[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one derivatives useful as inhibitors of wrn

Abstract

The present invention is directed to [1,2,4]triazolo[1,5-a]pyrimidin-7(4H)- one derivatives, pharmaceutical compositions containing them and their use in the treatment of diseases and conditions modulated by inhibition of WRN.

Description

[0001] [1 ,2,4]TRIAZOLO[1 ,5-A]PYRIMIDIN-7(4H)-ONE DERIVATIVES USEFUL AS INHIBITORS OF WRN

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority from United States Provisional Application Serial No. 63 / 678127 filed 01 August 2024, the contents of which is incorporated by reference in it’s entirety.

[0004] FIELD OF THE INVENTION

[0005] The present invention is directed to [1 ,2,4]triazolo[1 ,5-a]pyrimidin-7(4H)- one derivatives, pharmaceutical compositions containing them and their use in the treatment of diseases and conditions modulated by inhibition of WRN. More particularly, the compounds of the present invention are useful in the treatment of cancers with microsatellite instability (MSI) 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 Medical Association, 2011 , pp 2304-2310, 305(22). While recent clinical trials have demonstrated that anti-PD-1 monoclonal antibodies (alone or in combination with anti-CTLA-4 therapy) are efficacious for advanced MSI- H / dMMR colorectal, endometrial, and other cancers, (Overman, M et al., Lancet Oncology, 2017, pp 1182-1191 , 18(9); Overman, M et al., Journal of Clinical Oncology, 2018, pp 773-779, 36(8); Marabelle, A et al., Journal of Clinical Oncology, 2020, pp 1 -14, 38(1 ); Andre, T et al., New England Journal of Medicine, 2020, pp 2207-2218, 383(23); Le, D et al., Journal of Clinical Oncology, 2020, pp 11-19, 38(1 ); Lenz, H et al., Journal of Clinical Oncology, 2022, pp 161-170, 40(2); O’Malley, D et al., Journal of Clinical Oncology, 2022, pp 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.

[0008] 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 511-516, 568(7753)) Genetic depletion of WRN, which is an ATP-dependent DNA helicase of the RecQ family (Hickson, I, Nature Reviews Cancer, 2003, pp 169-178, 3(3)), resulted in the selective induction of DNA double-strand breaks (DSBs) in 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, 11 (8)). Interestingly, the ATP-dependent helicase activity of WRN was essential to the survival of MSI cancer cells, whereas its 3’-5’ exonuclease function was dispensable (Chan, E et al., Nature, 2019, pp 551-556, 568(67753); Kategaya, L et al., iScience, 2019, pp 488-497, 13; Lieb, S et al., eLife, 2019, 4333, 8; Behan, F et al., Nature, 2019, pp 511 - 516, 568(7753)). The dependence of MSI cancer cells on WRN was subsequently demonstrated to be mechanistically driven by prevalent expansion alterations in microsatellites characterized by a TA dinucleotide repeat motif, causing cruciform DNA structures that require WRN helicase activity for their resolution (van Wietmarschen, N et al., Nature, 2020, pp 292- 298, 586(7828)). In the absence of 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)).

[0009] 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).

[0010] BORDAS, V., et al., in PCT Publication W02022 / 249060 A1 , published 01 December 2022 described triazolo-pyrimidine analogues for treating diseases connected to the inhibition of Werner Syndrome RecQ Helicase (WRN).

[0011] EAGON, S., et al., in Bioorq. & Med. Chem. Lett., 2021 , Vol. 52 (including supplemental materials) described plasmodium falciparum falcilysin inhibitors. He, L-J. , et al., in Bioorq. & Med. Chem. Lett., 2019, pp549-555, Vol. 29(4) describe CDK8 inhibitor chemotypes. Scott, C.E. et al., in J. Chem. Inform. Model., (2016), pp 201-212, Vol. 561 (1 ) describe inverse agonists for the CB1 receptor. SUMMARY OF THE INVENTION

[0012] The present invention is directed to compounds of formula (I) wherein is selected from the group consisting of unsubstituted or substituted phenyl, unsubstituted or substituted 5 membered heteroaryl, and unsubstituted or substituted 6 membered heteroaryl; wherein the substituted phenyl, substituted 5 membered heteroaryl or substituted 6 membered heteroaryl is substituted with one or more independently selected from the group consisting of halogen, -OH, oxo, CN, Ci- 4alkyl, halogen substituted Ci-4alkyl, hydroxy substituted Ci-ealkyl, (fluoro substituted Ci-4alkyl)-OH, -(Ci-4alkyl)-CN, -(Ci-4alkyl)-O-(Ci-4alkyl), -(hydroxy substituted Ci-4alkyl)-O-(Ci-2alkyl), -O-(Ci-4alkyl), -O-(halogen substituted Ci-4alkyl), -O-(Ci-4alkyl)-CN, -C(O)-NRARB, -(Ci-4alkyl)-C(O)-NRARB, -NRARB, - (hydroxy substituted Ci-4alkyl)-NRARB, -NH-C(O)-NRARB, -NRA-SO2-(Ci-4alkyl), and -SO2-NRARB; and wherein RAand RBare each independently selected from the group consisting of hydrogen, Ci-4alkyl and hydroxy substituted Ci- 4alkyl; provided that when is unsubstituted phenyl, methylphenyl, chlorophenyl, thiophenyl or unsubstituted 6 membered heteroaryl, then a is 1 ; a is an integer from 0 to 1 ;

