Triazolo[4,5-b]pyridine 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] TRIAZOLO[4,5-B]PYRIDINE COMPOUNDS USEFUL AS INHIBITORS OF WERNER SYNDROME RECQ HELICASE (WRN)

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority from United States Provisional Applications Serial No. 63 / 750803 filed 29 January 2025 and United States Provisional Applications Serial No. 63 / 554225 filed on 16 February 2024 the contents of each of which are hereby incorporated by reference in their entirety.

[0004] Field of the Invention

[0005] 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 [1 ,2,3]triazolo[4,5-b]pyridin-7-one and [1 ,2,3]triazolo[4,5-c]pyridin-4-one derivatives, 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.

[0006] Background of the Invention

[0007] 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, 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 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 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, urothelial, gastric, and other cancers (Bonadona, V et al., Journal of the American

[0008] Medical Association 201 pp 2304-2310, 305(22). While recent clinical trials have demonstrated that anti-PD-1 monoclonal antibodies (alone or in combination with anti-

[0009] 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); 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

[0010] England Journal of Medicine 2020 pp 2207-2218, 383(23) Le, D et al Journal of

[0011] Clinical , 2020, pp 11 -19, 38(1 ); Lenz, H et al., Journal of Clinical Oncology,

[0012] 2022, pp 161 -170, 40(2); O’Malley, D et al., Journal of Clinical Oncology, 2022, pp 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.

[0013] Recent functional genomic studies have identified the Werner syndrome helicase WRN as a synthetic lethal dependency in preclinical models of MSI cancer (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 51 1 -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 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 molecularly targeted therapy (Picco, G et al., Cancer Discovery, 2021 , pp 1923-1937, 1 1 (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, 2019, pp 51 1 -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 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)).

[0014] Collectively, these data demonstrate that pharmacological inhibition of WRN 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).

[0015] BORDAS, V., et al., in PCT Publication W02022 / 249060 A1 , published 01 December 2022 described some triazolo-pyrimidine analogues for treating diseases connected to the inhibition of Werner Syndrome RecQ Helicase (WRN). Summary of the Invention

[0016] The present invention is directed to compounds of formula (I) wherein

[0017] R1is selected from the group consisting of Ci 4alkyl, wherein R5is selected from the group consisting of methyl, ethyl, 5-hydroxy-6- methyl-pyrimidin-4-yl and 3-hydroxy-pyridin-2-yl;

[0018] R2is methyl or ethyl;

[0019] R3is 2-chloro-4-trifluoromethyl-phenyl;

[0020] R4is 2-hydroxy-n-propan-2-yl; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof.

[0021] The present invention is further directed to compounds of formula (II) wherein

[0022] R11is selected from the group consisting , wherein R5is selected from the group consisting of methyl, ethyl, 5-hydroxy-6- methyl-pyrimidin-4-yl and 3-hydroxy-pyridin-2-yl;

[0023] R2is methyl or ethyl;

[0024] R3is 2-chloro-4-trifluoromethyl-phenyl;

[0025] R4is 2-hydroxy-n-propan-2-yl; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof.

[0026] The present invention is further directed to processes for the preparation of the compounds of formula (I) and / or the compounds of formula (II). The present invention is further directed to a product prepared according to any of processes described herein.

[0027] 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 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.

[0028] Exemplifying the invention are methods of 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, 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 administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.

[0029] In an embodiment, the present invention is directed to a compound of formula (I) or a compound of formula (II) for use as a medicament. In another embodiment, the present invention is directed to a compound of formula (I) or a compound of formula (II) 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, 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.

[0030] In another embodiment, the present invention is directed to a composition comprising a compound of formula (I) or a compound of formula (II) for the treatment of a disorder mediated by o 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, bladder, skin, prostate, brain, neuroendocrine, soft tissue, appendiceal, leukemia, lymphoma, and myeloma cancers.

[0031] 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 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) esophageal, (j) breast, (k) kidney, (I) 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.

[0032] 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, 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.

[0033] In some embodiments, the present invention is directed to compositions comprising (a) a compound of formula (I) or a compound of formula (II), 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) or a compound of formula (II), and (b) one or more additional therapeutic agents, for use in the preparation of a medicament for the treatment of a disorder 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) or a compound of formula (II), and (b) one or more additional therapeutic agents. In further embodiments, the present invention is directed to a composition comprising (a) a compound of formula (I) or a compound of formula (II), and (b) one or more additional therapeutic agents use in a method for treating a disorder mediated by or modulated by inhibition of WRN.

[0034] Detailed Description of the Invention

[0035] The present invention is directed to compounds of formula (I) wherein R1, R2, R3, and R4are as herein defined. The compounds of formula (I) of the 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, 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.

[0036] The present invention is further directed to compounds of formula (II) wherein R11, R2, R3, and R4are as herein defined. The compounds of formula (II) of the 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, 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.

[0037] The present invention is further directed to compositions (e.g., pharmaceutical compositions) comprising (a) a compound of formula (I) or a compound of formula (II) 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), 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.

[0038] One skilled in the art will recognize that some of variables (e.g., R2, R3, R4, etc.) appear in compounds of formula (I) and compounds of formula (II). One skilled in the art will further recognize that wherein a particular substituent is selected for a given variable for a compound of formula (I), said selection is not intended to limit the scope of said variable for compounds of formula (II). Similarly, the selection of a particular substituent for a given variable for a compound of formula (II), is not intended to limit the scope of said variable for compounds of formula (I).

[0039] Embodiments

[0040] In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is Ci-4alkyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R1 In some embodiments, the present invention is directed to compounds of formula (I) wherein In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is In some embodiments, the present invention is directed to compounds of formula (I) wherein In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is In some embodiments, the present invention is directed to compounds of formula (I) wherein In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is In some embodiments, the present invention is directed to compounds of formula (I) wherein In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is

[0041] In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of n-propan-2-yl, 1 -acetyl- piperidin-4-yl, 1 -(5-hydroxy-6-methyl-pyridin-4-yl-carbonyl)-piperidin-4-yl, 4-acetyl- piperazin-1 -yl, 4-(5-hydroxy-6-methyl-pyridin-4-yl-carbonyl)-piperazin-1 -yl, 4-(5- hydroxy-6-methyl-pyrimidin-4-yl-carbonyl)-3-methyl-piperazin-1 -yl, ((1 S*,6S*)-5-(5- hydroxy-6-methyl-pyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl, and ((1 R*,6R*)-5-(5-hydroxy-6-methyl-pyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan- 2-yl.

[0042] In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of n-propan-2-yl, 1 -acetyl- piperidin-4-yl, 1 -(5-hydroxy-6-methyl-pyridin-4-yl-carbonyl)-piperidin-4-yl, 4-acetyl- piperazin-1 -yl, and 4-(5-hydroxy-6-methyl-pyridin-4-yl-carbonyl)-piperazin-1 -yl.

[0043] In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of n-propan-2-yl, 4-acetyl- piperazin-1 -yl, 1 -(5-hydroxy-6-methyl-pyrimidin-4-yl-carbonyl)-piperidin-4-yl, 4-(5- hydroxy-6-methyl-pyridin-4-yl-carbonyl)-piperazin-1 -yl, 4-(5-hydroxy-6-methyl- pyrimidin-4-yl-carbonyl)-3 R-methyl-piperazin-1 -yl, 4-(5-hydroxy-6-methyl-pyrimidin-4- yl-carbonyl)-3S-methyl-piperazin-1 -yl, ((1 S*,6S*)-5-(5-hydroxy-6-methyl-pyrimidine-4- carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl, and ((1 R*,6R*)-5-(5-hydroxy-6-methyl- pyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl.

[0044] In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of n-propan-2-yl, 4-acetyl- piperazin-1 -yl and 4-(5-hydroxy-6-methyl-pyridin-4-yl-carbonyl)-piperazin-1 -yl.

[0045] In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is 1 -acetyl-piperidin-4-yl or 1 -(5-hydroxy-6-methyl-pyridin-4-yl- carbonyl)-piperidin-4-yl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of 1 -acetyl- piperidin-4-yl and 1 -(5-hydroxy-6-methyl-pyridin-4-yl-carbonyl)-piperidin-4-yl.

[0046] In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of 4-(5-hydroxy-6-methyl- pyrimidin-4-yl-carbonyl)-3R-methyl-piperazin-1 -yl or 4-(5-hydroxy-6-methyl-pyrimidin- 4-yl-carbonyl)-3S-methyl-piperazin-1 -yl.

[0047] In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is ((1 S*,6S*)-5-(5-hydroxy-6-methyl-pyrimidine-4-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl or ((1 R*,6R*)-5-(5-hydroxy-6-methyl-pyrimidine-4- carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl.

[0048] In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is n-propan-2-yl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is 1 -acetyl-piperidin-4-yl or 1 -(5- hydroxy-6-methyl-pyridin-4-yl-carbonyl)-piperidin-4-yl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is 4-acetyl- piperazin-1 -yl or 4-(5-hydroxy-6-methyl-pyridin-4-yl-carbonyl)-piperazin-1 -yl.

[0049] In some embodiments, the present invention is directed to compounds of formula (I) wherein R5is methyl or ethyl. 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 formula (I) wherein R5is 3-hydroxy-pyridin-2-yl.

[0050] In some embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of 4-acetyl-piperazin-1 -yl, 1 -(5-hydroxy-6-methyl-pyrimidin-4-yl-carbonyl)-piperidin-4-yl, 4-(5-hydroxy-6-methyl- pyridin-4-yl-carbonyl)-piperazin-1 -yl, 4-(5-hydroxy-6-methyl-pyrimidin-4-yl-carbonyl)- 3R-methyl-piperazin-1 -yl, 4-(5-hydroxy-6-methyl-pyrimidin-4-yl-carbonyl)-3S-methyl- piperazin-1 -yl, and ((1 S*,6S*)-5-(5-hydroxy-6-methyl-pyrimidine-4-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl.

[0051] In some embodiments, the present invention is directed to compounds of formula (II) wherein R11 In some embodiments, the present invention is directed to compounds of formula (II) wherein some embodiments, the present invention is directed to compounds of formula (II) wherein

[0052] In some embodiments, the present invention is directed to compounds of formula (II) wherein R11is selected from the group consisting of 1 -acetyl-piperidin-4-yl, 1 -(5-hydroxy-6-methyl-pyrimidin-4-yl-carbonyl)-piperidin-4-yl, 4-(5-hydroxy-6-methyl- pyrimidin-4-yl-carbonyl)-piperazin-1 -yl, and 4-(5-hydroxy-6-methyl-pyrimidin-4-yl- carbonyl)-3R-methyl-piperazin-1 -yl.

[0053] In some embodiments, the present invention is directed to compounds of formula (II) wherein R11is selected from the group consisting of 1 -(5-hydroxy-6- methyl-pyrimidin-4-yl-carbonyl)-piperidin-4-yl, 4-(5-hydroxy-6-methyl-pyrimidin-4-yl- carbonyl)-piperazin-1 -yl, and 4-(5-hydroxy-6-methyl-pyrimidin-4-yl-carbonyl)-3R- methyl-piperazin-1 -yl. In some embodiments, the present invention is directed to compounds of formula (II) wherein R11is 1 -(5-hydroxy-6-methyl-pyrimidin-4-yl- carbonyl)-pi peridi n-4-y I or 4-(5-hydroxy-6-methyl-pyrimidin-4-yl-carbonyl)-piperazin-1 - yl. In some embodiments, the present invention is directed to compounds of formula (II) wherein R11is 4-(5-hydroxy-6-methyl-pyrimidin-4-yl-carbonyl)-piperazin-1 -ylor 4- (5-hydroxy-6-methyl-pyrimidin-4-yl-carbonyl)-3R-methyl-piperazin-1 -yl.

[0054] In some embodiments, the present invention is directed to compounds of formula (II) wherein R11is selected from the group consisting of 1 -acetyl-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.

[0055] In some embodiments, the present invention is directed to compounds of formula (II) wherein R5is methyl or ethyl. In some embodiments, the present invention is directed to compounds of formula (II) wherein R5is methyl.

[0056] In some embodiments, the present invention is directed to compounds of formula (II) wherein R5is methyl or 5-hydroxy-6-methyl-pyrimidin-4-yl. In some embodiments, the present invention is directed to compounds of formula (II) wherein R5is 5-hydroxy-6-methyl-pyrimidin-4-yl. In some embodiments, the present invention is directed to compounds of formula (II) wherein R5is 3-hydroxy-pyridin-2-yl.

[0057] 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.

[0058] In some embodiments, the present invention is directed to compounds of formula (II) wherein R2is methyl. In some embodiments, the present invention is directed to compounds of formula (II) wherein R2is ethyl.

[0059] Additional embodiments of the present invention, include those wherein the substituents selected for one or more of the variables defined herein (i.e., R1, R2, R3, R4and R11) 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 compound or subset of compounds selected from the representative compounds listed in Tables 1 -2, below. Representative compounds of formula (I) and compounds of formula (II) of the present invention are listed in Tables 1 -2, below. Unless otherwise noted, wherein a stereogenic center is present in the listed compound, the compound was prepared as a mixture of stereo-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.

[0060] Table 1 : Representative Compounds of Formula (I)

[0061]

[0062] Table 2: Representative Compounds of Formula (II) In some embodiments, the present invention is directed to one or more compounds of formula (I) selected from the group consisting of

[0063] 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-triazolo[4,5-b]pyridin-4-yl]acetamide;

[0064] 2-[6-(4-acetylpiperazin-1 -yl)-2-[4-( 1 -hydroxy-1 -methyl-ethyl)phenyl]-5-methyl-7- oxo-triazolo[4,5-b]pyridin-4-yl]-N-[2-chloro-4-(trifluoromethyl)phenyl]acetamide;

[0065] 2-[6-(4-acetylpiperazin-1 -yl)-5-ethyl-2-[4-( 1 -hydroxy-1 -methyl-ethyl)phenyl]-7- oxo-triazolo[4,5-b]pyridin-4-yl]-N-[2-chloro-4-(trifluoromethyl)phenyl]acetamide;

[0066] N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[2-[4-(1 -hydroxy-1 -methyl- ethyl)phenyl]-6-isopropyl-5-methyl-7-oxo-triazolo[4,5-b]pyridin-4-yl]acetamide;

[0067] N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[5-ethyl-2-[4-(1 -hydroxy-1 -methyl- ethyl)phenyl]-6-[4-(5-hydroxy-6-methyl-pyrimidine-4-carbonyl)piperazin-1 -yl]-7-oxo- triazolo[4,5-b]pyridin-4-yl]acetamide;

[0068] 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-oxo-2,7- dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide;

[0069] (R)- / V-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-3-methylpiperazin-1 -yl)-2-(4-(2-hydroxypropan-2- yl)phenyl)-7-oxo-2 / - / -[1 ,2,3]triazolo[4,5-b]pyridin-4(7 / - / )-yl)acetamide;

[0070] (S)- / V-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-3-methylpiperazin-1 -yl)-2-(4-(2-hydroxypropan-2- yl)phenyl)-7-oxo-2 / - / -[1 ,2,3]triazolo[4,5-b]pyridin-4(7 / - / )-yl)acetamide;

[0071] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-((1 *S,6*S)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-7-oxo-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4- yl)acetamide;

[0072] N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-((1 *R,6*R)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-7-oxo-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4- yl)acetamide;

[0073] / V-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(1 -(5-hydroxy-6- methylpyrimidine-4-carbonyl)piperidin-4-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-7-oxo- 2,7-dihydro-4 / - / -[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof.

[0074] In some embodiments, the present invention is directed to one or more compounds of formula (II) selected from the group consisting of

[0075] 2-[5-(1 -acetyl-4-piperidyl)-2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6-methyl-4- oxo-triazolo[4,5-c]pyridin-7-yl]-N-[2-chloro-4-(trifluoromethyl)phenyl]acetamide;

[0076] 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-methyl-4-oxo-4,5- dihydro-2H-[1 ,2,3]triazolo[4,5-c]pyridin-7-yl)acetamide;

[0077] 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- dihydro-2H-[1 ,2,3]triazolo[4,5-c]pyridin-7-yl)acetamide;

[0078] 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-dihydro-2H-[1 ,2,3]triazolo[4,5-c]pyridin-7-yl)acetamide;

[0079] ( / ?)- / V-(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-dihydro-2H-[1 ,2,3]triazolo[4,5-c]pyridin-7- yl)acetamide;and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof.

[0080] In an embodiment, the present invention is directed to 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-triazolo[4,5-b]pyridin-4- yl]acetamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In an embodiment, the present invention is directed to 2-[6-(4- acetylpiperazin-1 -y l)-2-[4-( 1 -hydroxy-1 -methyl-ethyl)phenyl]-5-methyl-7-oxo- triazolo[4,5-b]pyridin-4-yl]-N-[2-chloro-4-(trifluoromethyl)phenyl]acetamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In an embodiment, the present invention is directed to 2-[6-(4-acetylpiperazin-1 -yl)-5-ethyl- 2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-7-oxo-triazolo[4,5-b]pyridin-4-yl]-N-[2-chloro-4- (trifluoromethyl)phenyl]acetamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In an embodiment, 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-triazolo[4,5-b]pyridin-4-yl]acetamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In an embodiment, the present invention is directed to N-[2-chloro-4- (trifluoromethyl)phenyl]-2-[5-ethyl-2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6-[4-(5- hydroxy-6-methyl-pyrimidine-4-carbonyl)piperazin-1 -yl]-7-oxo-triazolo[4,5-b]pyridin-4- yl]acetamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In an embodiment, the present invention is directed to 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-oxo-2,7-dihydro-4H-

[0081] [1 ,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In an embodiment, the present invention is directed to ( / ?)- / V-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-3-methylpiperazin-1 -yl)-2-(4-(2-hydroxypropan-2- yl)phenyl)-7-oxo-2 / - / -[1 ,2,3]triazolo[4,5-b]pyridin-4(7 / - / )-yl)acetamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In an embodiment, the present invention is directed to (S)- / V-(2-Chloro-4- (trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-3- methylpiperazin-1 -yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-7-oxo-2 / - / -[1 ,2,3]triazolo[4,5- b]pyridin-4(7 / - / )-yl)acetamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In an embodiment, the present invention is directed to N-(2- Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-((rS,6*S)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-7-oxo-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4- yl)acetamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In an embodiment, the present invention is directed to N-(2-Chloro-4- (trifluoromethyl)phenyl)-2-(5-ethyl-6-((1 *R,6*R)-5-(5-hydroxy-6-methylpyrimidine-4- carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-7- oxo-2, 7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In an embodiment, the present invention is directed to / V-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(1 - (5-hydroxy-6-methylpyrimidine-4-carbonyl)piperidin-4-yl)-2-(4-(2-hydroxypropan-2- yl)phenyl)-7-oxo-2,7-dihydro-4 / - / -[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof.

[0082] In an embodiment, the present invention is directed to 2-[5-(1 -acetyl-4- piperidyl)-2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6-methyl-4-oxo-triazolo[4, 5-c]pyridin- 7-yl]-N-[2-chloro-4-(trifluoromethyl)phenyl]acetamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In an embodiment, the present invention is directed to 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-methyl-4-oxo-4,5-dihydro-2H-[1 ,2,3]triazolo[4,5-c]pyridin-7-yl)acetamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In an embodiment, the present invention is directed to 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-dihydro-2H- [1 ,2,3]triazolo[4,5-c]pyridin-7-yl)acetamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In an embodiment, the present invention is directed to 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-dihydro-2H-[1 ,2,3]triazolo[4,5-c]pyridin-7-yl)acetamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof. In an embodiment, the present invention is directed to ( / ?)- / V-(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-dihydro-2H-[1 ,2,3]triazolo[4,5- c]pyridin-7-yl)acetamide; and stereoisomers, isotopologues and pharmaceutically acceptable salts thereof.

[0083] In some embodiments, the present invention is directed to compounds of formula (I) and / or compounds of formula (II) which, when tested according to the procedure as described in Biological Example 1 , which follows hereinafter, exhibit an IC50 of less than or equal to about 1 pM, preferably less than or equal to about 0.5 pM, more preferably less than or equal to about 0.2 pM, more preferably less than or equal to about 0.1 pM, more preferably less than or equal to about 0.05 pM, more preferably less than or equal to about 0.01 pM, more preferably less than or equal to about 0.005 pM, more preferably less than or equal to about 0.002 pM.

[0084] In some embodiments, the present invention is directed to compounds of formula (I) and / or compounds of formula (II) 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 pM, preferably less than or equal to about 0.5 pM, more preferably less than or equal to about 0.25 pM, more preferably less than or equal to about 0.1 pM, more preferably less than or equal to about 0.05 pM, more preferably less than or equal to about 0.02 pM.

[0085] In some embodiments, the present invention is directed to compounds of formula (I) and / or compounds of formula (II) which, when tested according to the procedure as described in Biological Example 2B, which follows hereinafter, exhibit an IC50 of less than or equal to about 30 pM, preferably less than or equal to about 25 pM, preferably less than or equal to about 20 pM, preferably less than or equal to about 15 pM, preferably less than or equal to about 10 pM, preferably less than or equal to about 5 pM. 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 a leaving group, said halogen is preferably bromo, chloro or iodo, more preferably bromo.

[0086] 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, Ci 4alkyl shall include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl (also known as t-butyl).

[0087] 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.

[0088] 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.

[0089] As used herein, the notation shall denote the presence of a stereogenic center.

[0090] 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.

[0091] 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%, 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 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%.

[0092] 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 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.

[0093] Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a “phenylCi- CealkylaminocarbonylCi-Cealkyl” substituent refers to a group of the formula

[0094] Abbreviations used in the specification, particularly the Schemes and Examples herein, are as follows:

[0095]

[0096] 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 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. In an embodiment of the present invention, the compound of formula (II) is present in an isolated form.

[0097] 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 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. In an embodiment of the present invention, the compound of formula (II) is present as a substantially pure form.

[0098] 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) (or compound of formula (II)) shall mean that mole percent of the corresponding salt form(s) in the isolated base of formula (I) (or compound of formula (II)) 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 form(s). In an embodiment of the present invention, the compound of formula (II) is present in a form which is substantially free of corresponding salt form(s).

[0099] 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 of such chemical entity in the medium in which the compound is being considered when named.

[0100] 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 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 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.

[0101] 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.

[0102] 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 approximations due to the experimental and / or measurement conditions for such given value.

[0103] 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 upper and lower bounds, but rather includes the full range from about amount X through about amount Y, or any amount or range therein.

[0104] 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, mesylate, tosylate, and the like.

[0105] 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 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.

[0106] As used herein, unless otherwise noted, the term “nitrogen protecting group” 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 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 Synthesis, John Wiley & Sons, 1991 .

[0107] 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, 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 .

[0108] General Synthesis Schemes:

[0109] Compounds of formula (I) of the present invention wherein R2is methyl may be prepared from (by reacting or functionalizing) 2-(6-bromo-2-(4-(2-hydroxypropan-2- yl)phenyl)-5-methyl-7-oxo-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(2- chloro-4-(trifluoromethyl)phenyl)acetamide as described in the Schemes which follow hereinafter.

[0110] 2-(6-Bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)-5-methyl-7-oxo-2,7-dihydro-

[0111] 4H-[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide may be prepared as described in Scheme 1 , below.

[0112] Scheme 1

[0113] Accordingly, 2-chloro-4-methoxy-6-methyl-3-nitropyridine, a known compound, is reacted with (4-methoxyphenyl)methanamine, a known compound, preferably in an amount of about 2 molar equivalents; in the presence of a suitably selected organic amine base such as TEA, DIPEA, pyridine, and the like; neat or in a suitably selected solvent such as 1 ,4-dioxane, THF, and the like; at an elevated temperature, for example at about 80°C; to yield 4-methoxy-N-(4-methoxybenzyl)-6-methyl-3- nitropyridin-2-amine. One skilled in the art will recognize that the chloro group on the 2-chloro-4-methoxy-6-methyl-3-nitropyridine is a suitable leaving group for the desired reaction; and that the 4-methoxy-benzyl group on the (4-methoxyphenyl)methanamine is a suitable nitrogen protecting group. One skilled in the art will further recognize that alternate suitable leaving and nitrogen protecting groups may also be used.

[0114] The 4-methoxy-N-(4-methoxybenzyl)-6-methyl-3-nitropyridin-2-amine is reacted with a Fe and NFUCI, in a suitable solvent or mixture of solvents such as EtOH / water, MeOH / water, and the like; at an elevated temperature, for example at about 80°C; to yield 4-methoxy-N2-(4-methoxybenzyl)-6-methylpyridine-2,3-diamine.

[0115] The 4-methoxy-N2-(4-methoxybenzyl)-6-methylpyridine-2,3-diamine is reacted with NaNO2, a known compound; in a suitably selected solvent such as AcOH, dilute aqueous HCI, and the like; to yield 7-methoxy-3-(4-methoxybenzyl)-5-methyl-3H- [1 ,2,3]triazolo[4,5-b] pyridine. The 7-methoxy-3-(4-methoxybenzyl)-5-methyl-3H-[1 ,2,3]triazolo[4,5-b]pyridine is deprotected by reacting with a suitably selected acid such as TFA, HCI, p-TsOH, and the like; at an elevated temperature, for example at about 80°C; to yield 7- methoxy-5-methyl-3H-[1 ,2,3]triazolo[4,5-b]pyridine.

[0116] The 7-methoxy-5-methyl-3H-[1 ,2,3]triazolo[4,5-b]pyridine is reacted with (4- (methoxycarbonyl)phenyl)(2,4,6-trimethoxyphenyl)iodonium tosylate (prepared for example as describe in J. Org. Chem. 2016, 81 , 1998-2009), a known compound; in a suitably selected solvent such as 1 ,4-dioxane, toluene, and the like; at an elevated temperature, for example at about 90°C; to yield methyl 4-(7-methoxy-5-methyl-2H- [1 ,2,3]triazolo[4,5-b]pyridin-2-yl)benzoate.

[0117] The methyl 4-(7-methoxy-5-methyl-2H-[1 ,2,3]triazolo[4,5-b]pyridin-2- yl)benzoate is reacted with methylmagnesium bromide, a known compound; in a suitably selected solvent such THF, diethyl ether, and the like; to yield 2-(4-(7- methoxy-5-methyl-2H-[1 ,2,3]triazolo[4,5-b]pyridin-2-yl)phenyl)propan-2-ol.

