 5 wherein , R1, R2, R3, and R4are as herein defined. The compounds of e present invention are useful as WRN inhibitors, or as intermediates in the synthesis of WRN inhibitors. WRN inhibitors are useful in the treatment of cancer, more specifically cancers characterized as microsatellite instability (MSI) or mismatch repair deficient (dMMR), such as colonic, gastric, rectal, 10 endometrial, adrenocortical, uterine, cervical, mesothelial, esophageal, breast, kidney, prostate, ovarian, pancreatic, germ cell, liver, lung, biliary tract / gallbladder, head / neck, thyroid, thymic, small bowel, bladder, skin, prostate, brain, neuroendocrine, soft tissue, appendiceal, leukemia, lymphoma, and myeloma cancers. The present invention is further directed to compositions (e.g., pharmaceutical 15 compositions) comprising (a) a compound of formula (I) as described herein and (b) one or more additional therapeutic agents (preferably one or more anti-cancer agents); and the use of said compositions in the treatment of a disorder mediated by or modulated by inhibition of WRN (preferably cancer, more preferably a cancer characterized as microsatellite instability (MSI) or mismatch repair deficient (dMMR), 20 such as colonic, gastric, rectal, endometrial, adrenocortical, uterine, cervical, mesothelial, esophageal, breast, kidney, prostate, ovarian, pancreatic, germ cell, liver, lung, biliary tract / gallbladder, head / neck, thyroid, thymic, small bowel, bladder, skin, prostate, brain, neuroendocrine, soft tissue, appendiceal, leukemia, lymphoma, and myeloma cancer. 25 Embodiments In some embodiments, the present invention is directed to compounds of formula (I) wherein ; compounds of formula (I-A) 9 PRD4322WOPCT1 5 A); and stereoisom y acceptable salts thereof. In some embodiments, the present invention is directed to compounds of ula 10 thereof. In some embodiments, the present invention is directed to compounds of is 15 kyl, PRD4322WOPCT1 55is containing heteroaryl; wherein the 6-membered N containing heteroaryl is substituted with -OH, and further substituted with halogen, hydroxy, methyl, ethyl or -CF3; and wherein R6is hydrogen or methyl; provided that whe 10 is , then R1is selected from the group consisting of C1-4alk , is methyl; R3is chloro; and R4is selected tituted C1-3alkyl, 1-hydroxy-cyclobut-1-yl, 1- hydroxy-cyclopent-1-yl, 1-hydroxy-cyclohex-1-yl, 3-hydroxy-tetrahydrofuran-3-yl and 4-hydroxy-tetrahydropyran-4-yl. 15 In some embodiments, the present invention is directed to compounds of is 5 is d N 20 containing heteroaryl is substituted with -OH and methyl; wherein R6is hydrogen; 11 PRD4322WOPCT1 5 provided that when , then R1is selected from the group consisting of C1-3alk nd s methyl; R3is chloro; R4is hydroxy substituted C1-4alkyl; and pologues and pharmaceutically acceptable salts thereof. In some embodiments, the present invention is directed to compounds of 10 formula (I) wherein ; alternative is ; R1is selected from the group consisting of ein ed N containing heteroaryl is substituted with -OH and methyl; wherein R6is hydrogen; 15 R2is methyl; R3is chloro; R4is hydroxy substituted C1-4alkyl; provided that when , then R1is selected from the group consisting of C1-3alkyl nd stereoisomers, isotop . 12 PRD4322WOPCT1 5 In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is C1-4alkyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is C1-3alkyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is C2-3alkyl. In some embodiments, the present invention is directed to compounds of formula (I) 10 wherein C3alkyl is isopropyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting , ts, ed15 from the group consisting nd . In some embodiments, the present invention is directed to rmula (I) wherein R1is selected from the group consisting of . In some embodiments, the present invention 13 PRD4322WOPCT1 5 is directed to compounds of formula (I) wherei or . mbodiments, the present invention is directed to compounds of formula (I) wherein R . In some embodiments, the present invention is directed to compounds of formula (I) wherein In 10 some embodiments, the present invention is directed to co wherein . In some embodiments, the present invention is directed to compounds of formula (I) wherei . In some embodiments, the present in ompounds of formula (I) wherein R1is selected from the group consisting of isopropyl, 1-(methyl-15 carbonyl)-3,6-dihydro-pyridin-4-yl, 1-(methyl-carbonyl)-piperidin-4-yl, 1-(5-hydroxy-6- methyl-pyrimidin-4-yl-carbonyl)-piperidin-4-yl, and 4-(5-hydroxy-6-methyl-pyrimidin-4- yl-carbonyl)-piperazin-1-yl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is isopropyl. In some embodiments, the present invention is directed to compounds of20 formula (I) wherein R1is selected from the group consisting of 1-(methyl-carbonyl)- 3,6-dihydro-pyridin-4-yl, 1-(methyl-carbonyl)-piperidin-4-yl, 1-(5-hydroxy-6-methyl- 14 PRD4322WOPCT1 5 pyrimidin-4-yl-carbonyl)-piperidin-4-yl, 1-(methyl-carbonyl)-piperazin-4-yl, 4-(5- hydroxy-6-methyl-pyrimidin-4-yl-carbonyl)-piperazin-1-yl, 4-(5-hydroxy-6-methyl- pyrimidiny-4-yl-carbonyl)-3-methyl-piperazin-1-yl, 4-(5-hydroxy-6-methyl-pyrimidiny-4- yl-carbonyl)-3R-methyl-piperazin-1-yl, 4-(5-hydroxy-6-methyl-pyrimidiny-4-yl- carbonyl)-3S-methyl-piperazin-1-yl, (rac)-5-(5-hydroxy-6-methyl-pyrimidin-4-yl-10 carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl, (1S*,6S*)-5-(5-hydroxy-6-methyl- pyrimidin-4-yl-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl, and (1R*,6R*)-5-(5- hydroxy-6-methyl-pyrimidin-4-yl-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of 1-(methyl-carbonyl)-15 piperidin-4-yl, 1-(5-hydroxy-6-methyl-pyrimidin-4-yl-carbonyl)-piperidin-4-yl, 1-(methyl- carbonyl)-piperazin-4-yl, 4-(5-hydroxy-6-methyl-pyrimidin-4-yl-carbonyl)-piperazin-1-yl and4-(5-hydroxy-6-methyl-pyrimidiny-4-yl-carbonyl)-3R-methyl-piperazin-1-yl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of 1-(5-hydroxy-6-methyl-20 pyrimidin-4-yl-carbonyl)-piperidin-4-yl, 4-(5-hydroxy-6-methyl-pyrimidin-4-yl-carbonyl)- piperazin-1-yl, (rac)-5-(5-hydroxy-6-methyl-pyrimidin-4-yl-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl, and (1S*,6S*)-5-(5-hydroxy-6-methyl-pyrimidin-4-yl- carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl. In some embodiments, the present invention is directed to compounds of25 formula (I) wherein R1is selected from the group consisting of 1-(methyl-carbonyl)- 3,6-dihydro-pyridin-4-yl, 1-(methyl-carbonyl)-piperidin-4-yl, 1-(5-hydroxy-6-methyl- pyrimidin-4-yl-carbonyl)-piperidin-4-yl, and 4-(5-hydroxy-6-methyl-pyrimidin-4-yl- carbonyl)-piperazin-1-yl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of 1-30 (methyl-carbonyl)-piperidin-4-yl, 1-(5-hydroxy-6-methyl-pyrimidin-4-yl-carbonyl)- piperidin-4-yl, and 4-(5-hydroxy-6-methyl-pyrimidin-4-yl-carbonyl)-piperazin-1-yl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of 1-(methyl-carbonyl)-3,6-dihydro- pyridin-4-yl, 1-(methyl-carbonyl)-piperidin-4-yl, and 1-(5-hydroxy-6-methyl-pyrimidin-4- 15 PRD4322WOPCT1 5 yl-carbonyl)-piperidin-4-yl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is 1-(5-hydroxy-6-methyl-pyrimidin-4-yl- carbonyl)-piperidin-4-yl or 4-(5-hydroxy-6-methyl-pyrimidin-4-yl-carbonyl)-piperazin-1- yl. In some embodiments, the present invention is directed to compounds of 10 formula (I) wherein R5is selected from the group consisting of methyl, ethyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl (preferably pyridinyl or pyrimidinyl); wherein the pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl is substituted with -OH, and further optionally substituted with one to two (preferably one) substituents independently selected from the group consisting of chloro, bromo, fluoro, methyl, ethyl, and CF3 15 (preferably chloro, fluoro or methyl). In some embodiments, the present invention is directed to compounds of formula (I) wherein R5is selected from the group consisting of methyl, ethyl, 3-hydroxy-pyridin-2-yl, 3-hydroxy-4-methyl-pyridin-2-yl, 3-hydroxy-4- methyl-pyridin-2-yl, 3-hydroxy-pyridin-2-yl, and 5-hydroxy-6-methyl-pyrimidin-4-yl. In some embodiments, the present invention is directed to compounds of 20 formula (I) wherein R5is methyl or 5-hydroxy-6-methyl-pyrimidin-4-yl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R5is methyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R5is 5-hydroxy-6-methyl-pyrimidin-4-yl. In some embodiments, the present invention is directed to compounds of 25 formula (I) wherein R6is hydrogen. In some embodiments, the present invention is directed to compounds of formula (I) wherein R6is methyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R2is methyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R2is ethyl. 30 In some embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting of hydroxy substituted C1- 4alkyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R4is hydroxy substituted C1-3alkyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R4is hydroxy 16 PRD4322WOPCT1 5 substituted C1-2alkyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R4is hydroxy substituted C3alkyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R4is 2-hydroxy-propan-2-yl (i.e. ). In some embodi invention is directed to compounds of 4 10 formula (I) wherein R is selected from the group consisting of hydroxy-methyl, 1- hydroxy-ethyl, 2-hydroxy-ethyl, 1-hydroxy-n-propan-1-yl, 2-hydroxy-n-propan-1-yl, 3- hydroxy-n-propan-1-yl, 1-hydroxy-propan-2-yl, 2-hydroxy-propan-2-yl, 1-hydroxy-n- butyl, 2-hydroxy-n-butyl, 3-hydroxy-n-butyl, 4-hydroxy-n-butyl, 1-hydroxy-sec-butyl, 2- hydroxy-sec-butyl, 3-hydroxy-sec-butyl, 4-hydroxy-sec-butyl, 1-hydroxy-iso-butyl, 2- 15 hydroxy-iso-butyl, 3-hydroxy-iso-butyl, and 2-hydroxy-tert-butyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting of hydroxy-methyl, 1-hydroxy-ethyl, 2- hydroxy-ethyl, 1-hydroxy-n-propan-1-yl, 2-hydroxy-n-propan-1-yl, 1-hydroxy-propan-2- yl, 2-hydroxy-propan-2-yl, 1-hydroxy-sec-butyl, 2-hydroxy-sec-butyl, 1-hydroxy-iso- 20 butyl, 2-hydroxy-iso-butyl, 3-hydroxy-isobutyl, and 2-hydroxy-tert-butyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting of hydroxy-methyl, 1-hydroxy-ethyl, 2- hydroxy-ethyl, 1-hydroxy-propan-2-yl, 2-hydroxy-propan-2-yl, 1-hydroxy-iso-butyl, 2- hydroxy-iso-butyl, and 2-hydroxy-tert-butyl. 25 In some embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting of 1-hydroxy-cyclobut-1- yl, 1-hydroxy-cyclopent-1-yl, 1-hydroxy-cyclohex-1-yl, 3-hydroxy-tetrahydrofuran-3-yl and 4-hydroxy-tetrahydropyran-4-yl. In some embodiments the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting 30 of 1-hydroxy-cyclobut-1-yl, 1-hydroxy-cyclopent-1-yl, and 1-hydroxy-cyclohex-1-yl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R4is 1-hydroxy-cyclobut-1-yl. In some embodiments, R4is 1-hydroxy- cyclopent-1-yl. In some embodiments, R4is 1-hydroxy-cyclohex-1-yl. 17 PRD4322WOPCT1 5 In some embodiments, the present invention is directed to compounds of formula (I) wherein R4is 3-hydroxy-tetrahydrofuran-3-yl or 4-hydroxy-tetrahydropyran- 4-yl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting of 3-hydroxy- tetrahydrofuran-3-yl, 3S*-hydroxy-tetrahydrofuran-3-yl, 3R*-hydroxy-tetrahydrofuran- 10 3-yl and 4-hydroxy-tetrahydropyran-4-yl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting of 3-hydroxy-tetrahydrofuran-3-yl, 3S*-hydroxy-tetrahydrofuran-3-yl, and 3R*-hydroxy-tetrahydrofuran-3-yl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R4is 4-hydroxy-tetrahydropyran-4-yl. 15 Additional embodiments of the present invention, include those wherein the substituents selected for one or more of the variables defined herein (e. , R1, R2, R3, R4, R5, etc.) are independently selected to be any individual substituent or any subset of substituents selected from the complete list as defined herein. In additional embodiments, the present invention is directed to any single 20 compound or subset of compounds selected from the representative compounds listed in Table 1, below. Representative compounds of formula (I) of the present invention are listed in Table 1, below. Unless otherwise noted, wherein a stereogenic center is present in the listed compound, the compound was prepared as a mixture of stereo- 25 configurations. Where a stereogenic center is present, S*- and R* designations are intended to indicate that, although the compound was prepared in an enantiomeric excess at the noted stereo-center, the exact stereo-configuration of said stereo-center was not been determined. 18 PRD4322WOPCT1 5 Table 1: Representative Compounds of Formula (I) ID No. Compound Structure and Name - e e 19 PRD4322WOPCT1 - 5- 6- 20 PRD4322WOPCT1 - - 21 PRD4322WOPCT1 - 22 PRD4322WOPCT1 23 PRD4322WOPCT1 - 5 thereof. In some embodiments, the present invention is directed to one or more compounds selected from the group consisting of 10 2-[6-(1-acetyl-4-piperidyl)-2-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-5-methyl-7- oxo-oxazolo[4,5-b]pyridin-4-yl]-N-[2-chloro-4-(trifluoromethyl)phenyl]acetamide; N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[2-[4-(1-hydroxy-1-methyl- ethyl)phenyl]-6-[1-(5-hydroxy-6-methyl-pyrimidine-4-carbonyl)-4-piperidyl]-5-methyl-7- oxo-oxazolo[4,5-b]pyridin-4-yl]acetamide; 24 PRD4322WOPCT1 5 N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[2-[4-(1-hydroxy-1-methyl- ethyl)phenyl]-6-[4-(5-hydroxy-6-methyl-pyrimidine-4-carbonyl)piperazin-1-yl]-5-methyl- 7-oxo-oxazolo[4,5-b]pyridin-4-yl]acetamide; N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[2-[4-(1-hydroxy-1-methyl- ethyl)phenyl]-5-[4-(5-hydroxy-6-methyl-pyrimidine-4-carbonyl)piperazin-1-yl]-6-methyl- 10 4-oxo-oxazolo[5,4-c]pyridin-7-yl]acetamide; N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[2-[4-(1-hydroxy-1-methyl- ethyl)phenyl]-5-[1-(5-hydroxy-6-methyl-pyrimidine-4-carbonyl)-4-piperidyl]-6-methyl-4- oxo-oxazolo[5,4-c]pyridin-7-yl]acetamide; 2-(6-(4-Acetylpiperazin-1-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-5-methyl-7- 15 oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide ; (R)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-3-methylpiperazin-1-yl)-2-(4-(2-hydroxypropan-2- yl)phenyl)-5-methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide ; (rac)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(6-((rac)-5-(5-hydroxy-6-20 methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-5-methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide ; N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(6-((1S*,6S*)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-5-methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide;25 N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(6-((1R*,6R*)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-5-methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide ; N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-5-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-4- 30 oxo-4,5-dihydrooxazolo[5,4-c]pyridin-7-yl)acetamide ; (R)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-3-methylpiperazin-1-yl)-2-(4-(2-hydroxypropan-2- yl)phenyl)-6-methyl-4-oxo-4,5-dihydrooxazolo[5,4-c]pyridin-7-yl)acetamide ;and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. 25 PRD4322WOPCT1 5 In some embodiments, the present invention is directed to one or more compounds selected from the group consisting of 2-[6-(1-acetyl-4-piperidyl)-2-[4-(1- hydroxy-1-methyl-ethyl)phenyl]-5-methyl-7-oxo-oxazolo[4,5-b]pyridin-4-yl]-N-[2-chloro- 4-(trifluoromethyl)phenyl]acetamide; N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[2-[4-(1- hydroxy-1-methyl-ethyl)phenyl]-6-[1-(5-hydroxy-6-methyl-pyrimidine-4-carbonyl)-4-10 piperidyl]-5-methyl-7-oxo-oxazolo[4,5-b]pyridin-4-yl]acetamide; N-[2-chloro-4- (trifluoromethyl)phenyl]-2-[2-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-6-[4-(5-hydroxy-6- methyl-pyrimidine-4-carbonyl)piperazin-1-yl]-5-methyl-7-oxo-oxazolo[4,5-b]pyridin-4- yl]acetamide; N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[2-[4-(1-hydroxy-1-methyl- ethyl)phenyl]-5-[4-(5-hydroxy-6-methyl-pyrimidine-4-carbonyl)piperazin-1-yl]-6-methyl-15 4-oxo-oxazolo[5,4-c]pyridin-7-yl]acetamide; N-[2-chloro-4-(trifluoromethyl)phenyl]-2- [2-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-5-[1-(5-hydroxy-6-methyl-pyrimidine-4- carbonyl)-4-piperidyl]-6-methyl-4-oxo-oxazolo[5,4-c]pyridin-7-yl]acetamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In some embodiments, the present invention is directed to 2-[6-(1-acetyl-3,6-20 dihydro-2H-pyridin-4-yl)-2-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-5-methyl-7-oxo- oxazolo[4,5-b]pyridin-4-yl]-N-[2-chloro-4-(trifluoromethyl)phenyl]acetamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In some embodiments, the present invention is directed to 2-[6-(1-acetyl-4-piperidyl)-2-[4-(1- hydroxy-1-methyl-ethyl)phenyl]-5-methyl-7-oxo-oxazolo[4,5-b]pyridin-4-yl]-N-[2-chloro- 25 4-(trifluoromethyl)phenyl]acetamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In some embodiments, the present invention is directed to N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[2-[4-(1-hydroxy-1- methyl-ethyl)phenyl]-6-isopropyl-5-methyl-7-oxo-oxazolo[4,5-b]pyridin-4-yl]acetamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In30 some embodiments, the present invention is directed to N-[2-chloro-4- (trifluoromethyl)phenyl]-2-[2-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-6-[1-(5-hydroxy-6- methyl-pyrimidine-4-carbonyl)-4-piperidyl]-5-methyl-7-oxo-oxazolo[4,5-b]pyridin-4- yl]acetamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In some embodiments, the present invention is directed to N-[2-chloro-4- 26 PRD4322WOPCT1 5 (trifluoromethyl)phenyl]-2-[2-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-6-[4-(5-hydroxy-6- methyl-pyrimidine-4-carbonyl)piperazin-1-yl]-5-methyl-7-oxo-oxazolo[4,5-b]pyridin-4- yl]acetamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In some embodiments, the present invention is directed to N-[2-chloro-4- (trifluoromethyl)phenyl]-2-[2-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-5-[4-(5-hydroxy-6-10 methyl-pyrimidine-4-carbonyl)piperazin-1-yl]-6-methyl-4-oxo-oxazolo[5,4-c]pyridin-7- yl]acetamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In some embodiments, the present invention is directed to N-[2-chloro-4- (trifluoromethyl)phenyl]-2-[2-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-5-[1-(5-hydroxy-6- methyl-pyrimidine-4-carbonyl)-4-piperidyl]-6-methyl-4-oxo-oxazolo[5,4-c]pyridin-7- 15 yl]acetamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In some embodiments, the present invention is directed to 2-(6-(4- acetylpiperazin-1-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-5-methyl-7-oxooxazolo[4,5- b]pyridin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide ; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In some20 embodiments, the present invention is directed to (R)-N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-3- methylpiperazin-1-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-5-methyl-7-oxooxazolo[4,5- b]pyridin-4(7H)-yl)acetamide ; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In some embodiments, the present25 invention is directed to (rac)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-((rac)-5-(5- hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-5-methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide ; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In some embodiments, the present invention is directed to N-(2-chloro-4-30 (trifluoromethyl)phenyl)-2-(6-((1S*,6S*)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)- 2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-5-methyl-7- oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In some embodiments, the present invention is directed to N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-((1R*,6R*)-5-(5- 27 PRD4322WOPCT1 5 hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-5-methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide ; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In some embodiments, the present invention is directed to N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(6-ethyl-5-(4-(5-hydroxy-6-methylpyrimidine-4-10 carbonyl)piperazin-1-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-4-oxo-4,5- dihydrooxazolo[5,4-c]pyridin-7-yl)acetamide ; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In some embodiments, the present invention is directed to (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-(4 (5-hydroxy- 6-methylpyrimidine-4-carbonyl)-3-methylpiperazin-1-yl)-2-(4-(2-hydroxypropan-2- 15 yl)phenyl)-6-methyl-4-oxo-4,5-dihydrooxazolo[5,4-c]pyridin-7-yl)acetamide ; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In some embodiments, the present invention is directed to compounds of formula (I) which, when tested according to the procedure as described in Biological 20 Example 1, which follows hereinafter, exhibit an IC50 of less than or equal to about 1 µM, preferably less than or equal to about 0.5 µM, preferably less than or equal to about 0.25 µM, preferably less than or equal to about 0.1 µM, preferably less than or equal to about 0.05 µM, preferably less than or equal to about 0.02 µM, preferably less than or equal to about 0.01 µM, preferably less than or equal to about 0.005 µM, 25 preferably less than or equal to about 0.002 µM. In some embodiments, the present invention is directed to compounds of formula (I) which, when tested according to the procedure as described in Biological Example 2A, which follows hereinafter, exhibit an IC50 of less than or equal to about 1 µM, preferably less than or equal to about 0.5 µM, preferably less than or equal to 30 about 0.25 µM, preferably less than or equal to about 0.1 µM, preferably less than or equal to about 0.09 µM, preferably less than or equal to about 0.05 µM, preferably less than or equal to about 0.03 µM, preferably less than or equal to about 0.02 µM, preferably less than or equal to about 0.01 µM. 28 PRD4322WOPCT1 5 In some embodiments, the present invention is directed to compounds of formula (I) which, when tested according to the procedure as described in Biological Example 2B, which follows hereinafter, exhibit an IC50of greater than or equal to about 1 µM, preferably greater than or equal to about 5 µM, preferably greater than or equal to about 10 µM, preferably greater than or equal to about 20 µM, preferably 10 greater than or equal to about 25 µM, preferably greater than or equal to about 30 µM. Definitions and Abbreviations As used herein, unless otherwise noted, the term ”halogen” shall mean chloro, bromo, fluoro and iodo. One skilled in the art will recognize that wherein the halogen is 15 a leaving group, said halogen is preferably bromo, chloro or iodo, more preferably bromo. As used herein, the term “CX-Yalkyl” wherein X and Y are integers, whether used alone or as part of a substituent group, shall include straight and branched chains containing between X and Y carbon atoms. For example, C1-4alkyl shall 20 include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl (also known as t-butyl). As used herein unless otherwise noted, the term “6-membered nitrogen containing heteroaryl” shall mean any monocyclic aromatic ring structure containing at least one ring N atom, optionally containing one to three (preferably one to two) 25 additional ring heteroatoms independently selected from the group consisting of N, O and S. The 6-membered nitrogen containing heteroaryl may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure. Suitable examples include, but are not limited to pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl (e.g.1,2,4-triazinyl, 1,3,5-triazinyl) and the like. 30 When a particular group is “substituted” (e.g., CX-Yalkyl, etc.), that group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents, independently selected from the list of substituents. 29 PRD4322WOPCT1 5 With reference to substituents, the term “independently” means that when more than one of such substituents is possible, such substituents may be the same or different from each other. As used herein, the “*” notation shall denote the presence of a stereogenic center. 10 Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. 15 Wherein the compound is present as an enantiomer, the enantiomer is preferably present at an enantiomeric excess of greater than or equal to about 80%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, 20 most preferably, at an enantiomeric excess of greater than or equal to about 99%. Similarly, wherein the compound is present as a diastereomer, the diastereomer is preferably present at an diastereomeric excess of greater than or equal to about 80%, more preferably, at an diastereomeric excess of greater than or equal to about 90%, more preferably still, at an diastereomeric excess of greater than 25 or equal to about 95%, more preferably still, at an diastereomeric excess of greater than or equal to about 98%, most preferably, at an diastereomeric excess of greater than or equal to about 99%. Furthermore, some of the crystalline forms for the compounds of the present invention may exist as polymorphs and as such are intended to be included in the 30 present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention. Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent 30 PRD4322WOPCT1 5 functionality toward the point of attachment. Thus, for example, a “phenylC1- C6alkylaminocarbonylC1-C6alkyl” substituent refers to a group of the formula . Abbreviations used in the specification, particularly the Schemes and 10 Examples herein, are as follows: Ac = Acetyl - 31 PRD4322WOPCT1 DCE = 1,2-Dichloroethane DCM = Dichloromethane id 32 PRD4322WOPCT1 Mesyl or Ms = Methylsulfonyl MOM = Methoxymethyl 33 PRD4322WOPCT1 TBAF = Tetra-n-butylammonium fluoride TCEP = (tris(2-carboxyethyl)phosphine) ′- 5 As used herein, unless otherwise noted, the term “isolated form” shall mean that the compound is present in a form which is separate from any solid mixture with 34 PRD4322WOPCT1 5 another compound(s), solvent system or biological environment. In an embodiment of the present invention, the compound of formula (I) is present in an isolated form. As used herein, unless otherwise noted, the term “substantially pure form” shall mean that the mole percent of impurities in the isolated compound is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than 10 about 0.5 mole percent, most preferably, less than about 0.1 mole percent. In an embodiment of the present invention, the compound of formula (I) is present as a substantially pure form. As used herein, unless otherwise noted, the term “substantially free of a corresponding salt form(s)” when used to described the compound of formula (I) shall 15 mean that mole percent of the corresponding salt form(s) in the isolated base of formula (I) is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably less than about 0.1 mole percent. In an embodiment of the present invention, the compound of formula (I) is present in a form which is substantially free of corresponding salt 20 form(s). As more extensively provided in this written description, terms such as “reacting” and “reacted” are used herein in reference to a chemical entity that is any one of: (a) the actually recited form of such chemical entity, and (b) any of the forms 25 of such chemical entity in the medium in which the compound is being considered when named. One skilled in the art will recognize that, where not otherwise specified, the reaction step(s) is performed under suitable conditions, according to known methods, to provide the desired product. One skilled in the art will further recognize that, in the 30 specification and claims as presented herein, wherein a reagent or reagent class / type (e.g. base, solvent, etc.) is recited in more than one step of a process, the individual reagents are independently selected for each reaction step and may be the same or different from each other. For example, wherein two steps of a process recite an organic or inorganic base as a reagent, the organic or inorganic base selected for the 35 PRD4322WOPCT1 5 first step may be the same or different than the organic or inorganic base of the second step. Further, one skilled in the art will recognize that wherein a reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems. 10 Examples of suitable solvents, bases, reaction temperatures, and other reaction parameters and components are provided in the detailed descriptions which follows herein. One skilled in the art will recognize that the listing of said examples is not intended, and should not be construed, as limiting in any way the invention set forth in the claims which follow thereafter. 15 To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about”. It is understood that whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including 20 approximations due to the experimental and / or measurement conditions for such given value. To provide a more concise description, some of the quantitative expressions herein are recited as a range from about amount X to about amount Y. It is understood that wherein a range is recited, the range is not limited to the recited 25 upper and lower bounds, but rather includes the full range from about amount X through about amount Y, or any amount or range therein. As used herein, unless otherwise noted, the term “leaving group” shall mean a charged or uncharged atom or group which departs during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, 30 mesylate, tosylate, and the like. During any of the processes for preparation of the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic 36 PRD4322WOPCT1 5 Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. As used herein, unless otherwise noted, the term “nitrogen protecting group” 10 shall mean a group which may be attached to a nitrogen atom to protect said nitrogen atom from participating in a reaction and which may be readily removed following the reaction. Suitable nitrogen protecting groups include, but are not limited to carbamates – groups of the formula –C(O)O-R wherein R is for example methyl, ethyl, tert-butyl, benzyl, phenylethyl, CH2=CH-CH2-, and the like; amides – groups of the 15 formula –C(O)-R’ wherein R’ is for example methyl, phenyl, trifluoromethyl, and the like; N-sulfonyl derivatives – groups of the formula –SO2-R” wherein R” is for example tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4- methoxybenzene, and the like. Other suitable nitrogen protecting groups may be found in texts such as T.W. Greene & P.G.M. Wuts, Protective Groups in Organic 20 Synthesis, John Wiley & Sons, 1991. As used herein, unless otherwise noted, the term “oxygen protecting group” shall mean a group which may be attached to an oxygen atom to protect said oxygen atom from participating in a reaction and which may be readily removed following the reaction. Suitable oxygen protecting groups include, but are not limited to, acetyl, 25 benzoyl, tert-butyl-dimethylsilyl, trimethylsilyl (TMS), MOM, THP, and the like. Other suitable oxygen protecting groups may be found in texts such as T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. General Synthesis Schemes 37 PRD4322WOPCT1 5 Compounds of formula (I) wherei ; (such that the core scaffold nd wherein R4is may be prepared, for example, as d 1, below. 10 PRD4322WOPCT1 5 Accordingly, a suitably substituted compound of formula (V), a known compound or compound prepared by known methods, is reacted with a suitably selected agent such as NH4Cl, AcOH, and the like; in the presence of a suitably selected catalyst such as Fe, and the like; in a suitably selected solvent or mixture of solvents such as a mixture of ethanol / water, THF / water, THF / ethanol / water and the 10 like; at a temperature in the range of from about 20˚C to about 100˚C, for example at about 80˚C; to yield the corresponding compound of formula (VI). The compound of formula (VI) is reacted with a suitably substituted compound of formula (VII) wherein LG1is a suitably selected leaving group such as Br, Cl, I, and the like, a known compound or compound prepared by known methods; in the 15 presence of a suitably selected coupling agent such as PPA, TsOH, POCl3, Eaton’s reagent (Phosphorus pentoxide, 7.7 wt. % in methanesulfonic acid) and the like; neat or in a suitably selected solvent such as xylene, NMP, 1,4-dioxane and the like; at a temperature in the range of from about 80˚C to about 220˚C, for example at about 130˚C; to yield the corresponding compound of formula (VIII). 20 The compound of formula (VIII) is reacted with a suitably selected agent such as NaOCH3, and the like (e.g. NaOCH3 formed in situ via reaction of NaH and MeOH); in a suitably selected solvent such as methanol, THF, DMSO, and the like; at a temperature in the range of from about 25˚C to about 140˚C, for example at about 80˚C; to yield the corresponding compound of formula (IX). 25 The compound of formula (IX) is reacted with a suitably substituted compound of formula (X), wherein LG2is a suitably selected leaving group such as I, Br, and the like, a known compound or compound prepared by known methods; in a suitably selected solvent such as toluene, 1,4-dioxane, and the like; at a temperature in the range of from about 80˚C to about 150˚C, for example at about 130˚C; to yield the 30 corresponding compound of formula (XI). The compound of formula (XI) is reacted with CO; in the presence of a suitably selected coupling agent such as Pd(dppf)Cl2•DCM, Pd(PPh3)4, Pd(PPh3)2Cl2, and the like; in the presence of a suitably selected organic amine base such as TEA, DIPEA, pyridine, and the like; in a suitably selected solvent or mixture of solvents such as 39 PRD4322WOPCT1 5 methanol / DMF, methanol / EtOAc, methanol / MeCN and the like; at a temperature in the range of from about 60˚C to about 120˚C, for example at about 80˚C; to yield the corresponding compound of formula (XII). The compound of formula (XII) is reacted with methyl magnesium bromide, a known compound or compound prepared by known methods; in a suitably selected 10 anhydrous solvent such as anhydrous THF, 1,4-dioxane, and the like; at a temperature in the range of from about -78˚C to about 25˚C, for example at about 0˚C; to yield the corresponding compound of formula (XIII). The compound of formula (XIII) is reacted with a suitably selected brominating agent such as NBS, Br2, and the like; in a suitably selected solvent such as DMF, 15 MeCN, and the like; at a temperature in the range of from about -20˚C to about 25˚C, for example at about 0˚C; to yield the corresponding compound of formula (XIV). The compound of formula (XIV) is reacted with a suitably substituted compound of formula (XV), wherein -B(R)2 represents a suitably substituted boronic acid (wherein each R is OH) or a suitably substituted boronic ester (wherein each R is 20 -O-C1-4alkyl or alternatively, the two R groups are taken together with the boron atom to which they are bound to for , and the like); a known compound or compound prepared by known under Suzuki coupling conditions (for example, in the presence of a suitably selected catalyst such as Pd(dppf)Cl2•DCM, Pd-118, Xphos Pd G3, CataCXium Pd G3, and the like; in the presence of a suitably 25 selected agent such as Cs2CO3, K2CO3, Na2CO3, K3PO4, and the like; in a suitably selected solvent or mixture of solvents such as 1,4-dioxane, toluene, DMF, DMSO, DMF / water, and the like; at a temperature in the range of from about 50˚C to about 100˚C, for example, at about 60°C; to yield the corresponding compound of formula (Ia). 30 Compounds of formula (I) wherein R4i may alternatively be prepared as described in Scheme 2, below. 40 PRD4322WOPCT1 5 10 Accordingly, a suitably substituted compound of formula (IX), prepared for example as described in Scheme 1 above, is reacted with CO; in the presence of a suitably selected coupling agent such as Pd(dppf)Cl2•DCM, Pd(PPh3)4, Pd(PPh3)2Cl2, XantPhos Pd G3 and the like; in the presence of a suitably selected organic amine base such as TEA, DIPEA, pyridine, and the like; in a suitably selected solvent or 15 mixture of solvents such as methanol / DMF, methanol / EtOAc, methanol / MeCN, and the like; at a temperature in the range of from about 60˚C to about 120˚C, for example at about 80˚C; to yield the corresponding compound of formula (XVI). 41 PRD4322WOPCT1 5 The compound of formula (XVI) is reacted with methyl magnesium bromide a known compound or compound prepared by known methods; in a suitably selected anhydrous solvent such as anhydrous THF, 1,4-dioxane, and the like; at a temperature in the range of from about -78˚C to about 25˚C, for example at about 0˚C; to yield the corresponding compound of formula (XVII). 10 The compound of formula (XVII) is reacted with a suitably selected brominating agent such as NBS, Br2, and the like; in a suitably selected solvent such as DMF, MeCN, and the like; at a temperature in the range of from about 0˚C to about 50˚C, for example at about 50˚C; to yield the corresponding compound of formula (XVIII). The compound of formula (XVIII) is reacted with a suitably substituted 15 compound of formula (XV), wherein -B(R)2 represents a suitably substituted boronic acid (wherein each R is OH) or a suitably substituted boronic ester (wherein each R is -O-C1-4alkyl or alternatively, the two R groups are taken together with the boron atom to which they are bound to for , and the like); a known compound or compound prepared by known under Suzuki coupling conditions (for 20 example, in the presence of a suitably selected catalyst such as Pd(dppf)Cl2•DCM, Pd-118, Xphos Pd G3, CataCXium Pd G3, and the like; in the presence of a suitably selected agent such as Cs2CO3, K2CO3, Na2CO3, K3PO4, and the like; in a suitably selected solvent or mixture of solvents such as 1,4-dioxane, toluene, DMF, DMSO, DMF / water, and the like; at a temperature in the range of from about 50˚C to about 25 100˚C, for example, at about 60°C; to yield the corresponding compound of formula (XIX). The compound of formula (XIX) is reacted with a suitably substituted compound of formula (XX), wherein LG3is a suitably selected leaving group such as Br, I, and the like, a known compound or compound prepared by known methods; in a 30 suitably selected solvent such as toluene, 1,4-dioxane, and the like; at a temperature in the range of from about 80˚C to about 150˚C, for example at about 120˚C; to yield the corresponding compound of formula (XXI). 42 PRD4322WOPCT1 5 The compound of formula (XXI) is de-protected to remove the benzyl protecting group, according to known methods, to yield the corresponding compound of formula (XXII). For example, the compound of formula (XXI) may be reacted with H2, in the presence of a suitably selected catalyst such as PtO2, and the like; in a suitably selected solvent such as MeOH, and the like; at about room temperature. 10 The compound of formula (XXII) is reacted with a suitably substituted compound of formula (XXIII), a known compound or compound prepared by known methods; in the presence of a suitably selected coupling agent such as Mukaiyama reagent, HATU, T3P and the like; in the presence of a suitably selected organic amine base such as TEA, DIPEA, pyridine, and the like; in a suitably selected solvent such 15 as DMF, MeCN, THF, and the like; at a temperature in the range of from about 25˚C to about 80˚C, for example at about 50˚C; to yield the corresponding compound of formula (Ia). Compounds of formula (I) wherein R4is selected from the group consisting of20 1-hydroxy-cyclobut-1-yl, 1-hydroxy-cyclopent-1-yl, 1-hydroxy-cyclohex-1-yl, 3- hydroxy-tetrahydrofuran-3-yl and 4-hydroxy-tetrahydropyran-4-yl may be prepared as described in Scheme 3, below. PRD4322WOPCT1 5 Accordingly a suitably substituted compound of formula (IX), prepared as described herein, is reacted with a suitably selected agent such as n-BuLi, iPrMgCl•LiCl, and the like; in a suitably selected solvent such as THF, Et2O, 1,4- dioxane, and the like; at a temperature in the range of from about -78˚C to about 25˚C, for example at about -78˚C; to yield an intermediate which is directly (without 10 isolation or purification) reacted with a suitably selected ketone derivative of R4(e.g. ii l l l entto about 25˚C, for example at about -78˚C; to yield the corresponding compound of formula (XXIIV). 15 The compound of formula (XXIV) is then substituted for the compound of formula (XVII) in Scheme 2, and reacted as described therein, to yield the corresponding compound of formula (I). Compounds of formula (I) may alternatively be prepared as described in 20 Scheme 4, below. 44 PRD4322WOPCT1 5 Accordingly, a suitably substituted compound of formula (XXV), prepared for example as described herein, is reacted with a suitably substituted and protected 10 compound of formula (XXVI), wherein R10is hydrogen and R6is as herein defined (i.e. ), or R10and R6are taken together with the carbon atoms to which they are bound to form cyclobutyl (i.e.3 ), and wherein PG is a suitably selected protecting group such as BOC, Cbz, Ac, and the like, a known compound or compound prepared by known methods; in the presence of a suitably selected 15 coupling agent such as Pd(OAc)2, Pd(dba)2, and the like; in the presence of a suitably selected agent such as BINAP, XPhos, and the like; in the presence of a suitably 45 PRD4322WOPCT1 5 selected base such as Cs2CO3, K2CO3, Na2CO3, and the like; in a suitably selected solvent such as 1,4-dioxane, DMF, and the like; at a temperature in the range of from about 80 ˚C to about 130˚C, for example at about 130˚C; to yield the corresponding compound of formula (XXVII). The compound of formula (XXVII) is reacted with a suitably substituted 10 compound of formula (X), wherein LG2is a suitably selected leaving group such as I, Br, and the like, a known compound or compound prepared by known methods; in a suitably selected solvent such as toluene, 1,4-dioxane, and the like; at a temperature in the range of from about 80˚C to about 130˚C, for example at about 120˚C; to yield the corresponding compound of formula (XXVIII). 15 The compound of formula (XXVIII) is deprotected according to known methods; to yield the corresponding compound of formula (XXIX). For example, wherein PG3is BOC, the compound of formula (XXVIII) is reacted with a suitably selected acid such as HCl, and the like. Alternatively, wherein PG3is BOC, the compound of formula (XXVII) may be de-protected by reacting with HFIP; at an elevated temperature. 20 The compound of formula (XXIX) is reacted with a suitably substituted compound of formula (XXX), a known compound or compound prepared by known methods; in the presence of a suitably selected coupling agent or mixture such as HOPO and EDCI, HATU, Mukaiyama’s reagent, and the like; in the presence of a suitably selected organic amine base such as DIPEA, Et3N, and the like; in a suitably 25 selected solvent such as 1,4-dioxane, DCM, NMP, DMF, and the like; at a temperature in the range of from about 25˚C to about 70˚C, for example at about 50˚C; to yield the corresponding compound of formula (Ib). Compounds of formula (I) wherein R1grou , may 30 alternatively be prepared as described in Scheme 5, eow. 46 PRD4322WOPCT1 5 Accordingly, a suitably substituted compound of formula (XXV), prepared as described herein, is reacted with a suitably substituted compound of formula (XXXI), 10 wherein PG4is a suitably selected nitrogen protecting group such as BOC, Cbz, Ac, and the like, a known compound or compound prepared by known methods; in the presence of a suitably selected palladium coupling agent such as CPhos Pd G3, P(PPh3)4, SPhos Pd G3 and the like; in the presence of a suitably selected agent such as LiCl, LiBr, and the like; in a suitably selected solvent such as DMA, THF, 15 DMF, 1,4-dioxane and the like; at a temperature in the range of from about 25˚C to about 80˚C, for example, at about 60°C; to yield the corresponding compound of formula (XXXII). The compound of formula (XXXII) is then substituted for the compound of formula (XXVII) in Scheme 4, and reacted as described therein, to yield the 20 corresponding compound of formula (Ic). Compounds of formula (I) wherein R1is isopropyl, may alternatively be prepared as described in Scheme 6, below. 47 PRD4322WOPCT1 5 Accordingly, a suitably substituted compound of formula (XIV), prepared as described herein, is reacted with a compound of formula (XXXIII), compound of formula ), wherein -B(R)2 represents a suitably substituted boronic acid (wherein each 10 R is OH) or a suitably substituted boronic ester (wherein each R is -O-C1-4alkyl or alternatively, the two R groups are taken together with the boron atom to which they are bound to form , and the like); a known compound or compound prepared by known methods; under Suzuki coupling conditions (for example, in the presence of a suitably selected catalyst such as Pd(dppf)Cl2•DCM, Pd-118, 15 CataCXium Pd G3, and the like; in the presence of a suitably selected agent such as Cs2CO3, K2CO3, Na2CO3, K3PO4, and the like; in a suitably selected solvent or mixture of solvents such as 1,4-dioxane, toluene, DMF, DMSO, DMF / water, and the like; at a temperature in the range of from about 60˚C to about 100˚C, for example, at about 90°C; to yield the corresponding compound of formula (XXXIV). 20 The compound of formula (XXXIV) is reacted with hydrogen; in the presence of a suitably selected catalyst such as Rh / Al2O3, Pt2O, and the like; in a suitably selected 48 PRD4322WOPCT1 5 solvent or mixture thereof such as THF, MeOH, EtOAc, and the like; at about room temperature; to yield the corresponding compound of formula (Id). Compounds of formula (I) wherei ; (such that the core scaffold ) may be prepared as described in 10 Scheme 7 below. PRD4322WOPCT1 5 Accordingly, a suitably substituted compound of formula (XL), wherein is selected from the group consisting of , bly selected ompound as described herein (e.g., as in Schemes 9-10 which follow herein) is reacted with a 10 suitably selected brominating agent such as NBS, Br2, and the like; in a suitably selected solvent such as DMF, MeCN, and the like; at a temperature in the range of from about 0˚C to about 50˚C, for example at about 0˚C, for example at about 50˚C; to yield the corresponding compound of formula (XLI). The compound of formula (XLI) is reacted with a compound of formula (XLII), a 15 known compound or compound prepared by known methods; in the presence of a suitably selected catalyst such as Pd(dppf)Cl2•DCM, Pd-118, Xphos Pd G3, CataCXium Pd G3, and the like; in the presence of a suitably selected agent such as XPhos, and the like; optionally in the presence of ZnF2, and the like; in a suitably selected solvent or mixture of solvents such as THF, 1,4-dioxane, and the like; at a 20 temperature in the range of from about 50˚C to about 120˚C, for example, at about 90°C; to yield the corresponding compound of formula(XLIII). The compound of formula (XLIII) is reacted with a suitably substituted compound of formula (XXIII), a known compound or compound prepared by known methods; in the presence of a suitably selected agent such as LiHMDS, NaHMDS, 25 and the like; in a suitably selected solvent such as THF, 1,4-dioxane, and the like; at a temperature in the range of from about 0˚C to about 25˚C, for example at about 0˚C; to yield the corresponding compound of formula (XLIV). The compound of formula (XLIV) is deprotected according to known methods; to yield the corresponding compound of formula (XLV). For example, wherein PG5is 30 BOC, the compound of formula (XLIV) is reacted with a suitably selected acid such as 50 PRD4322WOPCT1 5 HCl, and the like. Alternatively, wherein PG5is BOC, the compound of formula (XLIV) may be de-protected by reacting with HFIP; at an elevated temperature. The compound of formula (XLV) is reacted with a suitably substituted compound of formula (XXX), a known compound or compound prepared by known methods; in the presence of a suitably selected coupling agent or mixture such as 10 HOPO and EDCI, Mukaiyama’s reagent, HATU, and the like; in the presence of a suitably selected organic amine base such as DIPEA, Et3N, and the like; in a suitably selected solvent such as 1,4-dioxane, DCM, NMP, DMF, and the like; at a temperature in the range of from about 25˚C to about 70˚C, for example at about 50˚C; to yield the corresponding compound of formula (Ie). 15 Compounds of formula (XL) may be prepared as described in Scheme 8, below. 20 Accordingly, ethyl 4-bromooxazole-5-carboxylate, a known compound or compound prepared by known methods, is reacted with a suitably selected reagent such as tributyl(prop-1-yn-1-yl)stannane (also known as tributyl(1-propynyl)tin), 51 PRD4322WOPCT1 5 potassium trifluoro(prop-1-yn-1-yl)borate, but-1-yn-1-yltributylstannane, 2-(but-1-yn-1- yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and the like; in the presence of a suitably selected coupling agent such as Pd(dppf)Cl2, Pd-118, and the like; in the presence of CuI; in the presence of a suitably selected agent such as CsF, Cs2CO3, and the like; in a suitably selected solvent such as DMF, DMF / water, 1,4-dioxane / water, and the 10 like; at a temperature in the range of from about 80˚C to about 130˚C, for example at about 120˚C; to yield the corresponding compound of formula (XLVI). One skilled in the art will recognize that reacting ethyl 4-bromooxazole-5-carboxylate with tributyl(prop-1-yn-1-yl)stannane or potassium trifluoro(prop-1-yn-1-yl)borate, will yield the corresponding compound of formula (XLVI) wherein R2is methyl. Similarly,15 reacting ethyl 4-bromooxazole-5-carboxylate with but-1-yn-1-yltributylstannane or 2- (but-1-yn-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, will yield the corresponding compound of formula (XLVI) wherein R2is ethyl. The compound of formula (XLVI) is reacted with a suitably selected reducing agent such as a mixture of LiOH•H2O, NaOH, KOH, and the like; in a suitably selected20 solvent or mixture of solvents such as a mixture of THF, methanol and water, 1,4- dioxane / water, and the like; at about room temperature; to yield the corresponding compound of formula (XLVII). The compound of formula (XLVII) is reacted with a suitably substituted compound of formula (XLVIII), wherein is selected from the group 25 consisting , wherein PG5is a suitably se , and the like, a known compound or compound prepared by known methods; in the presence of a suitably selected coupling agent or mixture such as HOPO and EDCI, HATU, Mukaiyama’s reagent and the like; in the presence of a suitably selected organic amine base such 30 as DIPEA, Et3N, and the like; in a suitably selected solvent such as 1,4-dioxane, DCM, NMP, and the like; at a temperature in the range of from about 25˚C to about 52 PRD4322WOPCT1 5 70˚C, for example at about 50˚C; to yield the corresponding compound of formula (XLIX). The compound of formula (XLIX) is reacted with a suitably selected agent such as DBU, KOtBu, and the like; in a suitably selected solvent such as DMF, DMA, DMSO, and the like; at a temperature in the range of from about 80˚C to about 120˚C, 10 for example at about 100˚C; to yield the corresponding compound of formula (L). The compound of formula (L) is reacted with a suitably substituted compound of formula (LXI), wherein -B(R)2 represents a suitably substituted boronic acid (wherein each R is OH) or a suitably substituted boronic ester (wherein each R is -O- C1-4alkyl or alternatively, the two R groups are taken together with the boron atom to 15 which they are bound to form , and the like); a known compound or compound prepared by know s; in the presence of a suitably selected coupling agent such as Pd(OAc)2, PdCl2, and the like; in the presence of a suitably selected agent such as Cu(OAc)2, CuBr2, and the like; in the presence of a suitably selected ligand such as 1,10-phenanthroline, 2,2-bipyridyl, PPh3, and the like; in the 20 presence of a suitably selected base such as K3PO4, K2CO3, Cs2CO3, and the like; in a suitably selected solvent such as DMSO, DMF, NMP, MeCN, and the like; at a temperature in the range of from about 80˚C to about 120˚C, for example at about 100˚C; to yield the corresponding compound of formula (XL). 