[0013] R1is selected from the group consisting of Cs-ecycloalkyl, -(Ci-2alkyl)-C3- scycloalkyl, 4 to 6 membered heterocyclyl and -(Ci-2alkyl)-(4 to 6 membered heterocyclyl); wherein the Cs-ecycloalkyl or 4 to 6 membered heterocyclyl, whether alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, oxo, -CN, Ci-4alkyl, hydroxy substituted Ci-4alkyl, halogen substituted Ci- 4alkyl, -(Ci-4alkyl)-CN, -O-Ci-4alkyl, -O-(halogen substituted Ci-4alkyl), -C(0)- (Ci-4alkyl), -C(O)OH, -C(O)-O-(Ci-4alkyl), -NRCRD, -C(O)-NRCRD, -NRc-C(O)- (Ci-4alkyl), -NRc-C(O)-O-(Ci-4alkyl), -NRc-SO2-(Ci-4alkyl) and -SO2-(Ci-4alkyl); and wherein Rcand RDare each independently selected from the group consisting of hydrogen and Ci-4alkyl;

[0014] R2is selected from the group consisting of hydrogen, Ci-4alkyl, hydroxy substituted Ci-4alkyl, halogen substituted Ci-4alkyl, -(Ci-2alkyl)-CN, C2-4alkenyl, hydroxy substituted C2-4alkenyl, -(Ci-2alkyl)-O-(Ci-4alkyl), -(C2-4alkenyl)-O-(Ci- 4alkyl), -(C2-4alkenyl)-O-(Ci-4alkyl), Cs-ecycloalkyl, Cs-ecycloalkenyl, and 4 to 6 membered heterocycloalkyl; wherein the Cs-ecycloalkyl, Cs-ecycloalkenyl, phenyl or 4 to 6 membered heterocycloalkyl is optionally substituted one or more substituents independently selected from the group consisting of -OH, oxo, -Ci-4alkyl, -0- (Ci-4alkyl), -C(O)-(Ci-4alkyl), -C(O)-C3-6cycloalkyl, -C(O)OH, and -C(O)O-(Ci- 4alkyl);

[0015] R3is selected from the group consisting of Ci-4alkyl, hydroxy substituted Ci-4alkyl, -(Ci-2alkyl)-O-(Ci-4alkyl), and Cs-ecycloalkyl;

[0016] R4is selected from the group consisting of phenyl, and 5 to 6 membered heteroaryl; wherein the phenyl or 5 to 6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, pentafluorothio, Ci-4alkyl, halogen substituted Ci- 4alkyl, -O-Ci-4alkyl, -O-(halogen substituted Ci-4alkyl), and Cs-scycloalkyl; and stereoisomers, and pharmaceutically acceptable salts thereof.

[0017] The present invention is further directed to processes for the preparation of the compounds of formula (I). The present invention is further directed to a product prepared according to the process described herein.

[0018] 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.

[0019] Exemplifying the invention are methods of 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 comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.

[0020] In an embodiment, the present invention is directed to a compound of formula (I) for use as a medicament. In another embodiment, the present invention is directed to a compound of formula (I) for use in the treatment of a disorder mediated by 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.

[0021] In another embodiment, the present invention is directed to a composition comprising a compound of formula (I) for the treatment of 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.

[0022] 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 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.

[0023] 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 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.

[0024] DETAILED DESCRIPTION OF THE INVENTION

[0025] The present invention is directed to compounds of formula (I) wherein , a, R1, R2, R3, and R4are as herein defined. In the compounds of formula (I) of the present invention, the ring is substituted or unsubstituted independent of the (R1)agroup (such that the (R1)agroup is a further substitution on the ring).

[0026] 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.

[0027] In certain embodiments, the present invention is directed to compounds of formula (I -A) compounds of formula (I) wherein a is 0 and wherein , R2, R3, and

[0028] R4are as herein defined.

[0029] In certain embodiments, the present invention is directed to compounds of formula (l-B) compounds of formula (I) wherein a is 1 and wherein and R4are as herein defined. In certain embodiments, the present invention is directed to compounds of formula (I) wherein is phenyl, a is 1 and wherein R1is bound at the 4-position of the phenyl.

[0030] In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 0 and is selected from the group consisting of substituted phenyl, unsubstituted or substituted 5 membered heteroaryl, and substituted 6 membered heteroaryl.

[0031] In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 0 and is substituted phenyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 0 and is unsubstituted or substituted 5 membered heteroaryl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 0 and is substituted 6 membered heteroaryl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 1 and is selected from the group consisting of unsubstituted or substituted phenyl, unsubstituted or substituted 5 membered heteroaryl, and unsubstituted or substituted 6 membered heteroaryl.

[0032] In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 1 and is selected from the group consisting of unsubstituted phenyl, unsubstituted 5 membered heteroaryl and unsubstituted 6 membered heteroaryl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 1 and is selected from the group consisting of substituted phenyl, substituted 5 membered heteroaryl and substituted 6 membered heteroaryl.

[0033] In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 1 and is unsubstituted or substituted phenyl.

[0034] In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 1 and is unsubstituted or substituted 5 membered heteroaryl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 1 and is unsubstituted or substituted 6 membered heteroaryl.

[0035] In certain embodiments, the present invention is directed to compounds of formula (I) wherein is unsubstituted or substituted phenyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein is unsubstituted or substituted 5 membered heteroaryl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein is unsubstituted or substituted 6 membered heteroaryl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein is selected from the group consisting of unsubstituted or substituted phenyl and unsubstituted or substituted 5 membered heteroaryl.