[0118] The 2-(4-(7-methoxy-5-methyl-2H-[1 ,2,3]triazolo[4,5-b]pyridin-2- yl)phenyl)propan-2-ol is reacted with 2-chloro-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide; in the presence of a suitably selected salt such as KI, Nal, and the like; in a suitably selected solvent such as toluene, 1 ,4-dioxane, and the like; at an elevated temperature, for example at about 100°C; to yield N-(2-chloro- 4-(trifluoromethyl)phenyl)-2-(2-(4-(2-hydroxypropan-2-yl)phenyl)-5-methyl-7-oxo-2,7- dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide.

[0119] The N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(2-hydroxypropan-2- yl)phenyl)-5-methyl-7-oxo-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide is reacted with a suitably selected source of bromine such as NBS, bromine, and the like; in a suitably selected solvent such as 1 ,1 , 1 ,3, 3, 3- hexafluoro-2-propanol (HFIP), DMF, and the like; to yield 2-(6-bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)-5-methyl-7- oxo-2, 7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide. Compounds of formula (I) of the present invention wherein R2is ethyl may be prepared from (by reacting or functionalizing) 2-(6-bromo-5-ethyl-2-(4-(2- hydroxypropan-2-yl)phenyl)-7-oxo-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)-N- (2-chloro-4-(trifluoromethyl)phenyl)acetamide as described in Schemes which follow hereinafter.

[0120] 2-(6-Bromo-5-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-7-oxo-2,7-dihydro-4H-

[0121] [1 ,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(2-chloro-4-(trifluoromethyl)phenyl)acetamide may be prepared as described in Scheme 2, below.

[0122] Scheme 2

[0123] Accordingly, 2-(4-(7-methoxy-5-methyl-2H-[1 ,2,3]triazolo[4,5-b]pyridin-2- yl)phenyl)propan-2-ol (prepared for example as described in Scheme 1 above) is reacted with CH3I, a known compound; in the presence of a suitably selected catalyst such as LDA, LiHMDS, NaHMDS, and the like; in a suitably selected solvent such as THF, diethyl ether, and the like; at reduced temperature, for example at about -20°C; to yield 2-(4-(5-ethyl-7-methoxy-2H-[1 ,2,3]triazolo[4,5-b]pyridin-2-yl)phenyl)propan-2- ol.

[0124] The 2-(4-(5-ethyl-7-methoxy-2H-[1 ,2,3]triazolo[4,5-b]pyridin-2- yl)phenyl)propan-2-ol is reacted with a suitably selected reducing agent such as NaOCHs, NaSCHs, and the like; in a suitably selected solvent such as THF, 1 ,4- dioxane, and the like; at an elevated temperature, for example at about 80°C; to yield 5-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-2,4-dihydro-7H-[1 ,2,3]triazolo[4,5- b]pyridin-7-one.

[0125] The 5-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-2,4-dihydro-7H-

[0126] [1 ,2,3]triazolo[4,5-b]pyridin-7-one is reacted with N-(2-chloro-4- (trifluoromethyl)phenyl)-2-iodoacetamide, a known compound; in the presence of a suitably selected base such as TEA, DIPEA, and the like; in a suitably selected solvent such as DMF, THF, and the like; at an elevated temperature, for example at about 50°C; to yield N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-(2- hydroxypropan-2-yl)phenyl)-7-oxo-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4- yl)acetamide.

[0127] The N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-(2-hydroxypropan-2- yl)phenyl)-7-oxo-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide is reacted with is reacted with a suitably selected source of bromine such as NBS, bromine, and the like; in a suitably selected solvent such as 1 ,1 ,1 ,3,3,3-hexafluoro-2-propanol (HFIP), DMF, and the like; to yield 2-(6-bromo-5-ethyl-2-(4-(2-hydroxypropan-2- yl)phenyl)-7-oxo-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide.

[0128] The compound of formula (I) wherein R1is isopropyl and R2is methyl may be prepared as described in Scheme 3A, below.

[0129]

[0130] Scheme 3A Accordingly, 2-chloro-4-methoxy-6-methyl-3-nitropyridine, a known compound, is reacted with benzylamine, a known compound, preferably in an amount of about 1 molar equivalents; in the presence of a suitably selected catalyst such as rac-BINAP Pd G4, XPhos Pd G4, and the like; in the presence of a base such as KF, K2CO3, and the like; in a suitable solvent such as 1 ,4-dioxane, toluene, and the like; at an elevated temperature, for example at about 50°C; to yield 4-methoxy-N-(benzyl)-6-methyl-3- nitropyridin-2-amine. One skilled in the art will recognize that alternate suitable leaving and nitrogen protecting groups may also be employed in this reaction.

[0131] The 4-methoxy-N-(benzyl)-6-methyl-3-nitropyridin-2-amine is reacted with a suitably selected reducing agent such as Fe and NFUCI, and the like; in a suitably selected solvent or mixture of solvents such as a mixture of ethanol / water, methanol / water, and the like; at an elevated temperature, for example at about 80°C; to yield 4-methoxy-N2-(benzyl)-6-methylpyridine-2,3-diamine.

[0132] The 4-methoxy-N2-(benzyl)-6-methylpyridine-2,3-diamine is reacted with a suitably selected reagent such as NaNO2, and the like; in a suitably selected solvent such as AcOH, dilute aqueous HCI, and the like; to effect ring closure and yield 7- methoxy-3-(benzyl)-5-methyl-3H-[1 ,2,3]triazolo[4,5-b]pyridine.

[0133] The 7-methoxy-3-(benzyl)-5-methyl-3H-[1 ,2,3]triazolo[4,5-b]pyridine is reacted with a suitably selected source of bromine such as NBS, bromine, and the like; in a suitably selected solvent such as acetonitrile, HFIP, and the like; in the presence of a suitably selected additive such as AcOH, TFA, and the like; to yield 3-benzyl-6-bromo- 7-methoxy-5-methyl-3H-[1 ,2,3]triazolo[4,5-b]pyridine.

[0134] The 3-benzyl-6-bromo-7-methoxy-5-methyl-3H-[1 ,2,3]triazolo[4,5-b]pyridine is reacted 4,4,5,5-tetramethyl-2-(prop-1 -en-2-yl)-1 ,3,2-dioxaborolane, a known compound, under Suzuki coupling conditions (for example, in the presence of a suitably selected catalyst such as Pd(dppf)Cl2, Pd(PPh3)4, and the like; in the presence of a suitably selected agent such as CS2CO3, K2CO3, and the like; in a suitably selected solvent such as 1 ,4-dioxane, toluene, DMF, and the like); to yield 3- benzyl-7-methoxy-5-methyl-6-(prop-1 -en-2-yl)-3H-[1 ,2,3]triazolo[4,5-b]pyridine.

[0135] The 3-benzyl-7-methoxy-5-methyl-6-(prop-1 -en-2-yl)-3H-[1 ,2,3]triazolo[4,5- b]pyridine reacted with hydrogen; in the presence of a suitably selected catalyst such as Pd / C, and the like; in a suitably selected solvent such as MeOH, EtOH, and the like; to yield 6-isopropyl-7-methoxy-5-methyl-3H-[1 ,2,3]triazolo[4,5-b]pyridine.

[0136] The 6-isopropyl-7-methoxy-5-methyl-3H-[1 ,2,3]triazolo[4,5-b]pyridine is reacted with ((4-(2-hydroxypropan-2-yl)phenyl)(2,4,6-trimethoxyphenyl)iodonium trifluoroacetate (prepared for example as describe in J. Org. Chem. 2016, 81 , 1998- 2009), a known compound; in the presence of a suitably selected base such as K2CO3, CS2CO3; in a suitably selected solvent such as 1 ,4-dioxane, toluene, and the like; at an elevated temperature, for example at about 100°C; to yield 2-(4-(6- isopropyl-7-methoxy-5-methyl-2H-[1 ,2,3]triazolo[4,5-b]pyridin-2-yl)phenyl)propan-2-ol.

[0137] The 2-(4-(6-isopropyl-7-methoxy-5-methyl-2H-[1 ,2,3]triazolo[4,5-b]pyridin-2- yl)phenyl)propan-2-ol is reacted with 2-chloro-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide, a known compound; in the presence of a suitably selected additive such as KI, Nal, and the like; in a suitably selected solvent such as toluene, 1 ,4-dioxane, and the like; at an elevated temperature, for example at about 100°C; to yield the corresponding compound of formula (I) wherein R1is isopropyl and R2is methyl (also known as N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(2- hydroxypropan-2-yl)phenyl)-6-isopropyl-5-methyl-7-oxo-2,7-dihydro-4H- [1 ,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide).

[0138] Compounds of formula (I) wherein R1is Ci 4alkyl may alternatively be prepared as described in Scheme 3B, below.

[0139] Scheme 3B

[0140] Accordingly, a suitably substituted compound of formula (V), prepared for example as descried herein, is reacted with a suitably substituted compound of formula (VI), wherein A1is Ci 4alkyl and 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-Ci-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)CI2, Pd(PPh3)4, Xphos Pd G3, Pd-PEPPSI™-lpent, Pd(dppf) G4, cataCXium®Pd G4, 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 such as 1 ,4-dioxane, toluene, DMF, DMSO, and the like); at an elevated temperature greater than about 80 °C, for example, at about 100 °C; to yield the corresponding compound of formula (la).

[0141] Compounds of formula (I) wherein R1 and wherein R5is as herein defined may be prepared as described in Scheme 3C, below.

[0142]

[0143] Scheme 3C

[0144] Accordingly, a suitably substituted compound of formula (V), prepared for example as described in Scheme 1 or 2 above) is reacted with a suitably substituted compound of formula (VIII), a known compound; in a suitably selected solvent such as NMP, DMF, DMSO, and the like; at a temperature in the range of from about 100°C to about 170°C, for example at about 130°C; to yield the corresponding compound of formula (lb).

[0145] Alternatively, a suitably substituted compound of formula (V), prepared for example as described in Scheme 1 or 2 above) is reacted with piperazine, a known compound; in a suitably selected solvent such as NMP, DMF, DMSO, and the like; at a temperature in the range of from about 100°C to about 170°C, for example at about 130°C; to yield the corresponding compound of formula (VII). The compound of formula (VII) is then reacted with a suitably substituted compound of formula (IX), a known compound or compound prepared by known methods; in the presence of a suitably selected amide coupling reagent or mixture such as HOPO and EDCI, HATU, and the like; in a suitably selected solvent such as DCM, DMF, and the like; at a temperature in the range of from about 0°C to about 50°C, for example at about 25°C; to yield the corresponding compound of formula (I- Z).

[0146] Compounds of formula (I) wherein may be similarly prepared described in Scheme 3C above, as described in Scheme 3D below.

[0147] Scheme 3D

[0148] Accordingly, a suitably substituted compound of formula (V), prepared for example as described herein, is reacted with tert-butyl 2-methylpiperazine-1 - carboxylate, a known compound or compound prepared as described in for example the Examples which follow hereinafter; in a suitably selected solvent such as NMP, DMF, DMSO, and the like; at a temperature in the range of from about 100°C to about 170°C, for example at about 130°C; to yield the corresponding compound of formula (XLII).

[0149] The compound of formula (XLII) is de-protected according to known methods; to yield the corresponding compound of formula (XLIII). For example, the compound of formula (XLII) may be deprotected by reacting with a suitably selected acid such as TFA, HCI, p-TsOH, and the like; at an elevated temperature, for example at about 80°C.

[0150] The compound of formula (XLIII) is reacted with a suitably substituted compound of formula (IX), a known compound or compound prepared by known methods; in the presence of a suitably selected amide coupling reagent or mixture such as HOPO and EDCI, HATU, and the like; in a suitably selected solvent such as DCM, DMF, and the like; at a temperature in the range of from about 0°C to about 50°C, for example at about 25°C; to yield the corresponding compound of formula (I- M).

[0151] Compound of formula (I) wherein may be similarly prepared according to the procedure as described in Scheme 3D by substituting tertbutyl 2,5-diazabicyclo[4.2.0]octane-2-carboxylate for tert-butyl 2-methylpiperazine-1 - carboxylate and reacting as described therein, to yield the corresponding compound of formula (l-S)

[0152]

[0153] Compounds of formula (I) wherein R1 and wherein R5is as herein defined may be prepared as described in Scheme 3E, below.

[0154] Scheme 3E

[0155] Accordingly, a suitably substituted compound of formula (X), prepared for example as described in Scheme 1 and 2 above, is reacted with a suitably selected source of bromine such as NBS, bromine, and the like; in a suitably selected solvent such as acetonitrile, HFIP, and the like; in the presence of a suitably selected additive such as AcOH, TFA, and the like; to yield the corresponding compound of formula (XI).

[0156] The compound of formula (XI) is reacted with (1 -(tert-butoxycarbonyl)-1 ,2,3,6- tetrahydropyridin-4-yl)boronic acid (or suitably protected boronic acid or ester as would be readily recognized by those skilled in the art), a known compound; in the presence of a suitably selected palladium catalyst such as Xphos Pd G3, Pd- PEPPSI™-lpent, Pd(dppf) G4, cataCXium®Pd G4, and the like; in the presence of a suitably selected base such a CS2CO3, K2CO3, Na2CO3, K3PO4, and the like; in a suitably selected solvent or mixture of solvents, such as toluene, DMF, DMSO, water, 1 ,4-dioxane, and the like; at an elevated temperature greater than about 80 °C, for example, at about 100 °C; to yield the corresponding compound of formula (XII). One skilled in the art will recognize that the BOC group on the (l -(tert-butoxycarbonyl)- 1 ,2,3,6-tetrahydropyridin-4-yl)boronic acid acts as a nitrogen protecting group, and that alternate suitable nitrogen protecting groups may also be used.

[0157] The compound of formula (XII) is reacted with benzyl 2-bromoacetate, a known compound; in the presence of a suitably selected base such as DIPEA, TEA, and the like; in a suitably selected solvent such as toluene, 1 ,4-dioxane, and the like; at an elevated temperature, for example at about 130°C; to yield the corresponding compound of formula (XIII), wherein Bn is benzyl.

[0158] The compound of formula (XIII) is reacted with hydrogen; in the presence of a suitably selected catalyst such as PtC , Rh / C, and the like; in a suitably selected solvent such as MeOH, EtOH, and the like; to yield the corresponding compound of formula (XIV).

[0159] The compound of formula (XIV) is reacted with 2-chloro-4- (trifluoromethyl)aniline, a known compound; in the presence of 2-chloro-1 - methylpyridinium iodide (Mukayama reagent), a known compound; in the presence of a suitably selected base such as TEA, DIPEA, pyridine, and the like; in a suitably selected solvent such as DMF, toluene, and the like; to yield the corresponding compound of formula (XV).

[0160] The compound of formula (XV) is de-protected according to known methods, for example, wherein the nitrogen protecting group is BOC, by reacting with a suitably selected acid such as HCI, and the like; in a suitably selected solvent such as 1 ,4- dioxane, and the like) to yield the corresponding compound of formula (XVI).

[0161] The compound of formula (XVI) is reacted with a suitably substituted compound of formula (XVII), a known compound or compound prepared by known methods; in the presence of a suitably selected activating agent such as EDCI, HATU, and the like; in the presence of a suitably selected coupling agent such as HOPO, HOBt, and the like; in the presence of a suitably selected base such as TEA, DIPEA, and the like; in a suitably selected solvent such as anhydrous 1 ,4-dioxane, DCM, and the like; to yield the corresponding compound of formula (l-P). Compounds of formula (I) wherein R1is may alternatively be prepared as described in Scheme 3F, below.

[0162] Scheme 3F

[0163] Accordingly, a suitably substituted compound of formula (XI), prepared for example as described in Scheme 3E above, is reacted with (l -(tert-butoxycarbonyl)- 1 ,2,3,6-tetrahydropyridin-4-yl)zinc(l I) iodide, a known compound or compound prepared or example as described in the Examples which follow hereinafter; in the presence of a suitably selected coupling agent such as CPhos Pd G3, XPhos Pd G3, SPhos Pd G3, and the like; in the presence of a suitably selected salt additive such as LiCI, LiBr, and the like; in a suitably selected solvent such as DMA, DMF, and the like; at an elevated temperature, for example at about 60°C; to yield the corresponding compound of formula (XLIV).

[0164] The compound of formula (XLIV) is reacted with N-(2-chloro-4- (trifluoromethyl)phenyl)-2-iodoacetamide, a known compound or compound prepared by known methods; in a suitably selected solvent such as toluene, 1 ,4-dioxane, and the like; at an elevated temperature, for example at about 120°C; to yield the corresponding compound of formula (XV). The compound of formula (XV) is de-protected and then reacted with a suitably substituted compound of formula (XVII) as described in Scheme 3E; to yield the corresponding compound of formula (l-P).

[0165] Compounds of formula (II) may be prepared as described in Scheme 4, below.

[0166] Scheme 4

[0167] Accordingly, methyl 3-bromopropiolate, a known compound, is reacted with 1- (azidomethyl)-4-methoxybenzene, a known compound; in the presence of a suitably selected transition metal such as copper, and the like; in a suitably selected solvent such as THF, 1 ,4-dioxane, and the like; at about reflux temperature, for example at about 66°C; to yield methyl 4-bromo-1 -(4-methoxybenzyl)-1 H-1 ,2,3-triazole-5- carboxylate. The methyl 4-bromo-1 -(4-methoxybenzyl)-1 H-1 ,2,3-triazole-5-carboxylate is reacted with a suitably selected base such as NaOH, KOH, LiOH, and the like; in a suitably selected solvent or mixture of solvents such as THF / water, MeOH / water, 1 ,4- dioxane / water, and the like; to yield 4-bromo-1 -(4-methoxybenzyl)-1 H-1 ,2,3-triazole-5- carboxylic acid. The 4-bromo-1 -(4-methoxybenzyl)-1 H-1 ,2,3-triazole-5-carboxylic acid is reacted with a suitably selected compound of formula (XX), a known compound or compound prepared by known methods; in the presence of a suitably selected chlorinating agent such as oxalyl chloride, thionyl chloride, phosphorus oxychloride, and the like; in a suitably selected solvent such as DCM, toluene, and the like; at ambient temperature to yield the corresponding compound of formula (XXI).

[0168] The compound of formula (XXI) is reacted with a suitably selected acid such as TFA, and the like; at elevated temperature, for example at about 70 °C; to yield the corresponding compound of formula (XXII).

[0169] The compound of formula (XXII) is reacted with (4- (methoxycarbonyl)phenyl)(2,4,6-trimethoxyphenyl)iodonium tosylate, a known compound; in the presence of a suitably selected base such as cesium carbonate, potassium carbonate, and the like; in a suitably selected solvent such as 1 ,4-dioxane, THF, and the like; at elevated temperature, for example at about 100 °C; to yield the corresponding compound of formula (XXIII).

[0170] The compound of formula (XIII) is reacted with a suitably substituted compound of formula (XXIV), a known compound or compound prepared by known methods; in the presence of a suitably selected catalyst such as PdXantphos G3 and the like; in a suitably selected solvent such as toluene, THF, 1 -4, -dioxane and the like; at elevated temperature, for example at about 100 °C; to yield the corresponding compound of formula (XXV).

[0171] The compound of formula (XXV) is reacted with a suitably selected agent such as phosphorus oxychloride, and the like; neat or in a suitably selected solvent; at an elevated temperature, for example at about 70 °C; to yield the corresponding compound of formula (XXVI).

[0172] The compound of formula (XXVI) is reacted with a suitably selected agent such as a solution of methylmagnesium bromide, methyl lithium, and the like; in a suitably selected solvent such as diethyl ether, THF, and the like; at a temperature below room temperature, for example at about 0 °C; to yield the corresponding compound of formula (XXVII). The compound of formula (XXVII) is reacted with a suitably selected brominating agent such as N-bromosuccinimide, bromine, and the like; in a suitably selected solvent or mixture of solvents such as 1 ,1 ,1 ,3,3,3-hexafluoroisopropanol, DCM / acetic acid, and the like; to yield the corresponding compound of formula (XXVIII).

[0173] The compound of formula (XXVIII) is reacted with 1 -(tert-butyldimethylsilyloxy)- 1 -methoxyethene, a known compound; in the presence of a suitably selected catalyst such as PdXphos G3 and the like; in the presence of a suitably selected ligand such as Xphos, and the like; in a suitably selected solvent such as THF,1 ,4-dioxane, and the like; at an elevated temperature, for example at about 100°C; to yield the corresponding compound of formula (XXIX).

[0174] The compound of formula (XXIX) is reacted with 2-chloro-4- (trifluoromethyl)aniline, a known compound; in the presence of a suitably selected base such as lithium bis(trimethylsilyl)amide, lithium diisopropyl amide, and the like; in a suitably selected solvent such as THF, diethyl ether, 1 ,4-dioxane and the like; at low temperature, for example at about 0 °C; to yield the corresponding compound of formula (ll-P).

[0175] Compounds of formula (II) wherein R11is may be prepared as described in Scheme 5, below.

[0176] Accordingly, 1 H-1 ,2,3-triazole-5-carboxylic acid, a known compound is reacted with tert-butyl 4-aminopiperidine-1 -carboxylate, a known compound; in the presence of a suitably selected coupling agent such as propylphosphonic acid anhydride, HATU, and the like; in the presence of a suitably selected base such as DIPEA, TEA, pyridine, and the like; in a suitably selected solvent such as THF, DMF, and the like; to yield tert-butyl 4-(1 H-1 , 2, 3-triazole-5-carboxamido)piperidine-1 -carboxylate. One skilled in the art will recognize that the BOG group on the tert-butyl 4-aminopiperidine- 1 -carboxylate acts as a nitrogen protecting group, and that alternate suitable nitrogen protecting groups may also be used. The tert-butyl 4-(1 H-1 ,2,3-triazole-5-carboxamido)piperidine-1 -carboxylate is reacted with a suitably selected source of bromine such as NBS, bromine, and the like; in the presence of a suitably selected base such as K2CO3, CS2CO3, and the like; in a suitably selected solvent such as acetonitrile, THF, and the like; to yield tert-butyl 4-(4-bromo-1 H-1 ,2,3-triazole-5-carboxamido)piperidine-1 -carboxylate.

[0177] The tert-butyl 4-(4-bromo-1 H-1 ,2,3-triazole-5-carboxamido)piperidine-1 - carboxylate is reacted with (4-(methoxycarbonyl)phenyl)(2,4,6- trimethoxyphenyl)iodonium 4-methylbenzenesulfonate, a known compound; in the presence of a suitably selected base such as cesium carbonate, potassium carbonate, and the like; in a suitably selected solvent such as 1 ,4-dioxane, THF, and the like; at elevated temperature, for example at about 100 °C; to yield tert-butyl 4-(5- bromo-2-(4-(methoxycarbonyl)phenyl)-2H-1 ,2,3-triazole-4-carboxamido)piperidine-1 - carboxylate.

[0178] The tert-butyl 4-(5-bromo-2-(4-(methoxycarbonyl)phenyl)-2H-1 ,2,3-triazole-4- carboxamido)piperidine-1 -carboxylate 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 agent such as potassium propynyl-trifluoroborate, and the like; in the presence of a suitably selected base such as TEA, DIPEA, and the like; in a suitably selected solvent such as 1 ,4-dioxane, THF, and the like; to yield the corresponding compound of formula (XXXI).

[0179] The compound of formula (XXXI) is reacted with a suitably selected agent such as methylmagnesium bromide, methyl lithium, and the like; in a suitably selected solvent such as diethyl ether, THF, and the like; at a temperature below room temperature, for example at about 0 °C; to yield the corresponding compound of formula (XXXII).

[0180] The compound of formula (XXXII) is reacted with a suitably selected agent such as NaOt-Bu, DBU, and the like; in a suitably selected solvent such as DMF, and the like; at an elevated temperature, for example at about 100 °C; to yield the corresponding compound of formula (XXXIII). The compound of formula (XXXIII) is reacted with a suitably selected brominating agent such as N-bromosuccinimide, bromine, and the like; in a suitably selected solvent or mixture of solvents such as 1 ,1 ,1 ,3,3,3-hexafluoroisopropanol, DCM / acetic acid, and the like; to yield the corresponding compound of formula (XXXIV).

[0181] The compound of formula (XXXIV) is reacted with 1 -(tert-butyldimethylsilyloxy)- 1 -methoxyethene, a known compound; in the presence of a suitably selected catalyst such as XPhos Pd G4, Xphos Pd G3 and the like; in the presence of a suitably selected ligand such as Xphos, and the like; in a suitably selected solvent such as THF,1 ,4-dioxane, and the like; at an elevated temperature, for example at about 100°C; to yield the corresponding compound of formula (XXXV).

[0182] The compound of formula (XXXV) is reacted with 2-chloro-4- (trifluoromethyl)aniline, a known compound; in the presence of a suitably selected base such as lithium bis(trimethylsilyl)amide (LiHMDS), lithium diisopropyl amide, and the like; in a suitably selected solvent such as THF, diethyl ether, 1 ,4-dioxane and the like; at a reduced temperature, for example at about 0 °C; to yield the corresponding compound of formula (XXXVI).

[0183] The compound of formula (XXXVI) is de-protected according to known methods; for example, wherein the nitrogen protecting group is BOC, by reacting with a suitably selected acid such as HCI, and the like; in a suitably selected solvent such as DCM, and the like); to yield the corresponding compound of formula (XXXVII).

[0184] The compound of formula (XXXVII) is reacted with a suitably substituted compound of formula (XVII), a known compound or compound prepared by known methods; in the presence of a suitably selected activating agent such as EDCI, HATU, and the like; in the presence of a suitably selected coupling agent such as HOPO, HOBt, and the like; in the presence of a suitably selected base such as TEA, DIPEA, and the like; in a suitably selected solvent such as anhydrous 1 ,4-dioxane, DCM, and the like; to yield the corresponding compound of formula (ll-P). Compounds of formula (II) wherein wherein R2is methyl may be similarly prepared as described in Scheme 5 above, by substituting tert-butyl 4-(5-bromo-2-(4-(methoxycarbonyl)phenyl)-2H-1 ,2,3-triazole-4- carboxamido)-2-methylpiperazine-1 -carboxylate for tert-butyl 4-(5-bromo-2-(4- (methoxycarbonyl)phenyl)-2H-1 , 2, 3-triazole-4-carboxamido)-piperidine-1 -carboxylate, and reacting as described therein. tert-Butyl (R)-4-(5-bromo-2-(4- (methoxycarbonyl)phenyl)-2H-1 ,2,3-triazole-4-carboxamido)-2-methylpiperazine-1 - carboxylate may be prepared as described in Scheme 6, below.