25 Compounds of formula (XL) may alternatively be prepared as described in Scheme 9, below. PRD4322WOPCT1 5 Accordingly, ethyl 2,4-dibromooxazole-5-carboxylate, a known compound or compound prepared by known methods is reacted with a suitably substituted 10 compound of formula (LI), wherein -B(R)2 represents a suitably substituted boronic acid (wherein each R is OH) or a suitably substituted boronic ester (wherein each R is -O-C1-4alkyl or alternatively, the two R groups are taken together with the boron atom to which they are bound to for , and the like), a known compound or compound prepared by known n the presence of a suitably selected 15 coupling agent such as Pd(dppf)Cl2, Pd-118, Pd(PPh3)2Cl2 and the like; in the presence of a suitably selected inorganic base such as Na2CO3, Cs2CO3, K2CO3, K3PO4, and the like; in a suitably selected solvent or mixture of solvents such as a mixture of 1,4-dioxane / water, DMF / water, toluene / water and the like; at a temperature in the range of from about 60˚C to about 100˚C, for example at about 80˚C; to yield 20 the corresponding compound of formula (LII). The compound of formula (LII) is reacted with a suitably selected reagent such as tributyl(prop-1-yn-1-yl)stannane (also known as tributyl(1-propynyl)tin), potassium trifluoro(prop-1-yn-1-yl)borate, but-1-yn-1-yltributylstannane, 2-(but-1-yn-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane and the like; in the presence of a suitably selected 25 coupling agent such as Pd(dppf)Cl2, Pd-118, and the like; in the presence of CuI; in 54 PRD4322WOPCT1 5 the presence of a suitably selected agent such as CsF, Cs2CO3, and the like; in a suitably selected solvent such as DMF, 1,4-dioxane, DMF / water, 1,4-dioxane / water and the like; at a temperature in the range of from about 80 ˚C to about 120˚C, for example at about 120˚C; to yield the corresponding compound of formula (LIII). One skilled in the art will recognize that reacting the compound of formula (LII) with 10 tributyl(prop-1-yn-1-yl)stannane or potassium trifluoro(prop-1-yn-1-yl)borate, will yield the corresponding compound of formula (LIII) wherein R2is methyl. Similarly, reacting the compound of formula (LII) with but-1-yn-1-yltributylstannane or 2-(but-1- yn-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, will yield the corresponding compound of formula (LIII) wherein R2is ethyl. 15 The compound of formula (LIII) is reacted with a suitably selected reducing agent such as a mixture of LiOH•H2O, NaOH, KOH, and the like; in a suitably selected solvent or mixture of solvents such as a mixture of THF, methanol and water, 1,4- dioxane / water, THF / water, and the like; at about room temperature; to yield the corresponding compound of formula (LIV). 20 The compound of formula (LIV) is reacted with a suitably substituted compound of formula (XLVIII), wherei is selected from the group consisting of , wherein PG5is a suitably selected d the like, a known compound or compound prepared by known methods; in the presence of a suitably selected 25 coupling agent or mixture such as HOPO and EDCI, HATU, Mukaiyama’s reagent and the like; in the presence of a suitably selected organic amine base such as DIPEA, Et3N, and the like; in a suitably selected solvent such as 1,4-dioxane, DCM, NMP, DMF, and the like; at a temperature in the range of from about 25˚C to about 70˚C, for example at about 50˚C; to yield the corresponding compound of formula (LV). 30 The compound of formula (LV) is reacted with a suitably selected agent such as DBU, KOtBu, NaOtBu, and the like; in a suitably selected solvent such as DMF, 55 PRD4322WOPCT1 5 DMSO, and the like; at a temperature in the range of from about 80˚C to about 120˚C, for example at about 100˚C; to yield the corresponding compound of formula (XL). Compounds of formula (I) wherei ; (such that the core scaffold nd wherein R1is C1-4alkyl may be 10 similarly prepared accordin cribed in Scheme 7 above, by substituting a suitably substituted compound of formula (XXXV) V) for the compoun cribed therein. Compounds of formula (XXXV) may be prepared according to the procedures 15 described in Schemes 8 and 9 above, by substituting a suitably substituted (C1- 4alkyl)amine (a compound of the formula NH2(C1-4alkyl)), a known compound or compound prepared by known methods) for the compound of formula (LXVIII) and reacting as described therein. 56 PRD4322WOPCT1 5 Compounds of formula (I ; (such that or may alternatively be prepared as described in Scheme 10, below. 10 Accordingly, a suitably substituted compound of formula (XXV), a known compound or compound prepared as described herein is reacted with a suitably substituted compound of formula (LVI), wherein R10is hydrogen and R6is as herein 57 PRD4322WOPCT1 5 defined6are taken together with the carbon atoms to which they are bound to form cyclobuty , a known compound or compound prepared by known method suitably selected coupling agent such as Pd(OAc)2, Pd(dba)2, and the like; in the presence of a suitably selected agent such as BINAP, XPhos, and the like; in the presence of a suitably 10 selected base such as Cs2CO3, K2CO3, Na2CO3, and the like; in a suitably selected solvent such as 1,4-dioxane, DMF, and the like; at a temperature in the range of from about 80 ˚C to about 130˚C, for example at about 130˚C; to yield the corresponding compound of formula (LVII). The compound of formula (LVII) is reacted with a suitably substituted 15 compound of formula (X), a known compound or compound prepared by known methods; wherein LG2is a suitably selected leaving group such as I, Br, and the like, a known compound or compound prepared by known methods; in a suitably selected solvent such as toluene, 1,4-dioxane, and the like; at a temperature in the range of from about 80˚C to about 130˚C, for example at about 120˚C; to yield the 20 corresponding compound of formula (If). Compounds of formula (XL) may alternatively be prepared as described in Scheme 11, below. PRD4322WOPCT1 5 Accordingly, a suitably substituted compound of formula (LII) is reacted with a suitably selected reagent such as LiOH•H2O, NaOH, KOH, and the like; in a suitably selected solvent or mixture of solvents such as a mixture of THF, methanol and water, 10 1,4-dioxane / water, THF / water, and the like; at about room temperature; to yield the corresponding compound of formula (LVIII). The compound of formula (LVIII) is reacted with a suitably substituted compound of formula (XLVIII), wherein is selected from the group consisting , wherein PG5is a 15 suitably s and the like, a known compound or compound prepared by known methods; in the presence of a suitably selected coupling agent or mixture such as HOPO and EDCI, HATU, Mukaiyama’s reagent and the like; in the presence of a suitably selected organic amine base such as DIPEA, Et3N, and the like; in a suitably selected solvent such as 1,4-dioxane, 20 DCM, NMP, DMF, and the like; at a temperature in the range of from about 25˚C to about 70˚C, for example at about 50˚C; to yield the corresponding compound of formula (LIX). The compound of formula (LIX) is reacted with a suitably substituted compound of formula (LX), wherein -B(R)2 represents a suitably substituted boronic acid 25 (wherein each R is OH) or a suitably substituted boronic ester (wherein each R is -O- C1-4alkyl or alternatively, the two R groups are taken together with the boron atom to which they are bound to form , and the like), a known compound or 59 PRD4322WOPCT1 5 compound prepared by known methods; in the presence of a suitably selected coupling agent such as Pd(dppf)Cl2, Pd-118, Pd(PPh3)2Cl2 and the like; in the presence of a suitably selected inorganic base such as Na2CO3, Cs2CO3, K2CO3, K3PO4, and the like; in the presence of a suitably selected reagent such as CsF, TBAF, and the like; in a suitably selected solvent or mixture of solvents such as a 10 mixture of 1,4-dioxane / water, DMF / water, toluene / water and the like; at a temperature in the range of from about 60˚C to about 100˚C, for example at about 90˚C; to yield the corresponding compound of formula (XL). One skilled in the art will recognize that various substituent groups and / or 15 functional groups on said substituent groups (for example -OH, -NH2, -C(O)OH, etc.) may be protected prior to any reaction step, and then de-protected at a later step in the synthesis, as would be desirable or necessary, according to methods well known to those skilled in the art. Where the processes for the preparation of the compounds according to the 20 invention yield rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the 25 formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartaric acid and / or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the 30 compounds may be resolved using a chiral HPLC column. Additionally, chiral HPLC against a standard may be used to determine percent enantiomeric excess (%ee). The enantiomeric excess may be calculated as follows [ (Rmoles-Smoles) / (Rmoles+Smoles) ] X 100% 60 PRD4322WOPCT1 5 where Rmoles and Smoles are the R and S mole fractions in the mixture such that Rmoles+Smoles = 1. The enantiomeric excess may alternatively be calculated from the specific rotations of the desired enantiomer and the prepared mixture as follows: ee = ([^-obs] / [^-max]) X 100. 10 As used herein, unless otherwise noted, the term “isotopologues” shall mean molecules that differ only in their isotopic composition. More particularly, an isotopologue of a molecule differs from the parent molecule in that it contains at least one atom which is an isotope (i.e. has a different number of neutrons from its parent atom). For example, isotopologues of water include, but are not limited to, "light 15 water" (HOH or H2O), "semi-heavy water" with the deuterium isotope in equal proportion to protium (HDO or1H2HO), “heavy water” with two deuterium isotopes of hydrogen per molecule (d2O or2H2O), "super-heavy water" or tritiated water (T2O or 3H2O), where the hydrogen atoms are replaced with tritium (3H) isotopes, two heavy- oxygen water isotopologues (H218O and H217O) and isotopologues where the 20 hydrogen and oxygen atoms may each independently be replaced by isotopes, for example the doubly labeled water isotopologue d218O. As used herein, unless otherwise noted, the term “isotopomer” shall mean isomers with isotopic atoms, having the same number of each isotope of each element but differing in their position. Isotopomers include both constitutional isomers and 25 stereoisomers solely based on isotopic location. For example, CH3CHDCH3and CH3CH2CH2D are a pair of constitutional isotopomers of n-propane; whereas (R)- CH3CHDOH and (S)-CH3CHDOH or (Z)-CH3CH=CHD and (E)-CH3CH=CHD are examples of isotopic stereoisomers of ethanol and n-propene, respectively. In some embodiments of the present invention, any one or more element(s), in 30 particular when mentioned in relation to a compound of formula (I) shall comprise all isotopes and isotopic mixtures of said element(s), either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. In some embodiments of the present invention, the compounds of formula (I) include isotopologues and isotopomers thereof. For example, a reference to 61 PRD4322WOPCT1 5 hydrogen includes within its scope1H,2H (D), and3H (T). Similarly, references to carbon and oxygen include within their scope respectively12C,13C and14C and16O and18O. One skilled in the art will recognize that the isotopes may be radioactive or non-radioactive. Radiolabelled compounds of formula (I) may comprise one or more radioactive isotope(s) selected from the group of3H,11C,18F,122I,123I,125I,131I,75Br, 1076Br,77Br and82Br. Preferably, the radioactive isotope is selected from the group of 3H,11C and18F. In some embodiments, the present invention is directed to compounds of formula (I) wherein one or more atoms (preferably, one or more hydrogen, carbon, oxygen, nitrogen or fluorine atom) are replaced with a radioactive or non-radioactive 15 isotope. Pharmaceutically Acceptable Salts For use in medicine, the salts of the compounds of this invention refer to non- toxic “pharmaceutically acceptable salts.” Other salts may, however, be useful in the 20 preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, 25 benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. Thus, 30 representative pharmaceutically acceptable salts include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, 62 PRD4322WOPCT1 5 hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, 10 triethiodide and valerate. Representative acids which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: acids including acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-15 acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2- hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L-glutamic acid, ^-oxo-glutaric 20 acid, glycolic acid, hipuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL- mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5- disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, 25 salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid. Representative bases which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: bases 30 including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium 63 PRD4322WOPCT1 5 hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide. As used herein, unless otherwise noted, the terms “treating”, “treatment” and the like, shall include the management and care of a subject or patient (preferably 10 mammal, more preferably human) for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present invention to prevent the onset of the symptoms or complications, alleviate the symptoms or complications, or eliminate the disease, condition, or disorder. As used herein, the terms “combination therapy” and “co-therapy” refer to 15 combined administration of (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable salt thereof, and (b) one or more additional therapeutic agent (or “combination agent” or "co-agent"); administered independently at the same time or separately within time intervals. As used herein, the terms "co-administration" or "combined administration" and 20 the like are meant to encompass administration of the selected combination agents to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term "pharmaceutical combination" as used herein means a product that results from the mixing or combining of more than one 25 therapeutic agent and includes both fixed and non-fixed combinations of the therapeutic agents. The term "fixed dose composition" means that the therapeutic agents, e.g. (a) a compound of formula (I) and (b) one or more additional therapeutic agents, are administered to a patient simultaneously in the form of a single entity or dosage. The 30 term "non-fixed dose composition" means that the therapeutic agents, e.g. (a) a compound of formula (I) of the present invention and (b) one or more additional therapeutic agents, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the compounds in the body of 64 PRD4322WOPCT1 5 the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more therapeutic agents. The term “therapeutically effective amount” as used herein, means that amount of active compound(s), pharmaceutical agent(s), co-therapy or combination therapy that elicits the biological or medicinal response in a tissue system, animal or human that is 10 being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. Wherein the present invention is directed to co-therapy or combination therapy, “therapeutically effective amount” shall mean the amount of the combination of agents taken together, such that the combined effect elicits the desired biological or 15 medicinal response. For example, the therapeutically effective amount of co-therapy comprising administration of (a) a compound of formula (I) and (b) one or more (preferably one to two) therapeutic agents, would be the amount of (a) the compound of formula (I) and (b) the one or more therapeutic agents that when taken together or separately have a combined effect that is therapeutically effective. It will be 20 recognized by those skilled in the art that in the case of co-therapy or combination therapy with a therapeutically effective amount, the amount of the (a) compound of formula (I) and / or the amount of (b) the one or more therapeutic agents individually may or may not, individually, be a therapeutically effective. In some embodiments of the present invention, the combination therapy or co- 25 therapy comprising (a) a compound of formula (I) and (b) one or more additional therapeutic agents (for example chemotherapy agents) achieves a therapeutic effect that is greater than the therapeutic effect achieved by administration of only a single therapeutic agent. The terms “subject” and “patient” as used herein, refers to an animal, preferably a 30 mammal, most preferably a human, who is or has been the object of treatment, observation or experiment. Preferably, the subject or patient has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented. 65 PRD4322WOPCT1 5 As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. 10 Methods of Treatment A cancer that has "defective mismatch repair" (dMMR) or "dMMR character" includes cancer types associated with documented MLH1, PMS2, MSH2, MSH3, MSH6, MLH3, and PMS1 mutations or epigenetic silencing, microsatellite fragile sites, or other gene inactivation mechanisms, including but not limited to cancers of the 15 lung, breast, kidney, large intestine, ovary, prostate, upper aerodigestive tract, stomach, endometrium, liver, pancreas, haematopoietic and lymphoid tissue, skin, thyroid, pleura, autonomic ganglia, central nervous system, soft tissue, pediatric rhabdoid sarcomas, melanomas and other cancers. A cell or cancer with "defective" mismatch repair has a significantly reduced (e.g., at least about 25%, 30%, 40%, 20 50%, 60%, 70%, 80% or 90% decrease) amount of mismatch repair. In some cases, a cell or cancer which is defective in mismatch repair will perform no mismatch repair. The present invention is directed to method of treating disorders and / or diseases mediated by or modulated by inhibition of WRN comprising administration to a subject (e.g. patient) in need thereof a therapeutically effective amount of a 25 compound of formula (I) as described herein. The present invention is further directed to the use of any of the compounds described herein in the preparation of a medicament for the treatment of disorders and / or diseases mediated by or modulated by inhibition of WRN. The present invention is further directed to methods of treating disorders and / 30 or diseases mediated by or modulated by inhibition of WRN comprising administration of a compound of formula (I) as described herein to a subject in need thereof. In some embodiments, the present invention is directed to methods of treating disorders and / or diseases mediated by or modulated by inhibition of WRN which include, but 66 PRD4322WOPCT1 5 are not limited to, cancer, comprising administration of a compound of formula (I) to a subject in need thereof. In some embodiments, the present invention is directed to methods of treating cancers (preferably cancers characterized as microsatellite instability (MSI) or mismatch repair deficient (dMMR)) comprising administration of a compound of 10 formula (I) to a subject in need thereof. In some embodiments, the present invention is directed to methods of treating cancers (preferably cancers characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)) comprising administration of a compound of formula (I) to a subject in need thereof. In some embodiments, the present invention is directed to methods of treating 15 a cancer mediated by or modulated by inhibition of WRN is a cancer, wherein the cancer is selected from the group consisting of colonic, gastric, rectal, endometrial, adrenocortical, uterine, cervical, mesothelial, esophageal, breast, kidney, prostate, ovarian, pancreatic, germ cell, liver, lung, biliary tract / gallbladder, head / neck, thyroid, thymic, small bowel, bladder, skin, prostate, brain, neuroendocrine, soft tissue, 20 appendiceal, leukemia, lymphoma, and myeloma cancers. In some embodiments, the present invention is directed to methods of treating a cancer selected from the group consisting of colonic, gastric, rectal, endometrial, adrenocortical, uterine, cervical, mesothelial, esophageal, breast, kidney, prostate, ovarian, pancreatic, germ cell, liver, lung, biliary tract / gallbladder, head / neck, thyroid, 25 thymic, small bowel, bladder, skin, prostate, brain, neuroendocrine, soft tissue, appendiceal, leukemia, lymphoma, and myeloma cancers, comprising administration of a compound of formula (I) to a subject in need thereof. In some embodiments, the present invention is directed to methods of treating a cancer characterized as microsatellite instability (MSI) or mismatch repair deficient 30 (dMMR) selected from the group consisting of colonic, gastric, rectal, endometrial, adrenocortical, uterine, cervical, mesothelial, esophageal, breast, kidney, prostate, ovarian, pancreatic, germ cell, liver, lung, biliary tract / gallbladder, head / neck, thyroid, thymic, small bowel, bladder, skin, prostate, brain, neuroendocrine, soft tissue, appendiceal, leukemia, lymphoma, and myeloma cancers, comprising administration 67 PRD4322WOPCT1 5 of a compound of formula (I) to a subject in need thereof. Preferably, the cancer is selected from the group consisting of colonic, gastric, rectal, endometrial, adrenocortical, uterine, cervical, ovarian, and small bowel. The present invention is further directed to the use of any of the compounds of formula (I) of the present invention, as described herein, in the preparation of a 10 medicament or composition for the treatment of disorders and / or diseases mediated by or modulated by inhibition of WRN, either alone or in combination. The present invention is further directed to methods of treating a disorder or disease mediated by or modulated by inhibition of WRN comprising administration of (a) a compound of formula (I) in combination with and (b) one or more additional 15 therapeutic agents, to a subject (e.g. a patient) in need thereof. The additional therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment or nucleic acid, which is therapeutically active or enhances the therapeutic activity when administered to a patient in combination with a compound of formula (I) of the present invention. In some embodiments of the present invention, the 20 additional therapeutic agent is chemotherapy. The present invention is further directed to a composition comprising (a) a compound of formula (I) as described herein and (b) one or more, preferably one to two additional therapeutic agents. The additional therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment or nucleic acid, which is 25 therapeutically active or enhances the therapeutic activity when administered to a patient in combination with a compound of formula (I) of the present invention. The compositions comprising (a) a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, as described herein, and (b) one or more additional therapeutic agents may be fixed dose composition or a non-fixed dose 30 composition. In some embodiments, the additional therapeutical agent(s) is an anti-cancer agent. In some embodiments, the additional therapeutic agent(s) is a chemotherapy, preferably a chemotherapy selected from the group consisting of amsacrine (Amsidine®), arsenic trioxide (Trisenox®), asparaginase (Spectrila®, Erwinase®, 68 PRD4322WOPCT1 5 Oncaspar®, Rylaze®), azacitidine (Vidaza®, Onureg®), bendamustine (Levact), bendamustine hydrochloride (Belrapzo®, Bendeka®, Treanda®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), cabazitaxel (Jevtana®), calaspargase pegol- mknl (Asparlas®), capecitabine (Xeloda®), carboplatin (Paraplatin®), carmustine (BiCNU®), carmustine implant (Gliadel Wafer®), chlorambucil (Leukeran®), cisplatin 10 (Platinol®), cladribine (Mavenclad®), clofarabine (Evoltra®, Clolar®), cyclophosphamide (Cytoxan®), cytarabine (Cytosar-U®), dacabarzine (DTIC- Dome®), dactinomycin (Cosmegen®), daunorubicin hydrochloride (Cerubidine®, DaunoXome®), daunorubicin hydrochloride and cytarabine liposomal (Vyxeos®), decitabine (Dacogen®), decitabine and cedazuridine (Inqovi®), docetaxel 15 (Taxotere®), doxorubicin hydrochloride (Adriamycin®), doxorubicin hydrochloride liposomal (Doxil®, Lipodox®), epirubicin hydrochloride (Pharmorubicin®, Ellence®), eribulin mesylate (Halaven®), etoposide phosphate (Etopophos®), fludarabine phosphate (Fludara®), fluorouracil (Adrucil®, Carac®), fluorouracil phosphate (Carac®, Efudex®, Fluoroplex®, Tolak®), gemcitabine hydrochloride (Gemzar®, 20 Infugem®), hydroxycarbamide (Hydrea®), idarubicin hydrochloride (Idamycin®), ifosfamide (Mitoxana®), irinotecan hydrochloride (Campto®), irinotecan hydrochloride liposomal (Onivyde®), ixabepilone (Ixempra®), lomustine (Gleostine®), lurbinectedin (Zepzelca®), mechlorethamine hydrochloride (Valchlor®), melphalan (Alkeran®), melphalan hydrochloride (Evomela®, Hepzato®), mercaptopurine (Xaluprine®, 25 Purinethol®. Purixan®), methotrexate sodium (Otrexup®, Rasuvo®, RediTrex®, Trexall®, Xatmep®), mitomycin (Mitosol®, Mutamycin®, Jelmyto®), mitotane (Lysodren®), mitoxantrone hydrochloride (Novantrone®), nab-paclitaxel (Abraxane®), nelarabine (Arranon®), omacetaxine mepesuccinate (Ceflatonin®, Synribo®), oxaliplatin (Eloxatin®), paclitaxel (Taxol®), pegasparase (Oncaspar®), pemetrexed 30 sodium (Alimta®, Pemfexy®), pentostatin (Nipent®), pralatrexate (Folotyn®), procarbazine hydrochloride (Matulane®), raltitrexed (Tomudex®), streptozocin (Zanosar®), temozolomide (Temodar®), thioguanine (Tabloid®), thiotepa (Tepadina®), topotecan hydrochloride (Hycamtin®), trabectedin (Yondelis®), treosulfan (Trecondi®), tretinoin (Vesanoid®), trifluridine and tipiracil hydrochloride 69 PRD4322WOPCT1 5 (Lonsurf®), valrubicin (Valstar®), vinblastine sulfate (Velban®), vincristine sulfate (Oncovin®, Vincasar PES®, Vincrex®), and vinorelbine tartate (Navelbine®). In some embodiments, the chemotherapy is one or more selected from the group consisting of capecitabine (Xeloda®), cisplatin (Platinol®), fluorouracil (5- FU), irinotecan (Camptosar®), oxaliplatin (Eloxatin®), paclitaxel (Taxol®), and trifluridine 10 and tipiracil