[0036] In certain embodiments, the present invention is directed to compounds

[0037] (JAJ) of formula (I) wherein is selected from the group consisting of unsubstituted or substituted phenyl, unsubstituted or substituted 5 membered heteroaryl, substituted 5 membered heteroaryl, and unsubstituted or substituted 6 membered heteroaryl; wherein the substituted phenyl, substituted 5 membered heteroaryl or substituted 6 membered heteroaryl is substituted with one to three substituents independently selected from the group consisting of halogen, -OH, oxo, CN, Ci-2alkyl, halogen substituted Ci-4alkyl, hydroxy substituted Ci-ealkyl, (fluoro substituted Ci-4alkyl)-OH, -(Ci-3alkyl)-CN, -(hydroxy substituted Ci-4alkyl)-O-(Ci-2alkyl), -O-(Ci-2alkyl), -O-(halogen substituted Ci-2alkyl), O-(Ci-4alkyl)-CN, -(Ci-4alkyl)-O-(Ci-2alkyl), -C(O)-NRARB, -(Ci-2alkyl)- C(O)-NRARB, -NRARB, -(hydroxy substituted Ci-4alkyl)-NRARB, -NH-C(O)- NRARB, -NRA-SO2-(Ci-4alkyl), and -SO2-NRARB;and wherein RAand RBare each independently selected from the group consisting of hydrogen, Ci-2alkyl and hydroxy substituted Ci salkyl.

[0038] In certain embodiments, the present invention is directed to compounds of formula (I) wherein is selected from the group consisting of substituted phenyl, unsubstituted or substituted 5 membered heteroaryl, and substituted 6 membered heteroaryl; wherein the substituted phenyl, substituted 5 membered heteroaryl or substituted 6 membered heteroaryl is substituted with one to three substituents independently selected from the group consisting of halogen, -OH, oxo, CN, Ci-2alkyl, halogen substituted Ci-4alkyl, hydroxy substituted Ci-ealkyl, (fluoro substituted Ci-4alkyl)-OH, -(Ci-3alkyl)-CN, -(hydroxy substituted Ci- 4alkyl)-O-(Ci-2alkyl), -O-(Ci-2alkyl), -O-(halogen substituted Ci-2alkyl), O-(Ci-4alkyl)-CN, -(Ci-4alkyl)-O-(Ci-2alkyl), -C(0)-NRARB, -(Ci-2alkyl)-C(O)-NRARB, - NRARB, -(hydroxy substituted Ci-4alkyl)-NRARB, -NH-C(O)-NRARB, -NRA-SO2- (Ci-4alkyl), and -S02-NRARB;and wherein RAand RBare each independently selected from the group consisting of hydrogen, Ci-2alkyl and hydroxy substituted Ci salkyL

[0039] In certain embodiments, the present invention is directed to compounds of formula (I) wherein is selected from the group consisting of unsubstituted or substituted phenyl, unsubstituted or substituted 5 membered heteroaryl, and unsubstituted or substituted 6 membered heteroaryl; wherein the substituted phenyl, substituted 5 membered heteroaryl or substituted 6 membered heteroaryl is substituted with halogen or Ci-2alkyl.

[0040] In certain embodiments, the present invention is directed to compounds

[0041] A'A;) of formula (I) wherein is selected from the group consisting of phenyl, 2- fluoro-phenyl, 3-fluoro-phenyl, 4-chloro-phenyl, 2-methyl-phenyl, 3-methyl- phenyl, 4-methyl-phenyl, 2,6-dimethyl-phenyl, 4-hydroxy-methyl-phenyl, 4-(1 - hydroxy-ethyl)-phenyl, 4-(2-hydroxy-ethyl)-phenyl, 4-(1 -hydroxy-isopropyl)- phenyl, 2-fluoro-4-(1 -hydroxy-isopropyl)-phenyl, 4-(2-hydroxy-1 , 1 -dimethyl)- phenyl, 4-(3-hydroxy-n-propyl)-phenyl, 4-(2-hydroxy-3-methoxy-n-propyl)- phenyl, 4-(3-hydroxy-3-methyl-n-butyl)-phenyl, 4-(1 -methyl-3-hydroxy-n-butyl)- phenyl, 4-(2-methyl-2-hydroxy-methyl-3-hydroxy-n-propyl)-phenyl, 4- (1 ,1 ,1 ,3,3,3-hexafluoro-2-hydroxy-isopropyl)-phenyl, 4-(3,3,3-trifluoro-2- hydroxy-isopropyl)-phenyl, 2-methoxy-phenyl, 4-methoxy-phenyl, 2-methoxy-4- hydroxy-methyl-phenyl, 3-hydroxy-methyl-4-fluoro-phenyl, 4-difluoro-methoxy- phenyl, 4-(2,2-difluoro-ethoxy)-phenyl, 4-(methoxy-methyl)-phenyl, 4-(1 - methoxy-ethyl)-phenyl, 4-(2-methoxy-ethyl)-phenyl, 4-(2-methoxy-isopropyl)- phenyl, 3-fluoro-4-(methoxy-methyl)-phenyl, 3-cyano-phenyl, 2-fluoro-4-cyano- phenyl, 3-fluoro-4-cyano-methyl-phenyl, 4-cyano-methyl-phenyl, 4-(2-cyano- isopropyl)-phenyl, 4-(cyano-methoxy)-phenyl, 4-(amino-carbonyl)-phenyl, 2- fluoro-4-(amino-carbonyl)-phenyl, 4-(methyl-amino-carbonyl-amino)-phenyl, 4- (amino-carbonyl-methyl)-phenyl, 4-(3-hydroxy-n-propyl-amino-carbonyl)- phenyl, 4-(methyl-amino-carbonyl-methyl)-phenyl, 4-(3-amino-2-methyl-2- hydroxy-n-propyl)-phenyl, 4-(1 -methyl-3-(methyl-amino-carbonyl)-n-propyl)- phenyl, 4-(amino-sulfonyl)-phenyl, 4-(methyl-sulfonyl-amino)-phenyl, pyridin-3- yl, 2-methyl-pyridin-3-yl, 5-difluoromethyl-pyridin-3-yl, 6-hydroxy-methyl-pyridin-