[0185] Scheme 6

[0186] Accordingly, 4-bromo-1 H-1 ,2,3-triazole-5-carboxylate lithium, a known compound or compound prepared as described herein, is reacted with tert-butyl 4- amino-2-methylpiperazine-1 -carboxylate, a known compound or compound prepared for example as described in the Examples which follow hereinafter, in the presence of a suitably selected coupling agent such as a mixture of HOPO, HATU, and the like; in the presence of a suitably selected activating agent such as EDCI, DCC, and the like; in a suitably selected solvent such as DMF, DMSO, and the like; at an elevated temperature, for example at about 55°C; to yield tert-butyl 4-(4-bromo-1 H-1 ,2,3- triazole-5-carboxamido)-2-methylpiperazine-1 -carboxylate.

[0187] The tert-butyl 4-(4-bromo-1 H-1 ,2,3-triazole-5-carboxamido)-2- methylpiperazine-1 -carboxylate is reacted with (4-(methoxycarbonyl)phenyl)(2,4,6- trimethoxyphenyl)iodonium 2,2,2-trifluoroacetate, a known compound or compound prepared for example as described in the Examples which follow hereinafter, in the presence of a suitably selected base such as DIEA, sodium carbonate, potassium carbonate, cesium carbonate, and the like; in a suitably selected solvent such as 1 ,4- dioxane, THF, and the like; at elevated temperature, for example at about 105 °C; to yield tert-butyl 4-(5-bromo-2-(4-(methoxycarbonyl)phenyl)-2H-1 ,2,3-triazole-4- carboxamido)-2-methylpiperazine-1 -carboxylate.

[0188] The tert-butyl 4-(5-bromo-2-(4-(methoxycarbonyl)phenyl)-2H-1 ,2,3-triazole-4- carboxamido)-2-methylpiperazine-1 -carboxylate is then substituted for tert-butyl 4-(5- bromo-2-(4-(methoxycarbonyl)phenyl)-2H-1 ,2,3-triazole-4-carboxamido)piperidine-1 - carboxylate in Scheme 5 above, and reacted as described therein; to yield the corresponding compound of formula (ll-M).

[0189] One skilled in the art will recognize that the tert-butyl 4-amino-2- methylpiperazine-1 -carboxylate may be reacted as a racemate or as an enantiomerically enriched compound. If an enantiomerically enriched tert-butyl 4- amino-2-methylpiperazine-1 -carboxylate is used (e.g. tert-butyl 4-amino-2R- methylpiperazine-1 -carboxylate or tert-butyl 4-amino-2S-methylpiperazine-1 - carboxylate), the stereo-orientation at piperazine carbon atom bound to the methyl will be maintained throughout subsequent reaction steps, to yield the corresponding enantiomerically enriched compound of formula (ll-M). Compounds of formula (ll-M) wherein wherein R2is ethyl, may be similarly prepared, by reacting tert-butyl 4-(5-bromo-2-(4- (methoxycarbonyl)phenyl)-2H-1 ,2,3-triazole-4-carboxamido)-2-methylpiperazine-1 - carboxylate, a compound of the following structure: with for example, 2-(but-1 -yn-1 -yl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane, a known compound or compound prepared by known methods; in the presence of a suitably selected coupling agent such as Pd(dppf)Cl2, Pd(PPh3)2Cl2 and the like; in the presence of a suitably selected base such as CS2CO3, Na2CO3, K3PO4, and the like; in the presence of a suitably selected fluoride additive such as CsF, TBAF, and the like; in a suitably selected solvent or mixture of solvents such as DMF / water, DMSO / water, and the like; at an elevated temperature in the range of from about 80°C to about 150°C, for example at about 90°C or about 120°C; to yield tert-butyl 4-(5-(but- 1 -yn-1 -yl)-2-(4-(methoxycarbonyl)phenyl)-2H-1 ,2,3-triazole-4-carboxamido)-2- methylpiperazine-1 -carboxylate, a compound of the following structure:

[0190] The tert-butyl 4-(5-(but-1 -yn-1 -yl)-2-(4-(methoxycarbonyl)phenyl)-2H-1 ,2,3- triazole-4-carboxamido)-2-methylpiperazine-1 -carboxylate is then reacted to yield tertbutyl 4-(6-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-4-oxo-2,4-dihydro-5H- [1 ,2,3]triazolo[4,5-c]pyridin-5-yl)-2-methylpiperazine-1 -carboxylate, a compound of the following structure:

[0191] One skilled in the art will recognize that the tert-butyl 4-(5-(but-1 -yn-1 -yl)-2-(4- (methoxycarbonyl)phenyl)-2H-1 ,2,3-triazole-4-carboxamido)-2-methylpiperazine-1 - carboxylate may be substituted for the compound of formula (XXXI) in Scheme 5, and reacted as described therein, first with a suitably selected Grignard agent such as CHsMgBr, CHsLi, and the like (to effect conversion of the methyl ester substituent to the corresponding 2-hydroxy-n-propyl substituent); and then with a suitably selected agent such as NaOt-Bu, DBU, and the like (to effect ring closure); to yield tert-butyl 4- (6-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-4-oxo-2,4-dihydro-5H-[1 ,2,3]triazolo[4,5- c]pyridin-5-yl)-2-methylpiperazine-1 -carboxylate.

[0192] Alternatively, the tert-butyl 4-(5-(but-1 -yn-1 -yl)-2-(4-(methoxycarbonyl)phenyl)- 2H-1 ,2, 3-triazole-4-carboxamido)-2-methylpiperazine-1 -carboxylate may be first reacted with a suitably selected agent such as NaOt-Bu, DBU, and the like (as described in Scheme 5 above, to effect ring closure); and then with a suitably selected Grignard agent such as CHsMgBr, CHsLi, and the like (to effect conversion of the methyl ester substituent to the corresponding 2-hydroxy-n-propyl substituent); to yield tert-butyl 4-(6-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-4-oxo-2,4-dihydro-5H- [1 , 2, 3]triazolo[4,5-c]pyridin-5-yl)-2-methylpiperazine-1 -carboxylate.

[0193] The tert-butyl 4-(6-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-4-oxo-2,4-dihydro- 5H-[1 , 2, 3]triazolo[4,5-c]pyridin-5-yl)-2-methylpiperazine-1 -carboxylate is then substituted for the compound of formula (XXXIII) in Scheme 5 above, and reacted as described therein; to yield the desired compound of formula (I l-M) wherein R11is wherein R2is ethyl.

[0194] Compounds of formula (II) wherein R11is may be prepared as described in Scheme 7 , below.

[0195] Scheme 7 Accordingly, methyl 4-bromo-1 H-1 ,2,3-triazole-5-carboxylate, a known compound or compound prepared by known methods is reacted with a suitably selected source of hydroxide such as LiOH*H2O, KOH, and the like; in a suitably selected solvent or mixture of solvents such as a mixture of THF / methanol / water, 1 ,4- dioxane / water, and the like; at about room temperature; to yield 4-bromo-1 H-1 ,2,3- triazole-5-carboxylate lithium, which is preferably not isolated.

[0196] The 4-bromo-1 H-1 ,2,3-triazole-5-carboxylate lithium is reacted with a suitably protected amino-piperazine, for example, tert-butyl 4-aminopiperazine-1 -carboxylate, a known compound or compound prepared by known methods; in the presence of a suitably selected coupling agent such as a mixture of HOPO, HATU, and the like; in the presence of a suitably selected activating agent such as EDCI, DCC, and the like; in a suitably selected solvent such as DMF, DMSO, and the like; at an elevated temperature, for example at about 55°C; to yield tert-butyl 4-(4-bromo-1 H-1 ,2,3- triazole-5-carboxamido)piperazine-1 -carboxylate. One skilled in the art will recognize that the BOG group on the tert-butyl 4-aminopiperazine-1 -carboxylate acts as a nitrogen protecting group, and that alternate suitable nitrogen protecting groups may also be used.

[0197] The tert-butyl 4-(4-bromo-1 H-1 ,2,3-triazole-5-carboxamido)piperazine-1 - carboxylate is reacted with (4-(methoxycarbonyl)phenyl)(2,4,6- trimethoxyphenyl)iodonium 2,2,2-trifluoroacetate, a known compound or compound prepared for example as described in the Examples which follow hereinafter, in the presence of a suitably selected base such as sodium carbonate, potassium carbonate, cesium carbonate, and the like; in a suitably selected solvent such as 1 ,4- dioxane, THF, and the like; at elevated temperature, for example at about 105 °C; to yield tert-butyl 4-(5-bromo-2-(4-(methoxycarbonyl)phenyl)-2H-1 ,2,3-triazole-4- carboxamido)piperazine-1 -carboxylate.

[0198] The tert-butyl 4-(5-bromo-2-(4-(methoxycarbonyl)phenyl)-2H-1 ,2,3-triazole-4- carboxamido)piperazine-1 -carboxylate is reacted with a suitably selected reagent for introducing the R2group, such as for example tributyl(prop-1 -yn-1 -yl)stannane for introducing methyl as the R2group or for example 2-(but-1 -yn-1 -yl)-4,4,5,5- tetramethyl-1 ,3,2-dioxaborolane for introducing ethyl as the R2group; in the presence of a suitably selected coupling agent such as Pd(dppf)Cl2, Pd(PPh3)2Cl2 and the like; in the presence of a suitably selected base such as CS2CO3, Na2CO3, K3PO4 and the like; in the presence of a suitably selected fluoride source such as CsF, TBAF, and the like; in a suitably selected solvent or mixture of solvents such as DMF / water, DMSO / water, and the like; at an elevated temperature in the range of from about 80°C to about 150°C, for example at about 90°C or about 120°C; to yield the corresponding compound of formula (XXXIX).

[0199] The compound of formula (XXXIX) is reacted with a suitably selected organometallic agent such as CHsMgCI, CHsMgBr, , and the like; in a suitably selected solvent such as THF, 1 ,4-dioxane, and the like; at a reduced temperature, for example at about 0°C; to yield the corresponding compound of formula (XL).

[0200] The compound of formula (XL) is reacted with a suitably selected brominating agent such as N-bromosuccinimide, bromine, and the like; in a suitably selected solvent or mixture of solvents such as 1 ,1 ,1 ,3,3,3-hexafluoroisopropanol, DCM / acetic acid, and the like; to yield the corresponding compound of formula (XLI)

[0201] The compound of formula (XLI) is then reacted to yield the corresponding compound of formula (ll-Z). For example, the compound of formula (XL) may be substituted for the compound of formula (XXXIV) in Scheme 5, above, and reacted as described therein.

[0202] One skilled in the art will recognize that compounds of formula (II) wherein R11 may similarly be prepared as described in Scheme 7 above, by substituting tert-butyl 4-(5-bromo-2-(4-(methoxycarbonyl)phenyl)-2H-1 ,2,3-triazole-4- carboxamido)-2-methylpiperazine-1 -carboxylate for tert-butyl 4-(5-bromo-2-(4- (methoxycarbonyl)phenyl)-2H-1 , 2, 3-triazole-4-carboxamido)piperazine-1 -carboxylate, and reacting as described in Scheme 7. One skilled in the art will recognize that various substituent groups and / or 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.

[0203] Where the processes for the preparation of the compounds according to the 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 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 compounds may be resolved using a chiral HPLC column.

[0204] 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% 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 = ([oc-obs] / [oc-max]) X 100.

[0205] 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 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 (c / 2O or2H2O), "super-heavy water" or tritiated water (T2O or3H2O), where the hydrogen atoms are replaced with tritium (3H) isotopes, two heavy- oxygen water isotopologues (H218O and H217O) and isotopologues where the hydrogen and oxygen atoms may each independently be replaced by isotopes, for example the doubly labeled water isotopologue c / 218O.

[0206] 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 stereoisomers solely based on isotopic location. For example, CHsCHDCHsand CH3CH2CH2D are a pair of constitutional isotopomers of n-propane; whereas (F?)- CH3CHDOH and (S)-CH3CHDOH or (Z)-CH3CH=CHD and (E)-CH3CH=CHD are examples of isotopic stereoisomers of ethanol and n-propene, respectively.

[0207] In some embodiments of the present invention, any one or more element(s), in particular when mentioned in relation to a compound of formula (I) or compound of formula (II), 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) and compounds of formula (II) include isotopologues and isotopomers thereof. For example, a reference to 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) and compounds of formula (II) may comprise one or more radioactive isotope(s) selected from the group of3H,11C,18F,122l,123l,125l,1311,75Br,76Br,77Br and82Br. Preferably, the radioactive isotope is selected from the group of3H,11C and18F.

[0208] In some embodiments, the present invention is directed to compounds of formula (I) or compounds of formula (II) wherein one or more atoms (preferably, one or more hydrogen, carbon, oxygen, nitrogen or fluorine atom) are replaced with a radioactive or non-radioactive isotope.

[0209] Pharmaceutically Acceptable Salts

[0210] For use in medicine, the salts of the compounds of this invention refer to nontoxic “pharmaceutically acceptable salts.” Other salts may, however, be useful in the 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, 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, 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, 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, triethiodide and valerate.

[0211] 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- acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1 S)-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, oc-oxo-glutaric 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, 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.

[0212] Representative bases which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1 H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1 -(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

[0213] 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 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 combined administration of (a) a compound of formula (I) or compound of formula (II), or a pharmaceutically acceptable 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.

[0214] As used herein, the terms "co-administration" or "combined administration" and 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 therapeutic agent and includes both fixed and non-fixed combinations of the therapeutic agents.

[0215] The term "fixed dose composition" means that the therapeutic agents, e.g. (a) a compound of formula (I) or compound of formula (II) and (b) one or more additional therapeutic agents, are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed dose composition" means that the therapeutic agents, e.g. (a) a compound of formula (I) or compound of formula (II) 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 the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more therapeutic agents.

[0216] 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 being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.

[0217] 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 medicinal response. For example, the therapeutically effective amount of co-therapy comprising administration of (a) a compound of formula (I) or compound of formula (II) and (b) one or more (preferably one to two) therapeutic agents, would be the amount of (a) the compound of formula (I) or compound of formula (II) 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 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) or compound of formula (II) and / or the amount of (b) the one or more therapeutic agents individually may or may not, individually, be a therapeutically effective.

[0218] In some embodiments of the present invention, the combination therapy or co- therapy comprising (a) a compound of formula (I) or compound of formula (II) 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.

[0219] The terms “subject” and “patient” as used herein, refers to an animal, preferably a 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.

[0220] 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.

[0221] Methods of Treatment

[0222] 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 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%, 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.

[0223] 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 compound of formula (I) or compound of formula (II) 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.

[0224] The present invention is further directed to methods of treating disorders and / or diseases mediated by or modulated by inhibition of WRN comprising administration of a compound of formula (I) or compound of formula (II) 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 are not limited to, cancer, comprising administration of a compound of formula (I) or compound of formula (II), to a subject in need thereof.

[0225] 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 formula (I) or compound of formula (II) 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) or compound of formula (II) to a subject in need thereof.

[0226] In some embodiments, the present invention is directed to methods of treating 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, appendiceal, leukemia, lymphoma, and myeloma cancers.

[0227] 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, thymic, small bowel, bladder, skin, prostate, brain, neuroendocrine, soft tissue, appendiceal, leukemia, lymphoma, and myeloma cancers, comprising administration of a compound of formula (I) or compound of formula (II) to a subject in need thereof.

[0228] In some embodiments, the present invention is directed to methods of treating 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 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 of a compound of formula (I) or compound of formula (II) 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.

[0229] The present invention is further directed to the use of any of the compounds of formula (I) or compounds of formula (II) of the present invention, as described herein, in the preparation of a medicament or composition for the treatment of disorders and / or diseases mediated by or modulated by inhibition of WRN, either alone or in combination.

[0230] 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) or compound of formula (II) in combination with and (b) one or more additional 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) or compound of formula (II) of the present invention. In some embodiments of the present invention, the additional therapeutic agent is chemotherapy.

[0231] The present invention is further directed to a composition comprising (a) a compound of formula (I) or compound of formula (II) 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 therapeutically active or enhances the therapeutic activity when administered to a patient in combination with a compound of formula (I) or compound of formula (II) of the present invention. The compositions comprising (a) a compound of formula (I) or compound of formula (II) 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 composition.

[0232] 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®, 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 (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 (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®, 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®, 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 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 (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 and tipiracil hydrochloride (Lonsurf®).

[0233] 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®), 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®), 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®).

[0234] In some embodiments, the additional therapeutic agent(s) is a targeted 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 (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 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 (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 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 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®), 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®), 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 (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®), 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 (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 (Caprelsa®, Zactima®), vemurafenib (Zelboraf®), venetoclax (Venclyxto®), vismodegib (Erivedge®), vorinostat (Zolinza®), and zanubrutinib (Brukinsa®).

[0235] 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 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®).

[0236] 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), gotistobart (OncoC4), ipilimumab (Yervoy®), tremelimumab-actl (Imjuno®), and volrustomig (AstraZeneca).

[0237] 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 (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 (Incyte), balstilimab (AGEN2035, Agenus), sintilimab (InnoVent), 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).

[0238] 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 (Xofigo®).

[0239] 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 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).

[0240] In the compositions and methods of treatment comprising administration of said compositions as described herein (wherein the composition comprises (a) a compound of formula (I) or compound of formula (II) and (b) one or more additional therapeutic agents), the one or more additional therapeutic agent is one or more anticancer 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, 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.

[0241] Pharmaceutical Compositions

[0242] The present invention further comprises pharmaceutical compositions containing one or more compounds of formula (I) or compounds of formula (II) 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 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, 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 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.

[0243] 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. 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 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 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, 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 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, the severity of the condition being treated and the compound being employed. The use of either daily administration or periodic dosing may be employed.

[0244] 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 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 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 present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation 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 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 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 including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

[0245] 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 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, polyvinylpyrrolidone or gelatin.

[0246] 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 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 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.

[0247] Advantageously, compounds of the present invention may be administered in a 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 administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

[0248] 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 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. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

[0249] 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. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.

[0250] To prepare a pharmaceutical composition of the present invention, a compound of formula (I) or compound of formula (II) 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 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

[0251] The Handbook of Pharmaceutical , published by the American

[0252] Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

[0253] Methods of formulating pharmaceutical compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Tablets, Second

[0254] Edition, Revised and , Volumes 1 -3, edited by Lieberman et al;

[0255] Pharmaceutical Forms Parenteral Medications Volumes -2, edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1 -2, edited by Lieberman et al; published by Marcel Dekker, Inc.

[0256] 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.

[0257] 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 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 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.

[0258] The present invention is further directed a compound of formula (I) or compound of formula (II) for use in treating a disease or disorder mediated by or modulated by inhibition of WRN, wherein the compound of formula (I) or compound of formula (II) 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) or compound of formula (II).

[0259] The present invention is further directed to the use of a compound of formula (I) or compound of formula (II) 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 patient has previously (e.g. within 24 hours) been treated with a compound of formula (I) or compound of formula (II).

[0260] In some embodiments, the present invention is directed to a composition or product comprising (a) a compound of formula (I) or compound of formula (II) as described herein and (b) one or more additional therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. Products provided as a combined preparation include a composition comprising (a) a compound of formula (I) or compound of formula (II) and the (b) one or more additional therapeutic agent(s) together in the same pharmaceutical composition, or (a) a compound of formula (I) or compound of formula (II) and the (b) one or more additional the present invention and the other therapeutic agent(s) in separate form, e.g. in the form of a kit.

[0261] In some embodiments, the composition or product comprising (a) a compound of formula (I) or compound of formula (II), 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 desired dose prior to administration.

[0262] 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) or compound of formula (II) of the present invention. In some embodiments, the kit comprises means for separately retaining said compositions, such as a container, 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.

[0263] 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 compliance, the kit of the invention typically comprises directions for administration.

[0264] In the compositions and products of the present invention, the (a) compound of formula (I) or compound of formula (II), 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 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. Synthesis Examples

[0265] 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.

[0266] In the Examples which follow, some synthesis products are listed as having 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.

[0267] Example 1 . 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- methyl-7-oxo-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0268] Step A. 4-Methoxy-N-(4-methoxybenzyl)-6-methyl-3-nitropyridin-2-amine

[0269] A solution of 2-chloro-4-methoxy-6-methyl-3-nitropyridine (3.4 g, 16.8 mmol), 4- methoxybenzyl amine (2.6 ml, 20.1 mmol) and TEA (2.3 ml, 16.8 mmol) in 1 ,4- dioxane (56 mL) was heated to 80 °C overnight. The resulting mixture was concentrated and the residue taken up in EtOAc (75 mL), then washed with sat NaHCOs (2 x 75 mL). The mixture was concentrated and purified by flash column chromatography on a 25-g Biotage silica gel column eluting with 10-40% gradient of EtOAc / heptane to yield the title compound as a yellow solid. MS (ESI): mass calculated for C15H17N3O4, 303.1 ; m / z measured, 304.1 [M+H]+.

[0270] Step B. 4-Methoxy-N2-(4-methoxybenzyl)-6-methylpyridine-2,3-diamine A mixture of 4-methoxy-N-(4-methoxybenzyl)-6-methyl-3-nitropyridin-2-amine (1 .68 g, 5.5 mmol) and ammonium chloride (2.9 g 55 mmol) in a 2:1 vokvol mixture of ethanol / water (37 mL) was heated to 80 °C. Iron powder (1 .54 g, 27.6 mmol) was added and heating continued for 30 mins. The resulting mixture was filtered through CELITE, then concentrated. To the resulting reside was added EtOAc (50 mL) and the mixture was washed with sat. NaHCOs (2 x 50 mL) and brine (50 mL). The mixture was concentrated to yield the title compound as a brown oil, which was used in the next step without further purification. MS (ESI): mass calculated for C15H19N3O2, 273.1 ; m / z measured, 274.1 [M+H]+.

[0271] Step C. 7-Methoxy-3-(4-methoxybenzyl)-5-methyl-3H-[1 ,2,3]triazolo[4,5- b]pyridine

[0272] To a solution of 4-methoxy-N2-(4-methoxybenzyl)-6-methylpyridine-2,3-diamine (1 .5 g, 5.5 mmol) in AcOH (18 mL) was added a solution of sodium nitrite (0.42 g, 6.0 mmol) in a minimum of water. The mixture was stirred at 25 °C for 30 mins and then concentrated. Water (20 mL) was added and a precipitate was observed to form, which was collected by filtration to yield the title compound as a tan solid. MS (ESI): mass calculated for C15H16N4O2, 284.1 ; m / z measured, 285.1 [M+H]+.

[0273] Step D. 7-Methoxy-5-methyl-3H-[1 ,2,3]triazolo[4,5-b]pyridine

[0274] A solution of 7-methoxy-3-(4-methoxybenzyl)-5-methyl-3H-[1 ,2,3]triazolo[4,5- b]pyridine (0.90 g, 3.16 mmol) in TFA (15 mL) was heated to 79 °C for 8 hrs. The mixture was concentrated and then a sat. NaHCOs solution was added to yield a precipitate. The precipitate was collected by filtration and washed with diethyl ether to yield the title compound as a brown solid. MS (ESI): mass calculated for C7H8N4O, 164.1 ; m / z measured, 165.1 [M+H]+.

[0275] Step E. Methyl 4-(7-methoxy-5-methyl-2H-[1 ,2,3]triazolo[4, 5-b]pyridin-2- yl)benzoate

[0276] To a mixture of 7-methoxy-5-methyl-3H-[1 ,2,3]triazolo[4,5-b]pyridine (0.17 g, 1.02 mmol) and cesium carbonate (0.66 g, 2.03 mmol) in 1 ,4-dioxane (10 mL) at 100 °C was added (4-(methoxycarbonyl)phenyl)(2,4,6-trimethoxyphenyl)iodonium tosylate (0.73 g, 1.22 mmol, J. Org. Chem. 2016, 81 , 1998-2009) and mixture was heated for 1 hour. The mixture was cooled to room temperature, then filtered and washed with EtOAc. The filtrate was concentrated and the resulting residue was triturated with diethyl ether to yield the title compound as a tan solid. MS (ESI): mass calculated for C15H14N3O3, 298.1 ; m / z measured, 299.1 [M+H]+.

[0277] Step F. 2-(4-(7-Methoxy-5-methyl-2H-[1 ,2,3]triazolo[4,5-b]pyridi n-2- yl)phenyl)propan-2-ol

[0278] To a solution of the methyl 4-(7-methoxy-5-methyl-2H-[1 ,2,3]triazolo[4,5- b]pyridin-2-yl)benzoate (0.26 g, 0.87 mmol) in THF (8.7 mL) cooled in ice bath was added methyl magnesium bromide (3M diethyl ether solution 1.16 mL, 3.48 mmol) and the reaction mixture was stirred for 1 hr at 0 °C. The reaction was quenched with sat. NH4CI solution, then extracted with EtOAc. The organic layer was concentrated and the residue purified on silica gel with 20-100% EtOAc / heptane to yield the title compound as a white solid. MS (ESI): mass calculated for C16H18N4O2, 298.1 ; m / z measured, 299.1 [M+H]+.

[0279] Step G. N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(2-hydroxypropan-2- yl)phenyl)-5-methyl-7-oxo-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0280] A mixture of 2-(4-(7-methoxy-5-methyl-2H-[1 ,2,3]triazolo[4,5-b]pyridin-2- yl)phenyl)propan-2-ol (0.26 g, 0.88 mmol), KI (0.15 g, 0.88 mmol), and 2-chloro-1 -(2- chloro-4-(trifluoromethyl)phenyl)ethan-1 -one (0.36 g, 1.30 mmol) in toluene (4.4 mL) was heated to 120 °C for 12 hrs. The mixture was concentrated and purified on silica gel eluting with 0-20% EtOH / EtOAc to yield the title compound as a white solid. MS (ESI): mass calculated for C24H21CIF3N5O3, 519.1 ; m / z measured, 520.2 [M+H]+.