hydrochloride (Lonsurf®). In some embodiments, the additional therapeutic agent(s) is a hormonal therapy. In some embodiments, the additional therapeutic agent(s) is hormonal therapy selected from the group consisting of abiraterone acetate (Yonsa®, Zytiga®), anastrozole (Arimidex®), apalutamide (Erleada®), bicalutamide (Casodex®), 15 buserelin (Suprefact®), cyproterone acetate (Cyprostat®), darolutamide (Nubeqa®), degarelix (Firmagon®), elacestrant dihydrochloride (Orserdu®), enzalutamide (Xtandi®), exemestane (Aromasin®), flutamide (Eulexin®), fulvestrant (Faslodex®), goserelin acetate (Zoladex®), lanreotide acetate (Somatuline®), letrozole (Femara®), leuprolide acetate (Eligard®, Lupron Depot®), leuprorelin (Prostap®, Staladex®), 20 medroxyprogesterone acetate (Provera®), megestrol acetate (Megace®), nilutamide (Nilandron®), raloxifene acetate (Evista®), relugolix (Orgovyx®), tamoxifen citrate (Nolvadex®, Soltamox®), toremifene (Acapodene®), Fareston®), and triptoreline (Decapeptyl SR®, Gonapeptyl Depot®). In some embodiments, the additional therapeutic agent(s) is a targeted 25 therapy. In some embodiments, the additional therapeutic agent(s) is targeted therapy selected from the group consisting of abemaciclib (Verznios®), acalabrutinib (Calquence®), adagrasib (Krazati®), afatinib dimaleate (Giotrif®), aflibercept (Zaltrap®, Eylea®), aldesleukin (Proleukin®), alectinib (Alecensa®), alemtuzumab (Campath®, MabCampath®), alpelisib (Piqray®, Vijoice®), amivantamab-vmjw 30 (Rybrevant®), asciminib hydrochloride (Scemblix®), avapritinib (Ayvakit®), axitinib (Inlyta®), belinostat (Beleodaq®), belzutifan (Welireg®), bevacizumab (Avastin®, Alymsys®, Mvasi®, Zirabev®), binimetinib (Mektovi®), blinatumomab (Blincyto®), bortezomib (Velcade®), bosutinib (Bosulif®), brentuximab vedotin (Adcetris®), brigatinib (Alunbrig®), cabozantinib-S-malate (Cometriq®, Cabometyx®), capmatinib 70 PRD4322WOPCT1 5 hydrochloride (Tabrecta®), carfilzomib (Kyprolis®), ceritinib (Zykadia®), cetuximab (Erbitux®), cobimetinib fumarate (Cotellic®), copanlisib hydrochloride (Aliqopa®), crizotinib (Xalkori®), dabrafenib mesylate (Tafinlar®), dacomitinib (Vizimpro®), daratumumab (Darzalex®), daratumumab and hyaluronidase-fihj (Darzalex Faspro®), dasatinib (Sprycel®), dinutuximab (Unituxin®), duvelisib (Copiktra®), elotuzumab 10 (Empliciti®), elranatamab-bcmm (Elrexfio®), enasidenib mesylate (Idhifa®), encorafenib (Braftovi®), enfortumab vedotin-ejfv (Padcev®), entrectinib (Rozlytrek®), epcoritamab-bysp (Epkinly®), erdafitinib (Balversa®), erlotinib hydrochloride (Tarceva®), everolimus (Afinitor®, Votubia®, Zortress®), fedratinib hydrochloride (Inrebic®), fruquitinib, futibatinib (Lytgobi®), gefitinib (Iressa®), gemtuzumab 15 ozogamicin (Mylotarg®), gilteritinib fumarate (Xospata®), glasdegib maleate (Daurismo®), glofitamab-gxbm (Columvi®), ibrutinib (Imbruvica®), idelalisib (Zydelig®), imatinib mesylate (Gleevec®), infigratinib phosphate (Truseltiq®), inotuzumab ozogamicin (Besponsa®), isatuximab-irfc (Sarclisa®), ivosidenib (Tibsovo®), ixazomib citrate (Ninlaro®), lapatinib ditosylate (Tykerb®), larotrectinib 20 sulfate (Vitrakvi®), lazertinib (Leclaza®), lenalidomide (Revlimid®), lenvatinib mesylate (Lenvima®, Kisplyx®), loncastuximab tesirine-lpyl (Zynlonta®), lorlatinib (Lorviqua®), margetuximab-cmkb (Margenza®), midostaurin (Rydapt®), mirvetuximab soravtansine-gynx (Elahere®), mobocertinib (Exkivity®), mosunetuzumab-axgb (Lunsumio®), moxetumomab pasudotox-tdfk (Lumoxiti®), nab-sirolimus (Fyarro®), 25 naxitamab-gqgk (Danyelza®), necitumumab (Portrazza®), neratinib maleate (Nerlynx®), nilotinib (Tasigna®), nintedanib (Vargatef®), niraparib tosylate monohydrate (Zejula®), niraparib tosylate monohydrate and abiraterone acetate (Akeega®), obinutuzumab (Gazyva®), ofatumumab (Arzerra®), olaparib (Lynparza®), olutasidenib (Rezlidhia®), osimertinib mesylate (Tagrisso®), palbociclib (Ibrance®), 30 panitumumab (Vectibix®), panobinostat (Farydak®), pazopanib hydrochloride (Votrient®), pemigatinib (Pemazyre®), pertuzumab (Perjeta®), pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo®), pexidartinib hydrochloride (Turalio®), pirtobrutinib (Jaypirca®), polatuzumab vedotin-piiq (Polivy®), pomalidomide (Pomalyst®, Imnovid®), ponatinib hydrochloride (Iclusig®), pralsetinib 71 PRD4322WOPCT1 5 (Gavreto®), quizartinib dihydrochloride (Vanflyta®), ramucirumab (Cyramza®), regorafenib (Stivarga®), ribociclib (Kisqali®), ripretinib (Qinlock®), rituximab (Rituxan®, Ruxience®, Truxima®, Riabni®), rituximab and hyaluronidase (Rituxan Hycela®), romidepsin (Istodax®), rucaparib camsylate (Rubraca®), ruxolitinib phosphate (Jakavi®), sacituzumab govitecan-hziy (Trodelvy®), selinexor (Xpovio®), 10 selpercatinib (Retevmo®), sonidegib (Odomzo®), sorafenib tosylate (Nexavar®), sotorasib (Lumakras®), sunitinib malate (Sutent®), tafasitamab-cxix (Monjuvi®), tagraxofusp-erzs (Elzonris®), talazoparib tosylate (Talzenna®), talquetamab (Talvey®), tazemetostat hydrobromide (Tazverik®), tebentafusp-tebn (Kimmtrak®), teclistamab-cqyv (Tecvayli®), temsirolimus (Torisel®), tepotinib hydrochloride 15 (Tepmetko®), thalidomide (Contergan®, Thalomid®), tisotumab vedotin (Tivdak®), tivozanib hydrochloride (Fotivda®), trametinib dimethyl sulfoxide (Mekinist®), trastuzumab (Herceptin®, Herzuma®, Ontruzant®, Kanjinti®, Ogivri®, Trazimera®), trastuzumab and hyaluronidase-oysk (Herceptin Hylecta®), trastuzumab deruxtecan (Enhertu®), trastuzumab emtansine (Kadcyla®), tucatinib (Tukysa®), vandetanib 20 (Caprelsa®, Zactima®), vemurafenib (Zelboraf®), venetoclax (Venclyxto®), vismodegib (Erivedge®), vorinostat (Zolinza®), and zanubrutinib (Brukinsa®). In some embodiments, the additional therapeutic agent(s) is a cell therapy. In some embodiments, the additional therapeutic agent(s) is a cell therapy selected from the group consisting of axicabtagene ciloleucel (Yescarta®), brexucabtagene 25 autoleucel (Tecartus®), ciltacabtagene autoleucel (Carvykti®), idecabtagene vicleucel (Abecma®), lisocabtagene maraleucel (Breyanzi®), sipuleucel-T (Provenge®), and tisagenlecleucel (Kymriah®). In some embodiment, the cell therapy is selected from the group consisting of ciltacabtagene autoleucel (Carvykti®) and sipuleucel-T (Provenge®). 30 In some embodiments, the additional therapeutic agent(s) is a CTLA-4 inhibitor. In some embodiments, the additional therapeutic agent(s) is an anti-CTLA-4 antibody molecule, or a CTLA-4 inhibitor selected from the group consisting of botensilimab (Agenus), cadonilimab (Akesobio), erfonrilimab (Alphamab Oncology), 72 PRD4322WOPCT1 5 gotistobart (OncoC4), ipilimumab (Yervoy®), tremelimumab-actl (Imjuno®), and volrustomig (AstraZeneca). In some embodiments, the additional therapeutic agent(s) is a PD-1 inhibitor. In some embodiments, the additional therapeutic agent(s) is an anti-PD-1 antibody molecule, or a PD-1 inhibitor selected from the group consisting of PDR001 10 (Novartis), nivolumab (Opdivo®, Bristol-Myers Squibb), pembrolizumab (Keytruda®, Merck & Co), pidilizumab (CureTech), MEDI0680 (Medimmune), cemiplimab-rwlc (Libtayo®, REGN2810, Regeneron), dostarlimab-gxly (Jemperli®, TSR-042, Tesaro), PF-06801591 (Pfizer), tislelizumab (BGB-A317, Beigene), BGB-108 (Beigene), INCSHR1210 (lncyte), balstilimab (AGEN2035, Agenus), sintilimab (lnnoVent), 15 toripalimab (Shanghai Junshi Bioscience), camrelizumab (Jiangsu Hengrui Medicine Co.), cetrelimab (Johnson and Johnson), retifanlimab (Zynyz®, Incyte), AMP-224 (Amplimmune), penpulimab (Akeso Biopharma Inc), zimberelimab (Arcus Biosciences Inc) and prolgolimab (Biocad Ltd). In some embodiments, the PD-1 inhibitor is cetrelimab (Johnson and Johnson) or tislelizumab (BGB-A317, Beigene). 20 In some embodiments, the additional therapeutic agent(s) is a radiopharmaceutical. In some embodiments, the additional therapeutic agent(s) is radiopharmaceutical selected from the group consisting of ibritumomab tiuxetan (Zevalin®), iobenguane I 131 (Azedra®), lutetium Lu 177 vipivotide tetraxetan (Pluvicto®), lutetium Lu 177-dotatate (Lutathera®), and radium 223 dichloride 25 (Xofigo®). In some embodiments, the additional therapeutic agent(s) is an inhibitor of PD- 1, e.g., human PD-1. In another embodiment, the additional therapeutic agent(s) is an inhibitor of PD-L1, e.g., human PD-L1. In additional embodiments, the inhibitor of PD- 1 or PD-L1 is an antibody to PD-1 or PD-L1. In further embodiments, the additional 30 therapeutic agent(s) is an anti-PD-1 antibody. In some embodiments, the PD-1 antibody is selected from atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi). In the compositions and methods of treatment comprising administration of said compositions as described herein (wherein the composition comprises (a) a 73 PRD4322WOPCT1 5 compound of formula (I) and (b) one or more additional therapeutic agents), the one or more additional therapeutic agent is one or more anti-cancer agents, cytotoxic or cytostatic agents, hormone treatment, vaccines, and / or other immunotherapies. In additional embodiments, the compositions or methods of treatment may be further administered or used in combination with other therapeutic treatment modalities, 10 including surgery, radiation, cryosurgery, and / or thermotherapy. Such combination therapies may advantageously utilize lower dosages of the administered therapeutic agents, thus avoiding possible toxicities or complications associated with the treatment. 15 Pharmaceutical Compositions The present invention further comprises pharmaceutical compositions containing one or more compounds of formula (I) with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately 20 mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral). Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, 25 flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate major site of 30 absorption. For parenteral administration, the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives. 74 PRD4322WOPCT1 5 To prepare the pharmaceutical compositions of this invention, one or more compounds of the present invention as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular. 10 In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules, caplets, gelcaps and 15 tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For 20 parenterals, the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, 25 injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. The pharmaceutical compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 0.01 mg to about 1000 mg or any amount or range therein, and may be given at a dosage of from about 0.01 mg / kg / day 30 to about 300 mg / kg / day, or any amount or range therein, preferably from about 0.1 mg / kg / day to about 50 mg / kg / day, or any amount or range therein, preferably from about 0.05 mg / kg / day to about 15 mg / kg / day, or any amount or range therein. The dosages, however, may be varied depending upon the requirement of the patients, 75 PRD4322WOPCT1 5 the severity of the condition being treated and the compound being employed. The use of either daily administration or periodic dosing may be employed. Preferably these compositions are in unit dosage forms from such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or 10 suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing 15 solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the present20 invention, or a pharmaceutically acceptable salt thereof. When referring to these pre- formulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid pre-formulation composition is then subdivided into unit dosage forms of the 25 type described above containing from about 0.01 mg to about 1,000 mg, or any amount or range therein, of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in 30 the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be used for such enteric layers or coatings, such materials 76 PRD4322WOPCT1 5 including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate. The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with 10 edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl- pyrrolidone or gelatin. 15 The method of treating disorders mediated by or modulated by inhibition of WRN described in the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 0.01 mg and about 1000 mg of the compound, or any amount or range therein; preferably 20 from about 1.0 mg to about 500 mg of the compound, or any amount or range therein, and may be constituted into any form suitable for the mode of administration selected. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms, such as 25 pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixirs, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions. Advantageously, compounds of the present invention may be administered in a 30 single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art. To be 77 PRD4322WOPCT1 5 administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or 10 necessary, suitable binders; lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. 15 Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. The liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. 20 Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired. To prepare a pharmaceutical composition of the present invention, a compound of formula (I) as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding 25 techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral). Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association 30 and the Pharmaceutical Society of Great Britain. Methods of formulating pharmaceutical compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis 78 PRD4322WOPCT1 5 et al; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc. Compounds of the present invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of disorders or diseases of the present invention is required. 10 The daily dosage of the products may be varied over a wide range from about 0.01 mg to about 1,000 mg per adult human per day, or any amount or range therein. For oral administration, the compositions are preferably provided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the 15 dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg / kg to about 500 mg / kg of body weight per day, or any amount or range therein. Preferably, the range is from about 0.1 to about 50.0 mg / kg of body weight per day, or any amount or range therein. More preferably, from about 0.5 to about 15.0 mg / kg of body weight per day, or any amount or 20 range therein. More preferably, from about 1.0 to about 7.5 mg / kg of body weight per day, or any amount or range therein. The compounds may be administered on a regimen of 1 to 4 times per day. The present invention is further directed a compound of formula (I) for use in treating a disease or disorder mediated by or modulated by inhibition of WRN, 25 wherein the compound of formula (I) is administered in combination with one or more additional therapeutic agents. The present invention is further directed to one or more additional therapeutic agents for use in a method of treating a disease or condition mediated by inhibition of WRN, wherein the one or more additional therapeutic agents are administered in combination with a compound of formula (I). 30 The present invention is further directed to the use of a compound of formula (I) for treating a disease or condition mediated by inhibition of WRN, wherein the patient has previously (e.g. within 24 hours) been treated with another therapeutic agent. The present invention is further directed to the use of another therapeutic agent for treating a disease or condition mediated by inhibition of WRN, wherein the 79 PRD4322WOPCT1 5 patient has previously (e.g. within 24 hours) been treated with a compound of formula (I). In some embodiments, the present invention is directed to a composition or product comprising (a) a compound of formula (I) as described herein and (b) one or more additional therapeutic agent as a combined preparation for simultaneous, 10 separate or sequential use in therapy. Products provided as a combined preparation include a composition comprising (a) a compound of formula (I) and the (b) one or more additional therapeutic agent(s) together in the same pharmaceutical composition, or (a) a compound of formula (I) and the (b) one or more additional the present invention and the other therapeutic agent(s) in separate form, e.g. in the form 15 of a kit. In some embodiments, the composition or product comprising (a) a compound of formula (I) and (b) one or more additional therapeutic agent; wherein the individual components may be packaged in a kit or separately. One or more of the components (e.g., powders or liquids) of the combination therapy may be reconstituted or diluted to a 20 desired dose prior to administration. In some embodiments, the present invention is directed to a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) of the present invention. In some embodiments, the kit comprises means for separately retaining said compositions, such as a container, 25 divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like. The kit may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist 30 compliance, the kit of the invention typically comprises directions for administration. In the compositions and products of the present invention, the (a) compound of formula (I) and the (b) one or more additional therapeutic agents may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the present invention 80 PRD4322WOPCT1 5 and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of the present invention and the other therapeutic agent. 10 Synthesis Examples The following Examples are set forth to aid in the understanding of the invention and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter. In the Examples which follow, some synthesis products are listed as having 15 been isolated as a residue. It will be understood by one of ordinary skill in the art that the term “residue” does not limit the physical state in which the product was isolated and may include, for example, a solid, an oil, a foam, a gum, a syrup, a liquid, and the like. Unless otherwise noted, in the synthesis examples provided herein, wherein a 20 mixture of solvents is presented as a ratio, said ratio shall be understood to be a volume:volume (or volume / volume) ratio. Intermediate 1: N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide. Step A.2-Chloro-N-(2-chlo thyl)phenyl)acetamide. 25 To a solution of 2-chloro-4-(trifluoromethyl)aniline (3 g, 15.3 mmol) in DCM (35 mL) was added 2-chloroacetyl chloride (2.1 g, 19 mmol) at 0 °C. After 30 minutes at 0 °C, the mixture was warmed to room temperature and then stirred overnight. The suspension was filtered and washed with DCM (10 mL). The filtrate was concentrated under reduced pressure and dried under vacuo to yield the title compound as a white 30 powder. The white powder was directly used in the next step without further purification. MS (ESI): mass calculated for C9H6Cl2F3NO, 271.0; m / z measured 271.9 81 PRD4322WOPCT1 5 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.31 - 9.93 (m, 1H), 8.23 - 8.01 (m, 1H), 8.00 - 7.86 (m, 1H), 7.82 - 7.65 (m, 1H), 4.53 - 4.40 (m, 2H) ppm. Step B. N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide. A mixture of 2-chloro-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (1 g, 3.6 mmol) and KI (667 mg, 4.0 mol) in acetone (15 mL) was refluxed at 60 °C for 2 hours. 10 The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography (0-35% EtOAc / petroleum ether) to yield the title compound as a white powder. MS (ESI): mass calculated for C9H6ClF3INO, 362.9; m / z measured 363.7 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.23 - 9.90 (m, 1H), 8.14 - 7.99 (m, 1H), 7.97 - 7.88 (m, 1H), 7.82 - 7.67 (m, 1H), 4.19 - 3.80 (m, 2H) ppm. 15 Intermediate 2: 5-Hydroxy-6-methylpyrimidine-4-carboxylic acid. Step A.4,6-Dichloropyrimidi To a solution of 4,6-dichloro-5-methoxypyrimidine (50.0 g, 279 mmol) in DCE (800 mL) was added AlCl3 (50.4 g, 378 mmol, 20.6 mL) at 0 °C. The mixture was 20 warmed to 50 °C and stirred for 6 hrs. The reaction mixture was then cooled to 0 °C and aqueous HCl solution (1M, 400 mL) was added slowly, followed by addition of MeOH (100 mL). The mixture was stirred at 20 °C for 10 mins. The mixture was then diluted with H2O (500 mL) and extracted with EtOAc (800 mL). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated 25 under reduced pressure to yield the title product as a residue, which was used in the next step without further purification (26.0 g, 51% yield, 90% purity).1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 6.05 (br s, 1H) ppm. Step B.5-(Benzyloxy)-4,6-dichloropyrimidine. To a solution of 4,6-dichloropyrimidin-5-ol (26.0 g, 157 mmol) in DMF (520 mL) 30 was added benzyl bromide (48.5 g, 283 mmol, 33.6 mL) and K2CO3 (58.8 g, 425 mmol). The mixture was stirred at 60 °C for 2 hrs. The reaction mixture was then diluted with H2O (2.5 L) and extracted with EtOAc (800 mL x 3). The combined 82 PRD4322WOPCT1 5 organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-13% EtOAc / petroleum ether) to yield the title compound as a white solid. MS (ESI): mass calculated for C11H8Cl2N2O, 254.0; m / z measured 257.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 7.52 (dd, J = 1.9, 7.4 Hz, 2H), 7.46 10 - 7.36 (m, 3H), 5.18 (s, 2H) ppm. Step C.5-(Benzyloxy)-4-chloro-6-methylpyrimidine. To a solution of 5-(benzyloxy)-4,6-dichloropyrimidine (27 g, 105 mmol) in toluene (324 mL) and DMF (108 mL) were added Cs2CO3 (103 g, 317 mmol), methyl- boronic acid (6.9 g, 115 mmol) and Pd(PPh3)4 (6.1 g, 5.3 mmol). The mixture was 15 stirred at 110 °C for 5 hrs. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with water (600 mL) and extracted with EtOAc (300 mL x 4). The combined organic layers were washed with sat. aq. NaHCO3 (200 mL) and brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column 20 chromatography (SiO2, 0-11% EtOAc / petroleum ether) to yield the title compound as a yellow oil. MS (ESI): mass calculated for C12H11ClN2O, 234.1; m / z measured 235.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 7.54 - 7.33 (m, 5H), 5.07 (s, 2H), 2.43 (s, 3H) ppm. Step D. Methyl 5-(benzyloxy)-6-methylpyrimidine-4-carboxylate. 25 To a solution of 5-(benzyloxy)-4-chloro-6-methylpyrimidine (15.6 g, 66.5 mmol) in MeOH (156 mL) was added TEA (13.4 g, 132 mmol, 18.5 mL) and Pd(dppf)Cl2 (4.9 g, 6.6 mmol) under N2 atmosphere. The suspension was degassed and purged with CO three times. The mixture was stirred under CO (50 Psi) at 50 °C for 24 hrs. The reaction mixture was filtered and concentrated under reduced pressure. The residue 30 was purified by column chromatography (SiO2, 0-29% EtOAc / petroleum ether) to yield the title compound as a yellow oil. MS (ESI): mass calculated for C14H14N2O3, 258.1; m / z measured 259.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 7.51 - 7.32 (m, 5H), 5.07 (s, 2H), 3.98 (s, 3H), 2.55 (s, 3H) ppm. Step E.5-(Benzyloxy)-6-methylpyrimidine-4-carboxylic acid. 83 PRD4322WOPCT1 5 To a solution of methyl 5-(benzyloxy)-6-methylpyrimidine-4-carboxylate (10.0 g, 38.7 mmol) in THF (50 mL) and H2O (50 mL) was added NaOH (2.32 g, 58.0 mmol). The mixture was stirred at 20 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The resulting residue was diluted with H2O (150 mL) and extracted with MTBE (80 mL x 2). The aqueous phase was 10 acidified with 4M HCl to pH=2, the resulting precipitate was collected by filtration to yield the title compound as a white solid. MS (ESI): mass calculated for C13H12N2O3, 244.1; m / z measured 245.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 14.44 - 13.80 (m, 1H), 8.85 (s, 1H), 7.54 - 7.33 (m, 5H), 5.04 (s, 2H), 2.48 (s, 3H) ppm. Step F.5-Hydroxy-6-methylpyrimidine-4-carboxylic acid. 15 A solution of 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (1.3 g, 5.3 mmol) in TFA (14.0 mL) was stirred at 50 °C for 16 hours. The resulting mixture was combined with an additional three batches (which were prepared separately and in different amounts) and the combined mixture was concentrated in vacuum to yield a yellow solid. The yellow solid was washed with DCM and MeOH, filtered, and 20 concentrated filtered residue to dryness in vacuo to yield 5-hydroxy-6- methylpyrimidine-4-carboxylic acid as a yellow solid. MS (ESI): mass calculated for C6H6N2O3, 154.0; m / z measured 155.1[M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.65(s, 1H), 2.47 (s, 3H) ppm. Intermediate 3: 2-(4-Bromophenyl)-7-methoxy-5-methyloxazolo[4,5-b]pyridine. 25 Step A.2-Amino-4-brom ypy . To a 500 mL three-necked round bottom flask was added 4-bromo-6-methyl-2- nitropyridin-3-ol (5 g, 21.5 mmol), NH4Cl (6 g, 112 mmol), Fe (6 g, 107 mmol), and EtOH / H2O (v / v=5 / 1, 90 mL). The reaction vessel was allowed to gradually warm to 80 30 °C over the course of 5 minutes, after which time stirring was continued for 12 hours, before cooling to room temperature. The reaction solution was filtered through silica gel and the filter cake was washed with EtOH (200 mL). The combined filtrates were 84 PRD4322WOPCT1 5 concentrated to dryness to yield a black solid. The black solid was subjected to silica gel chromatography (0 - 20% MeOH / DCM) to yield the title compound as a brown solid. MS (ESI): mass calculated for C6H7BrN2O, 202.0; m / z measured 202.7 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 6.61 (s, 1H), 6.24 (br s, 2H), 2.18 (s, 3H) ppm. 10 Step B.7-Bromo-2-(4-bromophenyl)-5-methyloxazolo[4,5-b]pyridine. To a 250 mL three-necked round bottom flask was added 2-amino-4-bromo-6- methylpyridin-3-ol (5 g, 24.6 mmol), 4-bromobenzoic acid (5.1 g, 25.4 mmol) and PPA (100 mL). The reaction vessel was allowed to gradually warm to 130 °C over the course of 5 minutes, after which time stirring was continued for 12 hours, before 15 cooling it to room temperature. The reaction mixture was slowly poured into ice water (300 mL) and then stirred at room temperature for 30 minutes. The resulting solution was extracted with ethyl acetate. The organic layer was washed with brine then dried with anhydrous Na2SO4, filtered, and concentrated to yield a yellow gum. The residue was triturated with ACN (200 mL) then filtered. The resulting solid was rinsed with 20 ACN (100 mL), collected and dried to yield the title compound as a yellow solid. MS (ESI): mass calculated For C13H8Br2N2O, 367.9; m / z measured 368.8 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 8.5 Hz, 2H), 7.91 - 7.85 (m, 2H), 7.69 (s, 1H), 2.60 (s, 3H) ppm. Step C.2-(4-Bromophenyl)-7-methoxy-5-methyloxazolo[4,5-b]pyridine. 