[0042] 3-yl, 2-hydroxy-pyridin-4-yl, 2-methoxy-pyridin-4-yl, 6-methoxy-pyridin-3-yl, 2- cyano-pyridin-4-yl, 5-cyano-pyridin-3-yl, 6-cyano-pyridin-3-yl, 1 -methyl-2-oxo- pyridin-4-yl, 6-amino-pyridin-3-yl, 6-(methyl-amino-carbonyl)-pyridin-3-yl, pyrazol-4-yl, 3-methyl-pyrazo-4-yl, 3-methyl-pyrazol-5-yl, 1 -methyl-pyrazol-4-yl, 1 ,3-dimethyl-pyrazol-4-yl, 1 ,3-dimethyl-pyrazol-5-yl, 1 ,4-dimethyl-pyrazol-5-yl,

[0043] 1 ,5-dimethyl-pyrazol-4-yl, 1 -(difluoro-methyl)-pyrazol-4-yl, 1 -ethyl-5-fluoro- pyrazol-4-yl, 1 -(2,2-difluoro-ethyl)-pyrazol-4-yl, 1 -methyl-5-fluoro-pyrazol-4-yl, 1 -methyl-5-chloro-pyrazol-4-yl, 1 -methyl-3-methoxy-pyrazol-4-yl, 1 -(2-methoxy- ethyl)-pyrazol-4-yl, 1 -methyl-5-(methoxy-methyl)-pyrazol-4-yl, 1 -(2,2-difluoro- ethoxy)-pyrazol-4-yl, 1 -(2-hydroxy-ethyl)-pyrazol-4-yl, 1 -(2-hydroxy-n-propyl)- pyrazol-4-yl, 1 -hydroxy-ethyl-5-methyl-pyrazol-4-yl, 1 -(2-hydroxy-ethyl)-5- methyl-pyrazol-4-yl, 1 -hydroxy-ethyl-4-methyl-pyrazol-5-yl, 1 -(2-hydroxy-1 ,1- dimethyl-ethyl)-pyrazol-4-yl, 1 -(2-cyano-ethyl)-pyrazol-4-yl, 1 -methyl-5-cyano- pyrazol-4-yl, 1 -methyl-3-cyano-pyrazol-4-yl, 1-(amino-carbonyl-methyl)-pyrazol-

[0044] 4-yl, 1 -(methyl-amino-carbonyl-methyl)-pyrazol-4-yl, 6-methyl-pyridazin-4-yl, 1- methyl-imidazol-5-yl, 1 ,2-dimethyl-imidazol-5-yl, thiazol-4-yl, thiazol-5-yl, 2- methyl-thiazol-5-yl, 4-methyl-thiazol-5-yl, 2-hydroxy-methyl-thiazol-5-yl, oxazol-

[0045] 5-yl, 2-methyl-oxazol-5-yl, 2-(hydroxy-methyl)-oxazol-5-yl, 4-methyl-isothiazol- 5-yl, 3-methyl-isoxazol-5-yl, 5-hydroxy-methyl-furan-5-yl, 5-hydroxy-methyl- thiophen-3-yl, and 5-hydroxy-methyl-thiophen-5-yl.

[0046] In certain embodiments, the present invention is directed to compounds of formula (I) wherein is selected from the group consisting of phenyl, 2- fluoro-phenyl, 4-(hydroxy-methyl)-phenyl, 4-(1 -hydroxy-ethyl)-phenyl, 4-(2- hydroxy-ethyl)-phenyl, 4-(1 -hydroxy-isopropyl)-phenyl, 4-cyano-methyl-phenyl, 4-(2-hydroxy-1 , 1 -dimethyl)-phenyl, 4-(2-methyl-2-hydroxy-methyl-3-hydroxy-n- propyl)-phenyl, 4-difluoro-methoxy-phenyl, 4-(2,2-difluoro-ethoxy)-phenyl, 4- (cyano-methoxy)-phenyl, 4-(2-hydroxy-3-methoxy-n-propyl)-phenyl, 4-(3- hydroxy-3-methyl-n-butyl)-phenyl, 2-fluoro-4-(1 -hydroxy-isopropyl)-phenyl, 4- (3,3,3-trifluoro-2-hydroxy-isopropyl)-phenyl, 4-methoxy-methyl-phenyl, 4-(3- hydroxy-n-propyl-amino-carbonyl)-phenyl, 4-(amino-sulfonyl)-phenyl, 4-(methyl- sulfonyl-amino)-phenyl, 4-(methyl-amino-carbonyl-amino)-phenyl, 1 -methyl-5- fluoro-pyrazol-4-yl, and pyridin-3-yl.