[0281] Step H. 2-(6-Bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)-5-methyl-7-oxo-2,7- dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide

[0282] To a solution of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(2- hydroxypropan-2-yl)phenyl)-5-methyl-7-oxo-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5- b]pyridin-4-yl)acetamide (0.13 g, 0.25 mmol) in HFIP (1.25 mL) was added NBS (0.44 g, 0.25 mmol) and the mixture stirred for 1 hr at room temperature. The mixture was concentrated, the resulting residue was dissolved in DCM and then washed with sat. NaHCOs. The organic layer was concentrated and purified by flash column chromatography eluting with 20-100% EtOAc / heptanes to yield the title compound as a tan solid. MS (ESI): mass calculated for C24H2oBrCIF3N503, 597.0 / 599.0; m / z measured, 598.0 / 600.0 [M+H]+.

[0283] Step I. N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(2-hydroxypropan-2- yl)phenyl)-5-methyl-7-oxo-6-(piperazin-1 -yl)-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5- b]84yridine-4-yl)acetamide

[0284] A mixture of 2-(6-bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)-5-methyl-7-oxo- 2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]84yridine-4-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide (0.078 g, 0.13 mmol) and piperazine (0.056 g, 0.65 mmol) in NMP (0.52 mL) was heated to 150 °C in a Biotage microwave reactor for 2 hrs. The mixture was cooled to room temperature, and then water (10 mL) was added, resulting in a precipitate, which was collected by filtration to yield the title compound as a brown solid, which was used in the next step without further purification. MS (ESI): mass calculated for C28H29CIF3N5O3, 603.2; m / z measured, 604.2 [M+H]+.

[0285] Step J. 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- methyl-7-oxo-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]84yridine-4-yl)acetamide

[0286] 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)-2,7-dihydro-4H- [1 ,2,3]triazolo[4,5-b]84yridine-4-yl)acetamide (0.066 mg, 0.11 mmol), 2- hydroxypyridine N-oxide (0.0061 g, 0.055 mmol), and 5-hydroxy-6-methylpyrimidine- 4-carboxylic acid (0.021 g, 0.13 mmol) in DCM (1.1 mL) was added EDCI (0.023 g, 0.13 mmol) and the resulting mixture stirred at room temperature for 4 hrs. DCM was evaporated and the resulting residue was purified by RP-HPLC, on a Phenomenex Gemini 5uM C-18 110A 150 x 30 mm column eluting with a linear gradient of 50- 100% 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) 5 ppm 9.74 - 10.73 (m, 2 H), 8.53 (s, 1 H), 8.06 (s, 3 H), 7.97 (d, J=1.47 Hz, 1 H), 7.71 (d, J=8.80 Hz, 3 H), 5.38 (s, 2 H), 5.21 (s, 1 H), 4.49 (br d, J= 13.69 Hz, 1 H), 3.60 - 3.77 (m, 2 H), 3.44 - 3.55 (m, 1 H), 3.16 - 3.28 (m, 1 H), 2.92 - 3.05 (m, 1 H), 2.72 - 2.80 (m, 1 H), 2.64 (s, 3 H), 2.59 (br d, J=11 .25 Hz, 1 H), 2.43 (s, 3 H), 1 .47 (s, 6 H). MS (ESI): mass calculated for C34H33CIF3N9O5, 739.2; m / z measured, 740.2 [M+H]+.

[0287] Example 2. 2-(6-(4-acetylpiperazin-1 -yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-5-methyl-

[0288] 7-oxo-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridine-4-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide

[0289] A mixture of 2-(6-bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)-5-methyl-7-oxo- 2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]85yridine-4-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide (0.020 g, 0.033 mmol, prepared as in Example 1 , Step H) and 1 -(piperazin-1 -yl)ethan-1 -one (0.021 g, 0.167 mmol) in NMP (0.33 mL) was heated to 137 °C for 12 hrs. The reaction mixture was directly purified by RP- HPLC, on a Phenomenex Gemini 5uM C-18 1 10A 150 x 30 mm column eluting with a linear gradient of 40-100% 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.

[0290] 1H NMR (400 MHz, DMSO-d6) 5 ppm 10.42 (s, 1 H), 8.04 - 8.11 (m, 3 H), 7.98 (d, J=1 .47 Hz, 1 H), 7.71 (d, J=8.80 Hz, 3 H), 5.38 (s, 2 H), 5.21 (s, 1 H), 4.37 (br d, <7=12.23 Hz, 1 H), 3.78 - 3.85 (m, 1 H), 3.61 - 3.71 (m, 1 H), 3.46 - 3.55 (m, 1 H), 3.15 - 3.27 (m, 1 H), 2.63 (m, 6 H), 2.05 (s, 3 H), 1.47 (s, 6 H). MS (ESI): mass calculated for C30H31CIF3N7O4, 645.2; m / z measured, 646.2 [M+H]+.

[0291] Example 3. 2-(6-(4-Acetylpiperazin-1 -yl)-5-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-7- oxo-2, 7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridine-4-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide

[0292] Step A. 2-(4-(5-Ethyl-7-methoxy-2H-[1 ,2,3]triazolo[4,5-b]86yridine-2- yl)phenyl)propan-2-ol

[0293] To a solution of 2-(4-(7-methoxy-5-methyl-2H-[1 ,2,3]triazolo[4,5-b]86yridine-2- yl)phenyl)propan-2-ol (1.15 g, 3.85 mmol, prepared as in Example 1 , Step F) in THF (1 1 mL) at -20 °C was added LDA (9.64 mL, 1 M THF solution) and the reaction allowed to stir for 30 mins at -20 °C. To the resulting mixture was then added iodomethane (0.72 mL, 11 .56 mmol) and the mixture stirred for 5 mins at -20 °C. The reaction was quenched with water, and the mixture extracted with EtOAc, and the organic layer washed with brine. The organic layer was concentrated and purified by silica flash chromatography to yield the title compound. MS (ESI): mass calculated for C17H20N4O2, 312.2; m / z measured, 313.2 [M+H]+.

[0294] Step B. 5-Ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-2,4-dihydro-7H- [1 ,2,3]triazolo[4,5-b]86yridine-7-one

[0295] A mixture of 2-(4-(5-ethyl-7-methoxy-2H-[1 ,2,3]triazolo[4,5-b]86yridine-2- yl)phenyl)propan-2-ol (0.097 g, 0.31 mmol) and sodium methoxide (0.084 g, 1.56 mmol) in methanol (2 mL) was heated at 80 °C for 2 days. The mixture was poured into water and extracted with DCM to yield the title compound, which was used in the next step without further purification. MS (ESI): mass calculated for C16H18N4O2, 298.1 ; m / z measured, 299.1 [M+H]+.

[0296] Step C. N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-(2- hydroxypropan-2-yl)phenyl)-7-oxo-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]87yridine-4- yl)acetamide

[0297] A mixture of 5-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-2,4-dihydro-7H- [1 ,2,3]triazolo[4,5-b]87yridine-7-one (0.045 g, 0.15 mmol), 1 -(2-chloro-4- (trifluoromethyl)phenyl)-2-iodoethan-1 -one (0.082 g, 0.23 mmol), and DIEA (0.078 mL, 0.45 mmol) in DMF (0.75 mL) was heated at 60 °C overnight. The resulting mixture was diluted with EtOAc, then washed with NaHCOs, concentrated and purified by flash column chromatography (SiC , 0-20% EtOH / EtOAc) to yield the title compound as a tan solid. MS (ESI): mass calculated for C25H23CIF3N5O3, 533.1 ; m / z measured, 534.1 [M+H]+.

[0298] Step D. 2-(6-Bromo-5-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-7-oxo-2,7- dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide

[0299] To a solution of N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-(2- hydroxypropan-2-yl)phenyl)-7-oxo-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4- yl)acetamide (0.023 g, 0.043 mmol) in HFIP (0.43 mL) was added NBS (0.011 g, 0.060 mmol) and the mixture stirred at 25 °C for 30 mins. The mixture was then concentrated, diluted with DCM and washed with sat. NaHCOs. The organic layer was concentrated and purified by silica flash chromatography to yield the title compound as a white solid. MS (ESI): mass calculated for C25H22BrCIF3N5O3, 611 .1 ; m / z measured, 3612.0 [M+H]+.

[0300] Step E. 2-(6-(4-Acetylpiperazin-1 -yl)-5-ethyl-2-(4-(2-hydroxypropan-2- yl)phenyl)-7-oxo-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide

[0301] A mixture of 2-(6-bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)-5-methyl-7-oxo- 2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide (0.015 g, 0.024 mmol) and 1 -(piperazin-1 -yl)ethan- 1 -one (0.015 g, 0.122 mmol) in NMP (0.25 mL) was heated to 190 °C for 6 hrs in a Biotage microwave reactor. The reaction mixture was then directly purified by RP- HPLC, on a Phenomenex Gemini 5uM C-18 1 10A 150 x 30 mm column eluting with a linear gradient of 50-100% 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.

[0302] 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 8.52 (d, J=8.80 Hz, 1 H), 8.31 (s, 1 H), 8.18 (d, J=8.31 Hz, 2 H), 7.57 - 7.71 (m, 3 H), 7.54 (br d, J=10.27 Hz, 1 H), 5.16 (s, 2 H), 4.63 (br d, J=12.23 Hz, 1 H), 3.89 - 4.02 (m, 1 H), 3.80 (br d, J=11 .74 Hz, 2 H), 3.24 - 3.37 (m, 1 H), 3.06 - 3.19 (m, 2 H), 2.65 - 2.85 (m, 3 H), 2.15 (s, 3 H), 1 .62 (s, 6 H), 1 .31 (t, J=7.34 Hz, 3 H). MS (ESI): mass calculated for C31 H33CIF3N7O4, 659.2; m / z measured, 660.2 [M+H]+.

[0303] Example 4. N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(2-hydroxypropan-2- yl)phenyl)-6-isopropyl-5-methyl-7-oxo-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4- yl)acetamide

[0304] Step A. / V-benzyl-4-methoxy-6-methyl-3-nitropyridin-2-amine

[0305] To a solution of 2-chloro-4-methoxy-6-methyl-3-nitropyridine (500 mg, 2.5 mmol) in 1 ,4-dioxane (5 mL) were added BnNH2 (264.5 mg, 2.5 mmol), Pd(OAc)2 (55.5 mg, 0.25 mmol), BINAP (153.6 mg, 0.25 mmol), and KF (430 mg, 7.4 mmol). The mixture was then stirred at 50 °C for 18 hours. To the reaction mixture was added water (10 mL), and the aqueous layer was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo to yield a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0 - 6% ethyl acetate in petroleum ether) to yield title compound (323 mg, 41% yield) as yellow solid. MS (ESI): mass calculated for C14H15N3O3, 273.3; m / z measured 274.1 [M+H]+.

[0306] Step B. / \ / 2-benzyl-4-methoxy-6-methylpyridine-2,3-diamine

[0307] To a solution of N-benzyl-4-methoxy-6-methyl-3-nitropyridin-2-amine (323 mg, 1 .2 mmol) in EtOH (4 mL) and H2O (0.8 mL) was added NFUCI (632 mg, 11 .8 mmol) and Fe (660 mg, 11 .8 mmol). The mixture was then stirred at 75 °C for 0.5 hour. The reaction mixture was extracted with ethyl acetate (3 x 5 mL), and the organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to yield the title compound (257 mg, 80% yield) as yellow oil. MS (ESI): mass calculated for C14H17N3O, 243.3; m / z measured 244.1 [M+H]+.

[0308] Step C. 3-benzyl-7-methoxy-5-methyl-3 / - / -[1 ,2,3]triazolo[4,5-£>] pyridi ne

[0309] To a solution of N2-benzyl-4-methoxy-6-methylpyridine-2,3-diamine (257 mg, 1 .1 mmol) in THF (3 mL) and H2O (3 mL) was added NaNC (109.3 mg, 1 .6 mmol) and aq. HCI (2 M, 1 .6 mL, 3.2 mmol). The mixture was then stirred at 25 °C for 4 hours. The reaction mixture was extracted with ethyl acetate (3 x 10 mL), and the organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to yield the title compound as a yellow solid (268 mg, 94% yield). MS (ESI): mass calculated for C14H14N4O, 254.3; m / z measured 254.8 [M+H]+.

[0310] Step D. 3-benzyl-6-bromo-7-methoxy-5-methyl-3 / - / -[1 ,2,3]triazolo[4,5-b]pyridine To a solution of 3-benzyl-7-methoxy-5-methyl-3H-[1 ,2,3]triazolo[4,5-b]pyridine (268 mg, 1.1 mmol) in MeCN (3 mL) were added AcOH (189.9 mg, 3.2 mmol), and NBS (281 .3 mg, 1 .6 mmol). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was added H2O (5 mL), then extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, concentrated in vacuo to yield a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0 - 6% ethyl acetate in petroleum ether) to yield the title compound (312 mg, 86% yield) as a white solid. MS (ESI): mass calculated for CuHisBrlXLO, 333.2; m / z measured 334.6 [M+H]+.

[0311] Step E. 3-benzyl-7-methoxy-5-methyl-6-(prop-1 -en-2-yl)-3H-[1 , 2, 3]triazolo[4, 5- £>]pyridine

[0312] To a solution of 3-benzyl-6-bromo-7-methoxy-5-methyl-3H-[1 ,2,3]triazolo[4,5- b]pyridine (312 mg, 936.1 gmol) in 1 ,4-dioxane (3 mL) and H2O (0.6 mL) were added 4,4,5,5-tetramethyl-2-(prop-1 -en-2-yl)-1 ,3,2-dioxaborolane (236 mg, 1.4 mmol), CS2CO3 (915.3 mg, 2.8 mmol), and Pd(dppf)Cl2 (68.5 mg, 93.6 pmol). The mixture was degassed with N2 three times. The mixture was then stirred at 100 °C for 2 hours. To the reaction mixture was added water (5 mL), and the aqueous layer was extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, concentrated in vacuo to yield a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0 - 4% ethyl acetate in petroleum ether) to yield the title compound (200 mg, 70% yield) as colorless oil. MS (ESI): mass calculated for C17H18N4O, 294.3; m / z measured 295.1 [M+H]+.

[0313] Step F. 6-isopropyl-7-methoxy-5-methyl-3 / - / -[1 ,2,3]triazolo[4,5-b]pyridine

[0314] To a solution of 3-benzyl-6-isopropyl-7-methoxy-5-methyl-3H- [1 ,2,3]triazolo[4,5-b]pyridine (1.1 g, 3.7 mmol) in MeOH (20 mL) was added Pd / C (219 mg, 186 pmol). The mixture was degassed with N2 three times and degassed with H2 (50 Psi) three times. The mixture was then stirred at 70 °C for 48 hours. The mixture was concentrated in vacuo to yield a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0 - 42% ethyl acetate in petroleum ether) to yield the title compound (367 mg, 47% yield) as white solid. MS (ESI): mass calculated for C10H14N4O, 206.2; m / z measured 207.1 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 64.66 - 4.53 (m, 3H), 3.33 - 3.20 (m, 1 H), 2.57 (s, 3H), 1 .34 - 1 .24 (m, 6H) ppm.

[0315] Step G. 2-(4-(6-isopropyl-7-methoxy-5-methyl-3H-[1 ,2,3]triazolo[4,5-b]pyridin- 2-yl)phenyl)propan-2-ol

[0316] The title compound was prepared according to the procedure in Example 1 , Step E substituting 6-isopropyl-7-methoxy-5-methyl-3H-[1 ,2,3]triazolo[4,5-b]pyridine for 7-methoxy-5-methyl-3H-[1 ,2,3]triazolo[4,5-b]pyridine and substituting (4-(2- hydroxypropan-2-yl)phenyl)(2,4,6-trimethoxyphenyl)iodonium trifluoroacetate for (4- (methoxycarbonyl)phenyl)(2,4,6-trimethoxyphenyl)iodonium tosylate. MS (ESI): mass calculated for C19H24N4O2, 340.1 ; m / z measured, 341 .1 [M+H]+.

[0317] Step H. N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(2-hydroxypropan-2- yl)phenyl)-6-isopropyl-5-methyl-7-oxo-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4- yl)acetamide

[0318] The title compound was prepared according to the procedure as described in Example 1 , Step G substituting 2-(4-(6-isopropyl-7-methoxy-5-methyl-3H-

[0319] [1 .2.3]triazolo[4,5-b]pyridin-2-yl)phenyl)propan-2-ol for 2-(4-(7-methoxy-5-methyl-2H-

[0320] [1 .2.3]triazolo[4,5-b]pyridin-2-yl)phenyl)propan-2-ol.

[0321] 1H NMR (400 MHz, DMSO-d6) 5 ppm 10.25 - 10.57 (m, 1 H), 8.04 - 8.12 (m, 3 H), 7.97 (d, J=1.47 Hz, 1 H), 7.71 (d, J=8.80 Hz, 3 H), 5.38 (s, 2 H), 5.21 (s, 1 H), 3.37 - 3.46 (m, 1 H), 2.46 (s, 3 H), 1.47 (s, 6 H), 1.33 (d, J=7.34 Hz, 6 H). MS (ESI): mass calculated for C27H27CIF3N5O3, 561.2; m / z measured, 562.2 [M+H]+.

[0322] Example 5. 2-(5-(1 -acetylpiperidin-4-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl- 4-oxo-4,5-dihydro-2H-[1 ,2,3]triazolo[4,5-c]pyridin-7-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide

[0323] Step A. Methyl 4-bromo-1 -(4-methoxybenzyl)-1 H-1 ,2,3-triazole-5-carboxylate.

[0324] A solution of methyl 3-bromopropiolate (10.0g, 61 .4 mmol), 1 -(azidomethyl)-4- methoxybenzene (13.6 g, 83.6 mmol), and cuprous iodide (1 .06 g, 5.58 mmol) in THF (197 mL) was refluxed for 22 hours, then cooled to room temperature. The solvent was evaporated, and the residue was washed with methyl tert-butyl ether to yield the title compound (17.2 g, 52.6 mmol, 86% yield), which was used in the next step without further purification. MS (ESI): mass calculated for C^H^BrNaOaNa, 348.0.0; m / z measured 348.0 [M+Na]+.

[0325] Step B. 4-bromo-1 -(4-methoxybenzyl)-1 H-1 ,2,3-triazole-5-carboxylic acid.

[0326] To a solution of methyl 4-bromo-1 -(4-methoxybenzyl)-1 H-1 ,2,3-triazole-5- carboxylate (10.0 g, 30.7 mmol) in THF / water (1 :1 , 100 mL) was added NaOH (15.3 mL of 3 M solution, 46.0 mmol). The reaction was stirred at room temperature for 30 min. The reaction mixture was then poured into a separatory funnel and extracted twice with DCM / iPrOH (300 mL, 3:1 ) and 2 M HCI (300 mL). The organic layers were combined, dried over sodium sulfate and concentrated to yield the title compound (9.57 g, 28.7 mmol, 94% yield), which was used in the next step without further purification. (ESI): mass calculated for CnHioBrNsOsNa, 334.0; m / z measured, 334.0 [M+Na]+.

[0327] Step C. N-(1 -acetylpiperidin-4-yl)-4-bromo-1 -(4-methoxybenzyl)-1 H-1 ,2,3- triazole-5-carboxamide.

[0328] To a solution of 4-bromo-1 -(4-methoxybenzyl)-1 H-1 ,2,3-triazole-5-carboxylic acid (6.01 g, 19.3 mmol) and DMF (74.6 pL, 0.963 mmol) in DCM (96 mL) was added oxalyl chloride (4.08 mL, 48.2 mmol) dropwise at room temperature and stirred for 1 hour. The reaction was placed in an ice bath. A solution of 1 -(4-aminopiperidin-1 - yl)ethan-1 -one (11 .0 g, 77.1 mmol) and triethylamine (10.7 mL, 77.1 mmol) in acetonitrile (30 mL) was prepared and added dropwise to the reaction mixture in the ice bath. After addition, the reaction mixture was removed from the ice batch and stirred for 5 min. The reaction was quenched with water, the resulting mixture was transferred to a separatory funnel and extracted with DCM. The organic layers were collected, dried over sodium sulfate, and concentrated to yield the title compound (8.42 g, 19.3 mmol, 100% yield), which was used in the next step without further purification. MS (ESI): mass calculated for Ci8H22BrNsO3Na, 458.1 ; m / z measured, 458.0 [M+Na]+.

[0329] Step D. N-(1 -acetylpiperidin-4-yl)-4-bromo-1 H-1 ,2,3-triazole-5-carboxamide.

[0330] A solution of N-(1 -acetylpiperidin-4-yl)-4-bromo-1 -(4-methoxybenzyl)-1 H-1 ,2,3- triazole-5-carboxamide in TFA was heated at 70 °C overnight. The reaction mixture was concentrated and the residue was washed with diethyl ether to yield the title compound (3.25 g, 7.56 mmol, 40% yield), which was used in the next step without further purification. MS (ESI): mass calculated for CioHisBrNsC , 316.0; m / z measured, 316.0 [M+H]+.

[0331] Step E. Methyl 4-(4-((1 -acetylpiperidin-4-yl)carbamoyl)-5-bromo-2H-1 ,2,3- triazol-2-yl)benzoate.

[0332] To a solution of N-(1 -acetylpiperidin-4-yl)-4-bromo-1 H-1 ,2,3-triazole-5- carboxamide (3.0 g, 9.5 mmol) in 1 ,4-dioxane (100 mL) at 100 °C was added cesium carbonate (6.5 g, 19.9 mmol) followed by (4-(methoxycarbonyl)phenyl)(2,4,6- trimethoxyphenyl)iodonium benzenesulfonate. The reaction was heated at 100 °C for 30 minutes. The reaction mixture was cooled and loaded directly on a silica gel column, eluting with DCM / MeOH (0-5%) to yield the title compound (601 mg, 1.34 mmol, 14% yield), which was used in the next step without further purification. MS (ESI): mass calculated for Ci8H2iBrNsO4, 450.1 ; m / z measured, 450.1 [M+H]+.

[0333] Step F. Methyl 4-(4-((1 -acetylpiperidin-4-yl)carbamoyl)-5-(2-oxopropyl)-2H- 1 ,2,3-triazol-2-yl)benzoate.

[0334] A 40 mL vial was charged with N-(1 -acetylpiperidin-4-yl)-4-bromo-1 H-1 ,2,3- triazole-5-carboxamide (834 mg, 1.85 mmol) and Pd Xantphos G3 (216 mg, 0.229 mmol). The vial was purged with Argon for 10 minutes, then toluene (20 mL), isopropenyl acetate (816 pL, 7.41 mmol), and tri-n-butyltin methoxide (1.08 mL, 3.70 mmol) were added. The reaction was heated at 100 °C overnight, then cooled to room temperature. The resulting reaction mixture was loaded directly on a silica gel column eluting with heptane / EtOAc (0-100%) to yield the title compound (904 mg). MS (ESI): mass calculated for C21H26N5O5, 428.2; m / z measured, 428.1 [M+H]+.

[0335] Step G. Methyl 4-(5-(1 -acetylpiperidin-4-yl)-6-methyl-4-oxo-4,5-dihydro-2H- [1 ,2,3]triazolo[4,5-c]pyridin-2-yl)benzoate.

[0336] Methyl 4-(4-((1 -acetylpiperidin-4-yl)carbamoyl)-5-(2-oxopropyl)-2H-1 ,2,3- triazol-2-yl)benzoate was dissolved in phosphorus oxychloride (9.0 mL) and heated to 70 °C overnight. The reaction mixture was concentrated, and the resulting residue was quenched with sat. NaHCOs and then extracted with DOM. The organic layers were collected, dried over sodium sulfate, and concentrated to yield the title compound (744 mg, 1 .82 mmol, 86% yield). MS (ESI): mass calculated for C21 H24N5O4, 410.2; m / z measured, 410.1 [M+H]+.

[0337] Step H. 5-(1 -acetylpiperidin-4-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl- 2,5-dihydro-4H-[1 ,2,3]triazolo[4,5-c]pyridin-4-one.

[0338] To a solution of methyl 4-(5-(1 -acetylpiperidin-4-yl)-6-methyl-4-oxo-4,5-dihydro- 2H-[1 ,2,3]triazolo[4,5-c]pyridin-2-yl)benzoate (744 mg, 1.82 mmol) in THF (36 mL) was added methylmagnesium bromide (3.03 mL of 3.0 M solution in diethyl ether) dropwise at 0 °C. The reaction was stirred for 30 min at 0 °C, then quenched with sat. ammonium chloride. The mixture was extracted with DCM to yield the title compound (536 mg, 1 .31 mmol, 72% yield). MS (ESI): mass calculated for C22H28N5O3, 410.2; m / z measured, 410.2 [M+H]+.

[0339] Step I. 5-(1 -acetylpiperidin-4-yl)-7-bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)-6- methyl-2,5-dihydro-4H-[1 ,2,3]triazolo[4,5-c]pyridin-4-one.

[0340] A solution of 5-(1 -acetylpiperidin-4-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6- methyl-2,5-dihydro-4H-[1 ,2,3]triazolo[4,5-c]pyridin-4-one (536 mg, 1.31 mmol) in hexafluoroisopropanol (13 mL) was stirred for 10 minutes at room temperature. The reaction mixture was loaded directly on a silica gel column, eluting with EtOAc / MeOH (0-50%) to yield the title compound (248 mg, 0.508 mmol, 39% yield). MS (ESI): mass calculated for C22H2?BrN5O3, 488.1 ; m / z measured, 488.1 [M+H]+.

[0341] Step J. Methyl 2-(5-(1 -acetylpiperidin-4-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)- 6-methyl-4-oxo-4,5-dihydro-2H-[1 ,2,3]triazolo[4,5-c]pyridin-7-yl)acetate.

[0342] To a solution of 5-(1 -acetylpiperidin-4-yl)-7-bromo-2-(4-(2-hydroxypropan-2- yl)phenyl)-6-methyl-2,5-dihydro-4H-[1 ,2,3]triazolo[4,5-c]pyridin-4-one (248 mg, 0.508 mmol), Pd Xphos G3 (43.0 mg, 0.051 mmol), Xphos (24.7 mg, 0.051 mmol), and zinc fluoride (159 mg, 1.52 mmol) in 1 ,4-dioxane (5.1 mL) was added 1 -(tertbutyldimethylsilyloxy)-! -methoxyethene (489 pL, 2.23 mmol). The reaction mixture was then heated at 100 °C overnight. The reaction mixture was loaded directly on a silica gel column to yield the title compound (55 mg, 0.11 mmol, 23% yield). MS (ESI): mass calculated for C25H32N5O5, 482.2; m / z measured, 482.2 [M+H]+. Step K. 2-(5-(1 -acetylpiperidin-4-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6- methyl-4-oxo-4,5-dihydro-2H-[1 ,2,3]triazolo[4,5-c]pyridin-7-yl)-N-(2-chloro-4- (trifluoromethyl)phenyl)acetamide.