25 To a 500 mL three-necked round bottom flask was added 7-bromo-2-(4- bromophenyl)-5-methyloxazolo[4,5-b]pyridine (12 g, 30.7 mmol), NaOCH3 (85 mL, 459.0 mmol, 5.4 M, 15 eq.) and MeOH (100 mL). The reaction vessel was allowed to gradually warm to 80 °C over the course of 5 minutes, after which time stirring was continued for 2 hours, before cooling to room temperature. The reaction mixture was 30 filtered and the filter cake was rinsed with MeOH (100 mL). The solid was collected, dried in vacuo to yield the title compound as a yellow solid. MS (ESI): mass calculated for C14H11BrN2O2, 318.0 m / z, measured 319.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.15 - 8.10 (m, 2H), 7.84 (d, J = 8.5 Hz, 2H), 7.06 (s, 1H), 4.08 (s, 3H), 2.56 (s, 3H) ppm. 85 PRD4322WOPCT1 5 Intermediate 4: 2-(6-Bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)-5-methyl-7- oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide. Step A.2-(2-(4-Br lo[4,5-b]pyridin-4(7H)-yl)-N- (2-chloro-4-(trifluoromethyl)phenyl)acetamide. 10 To a solution of 2-(4-bromophenyl)-7-methoxy-5-methyloxazolo[4,5-b]pyridine (Intermediate 3, 1.0 g, 2.7 mmol, 88% purity) in toluene (20 mL), was added N-(2- chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide (Intermediate 1, 2.5 g, 6.7 mmol). The reaction mixture was allowed to gradually warm to 120 °C over the course of 20 minutes and then stirred at 120 °C for 12 hours. The resulting mixture was 15 concentrated under reduced pressure to remove solvent and yield a solid. The solid was subjected to silica gel column chromatography over (0 – 10% MeOH / DCM). The pure fractions were collected and concentrated in vacuum to yield the title compound as a brown solid. MS (ESI) calculated for C22H14BrClF3N3O3, 539.0 m / z, measured 541.7 [M+2+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.13 - 8.01 (m, 3H), 20 7.97 (d, J = 1.3 Hz, 1H), 7.84 (d, J = 8.6 Hz, 2H), 7.72 (dd, J = 1.5, 8.6 Hz, 1H), 6.30 (s, 1H), 5.35 (s, 2H), 2.39 (s, 3H);19F NMR (376 MHz, DMSO-d6) δ -60.8 ppm. Step B. Methyl 4-(4-(2-((2-Chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)- 5-methyl-7-oxo-4,7-dihydrooxazolo[4,5-b]pyridin-2-yl)benzoate. 2-(2-(4-Bromophenyl)-5-methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(2- 25 chloro-4-(trifluoromethyl)phenyl)acetamide (1140 mg, 2.0 mmol), Pd(dppf)Cl2•DCM (165 mg, 202 µmol), TEA (840 µL, 6.0 mmol) and MeOH / DMF = 2 / 1 (24.5 mL) were added to the reaction vessel at room temperature. The suspension was degassed under vacuum and purged with CO several times. The resulting mixture was stirred at 80 °C for 16 hours at 45 psi. To the mixture was added H2O (25 mL) and the resulting 86 PRD4322WOPCT1 5 mixture was extracted with ethyl acetate (50 mL). The organics were concentrated under reduced pressure to yield a solid. The solid was subjected to silica gel column chromatography (0 – 9% MeOH / DCM). The pure fractions were collected and concentrated to dryness in vacuo to yield the title compound as a brown solid. MS (ESI) calculated for C24H17ClF3N3O5, 519.1 m / z, measured 520.1 [M+H]+.1H NMR 10 (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.31 - 8.23 (m, 2H), 8.17 (d, J = 8.5 Hz, 2H), 8.09 (d, J = 8.5 Hz, 1H), 7.98 (d, J = 1.4 Hz, 1H), 7.72 (dd, J = 1.6, 8.5 Hz, 1H), 6.32 (s, 1H), 5.38 (s, 2H), 3.90 (s, 3H), 2.41 (s, 3H);19F NMR (376 MHz, DMSO-d6) δ -60.8 ppm. Step C. N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(2-hydroxypropan-2- 15 yl)phenyl)-5-methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide. To a solution of methyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl) -5-methyl-7-oxo-4,7-dihydrooxazolo[4,5-b]pyridin-2-yl)benzoate (960 mg, 1.7 mmol) in THF (7.8 mL) at 0 °C was added CH3MgBr (3 M in Et2O, 5.8 mL, 17.4 mmol). The mixture was stirred for 2 hours at 0 °C. The mixture was quenched with 20 NH4Cl (4 mL), then extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered to yield a solid. The solid was subjected to silica gel column chromatography (0 – 10% MeOH / DCM). The pure fractions were collected and concentrated to dryness in vacuo to yield the title compound as a yellow solid. MS (ESI) calculated for C25H21ClF3N3O4, 519.1 m / z, 25 measured 519.9 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.08 (d, J = 8.5 Hz, 3H), 7.97 (d, J = 1.5 Hz, 1H), 7.71 (d, J = 8.5 Hz, 3H), 6.28 (s, 1H), 5.36 (s, 2H), 5.24 (s, 1H), 2.41 - 2.38 (m, 3H), 1.46 (s, 6H);19F NMR (376 MHz, DMSO-d6) δ - 60.8 ppm. Step D.2-(6-Bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)-5-methyl-7- 30 oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide.. To a solution of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(2- hydroxypropan-2-yl)phenyl)-5-methyl -7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide (504.0 mg, 923.8 µmol) in DMF (23 mL) at 0 °C was added NBS (180.0 mg, 1.0 mmol) portion-wise. The mixture was stirred at 0 °C for 2 hours. The reaction was 87 PRD4322WOPCT1 5 quenched with water and the resulting mixture was extracted with EtOAc. The organic layers were dried with anhydrous Na2SO4, filtered, and concentrated to yield the title compound as a yellow solid. MS (ESI) calculated for C25H20BrClF3N3O4, 597.0 m / z, measured 600.0 [M+2+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.14 - 8.06 (m, 3H), 7.98 (d, J = 1.3 Hz, 1H), 7.73 (d, J = 8.5 Hz, 3H), 5.59 - 5.49 (m, 2H), 5.26 10 (br s, 1H), 2.68 (s, 3H), 1.46 (s, 6H);19F NMR (376 MHz, DMSO-d6) δ -60.8 ppm. Intermediate 5: 2-(4-(7-Methoxy-5-methyloxazolo[4,5-b]pyridin-2- yl)phenyl)propan-2-ol. Step A. Methyl 4-(7-m 4,5-b]pyridin-2-yl)benzoate.15 To a reaction vessel was added 2-(4-bromophenyl)-7-methoxy-5- methyloxazolo[4,5-b]pyridine (Intermediate 3, 1 g, 2.8 mmol, 88% purity), XantPhos Pd G3 (300 mg, 316.3 µmol), TEA (1.3 mL, 9.4 mmol) and MeOH / DMF=2 / 1 (60 mL). The suspension was degassed under vacuum and purged with CO several times. The resulting mixture was stirred at 80 °C for 16 hours at 45 psi. The mixture was filtered, 20 and the filter cake was rinsed with MeOH (10 mL). The filter cake was collected, triturated with DCM (50 mL), filtered and the filtrate was concentrated to yield the title compound as a white solid. MS (ESI) calculated for C16H14N2O4, 298.1 m / z, measured 299.1 [M+H]+.1H NMR (400MHz, CDCl3) δ 8.40 - 8.36 (m, J = 8.5 Hz, 2H), 8.22 - 8.18 (m, J = 8.5 Hz, 2H), 6.73 (s, 1H), 4.13 (s, 3H), 3.98 (s, 3H), 2.67 (s, 3H) ppm. 25 Step B.2-(4-(7-Methoxy-5-methyloxazolo[4,5-b]pyridin-2-yl)phenyl)propan-2-ol. To a solution of methyl 4-(7-methoxy-5-methyloxazolo[4,5-b]pyridin-2- yl)benzoate (630 mg, 2.0 mmol) in THF (20 mL) at 0 °C was added CH3MgBr (3 M in Et2O, 7 mL, 21 mmol). The mixture was stirred for 2.5 hours at 0 °C. The mixture was then diluted with H2O (50 mL) and the resulting mixture was extracted with ethyl 30 acetate. The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to yield a solid. The solid was subjected to silica gel column chromatography (0 – 70% EtOAc / petroleum ether) to yield the 88 PRD4322WOPCT1 5 title compound as a white solid. MS (ESI): mass calculated for C17H18N2O3, 298.1; m / z measured 299.2 [M+H]+.1H NMR (400MHz, CDCl3) δ 8.30 - 8.24 (m, 2H), 7.69 - 7.63 (m, 2H), 6.71 - 6.67 (m, 1H), 4.15 - 4.09 (m, 3H), 2.67 - 2.63 (m, 3H), 1.88 - 1.83 (m, 1H), 1.65 - 1.63 (m, 6H) ppm. Intermediate 6: 2-(4-(6-Bromo-7-methoxy-5-methyloxazolo[4,5-b]pyridin-2- 10 yl)phenyl)propan-2-ol. To a solution of 2-(4-( lo[4,5-b]pyridin-2- yl)phenyl)propan-2-ol (Intermediate 5, 539 mg, 1.8 mmol) in DMF (10 mL) at 0 °C was added NBS (350 mg, 2.0 mmol) portion-wise. The mixture was stirred at 50 °C for 2 15 hours. The reaction was quenched by addition of water (80 mL). The resulting solution was extracted with EtOAc. The organic layers were dried with anhydrous Na2SO4, filtered, and concentrated to yield a residue. The residue was triturated with petroleum ether: ethyl acetate = 3:1 (20 mL), then filtered to yield the title compound as a white solid. MS (ESI): mass calculated for C17H17BrN2O3, 376.0 / 378.0; m / z measured 20 377.0 / 379.0 [M+H]+.1H NMR (400MHz, CDCl3) δ 8.27 - 8.22 (m, 2H), 7.71 - 7.67 (m, 2H), 4.60 - 4.54 (m, 3H), 2.81 - 2.77 (m, 3H), 1.86 - 1.83 (m, 1H), 1.67 - 1.65 (m, 6H) ppm. Intermediate 7: 2-(4-(2-Hydroxypropan-2-yl)phenyl)-4-(prop-1-yn-1-yl)oxazole- 5-carboxylic acid. 25 Step A. Ethyl 4-bromo yl)phenyl)oxazole-5- carboxylate. A mixture of ethyl 2,4-dibromooxazole-5-carboxylate (1 g, 3.3 mmol), (4-(2- hydroxypropan-2-yl)phenyl)boronic acid (602 mg, 3.3 mmol), Pd(dppf)Cl2 (282 mg, 30 345 µmol) and Na2CO3 (1.1 g, 9.9 mmol) in 1,4-dioxane / H2O (v / v 7.5 / 1, 17 mL) was 89 PRD4322WOPCT1 5 stirred at 80 °C for 16 hours under N2. The reaction mixture was then extracted with EtOAc, and the organic layers were combined, dried over Na2SO4, filtered, and concentrated. The resulting yellow solid was subjected to prep-HPLC (C18, 150 × 40 mm; Mobile phase: A: water (FA). B: ACN, gradient elution: 45 - 75% B in A over 6 min, flow rate: 55 mL / min) to yield the title compound as a yellow solid. MS (ESI): 10 mass calculated for C15H16BrNO4, 353.0 / 354.0; m / z measured 355.0 / 355.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.92 - 8.01 (m, 2 H) 7.62 - 7.76 (m, 2 H) 5.13 - 5.36 (m, 1 H) 4.26 - 4.46 (m, 2 H) 1.40 - 1.54 (m, 6 H) 1.28 - 1.39 (m, 3 H) ppm. Step B. Ethyl 2-(4-(2-hydroxypropan-2-yl)phenyl)-4-(prop-1-yn-1-yl)oxazole-5- carboxylate. 15 A mixture of ethyl 4-bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)oxazole-5- carboxylate (420 mg, 1.2 mmol), tributyl(1-propynyl)tin (976 mg, 3.0 mmol), Pd(dppf)Cl2•DCM (145 mg, 178 µmol), CuI (45 mg, 235 µmol), and CsF (362 mg, 2.4 mmol) in DMF (10 mL) was stirred at 120 °C for 1 h under N2. The reaction mixture was extracted with EtOAc, and the organic layer was dried over Na2SO4, filtered, and 20 concentrated. The resulting yellow solid was purified by silica gel column chromatography (0-50% EtOAc / petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C18H19NO4, 313.1; m / z measured 313.9 [M+H].1H NMR (400 MHz, DMSO-d6) δ 7.91 - 8.02 (m, 2 H) 7.64 - 7.73 (m, 2 H) 5.14 - 5.26 (m, 1 H) 4.25 - 4.46 (m, 2 H) 2.06 - 2.22 (m, 3 H) 1.42 - 1.48 (m, 6 H) 1.31 - 25 1.39 (m, 3 H) ppm. Step C.2-(4-(2-Hydroxypropan-2-yl)phenyl)-4-(prop-1-yn-1-yl)oxazole-5- carboxylic acid. To a solution of ethyl 2-(4-(2-hydroxypropan-2-yl)phenyl)-4-(prop-1-yn-1- yl)oxazole-5-carboxylate (140 mg, 447 µmol) in MeOH (1.5 mL) and THF (1.5 mL) 30 was added LiOH (894 µL, 894 µmol), and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was then alkalified to pH~1 by addition of HCl (1 M) and extracted with DCM. The organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to yield the title compound as a yellow solid. MS (ESI): mass calculated for C16H15NO4, 285.1; m / z measured 285.9 [M+H].1H NMR 90 PRD4322WOPCT1 5 (400 MHz, DMSO-d6) δ 7.91 - 7.99 (m, 2 H) 7.63 - 7.72 (m, 2 H) 5.01 - 5.39 (m, 1 H) 2.06 - 2.25 (m, 3 H) 1.36 - 1.52 (m, 6 H) ppm. Example 1: 2-[6-(1-Acetyl-3,6-dihydro-2H-pyridin-4-yl)-2-[4-(1-hydroxy-1- methyl-ethyl)phenyl]-5-methyl-7-oxo-oxazolo[4,5-b]pyridin-4-yl]-N-[2-chloro-4- 10 (trifluoromethyl)phenyl]acetamide. To a solution of 2 2-yl)phenyl)-5-methyl-7- oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (Intermediate 4, 20.0 mg, 29.7 µmol, 89% purity) in DMF / H2O = 3 / 1 (0.6 mL) was15 added 1-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)- yl)ethan-1-one (8.4 mg, 33.4 µmol), Pd-118 (4.3 mg, 6.5 µmol), and Cs2CO3 (29.0 mg, 89.0 µmol). N2 was bubbled into the reaction mixture for 1 minute, and the mixture was then stirred at 60 °C for 3 hours under N2. The reaction was quenched with H2O and the resulting mixture was extracted with EtOAc. The organics were dried over 20 sodium sulfate, filtered and concentrated to yield a brown oil. The brown oil was purified by preparative reversed phase HPLC (Stationary phase: C18, 150 × 30 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) – ACN (B), gradient elution: 47 – 77% B in A over 2 min, flow rate: 25 mL / min) to yield the title compound as a white solid. MS (ESI) calculated for C32H30ClF3N4O5, 642.2 m / z, measured 643.3 [M+H]+.1H NMR 25 (400 MHz, DMSO-d6) δ 10.53 - 10.32 (m, 1H), 8.16 - 8.05 (m, 3H), 7.97 (s, 1H), 7.71 (d, J = 8.5 Hz, 3H), 5.50 (br s, 1H), 5.42 (s, 2H), 5.25 (s, 1H), 4.11 (br d, J = 3.8 Hz, 1H), 3.68 - 3.55 (m, 2H), 3.53 - 3.46 (m, 1H), 3.39 (br s, 2H), 2.38 (d, J = 3.5 Hz, 3H), 2.07 (d, J = 5.8 Hz, 3H), 1.46 (s, 6H);19F NMR (376 MHz, DMSO-d6) δ -60.8 ppm. 91 PRD4322WOPCT1 5 Example 2: 2-(6-(1-Acetylpiperidin-4-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-5- methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide. To a solution of 2 din-4-yl)-2-(4-(2-10 hydroxypropan -2-yl)phenyl)-5-methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(2- chloro-4-(trifluoromethyl)phenyl)acetamide (17.0 mg, 24.4 µmol) in MeOH / THF (v / v=5 / 1, 0.6 mL) was added PtO2 (3.5 mg, 15.4 µmol). The flask was placed under H2 atmosphere (15 Psi) and stirred for 3 hours at room temperature. The reaction mixture was filtered through a pad of CELITE®and the pad was washed with MeOH. The 15 filtrate was collected and concentrated under vacuum to yield a brown oil. The brown oil was taken up in MeoH and then separated by SFC (Stationary phase: DAICEL CHIRALPAK AD (250 mm × 30 mm,10 um); Mobile phase: Supercritical CO2 (A) – EtOH (0.1%NH3H2O) (B), gradient elution: 35% B in A at 80 mL / min) to yield the title compound as an off-white solid. MS (ESI) calculated for C32H32ClF3N4O5, 644.2 m / z, 20 measured 645.5 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.54 (d, J = 8.5 Hz, 1H), 8.22 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H), 7.60 (s, 1H), 7.55 (br d, J = 8.8 Hz, 1H), 5.39 - 5.31 (m, 1H), 5.23 (s, 2H), 4.78 (br d, J = 12.0 Hz, 1H), 4.00 - 3.88 (m, 1H), 3.22 - 3.09 (m, 1H), 2.69 - 2.62 (m, 1H), 2.61 (s, 3H), 2.23 (t, J = 7.7 Hz, 1H), 2.15 (s, 3H), 2.07 - 1.97 (m, 1H), 1.63 (s, 6H), 1.37 - 1.31 (m, 3H);19F NMR (376 25 MHz, CDCl3) δ -62.5 ppm. Example 3: N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(2-hydroxypropan-2- yl)phenyl)-6-isopropyl-5-methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide. 92 PRD4322WOPCT1 5 Step A. N-(2-Chlo 4-(2-hydroxypropan-2- yl)phenyl)-5-methyl-7-oxo-6-(prop-1-en-2-yl)oxazolo[4,5-b]pyridin-4(7H)-yl)acetamide. To a solution of 2-(6-bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)-5-methyl-7- oxooxazolo [4,5-b]pyridin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide 10 (Intermediate 4, 107 mg, 167 µmol) in 1,4-dioxane / H2O = 7.5 / 1 (3.5 mL) were added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (28.3 µL, 151 µmol), Pd(dppf)Cl2•DCM (31.5 mg, 38.5 µmol), and Cs2CO3 (163 mg, 500 µmol). N2 was bubbled into the mixture for 1 minute and the mixture was then stirred at 90 °C for 12 hours under N2. The reaction was quenched with H2O and the resulting mixture was 15 extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield a solid. The solid was subjected to silica gel column chromatography (0 – 6% MeOH / EtOAc) to yield the title compound as a light brown solid. MS (ESI) calculated for C28H25ClF3N3O4, 559.1 m / z, measured 560.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.09 (d, J = 8.5 Hz, 3H), 20 7.98 (s, 1H), 7.71 (d, J = 8.3 Hz, 3H), 5.45 - 5.38 (m, 2H), 5.29 (br s, 1H), 5.25 (s, 1H), 4.77 (s, 1H), 2.42 - 2.37 (m, 3H), 1.94 (s, 3H), 1.46 (s, 6H);19F NMR (376 MHz, DMSO-d6) δ -60.8 ppm. Step B. N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(2-hydroxypropan-2- yl)phenyl)- 6-isopropyl-5-methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide. 25 To a solution of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(2- hydroxypropan-2-yl)phenyl)-5-methyl-7-oxo-6-(prop-1-en-2-yl)oxazolo[4,5-b]pyridin- 4(7H)-yl)acetamide (45.0 mg, 70.1 µmol) in MeOH / THF (v / v=4 / 1, 1.8 mL) was added Rh / Al2O3 (289 mg, 140 µmol). The flask was placed under H2 atmosphere (15 Psi) and stirred for 30 hours at room temperature. The reaction mixture was filtered 93 PRD4322WOPCT1 5 through CELITE®and the pad washed with MeOH. The filtrate was collected and concentrated under vacuum to yield a brown oil. The brown oil was purified by preparative reversed phase HPLC (Stationary phase: C18, 5 µm, 150 × 30 mm; Mobile phase: water (NH4HCO3) (A) – ACN (B), gradient elution: 55 – 85% B in A over 1.8 min, flow rate: 25 mL / min) to yield the title compound as a white solid. MS (ESI) 10 calculated for C28H27ClF3N3O4, 561.2 m / z, measured 562.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.43 (br s, 1H), 8.14 - 8.03 (m, 3H), 7.97 (d, J = 1.3 Hz, 1H), 7.71 (br d, J = 8.5 Hz, 3H), 5.43 (s, 2H), 5.25 (s, 1H), 3.41 - 3.38 (m, 1H), 2.46 - 2.38 (m, 3H), 1.46 (s, 6H), 1.33 (d, J = 7.0 Hz, 6H);19F NMR (376 MHz, DMSO-d6) δ -60.8 ppm. 15 Example 4: N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(6-(1-(5-hydroxy-6- methylpyrimidine-4-carbonyl)piperidin-4-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-5- methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide. Step A. tert-B -7-methoxy-5- 20 methyloxazolo[4,5-b] pyridin-6-yl)piperidine-1-carboxylate. A mixture of 2-(4-(6-bromo-7-methoxy-5-methyloxazolo[4,5-b]pyridin-2- yl)phenyl)propan-2-ol (Intermediate 6, 200 mg, 526 µmol), Cphos Pd G3 (45 mg, 55.7 µmol, 0.1 eq.) and LiCl (70 mg, 1.7 mmol) was purged with N2 for 10 seconds. The reaction mixture was sealed with parafilm. DMA (5 mL) was injected through the25 syringe filter into the mixture, followed by addition of (1-(tert-butoxycarbonyl)piperidin- 4-yl)zinc(II) iodide (1.5 mL, 1.6 mmol, 1.06 M in THF). The mixture was stirred at 60 °C for 2 hours. The mixture was diluted with ethyl acetate (10 mL), washed with H2O. The organic layer was dried over Na2SO4, filtered, and concentrated to yield a yellow 94 PRD4322WOPCT1 5 oil. The yellow oil was purified by preparative reversed phase HPLC (Stationary phase: Phenomenex C18, 3 μm, 40 × 80 mm; Mobile phase: water (NH3H2O+NH4HCO3) (A) - Acetonitrile(B), gradient elution: 10 - 40% B in A over 8 min, flow rate: 30 mL / min) to yield the title compound \ as a yellow powder. MS (ESI): mass calculated for C27H35N3O5, 481.3; m / z measured 482.3 [M+H]+. 10 Step B. tert-Butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-5-methyl-7-oxo-4,7-dihydrooxazolo[4,5- b]pyridin-6-yl)piperidine-1-carboxylate. A mixture of tert-butyl 4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-7-methoxy-5- methyloxazolo[4,5-b]pyridine -6-yl)piperidine-1-carboxylate (120 mg, 198 µmol) and 15 N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide (Intermediate 1, 144 mg, 396 µmol) in toluene (3 mL) was heated at 120 °C for 12 hours. The solution was diluted with H2O, then extracted with EtOAc. The organic layers were dried with anhydrous Na2SO4, filtered, and concentrated to yield a yellow gum. The yellow gum was subjected to silica gel column chromatography (0 – 100% EtOAc / petroleum ether) to 20 yield the title compound as a light green solid. MS (ESI): mass calculated for C35H38ClF3N4O6, 702.2; m / z measured 703.3 [M+H]+. Step C. N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(2-hydroxypropan-2- yl)phenyl)-5- methyl-7-oxo-6-(piperidin-4-yl)oxazolo[4,5-b]pyridin-4(7H)-yl)acetamide. A mixture of tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-25 oxoethyl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-5-methyl-7-oxo-4,7-dihydrooxazolo[4,5- b]pyridin-6-yl)piperidine-1-carboxylate (80 mg, 94.9 µmol) in HCl (2 M in 1,4-dioxane, 1 mL) was stirred at room temperature for 1 hour. The mixture was concentrated to dryness in vacuo. The resulting residue was diluted with H2O (5 mL) and aq. NaHCO3 was added to adjust to pH>7. The aqueous phase was extracted with EtOAc. The 30 organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to yield the title compound as a white solid. MS (ESI): mass calculated for C30H30ClF3N4O4, 602.2; m / z measured 603.2 [M+H]+. 95 PRD4322WOPCT1 5 Step D. N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(6-(1-(5-hydroxy-6- methylpyrimidine-4- carbonyl)piperidin-4-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-5- methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide. A mixture of 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (Intermediate 2, 25 mg, 157 µmol), HOPO (24 mg, 216 µmol), EDCI (37.6 mg, 196 µmol) and DIEA 10 (77.6 µL, 445 µmol) in 1,4-dioxane (2 mL) was stirred under N2 at room temperature for 15 minutes. N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(2-hydroxypropan-2-yl) phenyl)-5-methyl-7-oxo-6-(piperidin-4-yl)oxazolo[4,5-b]pyridin-4(7H)-yl)acetamide (80 mg, 106 µmol) was then added. The mixture was allowed to gradually warm to 50 °C over the course of 5 minutes, after which time stirring was continued for 2 hours. The 15 mixture was cooled, then concentrated to dryness in vacuo. The resulting residue was diluted with H2O and the aqueous phase extracted with EtOAc. The organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to yield a light yellow gum. The light yellow gum was purified by preparative reversed phase HPLC (C18 150×30 mm; Mobile phase: water (NH3H2O+NH4HCO3) (A) - Acetonitrile(B), gradient 20 elution: 30 - 60% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as an off-white powder. MS (ESI): mass calculated for C36H34ClF3N6O6, 738.2; m / z measured 739.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.68 - 10.09 (m, 1H), 8.54 (s, 1H), 8.09 (s, 1H), 8.08 - 8.04 (m, 2H), 7.98 (d, J = 1.4 Hz, 1H), 7.74 - 7.71 (m, 2H), 7.70 (s, 1H), 5.45 (s, 2H), 5.25 (s, 1H), 4.68 - 4.56 (m, 1H), 3.64 - 3.52 (m, 2H), 3.20 - 25 3.05 (m, 3H), 2.85 (br t, J = 11.7 Hz, 1H), 2.48 - 2.46 (m, 3H), 2.44 - 2.42 (m, 3H), 1.59 - 1.50 (m, 1H), 1.46 (s, 6H), 1.41 - 1.32 (m, 1H);19F NMR (376 MHz, DMSO-d6) δ -60.8 ppm. Example 5: N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-5- 30 methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide. 96 PRD4322WOPCT1 5 Step A. N-(2-C 2-hydroxypropan-2- yl)phenyl)-5-methyl-7-oxo-6-(piperazin-1-yl)oxazolo[4,5-b]pyridin-4(7H)-yl)acetamide. To a 2 mL vial with a stir bar were added 2-(6-bromo-2-(4-(2-hydroxypropan-2- yl)phenyl)-5-methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(2-chloro-4- 10 (trifluoromethyl)phenyl)acetamide (Intermediate 4, 59.9 mg, 0.1 mmol), piperazine (43.1 mg, 0.5 mmol) and N-methyl-2-pyrrolidone (0.2 mL). The reaction mixture was heated to 150 °C and stirred for 1 hour. After cooling to room temperature, the reaction mixture was diluted with DMSO / H2O (10:1, 1.5 mL). The resulting solution was purified by prep-HPLC (stationary phase: Waters XSelect CSH C18, 5u, 19x150 15 mm; mobile phase A: water with 0.16% TFA, mobile phase B: Acetonitrile with 0.16% TFA, flow rate: 25 mL / min, gradient from 15% to 55% Acetonitrile, 12 min run time) to yield the title compound as a corresponding TFA salt. MS (ESI): mass calculated for C29H29ClF3N5O4, 603.2 m / z measured 604.1 [M+H]+. Step B. N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(5-hydroxy-6-20 methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-5- methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide. To a suspension of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(2- hydroxypropan-2-yl)phenyl)-5-methyl-7-oxo-6-(piperazin-1-yl)oxazolo[4,5-b]pyridin- 4(7H)-yl)acetamide (4.0 mg, 0.0066 mmol), 2-hydroxypyridine N-oxide (0.74 mg, 25 0.0066 mmol), and 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (Intermediate 2, 1.5 mg, 0.0099 mmol) in 20% NMP / DCM (0.13 mL) was added EDCI (1.9 mg, 0.0099 mmol) and the mixture was stirred at 49 °C for 30 mins. The resulting mixture was concentrated and the residue was purified by RP-HPLC on a Phenomenex Gemini 97 PRD4322WOPCT1 5 5uM C-18110Å 150 x 30 mm column eluting with a linear gradient of 25-80% B in A in 12 mins (A: 10 mM ammonium carbonate, 0.1% ammonium hydroxide in water; B: 10 mM ammonium carbonate, 0.1% ammonium hydroxide in 90% acetonitrile 10% water) to yield the title compound as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 10.32 - 10.58 (m, 1 H), 8.48 (br s, 1 H), 8.06 - 8.12 (m, 3 H), 7.97 (d, J=1.47 Hz, 10 1 H), 7.71 (d, J=8.80 Hz, 3 H), 5.41 (s, 2 H), 5.23 (s, 1 H), 4.48 (br d, J=12.23 Hz, 1 H), 3.65 - 3.77 (m, 2 H), 3.48 (br d, J=11.25 Hz, 1 H), 3.18 - 3.27 (m, 1 H), 2.92 - 3.03 (m, 1 H), 2.74 (br d, J=10.27 Hz, 1 H), 2.58 (m, 4 H), 2.41 (s, 3 H), 1.46 (s, 6 H). MS (ESI): mass calculated for C35H33ClF3N7O6, 740.2; m / z measured 740.2 [M+H]+. Example 6: N-[2-Chloro-4-(trifluoromethyl)phenyl]-2-[2-[4-(1-hydroxy-1-methyl-15 ethyl)phenyl]-5-[4-(5-hydroxy-6-methyl-pyrimidine-4-carbonyl)piperazin-1-yl]-6-methyl- 4-oxo-oxazolo[5,4-c]pyridin-7-yl]acetamide. Step A. tert-B -4-(prop-1-yn-1- yl)oxazole-5-carboxamido)piperazine-1-carboxylate. 