[0047] In certain embodiments, the present invention is directed to compounds of formula (I) wherein is selected from the group consisting of 2-fluoro- phenyl, 3-fluoro-phenyl, 4-chloro-phenyl, 2-methyl-phenyl, 3-methyl-phenyl, 4- methyl-phenyl, 2,6-dimethyl-phenyl, 4-hydroxy-methyl-phenyl, 4-(1 -hydroxy- ethyl)-phenyl, 4-(2-hydroxy-ethyl)-phenyl, 4-(1 -hydroxy-isopropyl)-phenyl, 2- fluoro-4-(1 -hydroxy-isopropyl)-phenyl, 4-(2-hydroxy-1 ,1 -dimethyl)-phenyl, 4-(3- hydroxy-n-propyl)-phenyl, 4-(2-hydroxy-3-methoxy-n-propyl)-phenyl, 4-(3- hydroxy-3-methyl-n-butyl)-phenyl, 4-(1 -methyl-3-hydroxy-n-butyl)-phenyl, 4-(2- methyl-2-hydroxy-methyl-3-hydroxy-n-propyl)-phenyl, 4-(1 ,1 ,1 ,3,3,3-hexafluoro- 2-hydroxy-isopropyl)-phenyl, 4-(3,3,3-trifluoro-2-hydroxy-isopropyl)-phenyl, 2- methoxy-phenyl, 4-methoxy-phenyl, 2-methoxy-4-hydroxy-methyl-phenyl, 3- hydroxy-methyl-4-fluoro-phenyl, 4-difluoro-methoxy-phenyl, 4-(2,2-difluoro- ethoxy)-phenyl, 4-(methoxy-methyl)-phenyl, 4-(1 -methoxy-ethyl)-phenyl, 4-(2- methoxy-ethyl)-phenyl, 4-(2-methoxy-isopropyl)-phenyl, 3-fluoro-4-(methoxy- methyl)-phenyl, 3-cyano-phenyl, 2-fluoro-4-cyano-phenyl, 3-fluoro-4-cyano- methyl-phenyl, 4-cyano-methyl-phenyl, 4-(2-cyano-isopropyl)-phenyl, 4-(cyano- methoxy)-phenyl, 4-(amino-carbonyl)-phenyl, 2-fluoro-4-(amino-carbonyl)- phenyl, 4-(methyl-amino-carbonyl-amino)-phenyl, 4-(amino-carbonyl-methyl)- phenyl, 4-(3-hydroxy-n-propyl-amino-carbonyl)-phenyl, 4-(methyl-amino- carbonyl-methyl)-phenyl, 4-(3-amino-2-methyl-2-hydroxy-n-propyl)-phenyl, 4-(1 - methyl-3-(methyl-amino-carbonyl)-n-propyl)-phenyl, 4-(amino-sulfonyl)-phenyl, 4-(methyl-sulfonyl-amino)-phenyl, 2-methyl-pyridin-3-yl, 5-difluoromethyl- pyridin-3-yl, 6-hydroxy-methyl-pyridin-3-yl, 2-hydroxy-pyridin-4-yl, 2-methoxy- pyridin-4-yl, 6-methoxy-pyridin-3-yl, 2-cyano-pyridin-4-yl, 5-cyano-pyridin-3-yl, 6-cyano-pyridin-3-yl, 1 -methyl-2-oxo-pyridin-4-yl, 6-amino-pyridin-3-yl, 6- (methyl-amino-carbonyl)-pyridin-3-yl, pyrazol-4-yl, 3-methyl-pyrazo-4-yl, 3- methyl-pyrazol-5-yl, 1 -methyl-pyrazol-4-yl, 1 ,3-dimethyl-pyrazol-4-yl, 1 ,3- dimethyl-pyrazol-5-yl, 1 ,4-dimethyl-pyrazol-5-yl, 1 ,5-dimethyl-pyrazol-4-yl, 1- (difluoro-methyl)-pyrazol-4-yl, 1 -ethyl-5-fluoro-pyrazol-4-yl, 1 -(2,2-difluoro- ethyl)-pyrazol-4-yl, 1 -methyl-5-fluoro-pyrazol-4-yl, 1 -methyl-5-chloro-pyrazol-4- yl, 1 -methyl-3-methoxy-pyrazol-4-yl, 1 -(2-methoxy-ethyl)-pyrazol-4-yl, 1 -methyl-

[0048] 5-(methoxy-methyl)-pyrazol-4-yl, 1 -(2,2-difluoro-ethoxy)-pyrazol-4-yl, 1 -(2- hydroxy-ethyl)-pyrazol-4-yl, 1 -(2-hydroxy-n-propyl)-pyrazol-4-yl, 1 -hydroxy- ethyl-5-methyl-pyrazol-4-yl, 1 -(2-hydroxy-ethyl)-5-methyl-pyrazol-4-yl, 1 - hydroxy-ethyl-4-methyl-pyrazol-5-yl, 1 -(2-hydroxy-1 , 1 -dimethyl-ethyl)-pyrazol-4- yl, 1 -(2-cyano-ethyl)-pyrazol-4-yl, 1 -methyl-5-cyano-pyrazol-4-yl, 1 -(amino- carbonyl-methyl)-pyrazol-4-yl, 1 -(methyl-amino-carbonyl-methyl)-pyrazol-4-yl,

[0049] 6-methyl-pyridazin-4-yl, 1 -methyl-imidazol-5-yl, 1 ,2-dimethyl-imidazol-5-yl, thiazol-4-yl, thiazol-5-yl, 2-methyl-thiazol-5-yl, 4-methyl-thiazol-5-yl, 2-hydroxy- methyl-thiazol-5-yl, oxazol-5-yl, 2-methyl-oxazol-5-yl, 2-(hydroxy-methyl)- oxazol-5-yl, 4-methyl-isothiazol-5-yl, 3-methyl-isoxazol-5-yl, 5-hydroxy-methyl- furan-5-yl, 5-hydroxy-methyl-thiophen-3-yl, and 5-hydroxy-methyl-thiophen-5-yl.

[0050] In certain embodiments, the present invention is directed to compounds of formula (I) wherein is selected from the group consisting of 4-hydroxy- methyl-phenyl, 4-(2-hydroxy-1 ,1 -dimethyl)-phenyl, 4-(1 -hydroxy-ethyl)-phenyl, 4-(2-hydroxy-ethyl)-phenyl, 4-(1 -hydroxy-isopropyl)-phenyl, 4-(2-methyl-2- hydroxy-methyl-3-hydroxy-n-propyl)-phenyl, 4-(2-hydroxy-3-methoxy-n-propyl)- phenyl, 4-(3-hydroxy-3-methyl-n-butyl)-phenyl, 4-(3,3,3-trifluoro-2-hydroxy- isopropyl)-phenyl, 2-fluoro-4-(1 -hydroxy-isopropyl)-phenyl, 4-difluoro-methoxy- phenyl, 4-(2,2-difluoro-ethoxy)-phenyl, 4-methoxy-methyl-phenyl, 4-cyano- methyl-phenyl, 4-(cyano-methoxy)-phenyl, 4-(3-hydroxy-n-propyl-amino- carbonyl)-phenyl, 4-(methyl-amino-carbonyl-amino)-phenyl, 4-(amino-sulfonyl)- phenyl, 4-(methyl-sulfonyl-amino)-phenyl, and 1 -methyl-5-fluoro-pyrazol-4-yl.