[0343] To a solution of methyl 2-(5-(1 -acetylpiperidin-4-yl)-2-(4-(2-hydroxypropan-2- yl)phenyl)-6-methyl-4-oxo-4,5-dihydro-2H-[1 ,2,3]triazolo[4,5-c]pyridin-7-yl)acetate (50 mg, 0.10 mmol) and 2-chloro-4-(trifluoromethyl)aniline (1 .39 g, 7.11 mmol) was added lithium hexamethyldisilazane (623 pL of 1 .0 M solution in THF) dropwise at 0 °C. The reaction mixture was then stirred for 1 hour at 0 °C. The reaction was quenched with 2.0 M HCI, the resulting mixture was transferred to a separatory funnel, and then extracted with ethyl acetate. The organic layer was collected, dried over sodium sulfate, and concentrated. The resulting residue was purified via basic prep HPLC to yield the title compound as a white solid.

[0344] 1H NMR (400 MHz, DMSO) 5 9.90 (s, 1 H), 8.11 (d, J = 8.3 Hz, 2H), 8.07 (d, J = 8.6 Hz, 1 H), 7.93 (s, 1 H), 7.74 - 7.64 (m, 3H), 5.23 (s, 1 H), 4.52 (d, J = 10.7 Hz, 2H), 4.10 (s, 2H), 3.94 (d, J = 13.4 Hz, 1 H), 3.19 (t, J = 12.9 Hz, 1 H), 2.92 - 2.76 (m, 1 H), 2.70 - 2.60 (m, 2H), 2.51 (s, 3H), 2.06 (s, 3H), 1 .78 - 1 .67 (m, 2H), 1.47 (s, 6H). 19F NMR (377 MHz, DMSO) 5 -60.74. MS (ESI): mass calculated for C31H33CIF3N6O4, 645.2; m / z measured, 645.1 [M+H]+.

[0345] Example 6. 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- methyl-4-oxo-4,5-dihydro-2H-[1 ,2,3]triazolo[4,5-c]pyridin-7-yl)acetamide Step A. tert-butyl 4-(1 H-1 ,2,3-triazole-5-carboxamido)piperidine-1 -carboxylate.

[0346] To a suspension of 1 H-1 ,2,3-triazole-5-carboxylic acid (4.00 g, 35.4 mmol), tert-butyl 4-aminopiperidine-1 -carboxylate (7.08 g, 35.4 mmol), and N-ethyl-N- isopropylpropan-2-amine (24.4 mL, 142 mmol) in THF (177 mL) was added propylphosphonic acid anhydride (50% wt. solution in EtOAc) at room temperature. The reaction mixture was then stirred for 30 min at room temperature. The reaction was quenched with a solution of concentrated sodium bicarbonate and extracted with ethyl acetate. The organic layers were collected, dried over sodium sulfate and concentrated to yield the title compound (1 1 .0 g, 37.2 mmol). MS (ESI): mass calculated for Ci3H2iNsO3Na, 318.2; m / z measured 318.1 [M+Na]+.

[0347] Step B. tert-butyl 4-(4-bromo-1 H-1 ,2,3-triazole-5-carboxamido)piperidine-1 - carboxylate.

[0348] N-bromosuccinimide (13.3 g, 74.5 mmol) was added to a solution of tert-butyl 4-(1 H-1 ,2, 3-triazole-5-carboxamido)piperidine-1 -carboxylate (10.0 g, 33.9 mmol) and potassium carbonate (11 .7 g, 84.6 mmol) in acetonitrile (226 mL). The reaction mixture was then heated at 75 °C for 2 hours. The reaction mixture was filtered and concentrated. The resulting residue was dissolved in EtOAc and extracted with a solution of 0.5 N HCI. The organic layers were collected and concentrated to yield the title compound (1 1 .0 g, 29.4 mmol). MS (ESI): mass calculated for Cis^oBrNsOsNa, 396.1 ; m / z measured 396.0 [M+Na]+.

[0349] Step C. tert-butyl 4-(5-bromo-2-(4-(methoxycarbonyl)phenyl)-2H-1 ,2,3-triazole- 4-carboxamido)piperidine-1 -carboxylate. tert-Butyl 4-(4-bromo-1 H-1 , 2, 3-triazole-5-carboxamido)piperidine-1 -carboxylate (9.0 g, 24.1 mmol) and potassium carbonate (3.32 g, 24.1 mmol) were dissolved in 1 ,4-dioxane (160 mL) and heated to 100 °C. (4-(Methoxycarbonyl)phenyl)(2,4,6- trimethoxyphenyl)iodonium 4-methylbenzenesulfonate (14.4 g, 24.1 mmol) was added at 100 °C and the reaction mixture was stirred for 2 hours. The reaction mixture was filtered and concentrated. The resulting residue was washed with diethyl ether to yield the title compound as a tan solid (6.90 g, 13.6 mmol). MS (ESI): mass calculated for C2iH26BrN50sNa, 530.1 ; m / z measured 530.1 [M+Na]+. Step D. tert-butyl 4-(2-(4-(methoxycarbonyl)phenyl)-5-(prop-1 -yn-1 -yl)-2H- 1 ,2,3-triazole-4-carboxamido)piperidine-1 -carboxylate. tert-Butyl 4-(5-bromo-2-(4-(methoxycarbonyl)phenyl)-2H-1 ,2,3-triazole-4- carboxamido)piperidine-1 -carboxylate (2.00 g, 3.93 mmol), [1 ,1 ’- bis(diphenylphosphino)ferrocene]dichloropalladium (II) (288 mg, 0.393 mmol), and potassium propynyltrifluoroborate were added to a 40 mL vial. The vial was sparged with argon for 10 minutes, then 1 ,4-dioxane (20 mL) and triethylamine (1.09 mL, 7.87 mmol) were added. The reaction mixture was heated at 100 °C overnight. Water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The resulting residue was purified via silica gel chromatography using heptane / EtOAc (0-50%) to yield the title compound (1 .44 g, 3.09 mmol). MS (ESI): mass calculated for C24H29N5O5Na, 490.2; m / z measured 490.2 [M+Na]+.

[0350] Step E. tert-butyl 4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-5-(prop-1 -yn-1 -yl)-2H- 1 ,2,3-triazole-4-carboxamido)piperidine-1 -carboxylate. tert-Butyl 4-(2-(4-(methoxycarbonyl)phenyl)-5-(prop-1 -yn-1 -yl)-2H- 1 ,2,3- triazole-4-carboxamido)piperidine-1 -carboxylate (1.44 g, 3.09 mmol) was dissolved in THF (6.2 mL) and cooled to 0 °C. Methylmagnesium bromide (5.14 mL of 3 M solution in diethyl ether, 15.4 mmol) was added dropwise at 0 °C. The reaction mixture was removed from the ice bath and stirred for 30 min. The reaction was quenched with saturated ammonium chloride and the resulting mixture was extracted with ethyl acetate. The organic layers were collected, dried over sodium sulfate and concentrated to yield the title compound (1 .44 g, 3.08 mmol), which was used in the next step without further purification. MS (ESI): mass calculated for C25H33NsO4Na, 490.2; m / z measured 490.2 [M+Na]+.

[0351] Step F. tert-butyl 4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-4-oxo-2,4- dihydro-5H-[1 , 2, 3]triazolo[4,5-c]pyridin-5-yl)piperidine-1 -carboxylate. tert-Butyl 4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-5-(prop-1 -yn-1 -y l)-2 H- 1 ,2,3- triazole-4-carboxamido)piperidine-1 -carboxylate (1.44 g, 3.08 mmol) was dissolved in DMF (9.8 mL) and sodium tert-butoxide (309 mg, 2.76 mmol) was added. The reaction mixture was then heated at 100 °C for 30 minutes. The reaction was quenched with saturated ammonium chloride and the resulting mixture was extracted with ethyl acetate. The organic layer was collected, dried over sodium sulfate, and concentrated. The resulting residue was purified via normal phase silica gel chromatography eluting with heptane / EtOAc (0-100%) to yield the title compound (759 mg, 1.62 mmol). MS (ESI): mass calculated for C25H33NsO4Na, 490.2; m / z measured 490.2 [M+Na]+.

[0352] Step G. tert-butyl 4-(7-bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-4- oxo-2, 4-dihydro-5H-[1 , 2, 3]triazolo[4,5-c]pyridin-5-yl)piperidine-1 -carboxylate. tert-Butyl 4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-4-oxo-2,4-dihydro- 5H-[1 ,2, 3]triazolo[4,5-c]pyridin-5-yl)piperidine-1 -carboxylate (759 mg, 1.62 mmol) was dissolved in HFIP (16 mL) and N-bromosuccinimide (404 mg, 2.27 mmol) was added. The reaction mixture was stirred for 10 min at room temperature, and then quenched with a 1 M aqueous solution of sodium metabisulfite. The reaction mixture was extracted with ethyl acetate. The organic layer was collected, dried over sodium sulfate, and concentrated to yield the title compound (354 mg, 0.648 mmol), which was used in the next step without further purification. MS (ESI): mass calculated for C2sH32BrN5O4Na, 568.1 ; m / z measured 568.1 [M+Na]+.

[0353] Step H. tert-butyl 4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-7-(2-methoxy-2- oxoethyl)-6-methyl-4-oxo-2,4-dihydro-5H-[1 ,2,3]triazolo[4,5-c]pyridin-5-yl)piperidine-1 - carboxylate.

[0354] A 20 mL vial was charged with tert-butyl 4-(7-bromo-2-(4-(2-hydroxypropan-2- yl)phenyl)-6-methyl-4-oxo-2,4-dihydro-5H-[1 ,2,3]triazolo[4,5-c]pyridin-5-yl)piperidine- 1 -carboxylate (332 mg, 0.608), PdXphos G3 (112 mg, 0.132 mmol), and Xphos ligand (64.4 mg, 0.132 mmol). The vial was sparged for argon for 10 min, then 1 ,4-dioxane (6.1 mL) was added, followed by addition of 1 -(tert-butyldimethylsilyloxy)-l - methoxyethene (1.33 mL, 6.08 mmol). The reaction mixture was then heated at 100 °C for 20 hours. The reaction mixture was concentrated and residue was purified via silica gel chromatography (100% ethyl acetate) to yield the title compound (285 mg, 0.528 mmol). MS (ESI): mass calculated for C28H37N5O6Na, 562.2; m / z measured 562.2 [M+Na]+.

[0355] Step I. tert-butyl 4-(7-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)- 2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-4-oxo-2,4-dihydro-5H-[1 ,2,3]triazolo[4,5- c]pyridin-5-yl)piperidine-1 -carboxylate. tert-Butyl 4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-7-(2-methoxy-2-oxoethyl)-6- methyl-4-oxo-2,4-dihydro-5H-[1 , 2, 3]triazolo[4,5-c]pyridin-5-yl)piperidine-1 -carboxylate (275 mg, 0.510 mmol) and 2-chloro-4-(trifluoromethyl)aniline (997 mg, 5.10 mmol) were dissolved in THF and cooled to 0 °C. Lithium hexamethyldisilazane (3.06 mL of 1 M solution in THF, 3.06 mmol) was added dropwise. After addition, the reaction mixture was warmed to room temperature and then stirred for 30 minutes. The reaction was quenched with sat. ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The residue was purified via silica gel chromatography, eluting with heptane / EtOAc (0-100%) to yield the title compound (342 mg, 0.486 mmol). 1 H NMR (400 MHz, DMSO) 5 9.88 (s, 1 H), 8.09 (d, J = 8.8 Hz, 2H), 8.05 (d, J = 8.7 Hz, 1 H), 7.92 (s, 1 H), 7.73 - 7.65 (m, 3H), 5.22 (s, 1 H), 4.42 - 4.38 (m, 1 H), 4.08 (s, 2H), 2.91 - 2.69 (m, 6H), 1 .65 (d, J = 10.1 Hz, 2H), 1.46 (s, 6H), 1.43 (s, 9H). 19F NMR (377 MHz, DMSO) 5 -60.75. MS (ESI): mass calculated for Cs^ssCIFsNeOsNa, 725.2; m / z measured 725.1 [M+H]+.

[0356] Step J. 4-(7-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-6-methyl-4-oxo-2,4-dihydro-5H-[1 ,2,3]triazolo[4,5- c]pyridin-5-yl) pi peridin- 1 -ium chloride. tert-Butyl 4-(7-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(4- (2-hydroxypropan-2-yl)phenyl)-6-methyl-4-oxo-2,4-dihydro-5H-[1 ,2,3]triazolo[4,5- c]pyridin-5-yl)piperidine-1 -carboxylate (50. mg, 0.071 mmol) was dissolved in DCM (0.4 mL). Hydrochloric acid (0.266 mL of 4 M solution in 1 ,4-dioxane, 1 .07 mmol) was added dropwise and the reaction was stirred for 30 min at room temperature. The reaction was concentrated to yield the title compound (45 mg, 0.070. mmol), which was used in the next step without further purification. MS (ESI): mass calculated for C29H30CIF3N6O3, 603.2; m / z measured 603.2 [M+H]+. Step K. 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- methyl-4-oxo-4,5-dihydro-2H-[1 ,2,3]triazolo[4,5-c]pyridin-7-yl)acetamide.

[0357] 4-(7-(2-((2-Chloro-4-(trifluoromethyl)phenyl)amino)-2-oxoethyl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-6-methyl-4-oxo-2,4-dihydro-5H-[1 ,2,3]triazolo[4,5- c]pyridin-5-yl)piperidin-1 -ium chloride (45 mg, 0.070. mmol), 5-hydroxy-6- methylpyrimidine-4-carboxylic acid (22 mg, 0.14 mmol), 2-hydroxypyridine N-oxide (3.9 mg, 0.035 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.015 mL, 0.088 mmol) were dissolved in DCM (0.70 mL). 3-(((Ethylimino)methylene)amino)-N,N- dimethylpropan-1 -aminium chloride (67 mg, 0.35 mmol) was then added. The reaction mixture was stirred for 30 min at room temperature. The reaction mixture was then concentrated and purified via basic prep HPLC to yield the title compound.1H N MR (400 MHz, MeOD) 5 8.56 (s, 1 H), 8.22 (d, J = 8.8 Hz, 2H), 8.18 (d, J = 8.5 Hz, 1 H), 7.75 (d, J = 2.0 Hz, 1 H), 7.70 (d, J = 8.8 Hz, 2H), 7.59 (dd, J = 8.7, 2.1 Hz, 1 H), 4.74 - 4.57 (m, 1 H), 4.30 (d, J = 13.4 Hz, 1 H), 4.17 (s, 2H), 3.23 - 3.09 (m, 2H), 3.09 - 2.97 (m, 1 H), 2.61 (s, 3H), 2.53 (s, 3H), 1 .95 (d, J = 12.0 Hz, 1 H), 1 .82 (d, J = 12.4 Hz, 1 H), 1 .57 (s, 6H).19F NMR (377 MHz, MeOD) 5 -63.96. MS (ESI): mass calculated for C35H34CIF3N8O5, 739.2; m / z measured 739.2 [M+H]+

[0358] Example 7. N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[5-ethyl-2-[4-(1 -hydroxy-1 -methyl- ethyl)phenyl]-6-[4-(5-hydroxy-6-methyl-pyrimidine-4-carbonyl)piperazin-1 -yl]-7-oxo- triazolo[4,5-b]pyridin-4-yl]acetamide The title compound was similarly prepared according to the procedures as described herein.1H NMR (400 MHz, Methanol-d4) d 8.57 (s, 1 H), 8.13 - 8.20 (m, 3 H), 7.82 (s, 1 H), 7.69 (d, J=8.8 Hz, 2 H), 7.58 - 7.63 (m, 1 H), 5.47 (s, 2 H), 4.70 (br d, J=12.4 Hz, 1 H), 4.09 (br d, J=12.8 Hz, 1 H), 3.89 - 3.98 (m, 2 H), 3.41 - 3.47 (m, 1 H), 3.13 - 3.21 (m, 3 H), 2.93 (br d, J=10.0 Hz, 1 H), 2.75 - 2.82 (m, 1 H), 2.53 (s, 3 H), 1 .57 (s, 6 H), 1 .34 (br t, J=7.6 Hz, 3 H);19F NMR (376 MHz, METHANOL-d4) d - 64.01 (3 F)

[0359] Example 8. 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-oxo-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0360] Step A 2-(4-(6-Bromo-7-methoxy-5-methyl-2 / - / -[1 ,2,3]triazolo[4,5-b]pyridin-2- yl)phenyl)propan-2-ol

[0361] To a solution of 2-(4-(7-methoxy-5-methyl-2H-[1 ,2,3]triazolo[4,5-b]pyridin-2- yl)phenyl)propan-2-ol (prepared as in Example 1 , Step G, 1.25 g, 4.19 mmol) in acetonitrile (21 mL) was added NBS (0.89 g, 5.03 mmol) and the mixture stirred for 12 hrs at 50 °C. The mixture was then cooled to room temperature and the resulting precipitate was collected by filtration and washed with diethyl ether to yield the title compound as a tan solid (0.97 g, 61 %). MS (ESI) calculated for Ci6Hi7BrN4O2, 376.1 m / z, found 377.1 [M+H]+.

[0362] Step B. tert-Butyl 4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-7-methoxy-5-methyl- 2 / - / -[1 ,2,3] triazolo[4,5-b]pyridin-6-yl)-3,6-dihydropyridine-1 (2 / - / )-carboxylate

[0363] A mixture of 2-(4-(6-bromo-7-methoxy-5-methyl-2 / - / -[1 ,2,3]triazolo[4,5-b]pyridin- 2-yl)phenyl)propan-2-ol (1.0 g, 2.7 mmol), anhydrous 1 ,4-dioxane (10.0 mL), H2O (2.0 mL), anhydrous CS2CO3 (2.6 g, 8.0 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)- 3,6-dihydropyridine-1 (2 / - / )-carboxylate (983.6 mg, 3.2 mmol), and Pd Xphos G3 (224.6 mg, 265.1 pmol) was stirred at 100 °C for 16 hours. The resulting mixture was cooled to 25 °C and diluted with H2O (200 mL), then extracted with ethyl acetate (200 mL x 3). The combined organic layer was washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness in vacuo to yield a residue. The residue was subjected to silica gel chromatography (0- 5%, MeOH / DCM) to yield tert-butyl 4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-7-methoxy- 5-methyl-2 / - / -[1 ,2,3]triazolo[4,5-b]pyridine-6-yl)-3,6-dihydropyridine-1 (2 / - / ) -carboxyl ate (100.0 mg, 71%) as light yellow solid. MS (ESI) calculated for C26H33N5O4, 479.5 m / z, found 480.2 [M+H]+.

[0364] Step C. tert-Butyl 4-(4-(2-(benzyloxy)-2-oxoethyl)-2-(4-(2-hydroxypropan-2- yl)phenyl)-5- methyl-7-oxo-4,7-dihydro-2 / - / -[1 ,2,3]triazolo[4,5-b]pyridin-6-yl)-3,6- dihydropyridine-1 (2 / - / )-carboxylate

[0365] A mixture of tert-butyl 4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-7-methoxy-5- methyl-2 / - / -[1 ,2,3]triazolo[4,5 -b]pyridin-6-yl)-3, 6-d ihydropyridi ne- 1 (2 / - / )-carboxylate (800.0 mg, 1 .7 mmol), anhydrous toluene (3.0 mL), benzyl 2-bromoacetate (573.2 mg, 2.5 mmol) and DIPEA (646.8 mg, 5.0 mmol) was stirred for 30 minutes at 130 °C. The mixture was concentrated and then subjected to silica gel chromatography (0- 100%, ethyl acetate / petroleum ether) to yield tert-butyl 4-(4-(2-(benzyloxy)-2- oxoethyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-5-methyl-7- oxo-4, 7-di hydro-2 H- [1 ,2,3]triazolo[4,5-b] pyrid in-6-yl)-3 , 6-di hyd ropyridine-1 (2 / - / ) -carboxyl ate (600.0 mg, 55%) as light yellow solid. MS (ESI) calculated for C34H39N5O6, 613.7 m / z, found 614.3 [M+H]+.

[0366] 1H NMR (400 MHz, DMSO-rt6) 68.07 - 7.98 (m, 2H), 7.74 - 7.66 (m, 2H), 7.41 - 7.27 (m, 5H), 5.52 - 5.43 (m, 1 H), 5.30 - 5.28 (m, 1 H), 5.26 - 5.22 (m, 3H), 4.00 - 3.88 (m, 2H), 3.61 - 3.46 (m, 2H), 3.20 - 3.15 (m, 1 H), 2.44 - 2.38 (m, 1 H), 2.37 - 2.33 (m, 3H), 2.07 - 1 .81 (m, 1 H), 1 .49 - 1 .47 (m, 6H), 1 .46 - 1 .42 (m, 9H) ppm.

[0367] Step D. 2-(6-(1 -(tert-butoxycarbonyl)piperidin-4-yl)-2-(4-(2-hydroxypropan-2- y I) pheny l)-5- methyl-7-oxo-2,7-dihydro-4 / - / -[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)acetic acid A mixture of tert-butyl 4-(4-(2-(benzyloxy)-2-oxoethyl)-2-(4-(2-hydroxypropan-2- yl)phenyl)-5-methyl-7-oxo-4,7-dihydro-2 / - / -[1 ,2,3]triazolo[4,5-b]pyridin-6-yl)-3,6- dihydropyridine-1 (2 / - / )-carboxylate (900.0 mg, 1.5 mmol), anhydrous MeOH (10.0 mL), PtO2 (199.8 mg, 879.9 pmol) and H2 (15 psi) in a 100 mL sealed tube was stirred for 16 hours at room temperature. The reaction was filtered, and the filtrate was concentrated under reduce pressure. The resulting residue was purified by preparative reversed phase HPLC (Stationary phase: Welch Xtimate C18, 5 pm, 150 x 30 mm; Mobile phase: water (FA)-ACN, gradient elution: 38 - 68% B in A over 10 min, flow rate: 55 mL / min) to yield the title compound (450.0 mg, 95% yield) as light yellow solid. MS (ESI) calculated for C27H35N5O6, 525.5 m / z, found 526.2 [M+H]+.

[0368] 1H NMR (400 MHz, DMSO-ofe) 68.13 - 7.97 (m, 2H), 7.76 - 7.59 (m, 2H), 5.27 - 5.17 (m, 1 H), 5.12 - 5.03 (m, 2H), 4.09 - 3.97 (m, 2H), 3.05 - 2.95 (m, 1 H), 2.86 - 2.68 (m, 2H), 2.46 - 2.41 (m, 3H), 2.41 - 2.31 (m, 2H), 1 .48 - 1 .45 (m, 6H), 1 .43 (s, 9H), 1.40 - 1.33 (m, 2H) ppm.

[0369] Step E. 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-dihydro-2 / - / - [1 ,2,3]triazolo[4,5-b] pyrid in-6-yl) pi peridi ne- 1 -carboxylate

[0370] A mixture of 2-(6-(1 -(tert-butoxycarbonyl)piperidin-4-yl)-2-(4-(2-hydroxypropan- 2-yl)phenyl)-5-methyl-7-oxo-2,7-dihydro-4 / - / -[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)acetic acid (40.0 mg, 71.2 pmol), DMF (80.0 pL), 2-chloro-1 -methylpyridinium iodide (36.5 mg, 142.3 pmol), TEA (38.8 pL, 284.7 pmol), and 2-chloro-4-(trifluoromethyl)aniline (16.7 mg, 85.4 pmol) was stirred for 16 hours at room temperature. Multiple batches were combined, diluted with H2O (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduce pressure to yield reside. The reside was purified by preparative reversed phase HPLC (Stationary phase: Welch Xtimate C18, 5 pm, 150 x 30 mm; Mobile phase: water (FA)-ACN, gradient elution: 50 - 80% B in A over 10 min, flow rate: 25 mL / min) to yield the title compound (70.0 mg) as white solid. MS (ESI) calculated for C34H38CIF3N6O5, 703.1 m / z, found 703.1 [M+H]+. Step F. / V-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(2-hydroxypropan-2- yl)phenyl)-5- methyl-7-oxo-6-(piperidin-4-yl)-2,7-dihydro-4 / - / -[1 ,2,3]triazolo[4,5- b]pyridin-4-yl)acetamide

[0371] A mixture of 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-dihydro-2 / - / -

[0372] [1 .2.3]triazolo[4,5-b]pyridin-6-yl)piperidine-1 -carboxylate (65.0 mg, 92.4 pmol) and HCI (1 mL, 2 M dioxane solution) was stirred for 16 hours at 30 °C. The resulting mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (20 mL x 1 ), dried over anhydrous Na2SO4, concentrated to yield / V-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2- (4-(2-hydroxypropan-2-yl)phenyl)-5-methyl-7-oxo-6-(piperidin-4-yl)-2,7-dihydro-4 / - / -

[0373] [1 .2.3]triazolo[4,5-b]pyridin-4-yl)acetamide (63.0 mg, 99%) as white solid. MS (ESI) calculated for C29H30CIF3N6O3, 603.0 m / z, found 603.2 [M+H]+.