20 A mixture of 2-(4-(2-hydroxypropan-2-yl)phenyl)-4-(prop-1-yn-1-yl)oxazole-5- carboxylic acid (Intermediate 7, 90 mg, 272 µmol), tert-butyl 4-aminopiperazine-1- carboxylate (55 mg, 273 µmol), HOPO (36 mg, 324 µmol) and EDCI (63 mg, 329 µmol) in 1,4-dioxane (3 mL) was stirred at 50 °C for 1 h. The resulting mixture was concentrated to dryness and the residue was combined with a second batch (which 25 was prepared separately and in a different amount). The combined mixture was purified by silica gel column chromatography (0-60% EtOAc / petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C25H32N4O5, 468.2; m / z, found 469.2 [M-55+H]+.1H NMR (400 MHz, DMSO-d6) δ = 9.66 (s, 1H), 98 PRD4322WOPCT1 5 8.04 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H), 5.20 (s, 1H), 3.42 (br s, 4H), 2.87 (br t, J = 4.6 Hz, 4H), 2.11 (s, 3H), 1.44 (s, 6H), 1.41 (s, 9H). Step B. tert-Butyl 4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-4- oxooxazolo[5,4-c]pyridin-5(4H)-yl)piperazine-1-carboxylate. A mixture of tert-butyl 4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-4-(prop-1-yn-1- 10 yl)oxazole-5-carboxamido)piperazine-1-carboxylate (88 mg, 181 µmol) and DBU (8.2 µL, 55 µmol) in DMF (0.9 mL) was stirred at 100 °C for 2 h. The reaction was diluted with water, then with EtOAc and extracted. The organic layers were dried with anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (0 - 60% petroleum ether / EtOAc) to yield the title 15 compound as a light yellow solid. MS (ESI) calculated for C25H32N4O5, 468.2 m / z, found 412.9 [M-55+H]+.1H NMR (400 MHz, DMSO-d6) δ = 8.09 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H), 6.67 (s, 1H), 5.24 (s, 1H), 3.89 (br s, 4H), 2.96 (br d, J = 10.0 Hz, 4H), 2.43 (s, 3H), 1.47 (s, 6H), 1.44 (s, 9H). Step C. tert-Butyl 4-(7-bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-4- 20 oxooxazolo[5,4-c]pyridin-5(4H)-yl)piperazine-1-carboxylate. To a solution of tert-butyl 4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-4- oxooxazolo[5,4-c]pyridin-5 (4H)-yl)piperazine-1-carboxylate (245 mg, 516 µmol) in DMF (11 mL) at 0 °C was added NBS (181 mg, 1.0 mmol) portion-wise. The mixture was stirred at 50 °C for 12 h, then diluted with water and EtOAc. The organics were 25 extracted, then dried over anhydrous Na2SO4, filtered and concentrated. The resulting brown gum was subjected to silica gel column chromatography (0 – 60% EtOAc / petroleum ether) to yield the title compound as a yellow solid. MS (ESI) calculated for C25H31BrN4O5, 546.1 m / z, measured 491.1 [M-55+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 8.3 Hz, 2H), 7.72 (d, J = 8.3 Hz, 2H), 5.26 (s, 1H), 4.07 30 - 3.76 (m, 4H), 3.00 (br d, J = 10.0 Hz, 4H), 2.56 (s, 3H), 1.47 (s, 6H), 1.43 (s, 9H) ppm. Step D. tert-Butyl 4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-7-(2-methoxy-2- oxoethyl)-6-methyl-4-oxooxazolo[5,4-c]pyridin-5(4H)-yl)piperazine-1-carboxylate. 99 PRD4322WOPCT1 5 A mixture of tert-butyl 4-(7-bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl- 4-oxooxazolo[5,4-c]pyridin-5(4H)-yl)piperazine-1-carboxylate (162 mg, 296 µmol), tert-butyl((1-methoxyvinyl)oxy)dimethylsilane (266 µL, 1.2 mmol), XPhos Pd G4(34 mg, 40 µmol) and XPhos (17 mg, 36 µmol) in THF (3.2 mL) was sparged with N2 then heated at 90 °C for 24 h. The mixture was diluted with EtOAc and water. The 10 organics were extracted and washed with brine, dried over Na2SO4, filtered and concentrated. The resulting brown gum was subjected to silica gel column chromatography (0 – 60% EtOAc / petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C28H36N4O7, 540.3; m / z, measured 485.2 [M-55+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.3 15 Hz, 2H), 5.24 (s, 1H), 4.00 - 3.84 (m, 6H), 3.65 (s, 3H), 2.92 (br d, J = 9.8 Hz, 4H), 2.40 (s, 3H), 1.46 (s, 6H), 1.44 (s, 9H) ppm. Step E. tert-Butyl 4-(7-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-4-oxooxazolo[5,4-c]pyridin- 5(4H)-yl)piperazine-1-carboxylate. 20 To a solution of tert-butyl 4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-7-(2-methoxy- 2-oxoethyl)-6-methyl-4-oxooxazolo[5,4-c]pyridin-5(4H)-yl)piperazine-1-carboxylate (164 mg, 1303 µmol) in THF (3.3 mL) at 0 °C was added LiHMDS (3.7 mL, 1.9 mmol) in portions. The reaction mixture was stirred for 30 minutes, then 2-chloro-4- (trifluoromethyl)aniline (460 mg, 2.4 mmol) was added, and the resulting mixture was 25 further stirred at 0 °C for 5 minutes, then warmed to room temperature for 2 hours. The reaction was quenched with H2O, followed by sat. aq. NH4Cl. The mixture was extracted with EtOAc and concentrated. The resulting brown gum was subjected to silica gel column chromatography (0 – 60% EtOAc / petroleum ether) to yield the title compound as a yellow solid. MS (ESI) calculated for C34H37ClF3N5O6, 703.2 m / z, 30 measured 704.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.16 - 8.05 (m, 3H), 7.93 (d, J = 1.5 Hz, 1H), 7.76 - 7.66 (m, 3H), 5.25 (s, 1H), 4.06 (d, J = 1.8 Hz, 2H), 3.99 - 3.86 (m, 4H), 2.93 (br d, J = 10.3 Hz, 4H), 2.46 (s, 3H), 1.46 (s, 6H), 1.44 (s, 9H);19F NMR (376 MHz, DMSO-d6) δ -60.7 ppm. 100 PRD4322WOPCT1 5 Step F. N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(2-hydroxypropan-2- yl)phenyl)-6-methyl-4-oxo-5-(piperazin-1-yl)-4,5-dihydrooxazolo[5,4-c]pyridin-7- yl)acetamide. A mixture of tert-butyl 4-(7-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-4-oxooxazolo[5,4-c]pyridin- 10 5(4H)-yl)piperazine-1-carboxylate (139 mg, 188 µmol) in 4M HCl / 1,4-dioxane (5.6 mL) was stirred at room temperature for 2 h. The mixture was then concentrated to yield the title compound as a white solid. MS (ESI) calculated for C29H29ClF3N5O4, 603.2 m / z, measured 604.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.17 - 8.07 (m, 3H), 7.93 (s, 1H), 7.72 (br d, J = 8.3 Hz, 3H), 5.24 (s, 1H), 4.08 - 4.03 (m, 15 2H), 4.01 - 3.94 (m, 2H), 2.91 (br d, J = 11.5 Hz, 2H), 2.85 - 2.71 (m, 4H), 2.44 (s, 3H), 1.47 (s, 6H), 1.26 - 1.22 (m, 1H);19F NMR (376 MHz, DMSO-d6) δ -60.7 ppm. Step G. N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6- methyl-4-oxo-4,5-dihydrooxazolo[5,4-c]pyridin-7-yl)acetamide. 20 A mixture of 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (Intermediate 2, 31 mg, 194 µmol), HOPO (9.0 mg, 81 µmol), EDCI (33 mg, 171 µmol) and DIEA (73 µL, 420 µmol) was stirred in 1,4-dioxane (4.0 mL) at room temperature for 0.5 h. N- (2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-4- oxo-5-(piperazin-1-yl)-4,5-dihydrooxazolo[5,4-c]pyridin-7-yl)acetamide (97 mg, 140 25 µmol) was added and the resulting mixture was warmed to 50 °C, then stirred for 2h. The resulting mixture was diluted with water and EtOAc, then extracted. The organic layers were dried with anhydrous Na2SO4, filtered, and concentrated. The resulting yellow gum was purified by preparative reverse phase HPLC (Stationary phase: C18 150 × 30 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) – ACN (B), gradient 30 elution: 20 – 50% B in A over 2 min, flow rate: 25 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C35H33ClF3N7O6, 739.2; m / z measured 740.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.57 (s, 1H), 8.14 - 8.06 (m, 3H), 7.93 (d, J = 1.5 Hz, 1H), 7.76 - 7.65 (m, 3H), 5.25 (s, 1H), 4.55 (br d, J = 11.3 Hz, 1H), 4.06 (s, 2H), 4.05 - 3.96 (m, 2H), 3.57 - 3.50 (m, 1H), 3.42 (br s, 1H), 3.10 (br 101 PRD4322WOPCT1 5 d, J = 10.3 Hz, 2H), 2.92 (br d, J = 10.0 Hz, 1H), 2.48 (br s, 3H), 2.44 (s, 3H), 1.46 (s, 6H);19F NMR (376 MHz, DMSO-d6) δ = -60.7 ppm. Example 7: N-[2-Chloro-4-(trifluoromethyl)phenyl]-2-[2-[4-(1-hydroxy-1-methyl- ethyl)phenyl]-5-[1-(5-hydroxy-6-methyl-pyrimidine-4-carbonyl)-4-piperidyl]-6-methyl-4- oxo-oxazolo[5,4-c]pyridin-7-yl]acetamide. 10 Step A. tert-B -4-(prop-1-yn-1- yl)oxazole-5-carboxamido)piperidine-1-carboxylate. To a solution of 2-(4-(2-hydroxypropan-2-yl)phenyl)-4-(prop-1-yn-1-yl)oxazole- 5-carboxylic acid (Intermediate 7, 2.1 g, 7.3 mmol) and tert-butyl 4-aminopiperidine-1- 15 carboxylate (2.9 g, 14.6 mmol) in 1,4-dioxane (30 mL) was added HOPO (1.6 g, 14.6 mmol) and EDCI (2.8 g, 14.6 mmol). The reaction mixture was stirred at 50 °C for 16 h, then concentrated and purified by silica gel column chromatography (0 – 50% EtOAc / petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C26H33N3O5, 467.2; m / z measured 412.2 [M-56+H]+. 20 Step B. tert-Butyl 4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-4- oxooxazolo[5,4-c] pyridin-5(4H)-yl)piperidine-1-carboxylate. A mixture of tert-butyl 4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-4-(prop-1-yn-1- yl)oxazole-5-carboxamido)piperidine-1-carboxylate (1 g, 2.1 mmol) and DBU (100 µL, 669 µmol) in DMF (20 mL) was stirred at 100 °C for 16 h. The reaction mixture was 25 concentrated and purified by silica gel column chromatography (0 – 50% EtOAc / petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C26H33N3O5, 467.2; m / z measured 412.2 [M-56+H]+. 102 PRD4322WOPCT1 5 Step C. tert-Butyl 4-(7-bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-4- oxooxazolo [5,4-c]pyridin-5(4H)-yl)piperidine-1-carboxylate. To a solution of tert-butyl 4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-4- oxooxazolo [5,4-c]pyridin-5(4H)-yl)piperidine-1-carboxylate (1.5 g, 2.9 mmol) in DMF (20 mL) was added NBS (565 mg, 3.2 mmol) at 0 °C. The mixture was stirred at 0 °C 10 for 2 hours, then diluted with EtOAc and H2O, and extracted. The organics were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was subjected to silica gel column chromatography (0 – 10% EtOAc / petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C26H32BrN3O5, 547.1; m / z measured 492.1 [M-56+H]+. 15 Step D. tert-Butyl 4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-7-(2-methoxy-2- oxoethyl)-6-methyl-4-oxooxazolo[5,4-c]pyridin-5(4H)-yl)piperidine-1-carboxylate. A mixture of tert-butyl 4-(7-bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl- 4-oxooxazolo[5,4-c]pyridin-5(4H)-yl)piperidine-1-carboxylate (700 mg, 1.1 mmol), tert- butyl((1-methoxyvinyl)oxy)dimethylsilane (855 mg, 4.5 mmol), XPhos (65 mg, 136 20 µmol) and XPhos Pd G4 (127 mg, 148 µmol) in THF (10 mL) was degassed and purged with N2. The mixture was stirred at 90 °C for 12 h, then concentrated and purified by silica gel column chromatography (0 – 60% EtOAc / petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C29H37N3O7, 539.2; m / z measured 484.3 [M-56+H]+. 25 Step E. tert-Butyl 4-(7-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-4-oxooxazolo[5,4-c]pyridin- 5(4H)-yl)piperidine-1-carboxylate. To a solution of tert-butyl 4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-7-(2-methoxy- 2-oxoethyl)-6-methyl-4-oxooxazolo[5,4-c]pyridin-5(4H)-yl)piperidine-1-carboxylate 30 (230 mg, 426 µmol) in THF (5 mL) at 0 °C was added LiHMDS (8.5 mL, 4.3 mmol) portion-wise. The reaction mixture was stirred for 0.5 h, then 2-chloro-4- (trifluoromethyl)aniline (1.7 g, 8.5 mmol) was added, and the resulting mixture was warmed to room temperature and stirred for 2 h. The reaction was quenched with saturated NH4Cl, and the resulting mixture was extracted with EtOAc. The organic 103 PRD4322WOPCT1 5 layers were dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was subjected to silica gel column chromatography (0 - 30% EtOAc / petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C35H38ClF3N4O6, 702.2; m / z measured 647.2 [M-56+H]+. Step F. N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(2-hydroxypropan-2-10 yl)phenyl)-6- methyl-4-oxo-5-(piperidin-4-yl)-4,5-dihydrooxazolo[5,4-c]pyridin-7- yl)acetamide. To a solution of tert-butyl 4-(7-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-4-oxooxazolo[5,4-c]pyridin- 5(4H)-yl)piperidine-1-carboxylate (230 mg, 327 µmol) in 1,4-dioxane (0.5 mL) was 15 added HCl / 1,4-dioxane (5 mL, 2M). The mixture was stirred at room temperature for 1, then concentrated to yield the title compound as a yellow solid. MS (ESI): mass calculated for C30H30ClF3N4O4, 602.2; m / z measured 603.1 [M-56+H]+. Step G. N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-(1-(5-hydroxy-6- methylpyrimidine-4-carbonyl)piperidin-4-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6- 20 methyl-4-oxo-4,5-dihydrooxazolo[5,4-c]pyridin-7-yl)acetamide. To a solution of 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (Intermediate 2, 22.6 mg, 147 µmol) in 1,4-dioxane (2 mL) were added HOPO (6.6 mg, 59 µmol), EDCI (24.6 mg, 128 µmol) and DIEA (56 µL, 319 µmol). The mixture was stirred at room temperature for 0.5 h, then N-(2-chloro-4-(trifluoromethyl)phenyl)- 2-(2-(4-(2-25 hydroxypropan-2-yl)phenyl)-6-methyl-4-oxo-5-(piperidin-4-yl)-4,5-dihydrooxazolo[5,4- c]pyridin-7-yl)acetamide (127 mg, 106 µmol) was added. The reaction mixture was warmed to 50 °C and stirred for 3 h, then concentrated. The resulting residue was purified by preparative reverse phase HPLC (Stationary phase: Welch Xtimate C18, 5 µm, 150×30 mm; Mobile phase: water (NH4HCO3) (A) -Acetonitrile(B), gradient 30 elution: 30 - 60% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as a yellow powder. MS (ESI): mass calculated for C36H34ClF3N6O6, 738.2; m / z measured 739.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1 H) 8.58 (s, 1 H) 8.10 (d, J=8.34 Hz, 3 H) 7.92 (d, J=1.43 Hz, 1 H) 7.68 - 7.73 (m, 3 H) 5.25 (s, 1 H) 4.53 - 4.71 (m, 2 H) 4.09 (s, 2 H) 3.61 (br d, J=11.56 Hz, 1 H) 3.23 (br t, J=12.34 Hz, 104 PRD4322WOPCT1 5 1 H) 2.90 - 3.04 (m, 3 H) 2.53 (s, 3 H) 2.45 (s, 3 H) 1.82 (br d, J=2.74 Hz, 1 H) 1.65 (br d, J=10.25 Hz, 1 H) 1.46 (s, 6 H);19F NMR (376 MHz, DMSO-d6) δ -60.7 ppm. Example 8.2-(6-(4-Acetylpiperazin-1-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-5-methyl- 7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide 10 Step A.1-(4-(2-( methoxy-5- methyloxazolo[4,5-b]pyridin-6-yl)piperazin-1-yl)ethanone A mixture of 2-(4-(6-bromo-7-methoxy-5-methyloxazolo[4,5-b]pyridin-2- yl)phenyl)propan-2-ol (200 mg, 530 µmol), 1-(piperazin-1-yl)ethan-1-one (625 mg, 4.9 mmol), Cs2CO3 (480.3 mg, 1.5 mmol), Pd(OAc)2 (21.9 mg, 97.5 µmol, 0.2 eq.), BINAP 15 (92.3 mg, 148.2 µmol) in 1,4-dioxane (7 mL) was heated at 110 °C for 12 hours, then cooled to room temperature. The reaction mixture was concentrated and purified by silica gel chromatography (0 - 10% MeOH / DCM) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C23H28N4O4, 424.2; m / z measured 425.1 [M+H]+. 20 Step B.2-(6-(4-Acetylpiperazin-1-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-5- methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide A mixture of 1-(4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-7-methoxy-5- methyloxazolo[4,5-b]pyridin-6-yl)piperazin-1-yl)ethan-1-one (70 mg, 143 µmol) and N- 25 (2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide (77.2 mg, 212.4 µmol) in toluene (4 mL) was heated at 120 °C for 12 hours, then cooled to room temperature. The mixture was concentrated and purified by prep-HPLC (Stationary phase: Welch Xtimate C18, 5 µm, 150 × 30 mm; Mobile phase: water (NH4HCO3) (A) – ACN (B), 105 PRD4322WOPCT1 5 gradient elution: 48 – 78% B in A over 7 min, flow rate: 25 mL / min) to yield title compound as a light yellow solid. MS (ESI): mass calculated for C31H31ClF3N5O5, 645.2 m / z, found 646.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.66 - 10.25 (m, 1H), 8.09 (br d, J = 8.0 Hz, 3H), 7.98 (s, 1H), 7.71 (br d, J = 8.0 Hz, 3H), 5.42 (br s, 2H), 5.27 (s, 1H), 4.37 (br d, J = 11.3 Hz, 1H), 3.81 (br d, J = 11.8 Hz, 1H), 3.70 (br t, 10 J = 11.1 Hz, 1H), 3.60 - 3.50 (m, 1H), 3.21 (br t, J = 11.5 Hz, 1H), 2.75 - 2.61 (m, 3H), 2.58 (s, 3H), 2.05 (s, 3H), 1.46 (s, 6H);19F NMR (376 MHz, DMSO-d6) δ -60.80 (3F) ppm. Example 9. (R)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-3-methylpiperazin-1-yl)-2-(4-(2-hydroxypropan-2- 15 yl)phenyl)-5-methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide Step A. tert-B nyl)-7-methoxy-5- methyloxazolo [4,5-b]pyridin-6-yl)-2-methylpiperazine-1-carboxylate A mixture of 2-(4-(6-bromo-7-methoxy-5-methyloxazolo[4,5-b]pyridin-2-20 yl)phenyl) propan-2-ol (500.0 mg, 1.3 mmol), (R)-tert-butyl 2-methylpiperazine-1- carboxylate (2.7 g, 13.3 mmol), BINAP (165 mg, 265 µmol), Pd(OAc)2 (29.8 mg, 132.5 µmol) and Cs2CO3(1.3 g, 4.0 mmol) in anhydrous 1,4-dioxane (10.0 mL) under N2was stirred for 16 hours at 130 °C. The mixture was filtered and concentrated. The resulting residue was purified by prep-HPLC (C18150 × 30 mm × 10 µm; Mobile 25 phase: water (FA) – ACN, gradient elution: 55 – 85% B in A over 7 min, flow rate: 25 mL / min) afforded the title compound as a light yellow solid. MS (ESI): mass calculated for C27H36N4O5496.61; m / z measured 497.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 106 PRD4322WOPCT1 5 8.14 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H), 5.24 (s, 1H), 4.39 (s, 3H), 4.25 - 4.09 (m, 1H), 3.75 (br s, 1H), 3.51 - 3.41 (m, 1H), 3.26 - 3.07 (m, 2H), 2.86 - 2.76 (m, 1H), 2.65 (br d, J = 11.8 Hz, 1H), 2.57 (s, 3H), 1.47 (s, 6H), 1.43 (s, 9H), 1.31 (br d, J = 5.1 Hz, 3H) ppm. Step B. tert-Butyl (R)-4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-10 oxoethyl)-2-(4- (2-hydroxypropan-2-yl)phenyl)-5-methyl-7-oxo-4,7-dihydrooxazolo[4,5- b]pyridin-6-yl)-2-methylpiperazine-1-carboxylate A mixture of tert-butyl (R)-4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-7-methoxy-5- methyloxazolo[4,5-b]pyridin-6-yl)-2-methylpiperazine-1-carboxylate (500 mg, 1.0 mmol), N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide (732.0 mg, 2.0 mmol) 15 in anhydrous 1,4-dioxane (5.0 mL) was stirred for 5 hours at 120 °C. The mixture was concentrated, then subjected to silica gel chromatography (0 – 70% ethyl acetate in petroleum ether) to yield the title compound as a brown solid. MS (ESI): mass calculated for C35H39ClF3N5O6717.3; m / z measured 718.2 [M+H]+. Step C. (R)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(2-hydroxypropan-2-20 yl)phenyl)-5 -methyl-6-(3-methylpiperazin-1-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)- yl)acetamide A mixture of tert-butyl (R)-4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-5-methyl-7-oxo-4,7-dihydrooxazolo[4,5- b]pyridin-6-yl)-2-methylpiperazine-1-carboxylate (520 mg, 724 mmol) in anhydrous 25 1,4-dioxane (5.0 mL) and HCl (5.0 mL, 10 mmol, 2 M in dioxane) was stirred for 2 hours at room temperature. The reaction mixture was adjust pH to 7–8 with aq. NaHCO3 and H2O (50.0 mL), then extracted with ethyl acetate. The organic phase was concentrated to yield the title compound as a brown solid, which was used in the next step without further purification. MS (ESI): mass calculated for C30H31ClF3N5O4 30 617.2; m / z measured 618.2 [M+H]+. Step D. (R)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(5-hydroxy-6- methylpyrimidine- 4-carbonyl)-3-methylpiperazin-1-yl)-2-(4-(2-hydroxypropan-2- yl)phenyl)-5-methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide 107 PRD4322WOPCT1 5 A mixture of 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (150 mg, 973 µmol), EDCI (200 mg, 1.0 mmol), DIPEA (250 mg, 1.9 mmol), and HOPO (60.0 mg, 540 µmol) in anhydrous 1,4-dioxane (5.0 mL) was stirred for 30 minutes at 50 °C. (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(2-hydroxypropan-2-yl)phenyl)-5- methyl-6-(3-methylpiperazin-1-yl)-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide (400 10 mg, 543.6 µmol) was then added and the resulting mixture was stirred for 16 hours at 50 °C. The mixture was then concentrated and subjected to prep-HPLC (C18150 × 30 mm × 10 µm; Mobile phase: water (FA) – ACN, gradient elution: 44 – 74% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as a light yellow solid. MS (ESI): mass calculated for C36H35ClF3N7O6753.2 ; m / z measured 754.3 [M+H]+.1H 15 NMR (400 MHz, DMSO-d6) δ 10.44 (br d, J = 2.1 Hz, 1H), 8.54 (br d, J = 5.0 Hz, 1H), 8.12 - 8.03 (m, 3H), 7.97 (d, J = 1.2 Hz, 1H), 7.71 (d, J = 8.5 Hz, 3H), 5.42 (s, 2H), 5.24 (s, 1H), 4.37 (br d, J = 11.8 Hz, 1H), 4.02 - 3.88 (m, 1H), 3.71 (br dd, J = 5.0, 10.0 Hz, 2H), 3.43 (br s, 1H), 3.23 - 3.14 (m, 1H), 2.79 - 2.63 (m, 1H), 2.60 (s, 3H), 2.44 (d, J = 3.9 Hz, 3H), 1.46 (s, 6H), 1.40 (br dd, J = 6.8, 11.7 Hz, 3H);19F NMR (376 20 MHz, DMSO-d6) δ -60.81 (3F) ppm. Example 10. (rac)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(6-((rac)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-5-methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide 25 Step A. (rac) enyl)-7-methoxy-5- methyloxazolo[4,5-b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylate A mixture of 2-(4-(6-bromo-7-methoxy-5-methyloxazolo[4,5-b]pyridin-2- yl)phenyl)propan-2-ol (500 mg, 1.3 mmol), (rac)-tert-butyl-2,5- 108 PRD4322WOPCT1 5 diazabicyclo[4.2.0]octane-2-carboxylate (420.6 mg, 2.0 mmol), Cs2CO3 (1.3 g, 4.0 mmol), Pd(OAc)2 (30.1 mg, 134.1 µmol), BINAP (165.8 mg, 266.3 µmol) in 1,4- dioxane (10 mL) was stirred at 130 °C for 12 hours, then cooled to room temperature. The reaction mixture was diluted with water (30 mL), then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and 10 concentrated. The resulting residue was purified by prep-HPLC (Stationary phase: Xtimate C18, 10 µm, 150 × 40 mm; Mobile phase: water (FA) (A) – ACN (B), gradient elution: 55 – 85% B in A over 10 min, flow rate: 55 mL / min) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C28H36N4O5, 508.3; m / z measured 509.6 [M+H]+. 15 Step B. (rac)-tert-Butyl 5-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-5-methyl-7-oxo-4,7-dihydrooxazolo[4,5- b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylate A mixture of (rac)-tert-butyl 5-(2-(4-(2-hydroxypropan-2-yl)phenyl)-7-methoxy- 5-methyloxazolo[4,5- b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylate (340 20 mg, 661.6 µmol) and N-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide (360.2 mg, 990.9 µmol) in toluene (4 mL) was stirred at 120 °C for 5 hours, then cooled to room temperature. The reaction mixture was diluted with water (30 mL), then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was subjected to 25 silica gel chromatography (0-100% ethyl acetate / petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C36H39ClF3N5O6, 729.3; m / z measured 730.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.14 - 8.03 (m, 3H), 7.98 (d, J = 1.4 Hz, 1H), 7.75 - 7.66 (m, 3H), 5.41 (s, 2H), 5.24 (s, 1H), 4.00 - 3.91 (m, 1H), 3.79 (br d, J = 7.0 Hz, 1H), 3.49 (br s, 1H), 3.17 (br s, 1H), 3.05 - 30 2.91 (m, 2H), 2.57 (s, 3H), 2.15 (br s, 1H), 1.99 (s, 1H), 1.95 - 1.82 (m, 1H), 1.76 - 1.64 (m, 1H), 1.49 - 1.45 (m, 6H), 1.41 (s, 9H);19F NMR (376 MHz, DMSO-d6) δ - 60.81 (3F) ppm. 109 PRD4322WOPCT1 5 Step C.2-(6-((rac)-2,5-Diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2-hydroxypropan-2- yl)phenyl)-5-methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide A mixture of (rac)-tert-butyl-5-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)- 2-oxoethyl)-2-(4- (2-hydroxypropan-2-yl)phenyl)-5-methyl-7-oxo-4,7- 10 dihydrooxazolo[4,5-b]pyridin-6-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylate (350 mg, 414.3 µmol) in 2 M HCl / 1,4-dioxane (15 mL, 30.0 mmol) was stirred for 1 hour at room temperature. The reaction mixture was then poured into H2O (30 mL) and the aqueous phase was washed with ethyl acetate. The aqueous phase was basified with sat. aq. NaHCO3 to pH = 10, then extracted with ethyl acetate. The combined extracts 15 were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to yield the title compound as a yellow solid. MS (ESI): mass calculated for C31H31ClF3N5O4, 629.2; m / z measured 630.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.80 - 10.09 (m, 1H), 8.08 (br d, J = 8.3 Hz, 3H), 7.97 (s, 1H), 7.71 (br d, J = 8.3 Hz, 3H), 5.39 (s, 2H), 5.24 (s, 1H), 3.76 - 3.62 (m, 2H), 2.99 - 2.82 (m, 2H), 2.58 (s, 3H), 20 2.55 (s, 2H), 1.94 (br d, J = 7.3 Hz, 1H), 1.74 - 1.57 (m, 2H), 1.47 (s, 6H), 1.41 - 1.33 (m, 1H);19F NMR (376 MHz, DMSO-d6) δ -60.79 (3F) ppm. Step D. N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(6-((rac)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-5-methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide25 A mixture of 2-(6-((rac)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-5-me thyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(2- chloro-4-(trifluoromethyl)phenyl)acetamide (240 mg, 365.9 µmol), 5-hydroxy-6- methylpyrimidine-4-carboxylic acid (108.6 mg, 553.1 µmol), HOPO (62.5 mg, 562.6 µmol), EDCI (83.1 mg, 433.5 µmol) in 1.4-dioxane (6 mL) was stirred at 50 °C for 12 30 hours, then cooled to room temperature. The reaction mixture was diluted with water (30 mL). The resulting solution was extracted with ethyl acetate. The organic layers were dried with anhydrous Na2SO4, filtered, and concentrate. The resulting residue was subjected to prep-HPLC (Stationary phase: C18, 150 × 30 mm; Mobile phase: water (FA) (A) – ACN (B), gradient elution: 42 – 72% B in A over 7 min, flow rate: 25 110 PRD4322WOPCT1 5 mL / min) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C37H35ClF3N7O6, 765.2 m / z, found 766.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.88 - 10.19 (m, 1H), 8.58 - 8.46 (m, 1H), 8.12 - 8.04 (m, 3H), 7.97 (d, J = 1.4 Hz, 1H), 7.72 (d, J = 8.6 Hz, 3H), 5.41 (s, 2H), 5.31 - 5.21 (m, 1H), 4.58 - 4.36 (m, 1H), 3.83 (br d, J = 7.9 Hz, 1H), 3.56 (br s, 2H), 3.13 (br d, J = 4.2 Hz, 2H), 2.59 (s, 3H), 10 2.42 (s, 3H), 1.61 - 1.52 (m, 1H), 1.46 (s, 6H), 1.39 - 1.28 (m, 2H), 1.21 - 1.09 (m, 1H);19F NMR (376 MHz, DMSO-d6) δ -60.81 (3F) ppm. Example 11. N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(6-((1S*,6S*)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-5-methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide 15 (rac)-N-(2-Ch -(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-5-methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide was separated by chiral SFC (Column: DAICEL CHIRALPAK 20 AD(250mm*30mm,10um, Mobile phase: A: CO2 B: i-PrOH(0.1% NH3H2O, gradient elution: 50% B in A at 150 mL / min) to yield the title compound, as the first eluting peak, as a light yellow powder. MS (ESI): mass calculated for C37H35ClF3N7O6, 765.2; m / z measured 766.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) d = 10.45 (br s, 1H), 8.56 (br s, 1H), 8.09 (br d, J = 7.7 Hz, 3H), 7.98 (br s, 1H), 7.72 (br d, J = 7.9 Hz, 3H), 5.41 25 (br s, 2H), 5.26 (s, 1H), 4.58 - 4.41 (m, 1H), 3.92 - 3.77 (m, 1H), 3.56 - 3.50 (m, 2H), 3.24 - 3.17 (m, 2H), 2.59 (br s, 3H), 2.44 (br s, 3H), 1.63 - 1.52 (m, 1H), 1.47 (s, 6H), 1.40 - 1.27 (m, 2H), 1.17 (br s, 1H); 19F NMR (376 MHz, DMSO-d6) = -60.81 (3F). 111 PRD4322WOPCT1 5 Example 12. N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(6-((1R*,6R*)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-5-methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide (rac)-N-(2-Ch (5-hydroxy-6-10 methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-5-methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide was separated by chiral SFC (Column: DAICEL CHIRALPAK AD(250mm*30mm,10um, Mobile phase: A: CO2 B: i-PrOH(0.1% NH3H2O, gradient elution: 50% B in A at 150 mL / min) to yield the title compound, as a second eluting 15 peak, as a light yellow powder. MS (ESI): mass calculated for C37H35ClF3N7O6, 765.2; m / z measured 766.