[0051] In certain embodiments, the present invention is directed to compounds

[0052] 6 ;) of formula (I) wherein is 4-(1 -hydroxy-isopropyl)-phenyl. In certain embodiments, the present invention is directed to compounds of formula (I)

[0053] ( A wherein is selected from the group consisting of phenyl, 2-fluoro-phenyl, pyridin-3-yl, pyrazol-4-yl, 1 -methyl-pyrazol-4-yl, thiazol-4-yl, and oxazol-5-yl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein is selected from the group consisting of phenyl, 2- fluoro-phenyl and pyridin-3-yl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein is phenyl.

[0054] In certain embodiments, the present invention is directed to compounds of formula (I) wherein is selected from the group consisting of phenyl, pyridin-3-yl, pyridin-4-yl, pyrazol-5-yl, pyrazol-4-yl, pyridazin-4-yl, thiazol-4-yl, thiazol-5-yl, oxazol-5-yl, imidazol-5-yl, furan-5-yl, thiophen-5-yl, thiophen-3-yl, isothiazol-5-yl, and isoxazol-5-yl; and wherein said groups may be further optionally substituted as herein described.

[0055] In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 0 and is other than unsubstituted phenyl, 2- methyl-phenyl, 3-methyl-phenyl, 2-chloro-phenyl, 4-chloro-phenyl, thiopheneyl, or unsubstituted 6 membered heteroaryl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 0 and is other than unsubstituted phenyl, substituted phenyl (wherein the phenyl is substituted with one chloro or Ci-2alkyl), thiophenyl, or unsubstituted 6 membered heteroaryl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 0 and is other than unsubstituted phenyl, substituted phenyl (wherein the phenyl is substituted with one halogen or Ci-4alkyl), thiophenyl, or unsubstituted 6 membered heteroaryl.

[0056] In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 0. In certain embodiments, the present invention is directed to compounds of formula (I) wherein a is 1 .

[0057] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of Cs-ecycloalkyl, -(Ci-2alkyl)-C3-5cycloalkyl, 4 to 6 membered heterocyclyl and -(Ci-2alkyl)-(4 to 6 membered heterocyclyl); wherein the Cs-ecycloalkyl or 4 to 6 membered heterocyclyl, whether alone or as part of a substituent group, is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, oxo, -CN, Ci-2alkyl, hydroxy substituted Cisalkyl, halogen substituted Ci-2alkyl, -(Ci-2alkyl)-CN, -O-Ci-2alkyl, -O-(halogen substituted Ci-2alkyl), -C(O)-(Ci-2alkyl), -C(O)OH, -C(O)-O-(Ci-4alkyl), -NRCRD, - C(O)-NRCRD, -NRc-C(O)-(Ci-2alkyl), -NRc-C(O)-O-(Ci-4alkyl), -NRC-SO2-(CI-4alkyl) and -SO2-(Ci-2alkyl); and wherein Rcand RDare each independently selected from the group consisting of hydrogen, and Ci-2alkyl.

[0058] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of Cs-ecycloalkyl, -(Ci-2alkyl)-Cs-5cycloalkyl, 4 to 6 membered heterocyclyl and -(Ci-2alkyl)-(4 to 6 membered heterocyclyl); wherein the Cs-ecycloalkyl or 4 to 6 membered heterocyclyl, whether alone or as part of a substituent group, is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, oxo, -CN, Ci-2alkyl, hydroxy substituted Cisalkyl, halogen substituted Ci-2alkyl, -(Ci-2alkyl)-CN, -O-Ci-2alkyl, -O-(halogen substituted Ci-2alkyl), -C(O)-(Ci-2alkyl), -C(O)OH, -C(O)-O-(Ci-4alkyl), -NRCRD, - C(O)-NRCRD, -NRc-C(O)-(Ci-2alkyl), -NRc-C(O)-O-(Ci-4alkyl), -NRC-SO2-(CI-4alkyl) and -SO2-(Ci-2alkyl); and wherein Rcand RDare each independently selected from the group consisting of hydrogen, and Ci-2alkyl.