[0374] Step G. 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-oxo-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0375] A mixture of 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (17.2 mg, 11 1 .6 pmol), anhydrous 1 ,4-dioxane (1.0 mL), EDCI (23.2 mg, 121.0 pmol), DIPEA (36 mg, 278.5 pmol), and HOPO (5.2 mg, 46.8 pmol) was stirred for 1 hour at 30 °C. To the resulting mixture was then added / V-(2-chloro-4-(trifluoromethyl)phenyl) -2-(2-(4-(2- hydroxypropan-2-yl)phenyl)-5-methyl-7-oxo-6-(piperidin-4-yl)-2,7-dihydro-4 / - / -

[0376] [1 ,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide (63.0 mg, 93.0 pmol). The resulting mixture was stirred for 16 hours at 50 °C. The mixture was then diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (20 mL x 1 ), dried over anhydrous Na2SO4, and concentrated under reduce pressure. The resulting reside was subjected to silica gel chromatography (0-10%, MeOH / DCM) to yield the title compound (40 mg) as white solid residue. The white solid residue was further purified by SFC (Stationary phase: DAICEL CHIRALCEL OJ (250mm x 30mm, 10pm); Mobile phase: Supercritical CO2- EtOH (0.1%NH3H2O) to yield the title compound as a white solid. MS (ESI): mass calculated for C35H34CIF3N8O5, 739.1 ; m / z measured 739.3 / 741 .3 [M+H]+.

[0377] 1H NMR (400 MHz, CHLOROFORM-d) 6 11 .90 - 11 .67 (m, 1 H), 8.62 - 8.58 (m, 1 H), 8.55 - 8.49 (m, 1 H), 8.42 - 8.37 (m, 1 H), 8.22 - 8.15 (m, 2H), 7.66 - 7.60 (m, 3H), 5.68 - 5.47 (m, 1 H), 5.23 - 5.17 (m, 2H), 4.99 - 4.78 (m, 1 H), 3.39 - 3.21 (m, 1 H), 3.00 - 2.82 (m, 1 H), 2.75 - 2.60 (m, 4H), 2.59 - 2.53 (m, 4H), 1 .78 - 1 .66 (m, 3H), 1 .64 - 1.62 (m, 6H);19F NMR (376 MHz, CHLOROFORM-d) 6 -62.51 (3F) ppm.

[0378] Example 9. 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-dihydro-2H-[1 ,2,3]triazolo[4,5-c]pyridin-7-yl)acetamide

[0379] Step A. Lithium 4-bromo-1 H-1 ,2,3-triazole-5-carboxylate

[0380] To a solution of methyl 4-bromo-1 H-1 ,2,3-triazole-5-carboxylate (10 g, 49 mmol) in THF (30 mL), methanol (30 mL) and H2O (30 mL) was added LiOH*H2O (4.1 g, 97 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated under vacuum to yield an off-white solid, which was triturated with EtOAc at room temperature for 10 minutes and then filtered. The filter cake was collected and dried under vacuum to yield the title compound as a white solid. MS (ESI): mass calculated for Cs^BrNsCh , 190.9 / 192.9; m / z measured 191.9 / 193.9 [M+H]+.

[0381] Step B. tert-Butyl 4-(4-bromo-1 H-1 ,2,3-triazole-5-carboxamido)piperazine-1 - carboxylate A mixture of lithium 4-bromo-1 H-1 ,2,3-triazole-5-carboxylate (1 1 g, 55 mmol), tert-butyl 4-aminopiperazine-1 -carboxylate (11.4 g, 57 mmol), HOPO (3 g, 27 mmol), and EDCI (11 g, 57 mmol) was stirred in DMF (150 mL) at 55 °C for 2 hours. The solution was poured into H2O, and the resulting mixture was then acidified to pH = 5~6 at 0 °C by 1 M HCI. The mixture was extracted with EtOAc, dried with anhydrous Na2SO4, filtered, and concentrate. The resulting residue was triturated with EtOAc at room temperature for 10 minutes and then filtered. The filter cake was collected and dried under vacuum to yield the title compound as a white solid. MS (ESI): mass calculated for C^HigBrNeOs, 374.1 / 376.1 ; m / z measured 319.0 / 321.0 [M-56+H]+.1H NMR (400 MHz, DMSO-ofe) 6 = 9.55 - 9.67 (m, 1 H) 3.37 - 3.43 (m, 4 H) 2.76 - 2.82 (m, 4 H) 1 .39 - 1 .43 (m, 9 H) ppm.

[0382] Step C. tert-Butyl 4-(5-bromo-2-(4-(methoxycarbonyl)phenyl)-2 / - / -1 ,2,3-triazole- 4-carboxamido)piperazine-1 -carboxylate

[0383] A solution of tert-butyl 4-(4-bromo-1 H-1 ,2,3-triazole-5-carboxamido)piperazine- 1 -carboxylate (9.7 g, 26 mmol) in 1 ,4-dioxane (250 mL) was heated at 105 °C in oil bath until the solid was dissolved (~ 20 minutes). Then (4- (methoxycarbonyl)phenyl)(2,4,6- trimethoxyphenyl)iodonium trifluoroacetate (15.4 g, 28 mmol) and Na2COs (3 g, 28 mmol) were added into the mixture at 105 °C and the mixture stirred for 75 minutes. The mixture was cooled to room temperature, filtered and the filtrate was concentrated under vacuum to yield a yellow-brown semi-solid. The semi-solid was triturated with EtOAc at room temperature for 15 minutes and then filtered. The filter cake was rinsed with EtOAc and dried under vacuum to yield the title compound as a white solid. MS (ESI): mass calculated for C2oH25BrNe05, 508.1 / 510.1 ; m / z measured 453.1 / 455.1 [M-56+H]+.1H NMR (400 MHz, DMSO-ofe) 6 = 9.91 (s, 1 H), 8.19 (s, 4H), 3.90 (s, 3H), 3.47 - 3.39 (m, 4H), 2.85 (br d, J - 4.8 Hz, 4H), 1.42 (s, 9H) ppm.

[0384] Step D. tert-Butyl 4-(2-(4-(methoxycarbonyl)phenyl)-6-methyl-4-oxo-2,4- dihydro-5H-[1 ,2,3] triazolo[4,5-c]pyridin-5-yl)piperazine-1 -carboxylate

[0385] A mixture of tert-butyl 4-(5-bromo-2-(4-(methoxycarbonyl)phenyl)-2 / - / -1 ,2,3- triazole-4-carboxamido)piperazine-1 -carboxylate (3.5 g, 6.9 mmol), tributyl(prop-1 -yn- 1 -yl)stannane (6.8 g, 20.7 mmol), Pd(dppf)Cl2 (280 mg, 383 pmol), Cui (310 mg, 1 .6 mmol) and CsF (2.1 g, 13.8 mmol) in DMF (140 mL) was stirred in an oil-bath at 125 °C for 2 hours. The solution was poured into H2O and extracted with EtOAc. The organic layers were dried with anhydrous Na2SO4, filtered, and concentrated to yield a brown solid. The resulting residue was subjected to column chromatography over silica gel (0 - 55% EtOAc / petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C23H28N6O5, 468.2; m / z measured 413.1 [M+H]+.1H NMR (400 MHz, CDCI3) 5 = 8.34 - 8.39 (m, 2 H) 8.18 - 8.24 (m, 2 H) 6.46 - 6.53 (m, 1 H) 4.09 - 4.24 (m, 4 H) 3.95 - 3.99 (m, 3 H) 2.95 - 3.12 (m, 2 H) 2.84 - 2.94 (m, 2 H) 2.43 - 2.48 (m, 3 H) 1 .49 - 1 .52 (m, 9 H) ppm.

[0386] Step E. tert-Butyl 4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-4-oxo-2,4- dihydro-5H- [1 ,2, 3]triazolo[4 ,5-c] py rid in-5-yl) pi perazine- 1 -carboxylate

[0387] A homogeneous solution of tert-butyl 4-(2-(4-(methoxycarbonyl)phenyl)-6- methyl-4-oxo-2,4-dihydro-5 / - / -[1 ,2, 3]triazolo [4,5-c]py rid in-5-yl) pi perazi ne- 1 - carboxylate (450 mg, 960 pmol) in THF (20 mL) was bubbled with N2 for 1 minute then the vial was sealed with a rubber septum and cooled to 0 °C. CHsMgCI (3 M in THF, 1 .7 mL, 5.1 mmol) was added to the reaction and stirred for 1 hour at 0 °C. Another batch (100 mg) was combined with this reaction for work-up. The combined mixture was poured into sat. NH4CI and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was subjected to column chromatography over silica gel (0 - 55% EtOAc / petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C24H32N6O4, 468.2; m / z measured 413.2 [M- 56+H]+.1H NMR (400 MHz, CDCI3) 6 = 8.18 - 8.29 (m, 2 H) 7.61 - 7.71 (m, 2 H) 6.44 - 6.53 (m, 1 H) 4.09 - 4.25 (m, 4 H) 2.95 - 3.12 (m, 2 H) 2.85 - 2.93 (m, 2 H) 2.42 - 2.48 (m, 3 H) 1 .63 - 1 .65 (m, 6 H) 1 .49 - 1 .52 (m, 9 H) ppm.

[0388] Step F. tert-Butyl 4-(7-bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-4- oxo-2, 4- dihydro-5 / - / -[1 ,2,3]triazolo[4,5-c]pyridin-5-yl) pi perazine-1 -carboxylate

[0389] A mixture of tert-butyl 4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-4-oxo- 2,4-dihydro -5H-[1 ,2, 3]triazolo[4,5-c]pyridin-5-yl)piperazine-1 -carboxylate (330 mg, 704.3 nmol) and NBS (135 mg, 758.5 pmol) in DMF (8 mL) was stirred at room temperature for 12 hours. The mixture was poured into H2O resulting in an orange precipitate. The mixture was filtered and the filter cake was rinsed with H2O, then dried under vacuum to yield the title compound as an orange solid. MS (ESI): mass calculated for C24H3iBrNeO4, 546.2 / 548.2; m / z measured 491 .1 / 493.1 [M-56+H]+.1H NMR (400 MHz, CDCI3) 6 = 8.25 - 8.30 (m, 2 H) 7.64 - 7.69 (m, 2 H) 4.07 - 4.24 (m, 4 H) 2.98 - 3.11 (m, 2 H) 2.83 - 2.90 (m, 2 H) 2.66 (s, 3 H) 1 .63 - 1 .65 (m, 6 H) 1 .49 - 1 .52 (m, 9 H) ppm.

[0390] Step G. tert-Butyl 4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-7-(2-methoxy-2- oxoethyl)-6-methyl-4-oxo-2,4-dihydro-5 / - / -[1 ,2,3]triazolo[4,5-c]pyridin-5-yl)piperazine- 1 -carboxylate

[0391] A solution of tert-butyl 4-(7-bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)-6- methyl-4-oxo-2,4-dihydro-5 / - / -[1 , 2, 3]triazolo[4,5-c]pyridin-5-yl)piperazine-1 -carboxylate (155 mg, 269 pmol), tert-butyl((1 -methoxyvinyl)oxy)dimethylsilane (250 pL, 1.1 mmol), XPhos Pd G4 (24 mg, 27.9 pmol) and XPhos (14 mg, 29.4 pmol) in THF (4.5 mL) was sparged with N2 and heated at 100 °C for 12 hours. The mixture was concentrated and subjected to to prep-TLC (eluent: petroleum ether / EtOAc=2 / 1 ) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C27H36N6O6, 540.3; m / z measured 485.1 [M-56+H]+.

[0392] Step H. tert-Butyl 4-(7-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-2- (4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-4-oxo-2,4-dihydro-5 / -t- [1 , 2,3]triazolo[4,5-c] pyrid in-5-yl) pi perazi ne- 1 -carboxylate

[0393] To a solution of tert-butyl 4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-7-(2-methoxy- 2-oxoethyl)-6-methyl-4-oxo- 2,4-dihydro-5H-[1 ,2,3]triazolo[4,5-c]pyridin-5- yl)piperazine-1 -carboxylate (133 mg, 246 pmol) in THF (1.5 mL) at 0 °C under N2 was added LiHMDS (0.5 M in toluene, 3 mL, 1.5 mmol) dropwise. The reaction mixture was stirred for 30 minutes and then 4-amino-3-chlorobenzotrifluoride (495 mg, 2.5 mmol) was added. The mixture was warmed to room temperature and stirred for 1 hour, then diluted with EtOAc and quenched with H2O and sat. NH4CI. The resulting mixture was extracted with EtOAc and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was subjected to column chromatography over silica gel (0 - 55% EtOAc / petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C33H37CIF3N7O5, 703.2; m / z measured 648.1 [M-56+H]+.

[0394] Step I. / V-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(2-hydroxypropan-2- y I) phenyl)- 6-methyl-4-oxo-5-(piperazin-1 -yl)-4,5-dihydro-2 / - / -[1 ,2,3]triazolo[4,5- c]pyridin-7-yl)acetamide

[0395] 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-oxo-2,4-dihydro-5 / -t- [1 ,2, 3]triazolo[4,5-c]pyridin-5-yl)piperazine-1 -carboxylate (145 mg, 206 pmol) in HCI / 1 ,4-dioxane (3 mL, 6 mmol, 2 M) was stirred at room temperature for 0.5 hour. The mixture was concentrated under vacuum to yield a yellow solid. The yellow solid was alkalized with sat. NaHCOs to pH = 8, then extracted with EtOAc. The organic layer was concentrated to yield the title compound as a yellow solid. MS (ESI): mass calculated for C28H29CIF3N7O3, 603.2; m / z measured 604.2[M+H]+.

[0396] Step J. / V-(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-dihydro-2 / - / -[1 ,2,3]triazolo[4,5-c]pyridin-7-yl)acetamide

[0397] A mixture of / V-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(2-hydroxypropan-2- yl)phenyl)-6-methyl-4-oxo-5-(piperazin-1 -yl)-4,5-dihydro-2 / - / -[1 ,2,3]triazolo[4,5- c]pyridin-7-yl)acetamide (120 mg, 198.7 pmol), 5-hydroxy-6-methylpyrimidine-4- carboxylic acid (39 mg, 245.5 pmol), HOPO (12 mg, 108.0 pmol) and EDCI (43 mg, 224.3 pmol) in 1 ,4-dioxane (7 mL) was warmed to 50 °C and stirred for 2 hours. The mixture was then concentrated and purified by prep-HPLC (Stationary phase: C18, 150 x 30 mm; Mobile phase: water (FA) (A) - ACN (B), gradient elution: 44 - 74% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound. MS (ESI): mass calculated for C34H33CIF3N9O5, 739.2; m / z measured 740.3 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 6 11 .73 - 11 .89 (m, 1 H) 8.43 - 8.64 (m, 3 H) 8.20 - 8.34 (m, 2 H) 7.63 - 7.72 (m, 2 H) 7.47 - 7.57 (m, 2 H) 5.73 - 5.93 (m, 1 H) 4.76 - 4.96 (m, 1 H) 4.24 - 4.43 (m, 2 H) 3.96 - 4.10 (m, 2 H) 3.43 - 3.64 (m, 1 H) 2.96 - 3.20 (m, 3 H) 2.53 - 2.69 (m, 6 H) 1 .81 - 1 .91 (m, 1 H) 1 .64 - 1 .68 (m, 6 H);19F NMR (376 MHz, DMSO-ofe) 5 -62.39 (3F) ppm.

[0398] Example 10. 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-dihydro-2H-[1 ,2,3]triazolo[4,5-c]pyridin-7-yl)acetamide

[0399] Step A. tert-Butyl 4-(6-ethyl-2-(4-(methoxycarbonyl)phenyl)-4-oxo-2,4-dihydro- 5H-[1 ,2,3] triazolo[4,5-c]pyridin-5-yl)piperazine-1 -carboxylate

[0400] A mixture of tert-butyl 4-(5-bromo-2-(4-(methoxycarbonyl)phenyl)-2 / - / -1 ,2,3- triazole-4-carboxamido) piperazine-1 -carboxylate (2.0 g, 3.9 mmol), 2-(but-1 -yn-1 -yl)- 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (1.12 g, 6.2 mmol), Pd(dppf)Cl2 (287.0 mg, 392.2 pmol), CS2CO3 (1.1 g, 8.1 mmol), CsF (743.0 mg, 11 .8 mmol) in DMF / H2O (26.0 mL, 25:1 ) were added to a 100 mL three-neck round-bottomed flask, which was subsequently subjected to three cycles of vacuum and recharging with N2. The reaction was stirred at 90 °C for 12 hours. The mixture was filtered and concentrated to dryness. The mixture was diluted with H2O and extracted with CH2CI2. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated. The resulting residue was triturated with DMSO to yield the title compound as a yellow solid. MS (ESI): mass calculated for C24H30N6O5, 482.5; m / z measured 427.1 [M-56+H]+.1H NMR (400 MHz, CDCI3) 68.38 (d, J = 8.8 Hz, 2H), 8.23 (d, J = 8.8 Hz, 2H), 6.49 (s, 1 H), 4.27 - 4.12 (m, 4H), 3.98 (s, 3H), 3.12 - 2.97 (m, 2H), 2.89 (br d, J = 9.6 Hz, 2H), 2.82 (q, J = 7.2 Hz, 2H), 1.59 (br s, 9H), 1.33 (t, J - 7.2 Hz, 3H) ppm. Step B. tert-Butyl 4-(6-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-4-oxo-2,4- dihydro-5H-[1 , 2, 3]triazolo[4,5-c]pyridin-5-yl)piperazine-1 -carboxylate

[0401] A mixture of tert-butyl 4-(6-ethyl-2-(4-(methoxycarbonyl)phenyl)-4-oxo-2,4- dihydro-5H-[1 ,2, 3]triazolo[4,5-c]pyridin-5-yl)piperazine-1 -carboxylate (1.04 g, 1.8 mmol) in THF (25.0 mL) at 0 °C was subjected to three cycles of vacuum and recharging with N2. The mixture was charged with CHsMgCI (3.2 mL, 9.6 mmol, 3 M in THF) via syringe over 5 min at 0 °C, and the resulting mixture was stirred at 0 °C for 6 hours. The reaction was then quenched with sat. aq. NH4CI and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was subjected to column chromatography over silica gel (gradient elution: 0 - 35% EtOAc / petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C25H34N6O4, 482.5; m / z measured 427.2 [M-56+H]+.1H NMR (400 MHz, CDCI3) 58.25 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 8.8 Hz, 2H), 6.49 (s, 1 H), 4.26 - 4.14 (m, 3H), 3.12 - 2.97 (m, 2H), 2.89 (br d, J - 9.6 Hz, 2H), 2.81 (q, J - 7.6 Hz, 2H), 1.65 (s, 6H), 1.52 (s, 9H), 1.33 (t, J = 7.2 Hz, 3H) ppm.

[0402] Step C. tert-Butyl 4-(7-bromo-6-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-4- oxo-2, 4-dihydro-5H-[1 , 2, 3]triazolo[4,5-c]pyridin-5-yl)piperazine-1 -carboxylate

[0403] A mixture of tert-butyl 4-(6-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-4-oxo-2,4- dihydro-5H-[1 ,2, 3]triazolo[4,5-c]pyridin-5-yl)piperazine-1 -carboxylate (587.0 mg, 1.1 mmol) and NBS (226.0 mg, 1.3 mmol) in DMF (10 mL) was stirred at room temperature for 12 hours. The reaction mixture was treated with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was subjected to column chromatography over silica gel (gradient elution: 0 - 30% EtOAc / petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C25H33BrN6O4, 560.2 / 563.2; m / z measured 505.1 / 507.1 [M-56+H]+.1H NMR (400 MHz, CDCI3) 58.28 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 8.8 Hz, 2H), 4.27 - 4.14 (m, 4H), 3.16 - 3.01 (m, 4H), 2.95 - 2.90 (m, 2H), 1.65 (s, 6H), 1.52 (s, 9H), 1.32 - 1.28 (m, 3H) ppm. Step D. tert-Butyl 4-(6-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-7-(2-methoxy- 2-oxoethyl)-4-oxo-2,4-dihydro-5H-[1 ,2,3]triazolo[4,5-c]pyridin-5-yl)piperazine-1 - carboxylate

[0404] A solution of tert-butyl 4-(7-bromo-6-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)- 4-oxo-2,4-dihydro-5 / - / -[1 ,2, 3]triazolo[4,5-c]py rid in-5-yl) pi perazine- 1 -carboxylate (465 mg, 828 pmol), tert-butyl((1 -methoxyvinyl)oxy)dimethylsilane (1.3 g, 6.9 mmol), XPhos Pd G4 (143 mg, 166 pmol) and XPhos (80 mg, 168 pmol) in THF (8.0 mL) was sparged with N2 for 1 minute. The mixture was warmed to 100 °C then stirred at 100 °C for 12 hours. The reaction mixture was treated with H2O and extracted with EtOAc. The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was subjected to column chromatography over silica gel (gradient elution: 0 - 30% EtOAc / petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C28H38N6O6, 554.3; m / z measured 499.2 [M-56+H]+.1H NMR (400 MHz, CDCI3) 58.25 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H), 4.32 - 4.15 (m, 4H), 3.87 (s, 2H), 3.76 (s, 3H), 3.13 - 2.99 (m, 2H), 2.92 (br d, J = 12.4 Hz, 2H), 2.84 (q, J = 7.6 Hz, 2H), 1 .65 (s, 6H), 1 .52 (s, 9H), 1.31 - 1 .26 (m, 3H) ppm.

[0405] Step E. tert-Butyl 4-(7-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-6-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-4-oxo-2,4-dihydro-5 / - / - [1 , 2,3]triazolo[4,5-c] pyrid in-5-yl) pi perazi ne- 1 -carboxylate

[0406] To a mixture of tert-butyl 4-(6-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-7-(2- methoxy-2-oxoethyl)-4-oxo-2,4-dihydro-5 / - / -[1 ,2,3]triazolo[4,5-c]pyridin-5- yl)piperazine-1 -carboxylate (285 mg, 513.8 pmol) in THF (5 mL) at 0 °C under N2 atmosphere was added LiHMDS (3 mL, 3 mmol, 1 M in THF) dropwise. The reaction mixture was stirred for 30 minutes, then 2-chloro-4-(trifluoromethyl)aniline (1 g, 5.1 mmol) was added and the resulting mixture further warmed to 25 °C and stirred for 1 hour. The reaction mixture was diluted with EtOAc, the reaction was quenched with H2O and sat. NH4CI. The aqueous layer was extracted with EtOAc. The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was subjected to column chromatography over silica gel (gradient elution: 0 - 55% EtOAc / petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C34H39CIF3N7O5, 717.3; m / z measured 662.2 [M-56+H]+.1H NMR (400 MHz, CDCI3) 68.53 - 8.59 (m, 2 H) 8.25 - 8.30 (m, 2 H) 7.64 - 7.70 (m, 2 H) 7.47 - 7.53 (m, 2 H) 4.13 - 4.29 (m, 4 H) 3.95 - 4.00 (m, 2 H) 2.98 - 3.12 (m, 4 H) 2.85 - 2.96 (m, 2 H) 1 .77 - 1 .87 (m, 1 H) 1 .65 (s, 6 H) 1 .50 (s, 9 H) 1 .28 - 1 .33 (m, 3 H);19F NMR (376 MHz, CDCI3) 6 -62.42 (3 F) ppm.

[0407] Step F. / V-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-2-(4-(2- hydroxypropan-2-yl)phenyl)-4-oxo-5-(piperazin-1 -yl)-4,5-dihydro-2 / - / -

[0408] [1 .2.3]triazolo[4,5-c]pyridin-7-yl)acetamide hydrochloride

[0409] A mixture of tert-butyl 4-(7-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-6-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-4-oxo-2,4-dihydro-5 / -t-

[0410] [1 .2.3]triazolo[4,5-c]pyridin-5-yl)piperazine-1 -carboxylate (900 mg, 1.2 mmol) in HCI / 1 ,4-dioxane (15 mL, 30 mmol, 2 M) was stirred at room temperature for 0.5 hour. The mixture was concentrated under vacuum to yield the title compound as a yellow solid, which was used in the subsequent step without further purification. MS (ESI): mass calculated for C29H31CIF3N7O3, 617.2; m / z measured 618.2 [M+H]+.

[0411] Step G. / V-(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-dihydro-2 / - / -[1 ,2,3]triazolo[4,5-c]pyridin-7-yl)acetamide

[0412] A mixture of / V-(2-chloro-4-(trifluoromethyl)phenyl)-2-(6-ethyl-2-(4-(2- hydroxypropan-2-yl)phenyl)-4-oxo-5-(piperazin-1 -yl)-4,5-dihydro-2 / -t-

[0413] [1 .2.3]triazolo[4,5-c]pyridin-7-yl)acetamide hydrochloride (800 mg, 1.2 mmol), 5- hydroxy-6-methylpyrimidine-4-carboxylic acid (400 mg, 2.0 mmol), HOPO (80 mg, 720.1 pmol), EDCI (270 mg, 1.4 mmol), and DIEA (420 pL, 2.5 mmol) in 1 ,4-dioxane (40 mL) was allowed to gradually warm to 50 °C over the course of 5 minutes, after which time stirring continued for 4 hours. The resulting mixture was subjected by prep-HPLC (Stationary phase: Welch Xtimate C18, 150 x 30 mm, 5 pm; Mobile phase: water (NH4HCO3) (A) - ACN (B), gradient elution: 38 - 68% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound. MS (ESI): mass calculated for C35H35CIF3N9O5, 753.2; m / z measured 754.3 [M+H]+.1H NMR (400 MHz, CDCI3) 6 1 1 .74 - 11 .91 (m, 1 H) 8.54 - 8.78 (m, 3 H) 8.25 - 8.30 (m, 2 H) 7.65 - 7.70 (m, 2 H) 7.52 - 7.54 (m, 1 H) 7.48 - 7.52 (m, 1 H) 5.78 - 5.88 (m, 1 H) 4.83 - 4.94 (m, 1 H) 4.31

[0414] - 4.47 (m, 2 H) 3.96 - 4.03 (m, 2 H) 3.49 - 3.63 (m, 1 H) 3.08 - 3.19 (m, 2 H) 2.99 - 3.08 (m, 3 H) 2.51 - 2.61 (m, 3 H) 1 .65 (s, 6 H) 1 .32 - 1 .38 (m, 3 H);19F NMR (376 MHz, CDCI3) 5 -62.40 (3F) ppm.

[0415] Example 1 1 . ( / ?)- / V-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-3-methylpiperazin-1 -yl)-2-(4-(2-hydroxypropan-2- yl)phenyl)-7-oxo-2 / - / -[1 ,2,3]triazolo[4,5-b]pyridin-4(7 / - / )-yl)acetamide.