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) d = 10.45 (br s, 1H), 8.56 (s, 1H), 8.14 - 8.03 (m, 3H), 7.98 (s, 1H), 7.72 (br d, J = 8.5 Hz, 3H), 5.41 (s, 2H), 5.26 (s, 1H), 4.55 - 4.43 (m, 1H), 3.93 - 3.72 (m, 1H), 3.56 - 3.49 (m, 2H), 3.26 - 3.19 (m, 2H), 2.59 (s, 3H), 2.44 (s, 3H), 1.62 - 1.53 (m, 1H), 1.47 (s, 6H), 1.34 (br s, 2H), 1.22 - 20 1.09 (m, 1H); 19F NMR (376 MHz, DMSO-d6) d = -60.81 (3F) Example 13. N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-5-(4-(5-hydroxy- 6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-4- oxo-4,5-dihydrooxazolo[5,4-c]pyridin-7-yl)acetamide 112 PRD4322WOPCT1 5 Step A.4-Bro azole-5-carboxylic acid To a solution of ethyl 4-bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)oxazole-5- carboxylate (6.0 g, 16.9 mmol) in tetrahydrofuran (40 mL), methanol (40 mL) and H2O (40 mL) was added LiOH•H2O (2.9 g, 67.8 mmol). The reaction mixture was stirred at 10 25 °C for 16 hours. The reaction mixture was concentrated to dryness in vacuo to yield the title compound as a yellow solid. MS (ESI): mass calculated for C16H15NO4, 325.0; m / z measured 328.0 [M+H]+. Step B. tert-Butyl 4-(4-bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)oxazole-5- carboxamido) piperazine-1-carboxylate 15 To a solution of 4-bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)oxazole-5- carboxylic acid (5.6 g, 17.1 mmol), tert-butyl 4-aminopiperazine-1-carboxylate (6.9 g, 34.4 mmol) in 1,4-dioxane (100 mL) was added HOPO (3.8 g, 34.4 mmol), EDCI (6.6 g, 34.4 mmol) and DIEA (9.0 mL, 51.6 mmol). The mixture was stirred at 50 °C for 16 hours, then concentrated. The resulting residue was subjected to column 20 chromatography over silica gel (gradient elution: 0 – 50% methanol in dichloromethane) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C22H29BrN4O5, 508.1 m / z, found 455.1 [M-56+H]+. Step C. tert-Butyl 4-(6-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-4- oxooxazolo[5,4-c] pyridin-5(4H)-yl)piperazine-1-carboxylate 25 A mixture of tert-butyl 4-(4-bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)oxazole- 5- carboxamido)piperazine-1-carboxylate (6.9 g, 13.5 mmol), 2-(but-1-yn-1-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (2.6 g, 14.2 mmol), Cs2CO3 (8.9 g, 27.1 mmol), CsF (6.2 g, 40.9 mmol) and Pd(dppf)Cl2 (1.0 g, 1.4 mmol) in DMF (80 mL) and H2O (3.2 113 PRD4322WOPCT1 5 mL) was degassed and purged with N2 for 3 times. The reaction mixture was stirred at 90 °C for 6 h. The reaction mixture was then filtered, concentrated and purified by column chromatography over silica gel (gradient elution: 0 - 60% ethyl acetate in petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated For C26H34N4O5, 482.2; m / z measured 427.1 [M-56+H]+. 10 Step D. tert-Butyl 4-(7-bromo-6-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-4- oxooxazolo [5,4-c]pyridin-5(4H)-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(6-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-4- oxooxazolo[5,4-c] pyridin-5(4H)-yl)piperazine-1-carboxylate (5.0 g, 10.4 mmol) in N,N- dimethylformamide (60 mL) was added NBS (1.9 g, 10.4 mmol). The mixture was 15 stirred at 0 °C for 2 hours, then diluted with ethyl acetate and H2O. The reaction was extracted with ethyl acetate, washed with brine, and concentrated. The resulting residue was subjected to column chromatography over silica gel (gradient elution: 0 – 30% EtOAc in petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated For C26H33BrN4O5, 560.2; m / z measured 505.2 [M-56+H]+.20 Step E. tert-Butyl 4-(6-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-7-(2-methoxy- 2-oxoethyl)-4-oxooxazolo[5,4-c]pyridin-5(4H)-yl)piperazine-1-carboxylate A mixture of tert-butyl 4-(7-bromo-6-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)- 4- oxooxazolo[5,4-c]pyridin-5(4H)-yl)piperazine-1-carboxylate (3.3 g, 5.2 mmol), tert- butyl((1-methoxyvinyl)oxy)dimethylsilane (7.8 g, 41.2 mmol), XPhos (551.1 mg, 1.2 25 mmol) and XPhos Pd G4 (901.8 mg, 1.0 mmol) in THF (80 mL) was degassed and purged with N2 then stirred at 90 °C for 16 hours. The reaction mixture was concentrated to dryness in vacuo to yield a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0 - 50% ethyl acetate in petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass 30 calculated for C29H38N4O7, 554.3; m / z measured 499.3 [M-56+H]+. Step F. tert-Butyl 4-(7-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-6-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-4-oxooxazolo[5,4-c]pyridin- 5(4H)-yl)piperazine-1-carboxylate 114 PRD4322WOPCT1 5 To a solution of tert-butyl 4-(6-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-7-(2- methoxy-2- oxoethyl)-4-oxooxazolo[5,4-c]pyridin-5(4H)-yl)piperazine-1-carboxylate (2.0 g, 3.6 mmol) in THF (40 mL) at 0 °C under N2atmosphere was added LiHMDS (44 mL, 22.0 mmol) in portions. The reaction mixture was stirred for 30 minutes, then 2-chloro-4-(trifluoromethyl)aniline (5.9 g, 29.1 mmol) was added, and the resulting 10 mixture warmed to 25 °C for 2 hours. The reaction mixture was quenched with sat. NH4Cl and diluted with H2O and ethyl acetate. The organics were extracted, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was subjected to column chromatography over silica gel (gradient elution: 0 - 40% ethyl acetate in petroleum ether) to yield the title compound as a yellow solid.15 MS (ESI): mass calculated for C35H39ClF3N5O6, 717.3; m / z measured 662.2 [M- 56+H]+. Step G. N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-2-(4-(2- hydroxypropan-2-yl) phenyl)-4-oxo-5-(piperazin-1-yl)-4,5-dihydrooxazolo[5,4-c]pyridin- 7-yl)acetamide 20 To a solution of tert-butyl 4-(7-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-6- ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-4-oxooxazolo[5,4-c]pyridin- 5(4H)-yl)piperazine-1-carboxylate (1.1 g, 1.0 mmol) in 1,4-dioxane (2 mL) was added HCl / 1,4-dioxane (8 mL, 16 mmol). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was then adjusted to pH=7 with sat. NaHCO3, diluted with H2O and 25 extracted with EtOAc. The organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuum to dryness to yield the title compound. MS (ESI): mass calculated for C30H31ClF3N5O4, 617.2; m / z measured 618.2 [M+H]+. Step H . N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-5-(4-(5-hydroxy-6- methyl pyrimidine-4-carbonyl)piperazin-1-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-4- 30 oxo-4,5-dihydrooxazolo[5,4-c]pyridin-7-yl)acetamide To a solution of 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (63.3 mg, 410.7 µmol) in 1,4-dioxane (5 mL) was added HOPO (18.6 mg, 167.4 µmol) and EDCI (70.8 mg, 369.3 µmol). The mixture was stirred at 25 °C for 30 minutes, then N-(2- chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-4-oxo- 115 PRD4322WOPCT1 5 5-(piperazin-1-yl)-4,5-dihydrooxazolo[5,4-c]pyridin-7-yl)acetamide (400 mg, 304 µmol) was added and the resulting mixture was stirred at 50 °C for 3 hours. The reaction mixture was diluted with ethyl acetate, poured into H2O and extracted. The organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by preparative reverse phase HPLC (Stationary phase: DI C18, 5 10 µm, 150×30 mm; Mobile phase: water (NH4HCO3) (A) - ACN (B), gradient elution: 29 - 59% B in A over 5 min, flow rate: 25 mL / min) to yield the title compound as a yellow powder. MS (ESI): mass calculated for C36H35ClF3N7O6, 753.2; m / z measured 754.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1 H) 8.55 (s, 1 H) 8.05 - 8.15 (m, 3 H) 7.93 (s, 1 H) 7.71 (br d, J=8.46 Hz, 3 H) 5.24 (s, 1 H) 4.51 - 4.65 (m, 1 H) 4.02 - 15 4.17 (m, 4 H) 3.56 (br d, J=12.04 Hz, 1 H) 3.01 - 3.21 (m, 3 H) 2.87 - 2.97 (m, 3 H) 2.43 (s, 3 H) 1.46 (s, 6 H) 1.19 (t, J=7.27 Hz, 3 H);19F NMR (376 MHz, DMSO-d6) δ - 60.73 (s, 3 F) ppm. Example 14. (R)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-3-methylpiperazin-1-yl)-2-(4-(2-hydroxypropan-2- 20 yl)phenyl)-6-methyl-4-oxo-4,5-dihydrooxazolo[5,4-c]pyridin-7-yl)acetamide Step A. tert-B nyl)-4-(prop-1-yn-1- yl)oxazole-5-carboxamido)-2-methylpiperazine-1-carboxylate To a solution of 2-(4-(2-hydroxypropan-2-yl)phenyl)-4-(prop-1-yn-1-yl)oxazole-25 5-carboxylic acid (2.0 g, 4.9 mmol), tert-butyl (R)-4-amino-2-methylpiperazine-1- carboxylate (2.3 g, 9.4 mmol) in dioxane (70.0 mL) was added HOPO (740 mg, 6.7 mmol), DIEA (2.6 mL, 14.9 mmol) and EDCI (1.2 g, 6.3 mmol). The reaction was stirred at 50 °C for 12 hours, then diluted with EtOAc and water. The mixture was 116 PRD4322WOPCT1 5 extracted with ethyl acetate and the combined organic layers were concentrated. The resulting residue was subjected to silica gel chromatography (0 – 70% ethyl acetate in petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C26H34N4O5, 482.3; m / z, found 427.2 [M-56+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.06 (br d, J = 8.3 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H), 5.20 (s, 10 1H), 4.27 - 4.07 (m, 2H), 3.83 - 3.66 (m, 2H), 3.17 - 2.98 (m, 3H), 2.11 (s, 3H), 1.45 (s, 6H), 1.42 (s, 9H), 1.25 (br d, J = 6.8 Hz, 3H) ppm. Step B. tert-Butyl (R)-4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-4- oxooxazolo[5,4-c]pyridin-5(4H)-yl)-2-methylpiperazine-1-carboxylate A mixture of tert-butyl (R)-4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-4-(prop-1-yn- 15 1-yl)oxazole-5-carbox amido)-2-methylpiperazine-1-carboxylate (1.8 g, 2.8 mmol) and DBU (132 µL, 882.7 µmol) in DMF (18.0 mL) was stirred at 100 °C for 2 hours. The reaction mixture was diluted with water and EtOAc, then extracted with EtOAc. The organic layers were dried with anhydrous Na2SO4, filtered, and concentrated. The resulting residue was subjected to column chromatography over silica gel (gradient 20 elution: 0 – 60% petroleum ether / ethyl acetate) to yield the title compound as a light yellow solid. MS (ESI): mass calculated for C26H34N4O5, 482.3; m / z, found 427.2 [M- 56+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 8.5 Hz, 2H), 6.66 (s, 1H), 5.22 (s, 1H), 4.38 - 4.19 (m, 1H), 4.15 - 4.04 (m, 1H), 3.96 - 3.76 (m, 2H), 3.28 (br s, 1H), 3.24 - 3.11 (m, 1H), 3.05 - 2.93 (m, 1H), 2.47 (s, 3H), 1.46 (s, 25 6H), 1.43 (s, 9H), 1.31 (br t, J = 7.9 Hz, 3H) ppm. Step C. tert-Butyl (R)-4-(7-bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl- 4-oxooxazolo[5,4-c]pyridin-5(4H)-yl)-2-methylpiperazine-1-carboxylate To a solution of tert-butyl (R)-4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl- 4-oxooxazolo[5,4-c] pyridin-5(4H)-yl)-2-methylpiperazine-1-carboxylate (920.0 mg, 1.8 30 mmol) in DMF (36.8 mL) at 0 °C was added NBS (662.4 mg, 3.7 mmol). The mixture was stirred at room temperature for 12 hours, then water was added. The mixture was extracted with ethyl acetate. The organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was subjected to column chromatography over silica gel (gradient elution: 0 – 60% ethyl acetate in petroleum 117 PRD4322WOPCT1 5 ether) to yield the title compound as a white solid. MS (ESI) calculated for C25H31BrN4O5, 560.2 / 562.2 m / z, found 505.2 / 507.2 [M-56+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 8.3 Hz, 2H), 5.25 (s, 1H), 4.38 - 4.21 (m, 1H), 4.14 - 4.02 (m, 1H), 3.95 - 3.78 (m, 2H), 3.29 - 3.13 (m, 1H), 3.12 - 3.01 (m, 1H), 2.93 (br s, 1H), 2.67 (s, 3H), 1.47 (s, 6H), 1.43 (s, 9H), 1.35 - 1.27 (m, 3H) 10 ppm. Step D. tert-Butyl (R)-4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-7-(2-methoxy-2- oxoethyl)-6-methyl-4-oxooxazolo[5,4-c]pyridin-5(4H)-yl)-2-methylpiperazine-1- carboxylate A mixture of tert-butyl 4-(7-bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl- 15 4-oxooxazolo[5,4-c]pyridine-5(4H)-yl)piperazine-1-carboxylate (715.0 mg, 1.2 mmol), tert-butyl((1-methoxyvinyl)oxy)dimethylsilane (1.2 mL, 5.3 mmol), XPhos Pd G4 (139.2 mg, 161.6 µmol) and XPhos (69.6 mg, 145.9 µmol) in THF (14.3 mL) under N2 was stirred at 90 °C for 12 hours. The mixture was diluted with ethyl acetate and H2O and extracted. The combined organic layers were concentrated and purified by silica 20 gel chromatography (0 – 60% ethyl acetate / petroleum ether) to yield the title compound as a white solid MS (ESI): mass calculated for C29H38N4O7, 554.3; m / z, found 499.2 [M-56+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H), 5.24 (s, 1H), 4.37 - 4.23 (m, 1H), 4.18 - 4.09 (m, 1H), 3.98 - 3.93 (m, 1H), 3.90 (s, 2H), 3.85 (br d, J = 2.0 Hz, 1H), 3.66 (s, 3H), 3.02 - 2.89 (m, 2H), 25 2.87 - 2.78 (m, 1H), 2.43 (s, 3H), 1.47 (s, 6H), 1.44 (s, 9H), 1.31 (br dd, J = 7.3, 10.0 Hz, 3H) ppm. Step E. tert-Butyl (R)-4-(7-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-4-oxooxazolo[5,4-c]pyridin- 5(4H)-yl)-2-methylpiperazine-1-carboxylate 30 To a solution of tert-butyl (R)-4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-7-(2- methoxy-2-ox oethyl)-6-methyl-4-oxooxazolo[5,4-c]pyridin-5(4H)-yl)-2- methylpiperazine-1-carboxylate (440.0 mg, 786.6 µmol) in THF (8.8 mL) at 0 °C under N2 was added LiHMDS (4.8 mL, 4.8 mmol) in portions. The reaction mixture was stirred for 30 minutes, then 2-chloro-4-(trifluoromethyl)aniline (1.2 g, 6.1 mmol) was 118 PRD4322WOPCT1 5 added. The resulting mixture was further stirred at 0 °C for 5 minutes, then warmed to room temperature for 2 hours. The reaction mixture was quenched with H2O and sat. aq. NH4Cl. The mixture was extracted with ethyl acetate and the combined organic layers were concentrated. The resulting residue was subjected to silica gel chromatography (0 – 60% ethyl acetate / petroleum ether) to yield the title compound10 as a yellow solid. MS (ESI) calculated for C35H39ClF3N5O6, 717.3 m / z, found 662.3 [M- 56+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.15 - 8.05 (m, 3H), 7.93 (s, 1H), 7.76 - 7.62 (m, 3H), 5.23 (s, 1H), 4.38 - 4.22 (m, 1H), 4.20 - 4.10 (m, 1H), 4.06 (s, 2H), 3.99 - 3.91 (m, 1H), 3.90 - 3.78 (m, 1H), 3.05 - 2.88 (m, 2H), 2.84 (br d, J = 10.3 Hz, 1H), 2.49 - 2.47 (m, 3H), 1.46 (s, 6H), 1.43 (s, 9H), 1.35 - 1.28 (m, 3H);19F 15 NMR (376 MHz, DMSO-d6) δ -60.73 (3F) ppm. Step F. (R)-N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(2-hydroxypropan-2- yl)phenyl)-6-methyl-5-(3-methylpiperazin-1-yl)-4-oxo-4,5-dihydrooxazolo[5,4-c]pyridin- 7-yl)acetamide A mixture of tert-butyl (R)-4-(7-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-20 oxoethyl)-2-(4-(2-hydro xypropan-2-yl)phenyl)-6-methyl-4-oxooxazolo[5,4-c]pyridin- 5(4H)-yl)-2-methylpiperazine-1-carboxylate (420 mg, 540.9 µmol) in HCl / 1,4-dioxane (16.8 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness in vacuo to yield a white solid. The white solid was diluted by addition of water (5.0 mL), followed by addition of sat. aq. NaHCO3 (20.0 mL). The 25 resulting mixture was then extracted with ethyl acetate. The organic layers were dried with anhydrous Na2SO4, filtered, and concentrated to yield the title compound as a yellow solid. MS (ESI) calculated for C30H31ClF3N5O4, 617.2 m / z, found 618.3 [M+H]+. Step G. (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-3-methylpiperazin-1-yl)-2-(4-(2-hydroxypropan-2- 30 yl)phenyl)-6-methyl-4-oxo-4,5-dihydrooxazolo[5,4-c]pyridin-7-yl)acetamide To a solution of (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(2- hydroxypropan-2-y l)phenyl)-6-methyl-5-(3-methylpiperazin-1-yl)-4-oxo-4,5- dihydrooxazolo[5,4-c]pyridin-7-yl)acetamide (365.0 mg, 518.8 µmol) in 1,4-dioxane (14 mL) were added 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (117.3 mg, 761.1 119 PRD4322WOPCT1 5 µmol), HOPO (73.0 mg, 657.1 µmol), DIEA (270.1 µL, 1.6 mmol) and EDCI (124.1 mg, 647.4 µmol). The resulting mixture was allowed to gradually warm to 50 °C, stirred for 3 hours, then cooled to room temperature. The resulting solution was diluted with H2O and the aqueous phase extracted with ethyl acetate. The organic layers were dried with anhydrous Na2SO4, filtered, and concentrated. The resulting 10 residue was purified by preparative reverse phase HPLC (Stationary phase: C18150 × 30 mm; Mobile phase: water (NH3H2O + NH4HCO3) (A) – ACN (B), gradient elution: 30 – 60% B in A over 2 min, flow rate: 25 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C36H35ClF3N7O6, 753.2; m / z measured 754.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.29 - 10.09 (br s, 1H), 9.88 (s, 1H), 15 8.57 (d, J = 3.3 Hz, 1H), 8.13 - 8.08 (m, 3H), 7.93 (s, 1H), 7.74 - 7.69 (m, 3H), 5.25 (s, 1H), 4.92 - 4.42 (m, 1H), 4.29 - 4.18 (m, 1H), 4.08 (s, 2H), 4.03 (br s, 1H), 3.84 - 3.52 (m, 1H), 3.18 - 3.09 (m, 1H), 3.04 - 2.92 (m, 1H), 2.84 (br d, J = 10.0 Hz, 1H), 2.45 (br d, J = 3.3 Hz, 6H), 1.47 (s, 6H), 1.45 - 1.41 (m, 3H);19F NMR (376 MHz, DMSO-d6) δ -60.73 (3F) ppm. 20 Biological Examples WRN Protein Expression and Purification WRN (Uniprot Q9H0K1) was expressed as a N-terminally 8His and FLAG- tagged protein (M.FLAG.8His.TEV.GG.WRN.500-1242) in baculovirus-infected Sf9 25 insect cells. The coding sequence was cloned into pVL1393 shuttle vector (Expression Systems, 91-012) and co-transfected into Sf9 cells with linearized BestBac™ Baculovirus DNA (Expression Systems 91-002) for baculovirus production. Sf9 cells were infected with P2 amplified baculovirus at MOI 5.0 for 72 hours at 27°C to a final viability of 79%. 30 All purification steps were carried out at 4°C. Harvested cells were suspended in 20 mM HEPES pH 7.5, 500 mM NaCl, 10% (v / v) glycerol, 20 mM imidazole, 0.1 mM TCEP, 0.02 mM ZnCl2, 5 mM MgCl2, 5 mM ATP, 0.1% NP-40, COMPLETE™ protease inhibitors (Roche, 1 tablet per 50 mL), TURBONUCLEASE™ (Accelagen, 12.5 U / mL lysate) at 5 mL / g of cell pellet and then lysed by pressure drop lysis 120 PRD4322WOPCT1 5 through a microfluidizer at 12,000 psi. Lysate was clarified by centrifugation. WRN protein was captured from the clarified supernatant by batch binding with HisPur™ Ni- NTA resin (ThermoFisher) for 90 minutes with gentle agitation. Protein-bound resin was washed with 5 column volumes (CVs) buffer A (20 mM HEPES pH 7.5, 500 mM NaCl, 10% (v / v) glycerol, 20 mM imidazole, 0.1 mM TCEP, 0.02 mM ZnCl2, 0.1% NP- 10 40), followed by 10 CVs buffer B (20 mM HEPES pH 7.5, 2000 mM NaCl, 10% (v / v) glycerol, 20 mM imidazole, 0.1 mM TCEP, 20 µM ZnCl2, 0.1% NP-40) and another 5 CVs buffer A. The purified protein was then eluted with buffer C (20 mM HEPES pH 7.5, 500 mM NaCl, 10% (v / v) glycerol, 200 mM imidazole, 0.1 mM TCEP, 0.02 mM ZnCl2, 0.01% NP-40). The salt concentration of the eluted protein was reduced to 250 15 mM by a 2 fold dilution with buffer D (20 mM HEPES pH 7.5, 10% (v / v) glycerol, 0.1 mM TCEP, 0.02 mM ZnCl2, 0.01% NP-40) and loaded onto a heparin column (HiTrap Heparin HP, Cytiva) pre-equilibrated with 75% buffer D and 25% buffer E (20 mM HEPES pH 7.5, 1000 mM NaCl, 10% (v / v) glycerol, 0.1 mM TCEP, 0.02 mM ZnCl2, 0.01% NP-40). The heparin column was washed with 10 CVs (75% buffer D, 25% 20 Buffer E) and eluted with a linear gradient of 250-1000 mM NaCl over 15 CVs. Fractions containing WRN were pooled, concentrated, and further purified using size exclusion chromatography (HiLoad Superdex 200, Cytiva) in buffer F (20 mM HEPES pH 7.5, 500 mM NaCl, 5% (v / v) glycerol, 0.5 mM TCEP). The final purified M.FLAG.8His.TEV.GG.WRN.500-1242 was concentrated to about 4 mg / mL, flash 25 frozen in liquid N2 and stored at -80°C. Biological Example 1: ADP-Glo Assay Format and Reagents (WRN ATPase Activity) The WRN ATPase enzyme activity assay was carried out using the ADP-Glo assay system (Promega Corporation). Prior to use, the ADP-Glo reagent (hereafter 30 referred to as “Glo1”) and kinase detection reagent (hereafter referred to as “Glo2”) were supplemented with 0.1% (w / v) 3-[(3-cholamidopropyl)-dimethylammonio]-1- propanesulfonate (CHAPS) to facilitate liquid handling. Forked dsDNA Preparation 121 PRD4322WOPCT1 5 A forked double-stranded DNA (dsDNA) substrate was designed to stimulate ATPase activity using the synthetic oligonucleotide sequences outlined below (Integrated DNA Technologies). The oligos were resuspended upon receipt at 0.2 mM in IDT Duplex Buffer and stored at -20°C. As needed, OLIGO-A and OLIGO-B were annealed at 0.05 mM in 10 mM Tris buffer pH 8.0, 1 mM EDTA, 10 mM MgCl2 and 50 10 mM NaCl, using a ThermoFisher Verity PCR thermal cycler to heat the solution to 95°C for 10 minutes and slowly cool to ambient room temperature over a period of 1-2 hours. OLIGO-A 5’- TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCGTACCCGATGTGTTCGTTC-3’ 15 OLIGO-B 5’- GAACGAACACATCGGGTACGTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT-3’ Activity Assay Assembly Assay buffer consisted of 25 mM Tris pH 7.5, 25 mM NaCl, 10 mM MgCl2, 20 0.05% (w / v) CHAPS, 0.1 mg / mL heat-shock fraction bovine serum albumin (BSA), 1 mM ethylenediaminetetraacetic acid (EDTA) and 1 mM dithiothreitol (DTT). Compounds were tested in single-dose format at 0.0125 mM or in 11-point, 3- fold serial dose-response, with a 0.1 mM top dose, and the following dilution / concentrations: Dilution No. Concentration 1 1 M 25 122 PRD4322WOPCT1 5 Dose-response plates were generated by acoustic dispensing 80 nL of a 50x compound titration (and DMSO controls) using the Labcyte Echo 655 into white 1536- well Corning cyclic olefin copolymer (COC) assay plates. WRN activity was measured in the presence of compound by combining 0.3 nM forked dsDNA, 0.8 nM WRN500-1242and 0.03 mM ATP for 30 minutes at room 10 temperature. Enzyme activity was stopped by addition of Glo1 to the reactions in 2:1 ratio of sample to Glo1 and samples were incubated at room temperature for 30 minutes. Luminescence signal was developed by addition of Glo2 reagent to samples in a 3:1 sample to Glo2 ratio. The signal was developed for no less than 30 minutes at room temperature, after which the signal is stable for 2 hours. Samples were read on 15 a PHERAstar FSX plate reader (BMG Labtech) using the LUM optical module with gain of 2000 and 0.1 second integration. Compound Data Analysis Dose-response data was analyzed using the Genedata Screener® software platform (Genedata AG). Samples were normalized to DMSO and no enzyme controls 20 as 0% and 100% compound activity, respectively, using the Percent-of-Control (Generic) method. Plate effects were corrected (if necessary) using the Assay Pattern (Additive) correction option. Curves were fit to a 4-parameter logistic dose-response model, as shown below. (^^^^^ − ^^ )^^ = ^^^ 0^^ + ^^025 where Sinf and S0 are the minimum compound activity values, respectively, IC50 is the compound concentration at the inflection point of the dose-response, H is the Hill coefficient, and [I] is the compound concentration. Additionally, per-plate and assay-wide performance were qualified by calculating robust Z-prime (RZprime) values for each dataset according to the formula 30 below, with 0.5 being set as the cutoff for passing quality assurance. 3(^^ )^^^^^^^^^^^^^^ = 1 − + + ^^−| PRD4322WOPCT1 5 Biological Example 2A: HCT-116 Cell Proliferation Assay (WRN Cellular Viability) Effect of compound treatment on cell proliferation was determined using the CellTiter-Glo Luminescent Cell Viability Assay (Promega #G8461). HCT-116 (ATCC #CCL-247TM) were maintained in McCoy’s 5A+Glumax (Thermo Fisher #36600021) supplemented with 10% heat inactivated fetal bovine serum (FBS; Invitrogen #16140). 10 Cells were seeded into 384-well white solid bottom TC-treated Microplate (Greiner #701080) at 200 cells per well in assay medium which consists of culture medium plus 1xPenStrep (Thermo Fisher #15140122). Cell seeded in the plates were incubated overnight at 37°C, 5% CO2 in a humidified incubator. Next day, serially diluted compounds, at the following dilutions / concentrations Dilution No. Concentration (uM) 1 30.00 µM 15 were added, and cells were returned to incubator for incubation until on day 5, at which point CellTiter-Glo assay was performed according to the manufacturer’s instructions. Luminescent signal was detected using a PHERAstar FSX microplate reader (BMG LabTech) and concentrations that achieve half-maximal inhibition 20 relative to DMSO control (IC50) were determined using Genedata Screener® software. Biological Example 2B: SW-620 Cell Proliferation Assay (WRN Cellular Viability) Effect of compound treatment on cell proliferation was determined using the CellTiter-Glo Luminescent Cell Viability Assay (Promega #G8461). SW-620 (ATCC 25 #CCL-227™) were maintained in RPMI1640+GlutaMax (Thermo Fisher # 61870036) supplemented with 10% heat inactivated fetal bovine serum (FBS; Invitrogen #16140). 124 PRD4322WOPCT1 5 Cells were seeded into 384-well white solid bottom TC-treated Microplate (Greiner #701080) at 400 cells per well in assay medium which consists of cell culture medium plus 1xPenStrep (Thermo Fisher #15140122) and incubated overnight at 37°C, 5% CO2 in a humidified incubator. Next day, serially diluted compounds were added, at the following dilutions / concentrations: Dilution No. Concentration (uM) 1 30.00 µM 10 and the cells we re returned to incubator for incubation until on day 5, at which point CellTiter-Glo assay was performed according to the manufacturer’s instructions. Luminescent signal was detected using a PHERAstar FSX microplate reader (BMG LabTech) and concentrations that achieve half-maximal inhibition relative to DMSO 15 control (IC50) were determined using Genedata Screener® software. Representative compounds of formula (I) of the present invention were tested according to the procedure described in Example 1, 2A and 2B above, with results as listed in Tables BIO-1, below. Where a compound of formula (I) of the present 20 invention was tested multiple times in any of the assays described herein, the values presented in Table BIO-1, below represent the average of said one or more individual measurements. Table BIO-1: Measured WRN Activity, Compounds of Formula (I) Example 1 Example 2A Example 2B 125 PRD4322WOPCT1 3 0.014 1.087 13.47 4 0.010 0.044 >26 5 Formu a o a pe o , a osage o op e c a pe As a specific embodiment of an oral composition, 100 mg of the compound prepared as in Example 4 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule. 10 While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and / or modifications as come within the scope of the following claims and their equivalents. 15 Throughout this application, various publications are cited. The disclosure of these publications is hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains. Where a conflict exists between the instant application and a reference provided herein, the instant application will be used. 20 126