[0059] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of 2-cyclopropyl, 5-cyclopropyl, 4-(1 -(hydroxy-methyl)-cycloprop-l -yl), 4-(1 -(1 -hydroxy-ethyl)- cycloprop-1 -yl), 4-(1 -cyano-cycloprop-1 -yl), 4-(1 -carboxy-cycloprop-1-yl), 4-(1 - (ethoxy-carbonyl)-cycloprop-l -yl), 4-(1 -amino-cycloprop-1 -yl), 4-(1 -amino- carbonyl-cycloprop-1 -yl), 4-(1 -methyl-amino-carbonyl-cycloprop-1 -yl), 4-(1 - (dimethyl-amino-carbonyl)-cycloprop-l -yl), 4-(1 -(methyl-carbonyl-amino)- cycloprop-1 -yl), 4-(1 -(methyl-sulfonyl-amino)-cycloprop-l -yl), 4-(1 -(tert-butoxy- carbonyl-amino)-cycloprop-1 -yl), 1 -cyclobutyl, 4-cyclobutyl, 1 -(3-hydroxy- cyclobut-1 -yl), 4-(3-hydroxy-cyclobut-1 -yl), 4-(1 -hydroxy-cyclobut-1 -yl), 4-(2- hydroxy-cyclobut-1 -yl), 4-(2R*-hydroxy-cyclobut-1 S*-yl), 4-(2S*-hydroxy- cyclobut-1 R*-yl),4-(3-hydroxy-cyclobut-1 -y I) , 1 -(3-hydroxymethyl-cyclobut-1 -y I ), 4-(2,2-dimethyl-3-hydroxy-cyclobut-1 -y I), 4-(2-methyl-3-hydroxy-cyclobut-1 -y I ), 4-(3-difluoro-methyl-cyclobut-1 -y I) , 1 -(3-methoxy-cyclobut-1 -y I), 4-(3-difluoro- methoxy-cyclobut-1 -y I) , 4-(2-methoxy-3-hydroxy-cyclobut-1 -y I) , 4-(3-methoxy-3- trifluoro-methyl-cyclobut-1 -y I ), 4-(3-cyano-methyl-cyclobut-1 -y I) , 4-(3-methyl-3- cyano-cyclobut-1 -y I), 4-(3-cyano-3-methoxy-carbonyl-cyclobut-1 -y I), 4-(1 -(tert- butoxy-carbonyl-amino)-cyclobut-1 -y I) , 1 -(2-hydroxy-cyclopent-1 -y I), 4-(3- hydroxy-cyclopent-1 -y I), 4R-(2S-(tert-butoxy-carbonyl-amino)-cyclopent-1 -y I), 4-(3,3-difluoro-5-hydroxy-cyclopent-1 -y I) , 4-(4-hydroxy-cyclohex-1 -y I) , 4-(4- hydroxy-cyclohex-1 -y I) , 4-cis-(4-hydroxy-cyclohex-1 -y I) , 4-trans-(4-hydroxy- cyclohex-1 -y I), 4-(4-methyl-4-hydroxy-cyclohex-1 -y I) , 4-(4-(hydroxy-methyl)- cyclohex-1 -y I), 4-cis-(4-(hydroxy-methyl)-cyclohex-1 -y I), 4-trans-(4-(hydroxy- methyl)-cyclohex-1 -y I) , 4-(3-difluoro-methyl-cyclohex-1 -y I) , 4-(4-methoxy- cyclohex-1 -yl), 4-(4-methoxy-cyclohex-1 -yl), 4-cis-(4-methoxy-cyclohex-1 -yl), 4- trans-(4-m ethoxy-cyclohex-1 -yl), 4-(2S-cyano-cyclohex-1 -yl), 4-(4-cyano- cyclohex-1 -yl), 4-(4-amino-cyclohex-1 -yl), 4-(amino-carbonyl-cyclohex-1 -yl), 4- (3-(methyl-sulfonyl)-cyclohex-1 -yl), 4-(1 -hydroxy-cycloprop-1 -yl-ethyl), 1 -(1 - cyano-cycloprop-1 -yl-methyl), 1 -(3-hydroxy-cyclobut-1 -yl-methyl), 4-(1 -hydroxy- cyclobut-1 -yl-methyl), 4-(3-hydroxy-cyclobut-1 -yl-methyl), 4-(1 -hydroxy-methyl- cyclobut-1 -yl-methyl), 4-(1 -hydroxy-cyclopent-1 -yl-methyl), 4-(3-hydroxy- cyclopent-1 -yl-methyl), 4-(1 -hydroxy-cyclohex-1 -yl-methyl), 4-(4-hydroxy- cyclohex-1 -yl-methyl), 4-cis-(4-hydroxy-cyclohex-1 -yl-methyl), 4-trans-(4- hydroxy-cyclohex-1 -yl-methyl), 4-(4-hydroxy-methyl-cyclohex-1 -yl-methyl), 4-(4- (hydroxy-methyl)-cyclohex-l -yl-methyl), 4-cis-(4-(hydroxy-methyl)-cyclohex-1 - yl-methyl), 4-trans-(4-(hydroxy-methyl)-cyclohex-1 -yl-methyl), 6-(3-hydroxy- azetidin-1 -yl), 6-(2-hydroxy-methyl-azetin-1 -yl), 1 S-(pyrrolidin-3-yl), 4-(3- hydroxy-pyrrolidin-1 -yl), 4-(4S-methoxy-pyrrolidin-3R*-yl), 3-(2-oxo-pyrrolidin-1 - yl), 4-(2-oxo-pyrrolidin-5-yl), 6-(2-oxo-pyrrolidin-1 -yl), 4-(1 -methyl-2-oxo- pyrrolidin-4-yl), 1 -(piperidin-4-yl), 6-(2-hydroxy-methyl-piperidin-1 -yl), 6-(3- hydroxy-methyl-piperidin-1 -yl), 4-(2-(ethoxy-carbonyl)-piperidin-4-yl), 4-(oxetan- 3-yl), 4-(3-hydroxy-oxetan-3-yl), 4-(2-methyl-oxetan-3-yl), 4-(tetrahydrofuran-2- yl), 1 -(tetrahydorfuran-3-yl), 4-(3-hydroxy-tetrahydro-furan-4-yl), 4-(4-fluoro- tetrahydrofuran-3-yl), 4-(4-methoxy-tetrahydrofuran-3-yl), 4-(4S*-hydroxy- tetrahydro-furan-3R*-yl), 4-(4R*-hydroxy-tetrahydro-furan-3S*-yl), 4- (tetrahydropyran-4-yl), 4-(4-hydroxy-tetrahydropyran-3-yl), 4-(4-hydroxy- tetrahydropyran-4-yl), 4-(4,5-dihydroxy-tetrahydropyran-2-yl), 4-(3-cyano- tetrahydropyran-4-yl), 2-(morpholin-4-yl), 6-(morpholin-4-yl), 4-(4-hydroxy- tetrahydrothiophen-3-yl-1 ,1 -dioxide), 4-(imidazol-3-yl), 1 -(oxetan-3-yl-methyl), 4-(oxetan-3-yl-methyl), 4-((2-oxo-3-methyl-oxazolidin-5R-yl)-methyl), 4-(3- hydroxy-tetrahydrofuran-3-yl-methyl), 4-(3-cyano-tetrahydrofuran-3-yl-methyl), 4-(4-hydroxy-tetrahydropyran-3-yl-methyl), 4-(4-hydroxy-tetrahydropyran-4-yl- methyl), 4-(4-methoxy-piperidin-4-yl-methyl), 4-(4R-hydroxy-pyrrolidin-2R-yl- methyl), 4-(2-oxo-4S-hydroxy-pyrrolidin-5R-yl-methyl), 4-(1 -methyl-2-oxo- pyrrol idi n-3-yl-m ethyl), 4-(2-(methoxy-carbonyl)-pyrrolidin-2-yl-methyl), 4-(1 - tert-butoxy-carbonyl-4S-fluoro-pyrrolidin-4R-yl-methyl), and 4-(1 -(tert-butoxy- carbonyl-3R-hydroxy-pyrrolidin-5S-yl-methyl).