[0416] Step A. (F?)-tert-Butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-5-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-7-oxo-4,7-dihydro-2 / - / - [1 , 2, 3]triazolo[4,5-b]pyridin-6-yl)-2-methylpiperazine-1 -carboxylate

[0417] A mixture of 2-(6-bromo-5-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-7-oxo-2 / - / - [1 ,2,3]triazolo[4,5-b]pyridin-4(7 / - / )-yl)-A / -(2-chloro-4-(trifluoromethyl)phenyl)acetamide (100.0 mg, 163 pmol) and (F?)-tert-butyl 2-methylpiperazine-1 -carboxylate (327 mg, 1.6 mmol) in DMSO (1.6 mL) was stirred for 16 hours at 130 °C. The reaction solution was then diluted with H2O and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated. The resulting residue was subjected to prep-HPLC (C18 150 x 30 mm x 10 pm; Mobile phase: water (FA)-ACN, gradient elution: 65 - 95% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C35H41CIF3N7O5 732.2; m / z measured 732.2 / 734.2 [M+H]+. Step B. (R)- / V-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-(2- hydroxypropan-2-yl)phenyl)-6-(3-methylpiperazin-1 -yl)-7-oxo-2H-[1 ,2,3]triazolo[4,5- b]pyridin-4(7H)-yl)acetamide

[0418] A mixture of (R)- tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-5-ethyl-2-(4- (2-hydroxypropan-2-yl)phenyl)-7-oxo-4,7-dihydro-2R- [1 ,2, 3]triazolo[4,5-b]pyridin-6-yl)-2-methylpiperazine-1 -carboxylate (20.0 mg, 27.3 pmol), in HCI (1 .0 mL, 2.0 mmol, 2 M in 1 ,4-dioxane) was stirred for 1 hour at room temperature. The reaction mixture was adjusted to pH 7 with aq. NaHCOs, then extracted with EtOAc. The organic phase was concentrated to yield the title compound as a white solid, which was used without further purification in the subsequent step. MS (ESI): mass calculated for C35H41CIF3N7O5 732.2; m / z measured 732.2 / 734.2 [M+H]+.

[0419] Step C. (R)- / V-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-3-methylpiperazin-1 -yl)-2-(4-(2-hydroxypropan-2- yl)phenyl)-7-oxo-2H-[1 ,2,3]triazolo[4,5-b]pyridin-4(7R)-yl)acetamide

[0420] A mixture of 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (5.0 mg, 32.4 pmol), EDCI (6.3 mg, 32.9 pmol), DIPEA (10.0 mg, 77.4 pmol) and HOPO (1.4 mg, 12.6 pmol) in anhydrous 1 ,4-dioxane (100.0 pL) was stirred for 30 minutes at 30 °C, then charged with (R)- / V-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-(2- hydroxypropan-2-yl)phenyl)-6-(3-methylpiperazin-1 -yl)-7-oxo-2H-[1 ,2,3]triazolo[4,5- b]pyridin-4(7H)-yl)acetamide (18.0 mg, 27.3 pmol) in one portion. The reaction was stirred for 16 hours at 30 °C. The reaction solution was diluted with H2O and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduce pressure. The resulting residue was purified by pre-HPLC (C18 150 x 30 mm x 10 pm; Mobile phase: water (FA)-ACN, gradient elution: 47 - 77% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C36H37CIF3N9O5 768.2; m / z measured 768.3 / 770.3 [M+H]+.1H NMR (400 MHz, DMSO-ofe) 6 10.44 (br d, J = 5.0 Hz, 1 H), 8.56 (d, J = 4.5 Hz, 1 H), 8.06 (d, J = 8.8 Hz, 3H), 7.96 (s, 1 H), 7.70 (br d, J = 8.8 Hz, 3H), 5.38 (s, 2H), 5.23 (s, 1 H), 4.85 - 4.35 (m, 1 H), 4.01 - 3.88 (m, 1 H), 3.74 - 3.67 (m, 2H), 3.20 - 3.13 (m, 2H), 3.02 - 2.94 (m, 1 H), 2.81 - 2.72 (m, 1 H), 2.69 - 2.59 (m, 2H), 2.44 (d, J = 4.0 Hz, 3H), 1 .50 - 1 .39 (m, 9H), 1 .23 (br t, J = 7.4 Hz, 3H);19F NMR (376 MHz, DMSO-d6) 6 -60.81 (3F) ppm.

[0421] Example 12. (S)- / V-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-3-methylpiperazin-1 -yl)-2-(4-(2-hydroxypropan-2- yl)phenyl)-7-oxo-2 / - / -[1 ,2,3]triazolo[4,5-b]pyridin-4(7 / - / )-yl)acetamide

[0422] Step A. (S)- tert- Butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-5-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-7-oxo-4,7-dihydro-2 / - / - [1 , 2, 3]triazolo[4,5-b]pyridin-6-yl)-2-methylpiperazine-1 -carboxylate

[0423] A mixture of 2-(6-bromo-5-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-7-oxo-2 / - / - [1 ,2,3]triazolo[4,5-b]pyridin-4(7 / - / )-yl)-A / -(2-chloro-4-(trifluoromethyl)phenyl)acetamide (100.0 mg, 163.2 pmol) and (S)-tert-butyl 2-methylpiperazine-1 -carboxylate (326.8 mg, 1.6 mmol) in DMSO (1.6 mL) was stirred for 16 hours at 130 °C. The reaction solution was diluted with H2O and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated. The resulting residue was purified by prep-HPLC (C18 150 x 30 mm x 10 urn; Mobile phase: water(FA)-ACN, gradient elution: 65 - 95% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C35H41CIF3N7O5 732.2; m / z measured 732.2 / 734.2 [M+H]+.

[0424] Step B. (S)- / V-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-(2- hydroxypropan-2-yl)phenyl)-6-(3-methylpiperazin-1 -yl)-7-oxo-2 / - / -[1 ,2,3]triazolo[4,5- b]pyndin-4(7H)-yl)acetamide A mixture of (S)-tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-5-ethyl-2- (4-(2-hydroxypropan-2-yl)phenyl)-7-oxo-4,7-dihydro-2 / - / - [1 ,2, 3]triazolo[4,5-b]pyridin-6-yl)-2-methylpiperazine-1 -carboxylate (25.0 mg, 34.1 pmol) in HCI (1 .0 mL, 2.0 mmol, 2 M in 1 ,4-dioxane) was stirred for 1 hour at room temperature. The reaction mixture was adjusted to pH 7 with aq. NaHCOs, then extracted with EtOAc. The organic phase was concentrated to yield the title compound, which was use as such in the subsequent reaction. MS (ESI): mass calculated for C30H33CIF3N7O3 632.1 ; m / z measured 632.2 / 634.2 [M+H]+.

[0425] Step C. (S)- / V-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-3-methylpiperazin-1 -yl)-2-(4-(2-hydroxypropan-2- yl)phenyl)-7-oxo-2 / - / -[1 ,2,3]triazolo[4,5-b]pyridin-4(7 / - / )-yl)acetamide

[0426] A mixture of 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (5.6 mg, 36.3 pmol), EDCI (7.2 mg, 37.6 pmol), DIPEA (11 .0 mg, 85.1 pmol) and HOPO (1 .5 mg, 13.5 pmol) in anhydrous 1 ,4-dioxane (100 pL) was stirred for 30 minutes at 30 °C. (S)- / V-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-(2-hydroxypropan-2- yl)phenyl)-6-(3-methylpiperazin-1 -yl)-7-oxo-2 / - / -[1 ,2,3]triazolo[4,5-b]pyridin-4(7 / - / )- yl)acetamide (18.0 mg, 27.3 pmol) was then added in one portion. The mixture was stirred for 16 hours at 30 °C, then diluted with H2O and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated. The resulting residue was purified by prep-HPLC (C18 150 x 30 mm x 10 urn; Mobile phase: water(FA)-ACN, gradient elution: 47 - 77% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C36H37CIF3N9O5 768.2; m / z measured 768.3 / 770.2 [M+H]+.1H NMR (400 MHz, DMSO-ofe) 6 10.66 - 10.19 (m, 1 H), 8.56 (d, J = 5.5 Hz, 1 H), 8.06 (br d, J = 8.5 Hz, 3H), 7.97 (s, 1 H), 7.70 (br d, J= 8.5 Hz, 3H), 5.38 (br s, 2H), 5.21 (br s, 1 H), 4.82 - 4.32 (m, 1 H), 4.01 - 3.88 (m, 1 H), 3.82 - 3.64 (m, 2H), 3.24 - 3.1 1 (m, 3H), 2.97 (td, J = 6.6, 13.1 Hz, 1 H), 2.76 (br d, J = 9.5 Hz, 1 H), 2.65 (br d, J= 12.3 Hz, 1 H), 2.44 (d, J= 4.0 Hz, 3H), 1 .48 - 1 .37 (m, 9H), 1 .23 (br t, J= 7.3 Hz, 3H);19F NMR (376 MHz, DMSO-ofe) <5 -60.81 (3F) ppm. Example 13. N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-((1 *S,6*S)-5-(5- hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-7-oxo-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4-

[0427] Step A. rac-tert-Butyl (1 S,6S)-5-(4-(2-((2-chloro-4- (trifluoromethyl)phenyl)amino)-2- oxoethyl)-5-ethyl-2-(4-(2-hydroxypropan-2- yl)phenyl)-7-oxo-4,7-dihydro-2 / - / -[1 ,2,3]triazolo[4,5-£>]pyridin-6-yl)-2,5- diazabicyclo[4.2.0]octane-2-carboxylate

[0428] A mixture of 2-(6-bromo-5-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-7-oxo-2 / - / - [1 ,2,3]triazolo[4,5-b]pyridin-4(7 / - / )-yl)-A / -(2-chloro-4-(trifluoromethyl)phenyl)acetamide (500 mg, 816 pmol) and rac-tert-butyl (1 S,6S)-2,5-diazabicyclo[4.2.0]octane-2- carboxylate (1.7 g, 8.2 mmol) in DMSO (5.0 mL) was stirred for 19 hours at 130 °C. The reaction was purified by prep-HPLC (C18 150 x 30 mm x 10 urn; Mobile phase: water(FA)-ACN, gradient elution: 55 - 85% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as a brown solid. MS (ESI): mass calculated for C36H41CIF3N7O5 743.3 / 745.3; m / z measured 744.2 / 746.2 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 6 10.42 (s, 1 H), 8.08 - 8.01 (m, 3H), 7.97 (d, J = 1 .4 Hz, 1 H), 7.70 (d, J = 8.8 Hz, 3H), 5.36 (s, 2H), 5.22 (s, 1 H), 4.00 - 3.88 (m, 1 H), 3.85 - 3.73 (m, 1 H), 3.57 - 3.46 (m, 1 H), 3.16 - 2.88 (m, 6H), 2.20 - 2.10 (m, 1 H), 1.98 - 1.83 (m, 1 H), 1.72 (q, J = 7.2 Hz, 1 H), 1.46 (s, 6H), 1.40 (s, 9H), 1.21 (t, J - 7.6 Hz, 3H);19F NMR (376 MHz, DMSO-cfe) <5 -60.81 (3F) ppm. Step B. rac-2-(6-((1 S,6S)-2,5-Diazabicyclo[4.2.0]octan-2-yl)-5-ethyl-2-(4-(2- hydroxypropan-2-yl)phenyl)-7-oxo-2,7-dihydro-4 / - / -[1 ,2,3]triazolo[4,5-£j]pyridin-4-yl)- / V- (2-chloro-4-(trifluoromethyl)phenyl)acetamide

[0429] A mixture of tert-butyl (rac-(1 S,6S)-5-(4-(2-((2-Chloro-4- (trifluoromethyl)phenyl)amino)-2-oxoethyl)-5- ethyl-2-(4-(2-hydroxypropan-2- yl)phenyl)-7-oxo-4,7-dihydro-2 / - / -[1 ,2,3]triazolo[4,5-£>]pyridin-6-yl)-2,5- diazabicyclo[4.2.0]octane-2-carboxylate (230.0 mg, 309 pmol) in HCI / 1 ,4-dioxane (4.0 mL, 1 M) was stirred at rt for 4 hours. The mixture was adjusted to pH ~ 8 with aq. NaHCOs and extracted with EtOAc. The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated to yield the title compound as a yellow solid, which was used without further purification in the subsequent step. MS (ESI) calculated for C31H33CIF3N7O3, 643.2 / 645.2; m / z measured 644.2 / 646.2 [M+H]+.

[0430] Step C. / V-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(rac-(1 S,6S)-5-(5- hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-7-oxo-2,7-dihydro-4 / - / -[1 ,2,3]triazolo[4,5-b]pyridin-4- yl)acetamide

[0431] A mixture of rac-2-(6-((1 S,6S)-2,5-diazabicyclo[4.2.0]octan-2-yl)-5-ethyl-2-(4- (2-hydroxypropan-2-yl)phenyl)-7-oxo-2,7-dihydro-4 / - / -[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)- / V-(2-chloro-4-(trifluoromethyl)phenyl)acetamide (214 mg, 304 pmol), 5-hydroxy-6- methylpyrimidine-4-carboxylic acid (70.5 mg, 457 pmol), HOPO (21.1 mg, 190 pmol), EDCI (88 mg, 459 pmol), and DIEA (220 pL, 1 .3 mmol) in DMF (4.0 mL) was stirred at 50 °C for 16 hours under N2. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was subjected to prep-HPLC (Stationary phase: Welch Xtimate C18, 5 pm, 150 x 30 mm; Mobile phase: water (NH4HCO3) (A) - ACN (B), gradient elution: 30 - 60% B in A over 7 min, flow rate: 25 mL / min) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C37H37CIF3N9O5, 779.3 / 781.3; m / z measured 780.3 / 782.3 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 6 10.54 - 10.37 (m, 1 H), 8.49 (br s, 1 H), 8.06 (d, J = 8.8 Hz, 3H), 7.98 (d, J = 1.6 Hz, 1 H), 7.71 (d, J= 8.8 Hz, 3H), 5.38 (s, 2H), 5.22 (s, 1 H), 4.52 - 4.42 (m, 1 H), 3.93 - 3.81 (m, 1 H), 3.61 - 3.49 (m, 1 H), 3.47 - 3.39 (m, 2H), 3.26 - 3.16 (m, 2H), 3.14 - 2.99 (m, 2H), 2.42 (s, 3H), 1 .59 (br d, J = 6.8 Hz, 1 H), 1 .47 (s, 6H), 1 .39 - 1 .28 (m, 2H), 1.23 (br t, J = 7.6 Hz, 3H);19F NMR (376 MHz, DMSO-de) 5 -60.79 (3F) ppm.

[0432] Step D. N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-((1 *S,6*S)-5-(5- hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-7-oxo-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4- yl)acetamide

[0433] The racemic mixture from Step C was separated by SFC (Stationary phase: Chiralpak AD-3 50 x 4.6 mm, 3 pm; Mobile phase: CO2 - iso-propanol (0.2% NH3) (B), gradient elution: 40% B in A at 3.5 mL / min) to yield the first eluting compound (99% purity, 100% ee) as an orange powder. MS (ESI): mass calculated for C37H37CIF3N9O5, 779.3; m / z measured 780.3 [M+H]+.1H NMR (400 MHz, DMSO-ok) 5 10.44 (s, 1 H), 8.50 (s, 1 H), 8.05 (d, J = 8.8 Hz, 3H), 7.98 - 7.95 (m, 1 H), 7.74 - 7.66 (m, 3H), 5.40 - 5.33 (m, 2H), 5.25 - 5.19 (m, 1 H), 4.54 - 4.41 (m, 1 H), 3.94 - 3.80 (m, 1 H), 3.64 - 3.49 (m, 1 H), 3.44 (br d, J = 0.7 Hz, 2H), 3.25 - 3.20 (m, 2H), 3.15 - 2.96 (m, 3H), 2.43 - 2.40 (m, 3H), 1 .64 - 1 .54 (m, 1 H), 1 .46 (s, 6H), 1 .37 - 1 .28 (m, 2H), 1 .24 - 1 .20 (m, 3H);19F NMR (376 MHz, DMSO-ok) 5 -60.81 (3F) ppm.

[0434] Example 14. N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-((1 *R,6*R)-5-(5- hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-7-oxo-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4- The second eluting compound from Example 13, step D was isolated (98% purity, 99% ee) as an orange powder. MS (ESI): mass calculated for C37H37CIF3N9O5, 779.3; m / z measured 780.3[M+H]+.1H NMR (400 MHz, DMSO-ok) 6 10.43 (s, 1 H), 8.56 (s, 1 H), 8.06 (d, J = 8.8 Hz, 3H), 7.99 - 7.95 (m, 1 H), 7.70 (d, J = 8.8 Hz, 3H), 5.37 (s, 2H), 5.21 (s, 1 H), 4.53 - 4.41 (m, 1 H), 3.95 - 3.82 (m, 1 H), 3.62 - 3.48 (m, 1 H), 3.47 - 3.38 (m, 2H), 3.28 - 3.18 (m, 2H), 3.14 - 2.96 (m, 2H), 2.43 (s, 3H), 1.64 - 1 .54 (m, 1 H), 1 .46 (s, 6H), 1.37 - 1 .28 (m, 2H), 1 .25 - 1 .21 (m, 3H);19F NMR (376 MHz, DMSO-cfe) <5 -60.81 (3F).

[0435] Example 15. (R)- / V-(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-dihydro-2H-[1 ,2,3]triazolo[4,5-c]pyridin-7-yl)acetamide

[0436] Step A. tert-Butyl (F?)-2-methyl-4-nitrosopiperazine-1 -carboxylate

[0437] To a solution of tert-butyl (F?)-2-methylpiperazine-1 -carboxylate (25 g, 125 mmol) dissolved in H2O (250 mL) and AcOH (113 mL) was slowly added an aqueous sodium nitrite solution (NaNC (52.4 g, 749 mmol) dissolved in H2O (250 mL)) dropwise at 0 °C. The reaction was stirred at 25 °C for 16 hours. The reaction mixture was filtered and concentrated to dryness in vacuo to yield a residue. The 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 C10H19N3O3, 229.1 ; m / z measured 174.1 [M-56+H]+.

[0438] Step B. tert-Butyl (F?)-4-amino-2-methylpiperazine-1 -carboxylate To a solution of tert-butyl (R)-2-methyl-4-nitrosopiperazine-1 -carboxylate (21.9 g, 95.5 mmol) in THF (220 mL) and H2O (220 mL) was added NFUCI (60.1 g, 1.1 mol). To this mixture was added Zn (31 .5 g, 481 mmol) portion-wise over 1 hour the resulting mixture was stirred at 25 °C for 12 hours. The reaction mixture was filtered. The filtrate was diluted with EtOAc and extracted. The organic layers were dried over anhydrous Na2SO4, filtered and concentrated to yield the title compound as a yellow oil. MS (ESI): mass calculated for C10H21N3O2, 215.2; m / z measured 160.2 [M-56+H]+.

[0439] Step C. tert-Butyl (R)-4-(4-bromo-1 H-1 ,2,3-triazole-5-carboxamido)-2- methylpiperazine -1 -carboxylate

[0440] A mixture of lithium 4-bromo-1 H-1 ,2,3-triazole-5-carboxylate (5 g, 25.1 mmol), tert-butyl (R)-4-amino-2-methylpiperazine-1 -carboxylate (6 g, 25.1 mmol), HOPO (2.8 g, 25.2 mmol) and EDCI (4.8 g, 25.0 mmol) in / V, / V-dimethylformamide (60 mL) was stirred at 55 °C for 2 hours. The solution was poured into H2O (100 mL) and acidified to pH = 6 at 0 °C by 1 M HCI, 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 elution: 0 - 40% EtOAc in petroleum ether) to yield the title compound as a yellow gum. MS (ESI) calculated for Ci3H2iBrN6O3, 388.1 / 390.1 ; m / z measured 333.0 / 335.0 [M-56+H]+.

[0441] Step D. tert-Butyl (R)-4-(5-bromo-2-(4-(methoxycarbonyl)phenyl)-2 / - / -1 ,2,3- triazole-4- carboxamido)-2-methylpiperazine-1 -carboxylate

[0442] A mixture of tert-butyl (R)-4-(4-bromo-1 H-1 ,2,3-triazole-5-carboxamido)-2- methylpiperazine-1 -carboxylate (5 g, 10.9 mmol) in 1 ,4-dioxane (100 mL) was heated at 105 °C until the solid was dissolved. Then (4-(methoxycarbonyl) phenyl)(2,4,6- trimethoxyphenyl)iodonium 2,2,2-trifluoroacetic acid (6.4 g, 11 .5 mmol) and DIEA (3.6 mL, 21 .8 mmol) were added into the mixture at 105 °C and the resulting mixture was stirred for 75 minutes. The mixture was then concentrated under vacuum to yield a yellow-brown solid, which was triturated with tert-butyl methyl ether (100 mL) at 25 °C for 20 minutes. The mixture was filtered to yield the title compound as a brown solid. MS (ESI) calculated for C2iH27BrNeO5, 522.1 ; m / z measured 467.0 [M-56+H]+. Step E. tert-Butyl (F?)-4-(2-(4-(methoxycarbonyl)phenyl)-5-(prop-1 -yn-1 -yl)-2 / -t- 1 ,2,3- triazole-4-carboxamido)-2-methylpiperazine-1 -carboxylate

[0443] A mixture of tert-butyl (F?)-4-(5-bromo-2-(4-(methoxycarbonyl)phenyl)-2H-1 ,2,3- triazole- 4-carboxamido)-2-methylpiperazine-1 -carboxylate (2.4 g, 4.6 mmol), ((prop- 1 -yn-1 -ylboraneylidene)-l3-fluoraneyl)potassium(lll) fluoride (2.0 g, 13.9 mmol), TEA (811 pL, 9.0 mmol) and Pd(dppf)Cl2*CH2Cl2 (324.5 mg, 443.5 pmol) was degassed and purged with N2 for 3 times. The reaction mixture was stirred at 100 °C for 3 hours under N2 atmosphere. The reaction mixture was poured into H2O (100 mL) which resulted in the formation of a yellow precipitate. The mixture was filtered and the filter cake was triturated with tert-butyl methyl ether (30 mL) at 25 °C for 20 minutes to yield the title compound as a yellow solid. MS (ESI): mass calculated for C24H30N6O5, 482.2; m / z measured 427.1 [M-56+H]+.

[0444] Step F. tert-Butyl (2F?)-4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-5-(prop-1 -yn-1 - y\)-2H- imidazole-4-carboxamido)-2-methylpiperazine-1 -carboxylate

[0445] To a solution of tert-butyl (F?)-4-(2-(4-(methoxycarbonyl)phenyl)-5-(prop-1 -yn-1 - yl)- 2 / - / -1 ,2, 3-triazole-4-carboxamido)-2-methylpiperazine-1 -carboxylate (1.8 g, 3.7 mmol) in THF was added CHsMgBr (6.3 mL, 18.9 mmol) dropwise at 0 °C under N2 atmosphere. The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was poured into H2O (30 mL) and a yellow solid precipitated out. The mixture was filtered to yield the title compound. MS (ESI): mass calculated for C25H34N6O4, 481 .3 m / z measured 427.2 [M-56+H]+.

[0446] Step G. tert-Butyl (F?)-4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-4-oxo- 2,4-dihydro- 5H-[1 ,2,3]triazolo[4,5-c]pyridin-5-yl)-2-methylpiperazine-1 -carboxylate

[0447] A mixture of tert-butyl (2R)-4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-5-(prop-1 -yn- 1 -yl) -2H-imidazole-4-carboxamido)-2-methylpiperazine-1 -carboxylate (1.7 g, 2.6 mmol) and DBU (1.2 mL, 8.0 mmol) in / V, / V-dimethylformamide (30 mL) was stirred at 100 °C for 2 hours. The reaction mixture was poured into H2O (100 mL), a yellow solid precipitate out. The yellow solid 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 C25H34N6O4, 482.3; m / z measured 427.2 [M-56+H]+.

[0448] Step H. tert-Butyl (R)-4-(7-bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl- 4-oxo-2,4- di hydro-5H-[ 1 ,2,3]triazolo[4,5-c]pyridin-5-yl)-2-methylpiperazine-1 - carboxylate

[0449] To a solution of tert-butyl (R)-4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl- 4-oxo-2,4- dihydro-5H-[1 ,2,3]triazolo[4,5-c]pyridin-5-yl)-2-methylpiperazine-1 - carboxylate (810 mg, 1.7 mmol) in / V, / V-dimethylformamide (8 mL) was added NBS (300 mg, 1 .7 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours then diluted with EtOAc and H2O and extracted. Th organics were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to yield the title compound as a yellow solid. MS (ESI): mass calculated for C25H33BrNeO4, 560.2; m / z measured 505.1 [M-56+H]+.

[0450] Step I. tert-Butyl (R)-4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-7-(2-methoxy-2- oxoethyl)- 6-methyl-4-oxo-2,4-dihydro-5 / - / -[1 ,2,3]triazolo[4,5-c]pyridin-5-yl)-2- methylpiperazine-1 -carboxylate

[0451] A mixture of tert-butyl (R)-4-(7-bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)-6- methyl- 4-oxo-2,4-dihydro-5 / - / -[1 ,2,3]triazolo[4,5-c]pyridin-5-yl)-2-methylpiperazine-1 - carboxylate (1.2 g, 2.1 mmol), tert-butyl((1 -methoxyvinyl)oxy)dimethylsilane (3.2 g, 17.0 mmol), Xphos (228 mg, 478.3 pmol) and XPhos Pd G4 (378 mg, 438.8 pmol) in THF (15 mL) was degassed and purged with N2 then stirred at 90 °C for 16 hours. The reaction mixture was filtered and concentrated to dryness to yield a residue. The residue was subjected to column chromatography over silica gel (gradient elution: 0 - 45% EtOAc in petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C28H38N6O6, 554.3; m / z measured 499.2 [M-56+H]+.