Claims

PRD4322WOPCT1 5 What is Claimed:

1. A compound of formula (I) 10 ,d 6- 15 membered nitrogen containing heteroaryl; wherein the 6-membered N containing heteroaryl is substituted with -OH, and further optionally substituted with one or two substituents independently selected from the group consisting of halogen, hydroxy, methyl, ethyl, -CF3, -CH2CF3, methoxy, ethoxy, -C(O)OH, -C(O)O-(C1-4alkyl), NRARB; wherein RAand RBare each independently selected from the group consisting of 20 hydrogen and C1-4alkyl; and wherein R6is hydrogen or methyl; 127PRD4322WOPCT1 5 provided that whe , then R1isselected from the group consistin ,; ethyl;R3is chloro; 10 R4is selected from the group consisting of hydroxy substituted C1-4alkyl, 1- hydroxy-cyclobut-1-yl, 1-hydroxy-cyclopent-1-yl, 1-hydroxy-cyclohex-1-yl, 3-hydroxy- tetrahydrofuran-3-yl and 4-hydroxy-tetrahydropyran-4-yl; or a pharmaceutically acceptable salt thereof. 15 2. A compound as in Claim 1, wherei ; r a pharmaceutically acceptable salt the3. A compound as in Claim 1, wherei ; or a pharmaceutically acceptable salt the. 20 4. A compound as in Claim 1, wherein R4is ; or a pharmaceutically acceptable salt thereof.

5. A compound as in Claim 1, wherein 128PRD4322WOPCT1 5 R1is selected from the group consisting of 1-(methyl-carbonyl)-3,6-dihydro- pyridin-4-yl, 1-(methyl-carbonyl)-piperidin-4-yl, 1-(5-hydroxy-6-methyl-pyrimidin-4-yl- carbonyl)-piperidin-4-yl, 1-(methyl-carbonyl)-piperidin-4-yl, 4-(5-hydroxy-6-methyl- pyrimidin-4-yl-carbonyl)-piperazin-1-yl, 4-(5-hydroxy-6-methyl-pyrimidiny-4-yl- carbonyl)-3-methyl-piperazin-1-yl, 4-(5-hydroxy-6-methyl-pyrimidiny-4-yl-carbonyl)-10 3R-methyl-piperazin-1-yl, 4-(5-hydroxy-6-methyl-pyrimidiny-4-yl-carbonyl)-3S-methyl- piperazin-1-yl, (rac)-5-(5-hydroxy-6-methyl-pyrimidin-4-yl-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl, (1S*,6S*)-5-(5-hydroxy-6-methyl-pyrimidin-4-yl- carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl, and (1R*,6R*)-5-(5-hydroxy-6-methyl- pyrimidin-4-yl-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl; 15 or a pharmaceutically acceptable salt thereof.

6. A compound as in Claim 1, wherein R1is selected from the group consisting of 1-(methyl-carbonyl)-piperidin-4-yl, 1-(5-hydroxy-6-methyl-pyrimidin-4-yl-carbonyl)-piperidin-4-yl, 1-(methyl-carbonyl)-20 piperazin-4-yl, 4-(5-hydroxy-6-methyl-pyrimidin-4-yl-carbonyl)-piperazin-1-yl and4-(5- hydroxy-6-methyl-pyrimidiny-4-yl-carbonyl)-3R-methyl-piperazin-1-yl or a pharmaceutically acceptable salt thereof.

7. A compound as in Claim 1, wherein 25 R1is selected from the group consisting of isopropyl, 1-(methyl-carbonyl)-3,6- dihydro-pyridin-4-yl, 1-(methyl-carbonyl)-piperidin-4-yl, 1-(5-hydroxy-6-methyl- pyrimidin-4-yl-carbonyl)-piperidin-4-yl, and 4-(5-hydroxy-6-methyl-pyrimidin-4-yl- carbonyl)-piperazin-1-yl;; or a pharmaceutically acceptable salt thereof. 30 8. A compound as in Claim 1, wherein ; 9PRD4322WOPCT1 5 alternatively, ;R1is selected from the group consistin ,; ining heteroaryl; whereinthe 6-membered N containing heteroaryl is substituted with -OH and methyl; and 10 wherein R6is hydrogen; provided that whe , then R1isselected from the group consistin nd;yl; 15 R3is chloro; R4is hydroxy substituted C1-4alkyl; or a pharmaceutically acceptable salt thereof.

9. A compound as in Claim 1, wherein 20 ; 0PRD4322WOPCT1 5 alternatively, ;R1is selected from the group consisting of isoprop ,; idin-4-yl; and wherein R6ishydrogen or methyl; 10 is ndR3is chloro; 15 R4is 2-hydroxy-n-propan-2-; or a pharmaceutically acceptable salt thereof.

10. A compound as in Claim 1, selected from the group consisting of 2-[6-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)-2-[4-(1-hydroxy-1-methyl-20 ethyl)phenyl]-5-methyl-7-oxo-oxazolo[4,5-b]pyridin-4-yl]-N-[2-chloro-4- (trifluoromethyl)phenyl]acetamide; 131PRD4322WOPCT1 5 2-[6-(1-acetyl-4-piperidyl)-2-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-5-methyl-7- oxo-oxazolo[4,5-b]pyridin-4-yl]-N-[2-chloro-4-(trifluoromethyl)phenyl]acetamide; N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[2-[4-(1-hydroxy-1-methyl- ethyl)phenyl]-6-isopropyl-5-methyl-7-oxo-oxazolo[4,5-b]pyridin-4-yl]acetamide; N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[2-[4-(1-hydroxy-1-methyl-10 ethyl)phenyl]-6-[1-(5-hydroxy-6-methyl-pyrimidine-4-carbonyl)-4-piperidyl]-5-methyl-7- oxo-oxazolo[4,5-b]pyridin-4-yl]acetamide; N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[2-[4-(1-hydroxy-1-methyl- ethyl)phenyl]-6-[4-(5-hydroxy-6-methyl-pyrimidine-4-carbonyl)piperazin-1-yl]-5-methyl- 7-oxo-oxazolo[4,5-b]pyridin-4-yl]acetamide; 15 N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[2-[4-(1-hydroxy-1-methyl- ethyl)phenyl]-5-[4-(5-hydroxy-6-methyl-pyrimidine-4-carbonyl)piperazin-1-yl]-6-methyl- 4-oxo-oxazolo[5,4-c]pyridin-7-yl]acetamide; N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[2-[4-(1-hydroxy-1-methyl- ethyl)phenyl]-5-[1-(5-hydroxy-6-methyl-pyrimidine-4-carbonyl)-4-piperidyl]-6-methyl-4- 20 oxo-oxazolo[5,4-c]pyridin-7-yl]acetamide; 2-(6-(4-acetylpiperazin-1-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-5-methyl-7- oxooxazolo[4,5-b]pyridin-4(7H)-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide ; (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-3-methylpiperazin-1-yl)-2-(4-(2-hydroxypropan-2- 25 yl)phenyl)-5-methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide ; (rac)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-((rac)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-5-methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide ; N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-((1S*,6S*)-5-(5-hydroxy-6-30 methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-5-methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide; N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-((1R*,6R*)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-5-methyl-7-oxooxazolo[4,5-b]pyridin-4(7H)-yl)acetamide ; 132PRD4322WOPCT1 5 N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-5-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)piperazin-1-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-4- oxo-4,5-dihydrooxazolo[5,4-c]pyridin-7-yl)acetamide ; (R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-3-methylpiperazin-1-yl)-2-(4-(2-hydroxypropan-2- 10 yl)phenyl)-6-methyl-4-oxo-4,5-dihydrooxazolo[5,4-c]pyridin-7-yl)acetamide ; and pharmaceutically acceptable salts thereof.

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound as in Claim 1. 15 12. A pharmaceutical composition made by mixing a compound as in Claim 1 and a pharmaceutically acceptable carrier.

13. A process for making a pharmaceutical composition comprising mixing a 20 compound as in Claim 1 and a pharmaceutically acceptable carrier.

14. A method of treating a disorder mediated by or modulated by inhibition of WRN, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as in Claim 1. 25 15. The method of Claim 14, wherein the disorder mediated by or modulated by inhibition of WRN is a cancer.

16. The method of Claim 14, wherein the disorder mediated by or modulated by 30 inhibition of WRN is a cancer characterized as microsatellite instability (MSI) or mismatch repair deficient (dMMR).

17. The method of Claim 1, wherein the disorder mediated by or modulated by inhibition of WRN is a cancer selected from the group consisting of colonic, gastric, 133PRD4322WOPCT1 5 rectal, endometrial, adrenocortical, uterine, cervical, mesothelial, esophageal, breast, kidney, prostate, ovarian, pancreatic, germ cell, liver, lung, biliary tract / gallbladder, head / neck, thyroid, thymic, small bowel, bladder, skin, prostate, brain, neuroendocrine, soft tissue, appendiceal, leukemia, lymphoma, and myeloma cancers. 10 18. A method of treating a cancer selected from the group consisting of colonic, gastric, rectal, endometrial, adrenocortical, uterine, cervical, mesothelial, esophageal, breast, kidney, prostate, ovarian, pancreatic, germ cell, liver, lung, biliary tract / gallbladder, head / neck, thyroid, thymic, small bowel, bladder, skin, prostate, 15 brain, neuroendocrine, soft tissue, appendiceal, leukemia, lymphoma, and myeloma cancers, comprising administering to a subject in need thereof a therapeutically effective amount of the compound as in Claim 1.

19. A method of treating a cancer mediated by or modulated by inhibition of WRN 20 comprising administering to a subject in need thereof a therapeutically effective amount of the composition of Claim 11.

20. A method of treating a cancer mediated by or modulated by inhibition of WRN wherein the is a cancer characterized as microsatellite instability (MSI) or mismatch 25 repair deficient (dMMR) comprising administering to a subject in need thereof a therapeutically effective amount of the composition of Claim 11.

21. A method of treating a cancer selected from the group consisting of colonic, gastric, rectal, endometrial, adrenocortical, uterine, cervical, mesothelial, esophageal, 30 breast, kidney, prostate, ovarian, pancreatic, germ cell, liver, lung, biliary tract / gallbladder, head / neck, thyroid, thymic, small bowel, bladder, skin, prostate, brain, neuroendocrine, soft tissue, appendiceal, leukemia, lymphoma, and myeloma cancers, comprising administering to a subject in need thereof, a therapeutically effective amount of the composition of Claim 11. 134PRD4322WOPCT1 5 22. The use of a compound as in Claim 1 for the preparation of a medicament for treating: (a) colonic, (b) gastric, (c) rectal, (d) endometrial, (e) adrenocortical, (f) uterine, (g) cervical, (h) mesothelial, (i) esophageal, (j) breast, (k) kidney, (l) prostate, (m) ovarian, (n) pancreatic, (o) germ cell, (p) liver, (q) lung, (r) biliary tract / gallbladder, 10 (s) head / neck, (t) thyroid, (u) thymic, (v) small bowel, (w) bladder, (x) skin, (y) prostate, (z) brain, (aa) neuroendocrine, (ab) soft tissue, (ac) appendiceal, (ad) leukemia, (ae) lymphoma, or (af) myeloma cancers, in a subject in need thereof.

23. The use of a compound as in Claim 1, for use in a methods for treating a 15 disorder mediated by inhibition of WRN, more particularly cancers characterized as microsatellite instability (MSI) or mismatch repair deficient (dMMR), selected from the group consisting of colonic, gastric, rectal, endometrial, adrenocortical, uterine, cervical, mesothelial, esophageal, breast, kidney, prostate, ovarian, pancreatic, germ cell, liver, lung, biliary tract / gallbladder, head / neck, thyroid, thymic, small bowel, 20 bladder, skin, prostate, brain, neuroendocrine, soft tissue, appendiceal, leukemia, lymphoma, and myeloma cancers, in a subject in need thereof.

24. A compound as in Claim 1 for use as a medicament. 25 25. A compound as in Claim 1 for use in the treatment of a disorder mediated by or modulated by inhibition of WRN.

26. A compound as in Claim 1 for use in the treatment of a cancer characterized as microsatellite instability (MSI) or mismatch repair deficient (dMMR). 30 27. A compound as in Claim 1 for use in the treatment of a cancer characterized as microsatellite instability (MSI) or mismatch repair deficient (dMMR) selected from the group consisting of colonic, gastric, rectal, endometrial, adrenocortical, uterine, cervical, mesothelial, esophageal, breast, kidney, prostate, ovarian, pancreatic, germ 135PRD4322WOPCT1 5 cell, liver, lung, biliary tract / gallbladder, head / neck, thyroid, thymic, small bowel, bladder, skin, prostate, brain, neuroendocrine, soft tissue, appendiceal, leukemia, lymphoma, and myeloma cancers.

28. A composition comprising a compound as in Claim 1 for use in the treatment of 10 a disorder mediated by or modulated by inhibition of WRN.

29. A composition comprising a compound as in Claim 1 for use in the treatment of a cancer characterized as microsatellite instability (MSI) or mismatch repair deficient (dMMR). 15 30. A composition comprising a compound as in Claim 1 for use in the treatment of a cancer characterized as microsatellite instability (MSI) or mismatch repair deficient (dMMR) selected from the group consisting of colonic, gastric, rectal, endometrial, adrenocortical, uterine, cervical, mesothelial, esophageal, breast, kidney, prostate, 20 ovarian, pancreatic, germ cell, liver, lung, biliary tract / gallbladder, head / neck, thyroid, thymic, small bowel, bladder, skin, prostate, brain, neuroendocrine, soft tissue, appendiceal, leukemia, lymphoma, and myeloma cancers.

31. A composition comprising a compound of as in Claim 1, and one or more 25 additional therapeutically active agents.

32. A composition as in Claim 31, wherein an additional therapeutically active agent is an anti-cancer agent. 30 33. A composition as in Claim 31, wherein an additional therapeutically active anti­ cancer agent is a chemotherapy.

34. A composition as in Claim 31, wherein an additional therapeutically active agent is a chemotherapy selected from the group consisting of anastrozole 136PRD4322WOPCT1 5 (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4- pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside 10 (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC­ Dome®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil 15 (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine (difluorodeoxycitidine), hydroxyurea (Hydrea®), ldarubicin (ldamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L­ asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), phoenix (Yttrium90 / MX- 20 DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®). 25 35. A composition as in Claim 31, wherein an additional therapeutically active agent is a PD-1 inhibitor.

36. A composition as in Claim 31, wherein an additional therapeutically active agent is an anti-PD-1 antibody molecule. 30 37. A composition as in Claim 31, wherein an additional therapeutically active agent is a PD-1 inhibitor selected from PDR001 (Novartis), Nivolumab (Bristol-Myers Squibb), Pembrolizumab (Merck & Co), Pidilizumab (CureTech), MEDI0680 137PRD4322WOPCT1 5 (Medimmune), Cemiplimab (REGN2810, Regeneron), Dostarlimab (TSR-042, Tesaro), PF-06801591 (Pfizer), Tislelizumab (BGB-A317, Beigene), BGB-108 (Beigene), INCSHR1210 (lncyte), Balstilimab (AGEN2035, Agenus), Sintilimab (lnnoVent), Toripalimab (Shanghai Junshi Bioscience), Camrelizumab (Jiangsu Hengrui Medicine Co.), and AMP-224 (Amplimmune). 10 38. A method of treating a disorder mediated by or modulated by inhibition of WRN comprising administration of a composition as in Claim 31.

39. A method of treatment as in Claim 38, wherein the disorder mediated by or 15 modulated by inhibition of WRN is a cancer characterized as microsatellite instability (MSI) or mismatch repair deficient (dMMR).

40. A method of treatment as in Claim 38, wherein an additional therapeutically active agent is an anti-cancer agent. 20 41. A method of treatment as in Claim 38, wherein an additional therapeutically active anti­ cancer agent is a chemotherapy.

42. A method of treatment as in Claim 38, wherein an additional therapeutically 25 active agent is a chemotherapy selected from the group consisting of anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4- pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), 30 cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC­ Dome®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, 138PRD4322WOPCT1 5 Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine (difluorodeoxycitidine), hydroxyurea (Hydrea®), ldarubicin (ldamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L­ asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®),10 mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), phoenix (Yttrium90 / MX- DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®). 15 43. A method of treatment as in Claim 38, wherein an additional therapeutically active agent is a PD-1 inhibitor.

44. A method of treatment as in Claim 38, wherein an additional therapeutically 20 active agent is an anti-PD-1 antibody molecule.

45. A method of treatment as in Claim 38, wherein an additional therapeutically active agent is a PD-1 inhibitor selected from PDR001 (Novartis), Nivolumab (Bristol- Myers Squibb), Pembrolizumab (Merck & Co), Pidilizumab (CureTech), MEDI0680 25 (Medimmune), Cemiplimab (REGN2810, Regeneron), Dostarlimab (TSR-042, Tesaro), PF-06801591 (Pfizer), Tislelizumab (BGB-A317, Beigene), BGB-108 (Beigene), INCSHR1210 (lncyte), Balstilimab (AGEN2035, Agenus), Sintilimab (lnnoVent), Toripalimab (Shanghai Junshi Bioscience), Camrelizumab (Jiangsu Hengrui Medicine Co.), and AMP-224 (Amplimmune). 30 46. A compound, composition, pharmaceutical composition, method of preparation or method of treatment as described here. 139

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