[0452] Step J. tert-Butyl (R)-4-(7-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-2-(4- (2-hydroxypropan-2-yl)phenyl)-6-methyl-4-oxo-2,4-dihydro-5 / -t- [1 , 2, 3]triazolo[4,5-c]pyridin-5-yl)-2-methylpiperazine-1 -carboxylate

[0453] To a solution of tert-butyl (R)-4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-7-(2- methoxy- 2-oxoethyl)-6-methyl-4-oxo-2,4-dihydro-5 / - / -[1 ,2,3]triazolo[4,5-c]pyridin-5-yl)- 2-methylpiperazine-1 -carboxylate (570 mg, 1.0 mmol) in THF (10 mL) at 0 °C was added LiHMDS (20 mL, 10.0 mmol, 0.5 M in THF) in portions. The reaction mixture was stirred for 30 minutes, and then 2-chloro-4-(trifluoromethyl)aniline (4 g, 20.5 mmol) was added. The mixture was slowly warmed to 25 °C and stirred for 2 hours. The reaction was quenched with sat. NH4CI, diluted with EtOAc and extracted. 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 - 70% EtOAc in petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C34H39CIF3N7O5, 717.3; m / z measured 662.3 [M- 56+H]+.

[0454] Step K. (F?)- / V-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(2-hydroxypropan-2- yl)phenyl)- 6-methyl-5-(3-methylpiperazin-1 -yl)-4-oxo-4,5-dihydro-2 / - / -

[0455] [1 .2.3]triazolo[4,5-c]pyridin-7-yl)acetamide

[0456] A mixture of tert-butyl (F?)-4-(7-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)- 2-oxoethyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-4-oxo-2,4-dihydro-5H-

[0457] [1 .2.3]triazolo[4,5-c]pyridin-5-yl)-2-methylpiperazine-1 -carboxylate (632 mg, 880.0 pmol) in 2M HCI / 1 ,4-dioxane (6 mL, 12 mmol) was stirred at 25 °C for 1 hour. The reaction was quenched with sat. aq. NaHCOs (20 mL) at 0 °C, the resulting mixture was diluted with EtOAc / water and extracted. The organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was triturated with tert-butyl methyl ether (30 mL) at 25 °C for 30 minutes. The mixture was filtered to yield the title compound as a yellow solid. MS (ESI): mass calculated for C29H31CIF3N7O3, 617.2; m / z measured 618.3 [M+H]+.

[0458] Step L. (F?)- / V-(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-dihydro-2 / - / -[1 ,2,3]triazolo[4,5-c]pyridin-7-yl)acetamide A mixture of 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (61 .1 mg, 31 1 pmol), HOPO (17.1 mg, 154 pmol) and EDCI (53.1 mg, 277.0 pmol) in 1 ,4-dioxane (10 mL) was stirred at 25 °C for 20 minutes. (F?)- / V-(2-chloro-4- (trifluoromethyl)phenyl)-2-(2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-5-(3- methylpiperazin-1 -yl)-4-oxo-4,5-dihydro-2 / - / -[1 ,2,3]triazolo[4,5-c]pyridin-7-yl)acetamide (425 mg, 227.3 pmol) was then added. The mixture was stirred at 50 °C for 16 hours, then diluted with EtOAc / water 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: 52-Welch Xtimate C18 150 x 30 mm, 5 pm; Mobile phase: water (NH4HCO3) (A) - MeCN (B), gradient elution: 36 - 66% 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 C35H35CIF3N9O5, 753.2; m / z measured 754.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 69.89 (s, 1 H) 8.57 (br d, J=3.22 Hz, 1 H) 8.11 (br d, J=8.46 Hz, 2 H) 8.05 (br d, J=8.23 Hz, 1 H) 7.92 (s, 1 H) 7.66 - 7.73 (m, 3 H) 5.19 - 5.30 (m, 1 H) 4.42 - 4.90 (m, 1 H) 4.12 - 4.21 (m, 1 H) 4.07 (br s, 2 H) 3.97 (br d, J=10.73 Hz, 1 H) 3.79 (br s, 1 H) 3.14 (br d, J=9.42 Hz, 1 H) 2.98 (br dd, J=14.96, 11.38 Hz, 1 H) 2.85 (br d, J= 10.25 Hz, 1 H) 2.50 (br s, 3 H) 2.45 (br d, <7=2.74 Hz, 3 H) 1 .46 (s, 6 H) 1 .39 - 1 .44 (m, 3 H);19F NMR (376 MHz, DMSO-d6) 6 - 60.75 (3 F) ppm.

[0459] Example 16. / V-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(1 -(5-hydroxy-6- methylpyrimidine-4-carbonyl)piperidin-4-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-7-oxo- 2,7-dihydro-4 / - / -[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0460] Step A. 2-(4-(6-bromo-5-ethyl-7-methoxy-2 / - / -[1 ,2 ,3]triazolo[4,5-b]py ridin-2- yl)phenyl)propan-2-ol

[0461] To a solution of 2-(4-(5-ethyl-7-methoxy-2 / - / -[1 ,2,3]triazolo[4,5-b]pyridin-2- yl)phenyl)propan-2-ol (500 mg, 1.6 mmol) in DMF (5 mL) was added NBS (287 mg, 1 .6 mmol). The mixture was stirred at 50 °C for 12 hours. To the mixture was added brine (20 mL) and the aqueous phase extracted with ethyl acetate. The organic layers were dried with anhydrous Na2SO4, filtered, 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 light yellow solid. MS (ESI): mass calculated for CiyHigBrlShC , 390.1 / 392.1 ; m / z measured 391.1 / 393.1 [M+H]+.1H NMR (400 MHz, DMSO-ofe) 68.27 - 8.22 (m, 2H), 7.78 - 7.74 (m, 2H), 5.24 (s, 1 H), 4.67 (s, 3H), 3.11 - 3.03 (m, 2H), 1 .52 - 1 .47 (m, 6H), 1 .33 - 1 .28 (m, 3H) ppm.

[0462] Step B. tert-Butyl 4-(5-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-7-methoxy-2 / -t-

[0463] [1 .2.3] triazolo[4, 5-b]pyridin-6-yl) pi peridine-1 -carboxylate

[0464] The mixture of 2-(4-(6-bromo-5-ethyl-7-methoxy-2 / - / -[1 ,2,3]triazolo[4,5- b]pyridin-2-yl) phenyl)propan-2-ol (590 mg, 1.5 mmol), CPhos Pd Gs (120 mg, 148.6 pmol) and LiCI (190 mg, 4.5 mmol) was purged with N2 for 10 seconds. The reaction mixture was sealed with parafilm. DMA (15 mL) was injected through the syringe filter into the mixture followed by (1 -(tert-butoxycarbonyl)piperidin-4-yl)zinc(ll) iodide (4.4 mL, 4.7 mmol, 1 .06 M). The mixture was stirred at 60 °C for 2 hours. The mixture was subjected by prep-HPLC (Stationary phase: Xtimate C18, 10 pm, 150 x 40 mm; Mobile phase: water (FA) (A) - ACN (B), gradient elution: 56 - 86% B in A over 10 min, flow rate: 25 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C27H37N5O4, 495.3; m / z measured 496.4[M+H]+.1H NMR (400 MHz, DMSO-ofe) 68.26 - 8.17 (m, 2H), 7.79 - 7.69 (m, 2H), 5.27 - 5.22 (m, 1 H), 4.53 - 4.46 (m, 3H), 4.10 - 4.06 (m, 1 H), 3.64 - 3.56 (m, 2H), 3.07 - 2.97 (m, 2H), 2.26 - 2.13 (m, 2H), 1.79 - 1 .72 (m, 2H), 1 .60 - 1 .52 (m, 2H), 1 .50 - 1 .47 (m, 6H), 1 .45 (s, 9H), 1 .31 - 1 .24 (m, 3H) ppm.

[0465] Step C. tert-Butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-5-ethyl-2- (4-(2-hydroxypropan-2-yl)phenyl)-7-oxo-4,7-dihydro-2 / -t-

[0466] [1 .2.3]triazolo[4,5-b] pyrid in-6-yl) pi peridi ne- 1 -carboxylate

[0467] A mixture of tert-butyl 4-(5-ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-7- methoxy-2 / - / - [1 ,2, 3]triazolo[4,5-b]pyridin-6-yl)piperidine-1 -carboxylate (150.0 mg, 302.7 pmol), / V-(2-chloro-4-(trifluoromethyl)phenyl)-2-iodoacetamide (220.0 mg, 605.3 nmol) and toluene (10 mL) was stirred at 120 °C for 12 hours. The suspended solid was filtered and collected to yield the title compound as a white solid. MS (ESI): mass calculated for C35H40CIF3N6O5, 716.3; m / z measured 717.2[M+H]+.1H NMR (400 MHz, DMSO-cfe) <5 10.43 (s, 1 H), 8.10 - 8.03 (m, 3H), 7.98 (d, J= 1.4 Hz, 1 H), 7.73 - 7.67 (m, 3H), 5.39 (s, 2H), 5.21 (s, 1 H), 4.12 - 3.98 (m, 2H), 2.84 (br d, J = 7.7 Hz, 5H), 2.54 (s, 2H), 1.46 (s, 6H), 1.44 (s, 9H), 1.41 - 1.34 (m, 2H), 1.21 (s, 3H);19F NMR (376 MHz, DMSO-ofe) 6 -60.78 (3F) ppm.

[0468] Step D. / V-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-(2- hydroxypropan-2-yl)phenyl) -7-oxo-6-(piperidin-4-yl)-2,7-dihydro-4 / - / -

[0469] [1 .2.3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0470] The mixture of tert-butyl 4-(4-(2-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2- oxoethyl)-5- ethyl-2-(4-(2-hydroxypropan-2-yl)phenyl)-7-oxo-4,7-dihydro-2 / - / -

[0471] [1 .2.3]triazolo[4,5-b]pyridin-6-yl)piperidine-1 -carboxylate (110 mg, 153.4 pmol) in HCI / 1 ,4-dioxane (2.5 mL, 2 M) was stirred at room temperature for 0.5 hour. The mixture was concentrated under vacuum to yield a yellow solid. The yellow solid was basified with sat. NaHCOs to pH = 8, then extracted with ethyl acetate. The organic layer was concentrated to yield the title compound as white solid. MS (ESI): mass calculated for C30H32CIF3N6O3, 616.2; m / z measured 616.8[M+H]+.

[0472] Step E. / V-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(1 -(5-hydroxy-6- methylpyrimidine-4-carbonyl)piperidin-4-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-7-oxo- 2,7-dihydro-4 / - / -[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide

[0473] A mixture of 5-hydroxy-6-methylpyrimidine-4-carboxylic acid (18.0 mg, 113.3 pmol), HOPO (6.0 mg, 54.0 pmol), EDCI (20.0 mg, 104.3 pmol), and DIEA (40 pL, 293.3 pmol) in 1 ,4-dioxane (3 mL) was stirred under N2 at room temperature for 30 minutes. / V-(2-chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-2-(4-(2-hydroxypropan-2- yl)phenyl)-7-oxo-6-(piperidin-4-yl)-2,7-dihydro-4 / - / -[1 ,2,3]triazolo[4,5-b]pyridin-4- yl)acetamide (60 mg, 91 .3 pmol) was then added. The mixture was warmed to 50 °C and stirred for 12 h, before cooling to room temperature. The mixture was subjected to prep-HPLC (Stationary phase: Xtimate C18, 10 pm, 150 x 40 mm; Mobile phase: water (FA) (A) - ACN (B), gradient elution: 39 - 69% B in A over 10 min, flow rate: 25 mL / min) to yield the title compound. MS (ESI): mass calculated for C36H36CIF3N8O5, 752.2; m / z measured 753.3 [M+H]+.1H NMR (400 MHz, DMSO-ofe) 6 10.56 - 10.32 (m, 1 H), 8.55 (s, 1 H), 8.10 - 8.03 (m, 3H), 7.97 (s, 1 H), 7.70 (br d, J = 8.7 Hz, 3H), 5.39 (s, 2H), 5.21 (br s, 1 H), 4.64 (br d, J= 11.1 Hz, 1 H), 3.61 (br d, J = 12.3 Hz, 1 H), 3.20 - 3.11 (m, 2H), 2.95 - 2.81 (m, 4H), 2.76 - 2.59 (m, 2H), 2.44 (s, 3H), 1 .55 (br d, J = 10.8 Hz, 1 H), 1.46 (s, 6H), 1.38 (br d, J = 10.6 Hz, 1 H), 1.23 (br t, J = 7.3 Hz, 3H);19F NMR (376 MHz, DMSO-de) 5 -60.80 (3F) ppm.

[0474] Biological Examples

[0475] WRN Protein Expression and Purification

[0476] 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 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%.

[0477] All purification steps were carried out at 4°C. Harvested cells were suspended in 20 mM HEPES pH 7.5, 500 mM NaCI, 10% (v / v) glycerol, 20 mM imidazole, 0.1 mM TCEP, 0.02 mM ZnCL, 5 mM MgCL, 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 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 NaCI, 10% (v / v) glycerol, 20 mM imidazole, 0.1 mM TCEP, 0.02 mM ZnCL, 0.1% NP-40), followed by 10 CVs buffer B (20 mM HEPES pH 7.5, 2000 mM NaCI, 10% (v / v) glycerol, 20 mM imidazole, 0.1 mM TCEP, 20 pM ZnCL, 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 NaCI, 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 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 NaCI, 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% Buffer E) and eluted with a linear gradient of 250-1000 mM NaCI 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 NaCI, 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 frozen in liquid N2 and stored at -80°C.

[0478] 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 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.

[0479] Forked dsDNA Preparation

[0480] 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 MgCL and 50 mM NaCI, 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.

[0481] OLIGO-A 5’- TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCGTACCCGATGTGTTCGTTC-3’

[0482] OLIGO-B

[0483] 5’- GAACGAACACATCGGGTACGTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT-3’

[0484] Activity Assay Assembly

[0485] Assay buffer consisted of 25 mM Tris pH 7.5, 25 mM NaCI, 10 mM MgCl2, 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).

[0486] 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:

[0487] 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.

[0488] 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 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 a PHERAstar FSX plate reader (BMG Labtech) using the LUM optical module with gain of 2000 and 0.1 second integration.

[0489] Compound Data Analysis

[0490] Dose-response data was analyzed using the Genedata Screener® software platform (Genedata AG). Samples were normalized to DMSO and no enzyme controls 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. where Sint and So are the fitted maximum and 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.

[0491] Additionally, per-plate and assay-wide performance were qualified by calculating robust Z-prime (RZprime) values for each dataset according to the formula below, with 0.5 being set as the cutoff for passing quality assurance.

[0492] Biological Example 2A: HCT-116 Cell Proliferation Assay (WRN Cellular Viability) Effect of compound treatment on cell proliferation was determined using the

[0493] CellTiter-Glo Luminescent Cell Viability Assay (Promega #G8461 ). HCT-1 16 (ATCC #CCL-247TM) were maintained in McCoy’s 5A+Glumax (Thermo Fisher #36600021 ) supplemented with 10% heat inactivated fetal bovine serum (FBS; Invitrogen #16140). 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 I xPenStrep (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 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 relative to DMSO control (IC50) were determined using Genedata Screener® software.

[0494] 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 #CCL-227™) were maintained in RPMI1640+GlutaMax (Thermo Fisher # 61870036) supplemented with 10% heat inactivated fetal bovine serum (FBS; Invitrogen #16140). 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 I xPenStrep (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: and the 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 relative to DMSO control (IC50) were determined using Genedata Screener® software.

[0495] Representative compounds of formula (I) and compounds of formula (II) 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 and BIO-2, below. Where a compound of formula (I) or compound of formula (II) of the present invention was tested multiple times in any of the assays described herein, the values presented in Tables BIO-1 and BIO-2, below represent the average of said one or more individual measurements.

[0496] Table BIO-1 : Measured WRN Activity, Compounds of Formula (I) Table BIO-2: Measured WRN Activity, Compounds of Formula (II)

[0497] Formulation Example 1 : Solid, Oral Dosage Form - Prophetic Example

[0498] As a specific embodiment of an oral composition, 100 mg of the compound prepared as in Example 1 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.

[0499] 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.

[0500] 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.

Claims

What is Claimed:

1. A compound of formula (I)whereinR1is selected from the group consisting of Ci 4alkyl,wherein R5is selected from the group consisting of methyl, ethyl, 5-hydroxy-6- methyl-pyrimidin-4-yl and 3-hydroxy-pyridin-2-yl;R2is methyl or ethyl;R3is 2-chloro-4-trifluoromethyl-phenyl;R4is 2-hydroxy-n-propan-2-yl; or a pharmaceutically acceptable salt thereof.

2. A compound as in Claim 1 , wherein R1is Ci 4alkyl .

3. A compound as in Claim 2, wherein R1is propan-2-yl.

4. A compound as in Claim 1 , wherein R15. A compound as in Claim 1 , wherein6. A compound as in Claim 1 , wherein7. A compound as in Claim 1 , wherein R5is selected from the group consisting of methyl, ethyl, 5-hydroxy-6-methyl-pyrimidin-4-yl and 3-hydroxy-pyridin-2-yl.

8. A compound as in Claim 1 , wherein R5is methyl or 5-hydroxy-6-methyl- pyrimidin-4-yl.

9. A compound as in Claim 1 , wherein R1is selected from the group consisting of 4-acetyl-piperazin-1 -yl, 1 -(5-hydroxy-6-methyl-pyrimidin-4-yl-carbonyl)-piperidin-4-yl, 4-(5-hydroxy-6-methyl-pyridin-4-yl-carbonyl)-piperazin-1 -yl, 4-(5-hydroxy-6-methyl- pyrimidin-4-yl-carbonyl)-3R-methyl-piperazin-1 -yl, 4-(5-hydroxy-6-methyl-pyrimidin-4- yl-carbonyl)-3S-methyl-piperazin-1 -yl, and ((1 S*,6S*)-5-(5-hydroxy-6-methyl- pyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl.

10. A compound as in Claim 1 , wherein R2is methyl.1 1. A compound as in Claim 1 , wherein R2is ethyl.

12. A compound as in Claim 1 selected from the group consisting ofN-[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-triazolo[4,5-b]pyridin-4-yl]acetamide;2-[6-(4-acetyl pi perazi n- 1 -yl)-2-[4-( 1 -hydroxy-1 -methyl-ethyl)phenyl]-5-methyl-7- oxo-triazolo[4,5-b]pyridin-4-yl]-N-[2-chloro-4-(trifluoromethyl)phenyl]acetamide;2-[6-(4-acetylpiperazin-1 -yl)-5-ethyl-2-[4-( 1 -hydroxy-1 -methyl-ethyl)phenyl]-7- oxo-triazolo[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-triazolo[4,5-b]pyridin-4-yl]acetamide;N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[5-ethyl-2-[4-(1 -hydroxy-1 -methyl- ethyl)phenyl]-6-[4-(5-hydroxy-6-methyl-pyrimidine-4-carbonyl)piperazin-1 -yl]-7-oxo- triazolo[4,5-b]pyridin-4-yl]acetamide;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-oxo-2,7- dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide;(R)- / V-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-3-methylpiperazin-1 -yl)-2-(4-(2-hydroxypropan-2- yl)phenyl)-7-oxo-2 / - / -[1 ,2,3]triazolo[4,5-b]pyridin-4(7 / - / )-yl)acetamide;(S)- / V-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(4-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-3-methylpiperazin-1 -yl)-2-(4-(2-hydroxypropan-2- yl)phenyl)-7-oxo-2 / - / -[1 ,2,3]triazolo[4,5-b]pyridin-4(7 / - / )-yl)acetamide;N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-((1 *S,6*S)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-7-oxo-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4- yl)acetamide;N-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-((1 *R,6*R)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-7-oxo-2,7-dihydro-4H-[1 ,2,3]triazolo[4,5-b]pyridin-4- yl)acetamide; / V-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(5-ethyl-6-(1 -(5-hydroxy-6- methylpyrimidine-4-carbonyl)piperidin-4-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-7-oxo- 2,7-dihydro-4 / - / -[1 ,2,3]triazolo[4,5-b]pyridin-4-yl)acetamide; and pharmaceutically acceptable salts thereof.

13. A compound of formula (II)whereinR11is selected from the group consistingwherein R5is selected from the group consisting of methyl, ethyl, 5-hydroxy-6- methyl-pyrimidin-4-yl and 3-hydroxy-pyridin-2-yl;R2is methyl or ethyl;R3is 2-chloro-4-trifluoromethyl-phenyl;R4is 2-hydroxy-n-propan-2-yl; or a pharmaceutically acceptable salt thereof.

14. A compound as in Claim 13, wherein R1115. A compound as in Claim 13, wherein16. A compound as in Claim 13, wherein R11is.

17. A compound as in Claim 13, wherein R5is selected from the group consisting of methyl, 5-hydroxy-6-methyl-pyrimidin-4-yl and 3-hydroxy-pyridin-2-yl.

18. A compound as in Claim 13, wherein R5is methyl or 5-hydroxy-6-methyl- pyrimidin-4-yl.

19. A compound as in Claim 13, wherein R11is selected from the group consisting of 1 -acetyl-piperidi n-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.

20. A compound as in Claim 13, wherein R2is methyl.21 . A compound as in Claim 13, wherein R2is ethyl.

22. A compound as in Claim 13 selected from the group consisting of2-[5-(1 -acetyl-4-piperidyl)-2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6-methyl-4- oxo-triazolo[4,5-c]pyridin-7-yl]-N-[2-chloro-4-(trifluoromethyl)phenyl]acetamide;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-methyl-4-oxo-4,5- dihydro-2H-[1 ,2,3]triazolo[4,5-c]pyridin-7-yl)acetamide;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- dihydro-2H-[1 ,2,3]triazolo[4,5-c]pyridin-7-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- oxo-4, 5-dihydro-2H-[1 ,2,3]triazolo[4,5-c]pyridin-7-yl)acetamide;(R)-A / -(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-dihydro-2H-[1 ,2,3]triazolo[4,5-c]pyridin-7-yl)acetamide; and pharmaceutically acceptable salts thereof.

23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound as in Claim 1 or 13.

24. A pharmaceutical composition made by mixing a compound as in Claim 1 or 13and a pharmaceutically acceptable carrier.

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

26. 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 or 13.

27. The method of Claim 26, wherein the disorder mediated by or modulated by inhibition of WRN is a cancer.

28. The method of Claim 26, wherein the disorder mediated by or modulated by inhibition of WRN is a cancer characterized as microsatellite instability (MSI) or mismatch repair deficient (dMMR).

29. The method of Claim 26, wherein the disorder mediated by or modulated by inhibition of WRN is 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, brain,neuroendocrine, soft tissue, appendiceal, leukemia, lymphoma, and myeloma cancers.

30. 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, 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 or 13.31 . A method of treating a cancer mediated by or modulated by inhibition of WRN comprising administering to a subject in need thereof a therapeutically effective amount of the composition of Claim 23.

32. 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 repair deficient (dMMR) comprising administering to a subject in need thereof a therapeutically effective amount of the composition of Claim 23.

33. 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, 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 23.

34. The use of a compound as in Claim 1 or 13 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, (I) 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.

35. The use of a compound as in Claim 1 or 13, for use in a methods for treating a 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, bladder, skin, prostate, brain, neuroendocrine, soft tissue, appendiceal, leukemia, lymphoma, and myeloma cancers, in a subject in need thereof.

36. A compound as in Claim 1 or 13 for use as a medicament.

37. A compound as in Claim 1 or 13 for use in the treatment of a disorder mediated by or modulated by inhibition of WRN.

38. A compound as in Claim 1 or 13 for use in the treatment of a cancer characterized as microsatellite instability (MSI) or mismatch repair deficient (dMMR).

39. A compound as in Claim 1 or 13 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 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.

40. A composition comprising a compound as in Claim 1 or 13 for use in the treatment of a disorder mediated by or modulated by inhibition of WRN.41 . A composition comprising a compound as in Claim 1 or 13 for use in the treatment of a cancer characterized as microsatellite instability (MSI) or mismatch repair deficient (dMMR).

42. A composition comprising a compound as in Claim 1 or 13 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 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.

43. A composition comprising a compound of as in Claim 1 or 13, and one or more additional therapeutically active agents.

44. A composition as in Claim 43, wherein an additional therapeutically active agent is an anti-cancer agent.

45. A composition as in Claim 43, wherein an additional therapeutically active anticancer agent is a chemotherapy.

46. A composition as in Claim 43, wherein an additional therapeutically 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®), 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®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine (difluorodeoxycitidine), hydroxyurea (Hydrea®), Idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L- asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), 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®).

47. A composition as in Claim 43, wherein an additional therapeutically active agent is a PD-1 inhibitor.

48. A composition as in Claim 43, wherein an additional therapeutically active agent is an anti-PD-1 antibody molecule.

49. A composition as in Claim 43, 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 (Medimmune), Cemiplimab (REGN2810, Regeneron), Dostarlimab (TSR-042, Tesaro), PF-06801591 (Pfizer), Tislelizumab (BGB-A317, Beigene), BGB-108(Beigene), INCSHR1210 (Incyte), Balstilimab (AGEN2035, Agenus), Sintilimab (InnoVent), Toripalimab (Shanghai Junshi Bioscience), Camrelizumab (Jiangsu Hengrui Medicine Co.), and AMP-224 (Amplimmune).

50. A method of treating a disorder mediated by or modulated by inhibition of WRN comprising administration of a composition as in Claim 43.51 . A method of treatment as in Claim 50, wherein the disorder mediated by or modulated by inhibition of WRN is a cancer characterized as microsatellite instability (MSI) or mismatch repair deficient (dMMR).

52. A method of treatment as in Claim 50, wherein an additional therapeutically active agent is an anti-cancer agent.

53. A method of treatment as in Claim 50, wherein an additional therapeutically active anti- cancer agent is a chemotherapy.

54. A method of treatment as in Claim 50, wherein an additional therapeutically 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®), 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®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine(difluorodeoxycitidine), hydroxyurea (Hydrea®), Idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L- asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), 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®).

55. A method of treatment as in Claim 50, wherein an additional therapeutically active agent is a PD-1 inhibitor.

56. A method of treatment as in Claim 50, wherein an additional therapeutically active agent is an anti-PD-1 antibody molecule.

57. A method of treatment as in Claim 50, 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 (Medimmune), Cemiplimab (REGN2810, Regeneron), Dostarlimab (TSR-042, Tesaro), PF-06801591 (Pfizer), Tislelizumab (BGB-A317, Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), Balstilimab (AGEN2035, Agenus), Sintilimab (InnoVent), Toripalimab (Shanghai Junshi Bioscience), Camrelizumab (Jiangsu Hengrui Medicine Co.), and AMP-224 (Amplimmune).

58. A compound, composition, pharmaceutical composition, method of preparation or method of treatment as described here.

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