[0060] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of 4-(1 -(hydroxy- methyl)-cycloprop-1 -yl), 4-(1 -(1 -hydroxy-ethyl)-cycloprop-1 -yl), 4-(1 -carboxy- cycloprop-1 -yl), 4-(1 -(tert-butoxy-carbonyl-amino)-cycloprop-l -yl), 4-(1 -cyano- cycloprop-1 -yl), 4-(1 -amino-cycloprop-1 -yl), 4-(1 -(methyl-carbonyl-amino)- cycloprop-1 -yl), 4-(1 -(methyl-amino-carbonyl)-cycloprop-l -yl), 4-(1 -(dimethyl- amino-carbonyl)-cycloprop-1 -yl), 4-(1 -(methyl-sulfonyl-amino)-cycloprop-l -yl), 4-(2R*-hydroxy-cyclobut-1 S*-yl), 4-(2S*-hydroxy-cyclobuty-1 R*-yl), 4-(3- hydroxy-cyclobut-1 -yl), 4-(2-hydroxy-cyclobut-1 -yl), 4-(1 -hydroxy-cyclobut-1 -yl), 4-(4-hydroxy-cyclohex-1 -yl), 4-(2,2-dimethyl-3-hydroxy-cyclobut-1 -yl), 4-(2- methyl-3-hydroxy-cyclobut-1 -yl), 4-(3-cyano-methyl-cyclobut-1 -yl), 4-(3-methyl-

[0061] 3-cyano-cyclobut-1 -yl), 4-(3-cyano-3-methoxy-carbonyl-cyclobut-1 -yl), 4-(1 - (tert-butoxy-carbonyl-amino)-cyclobut-l -yl), 4-(3-hydroxy-cyclopent-1 -yl), 4- (3,3-difluoro-5-hydroxy-cyclopent-1 -yl), 4-(4-hydroxy-methyl-cyclohex-1 -yl), 4- (4-m ethoxy-cyclohex-1 -yl), 4-(4-cyano-cyclohex-1 -yl), 4-(2S-cyano-cyclohex-1 - yl), 4R-(2S-(tert-butoxy-carbonyl-amino)-cyclopent-1 -yl), 4-(4-amino-cyclohex- 1 -yl), 4-(3-(methyl-sulfonyl)-cyclohex-1 -yl), 4-(1 -hydroxy-cycloprop-1 -yl-ethyl),

[0062] 4-(1 -hydroxy-cyclobut-1 -yl-methyl), 4-(3-hydroxy-cyclobut-1 -yl-methyl), 4-(3- hydroxy-cyclopent-1 -yl-methyl), 4-(oxetan-3-yl), 4-(2-methyl-oxetan-2-yl), 4-(3- hydroxy-tetrahydro-furan-4-yl), 4-(3-hydroxy-pyrrolidin-1 -yl), 4-(1 -methyl-2-oxo- pyrrolidin-4-yl), 4-(tetrahydro-furan-2-yl), 4-(4S*-hydroxy-tetrahydro-furan-3R*- yl), 4-(4R*-hydroxy-tetrahydro-furan-3S*-yl), 4-(4-fluoro-tetrahydrofuran-3-yl), 4- (3-hydroxy-tetrahydro-furan-3-yl-methyl), 4-(4-hydroxy-tetrahydro-pyran-4-yl- methyl), 4-(tetrahydro-pyran-4-yl), 4-(4-hydroxy-tetrahydropyran-3-yl), 4-(4- hydroxy-tetrahydro-pyran-4-yl), 4-(3-cyano-tetrahydropyran-4-yl), 4-(4,5- dihydroxy-tetrahydro-pyran-2-yl), 4-(4-hydroxy-tetrahydro-pyran-3-yl-methyl), 6- (2-hydroxy-methyl-piperidin-1 -y I) , 4-(4-hydroxy-tetrahydro-thiophen-3-yl-1 , 1 - dioxide), 4-(imidazol-3-yl), and 4-((2-oxo-3-methyl-oxazolidin-5R-yl)-methyl).

[0063] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of cyclopropyl, 1 - (hydroxy-methyl)-cycloprop-l -yl, 1 -(1 -hydroxy-ethyl)-cycloprop-1 -yl, 1 -cyano- cycloprop-1 -yl, 1 -carboxy-cycloprop-1 -yl, 1 -(ethoxy-carbonyl)-cycloprop-1 -yl, 1- amino-cycloprop-1 -yl, 1 -amino-carbonyl-cycloprop-1 -yl, 1 -methyl-amino- carbonyl-cycloprop-1 -yl, 1 -(dimethyl-amino-carbonyl)-cycloprop-l -yl, 1 -(methyl- carbonyl-amino)-cycloprop-1 -yl, (1 -(methyl-sulfonyl-amino)-cycloprop-l -yl, (1 - (tert-butoxy-carbonyl-amino)-cycloprop-l -yl, cyclobutyl, 3-hydroxy-cyclobut-1 - yl, 1 -hydroxy-cyclobut-1 -yl, 2-hydroxy-cyclobut-1 -yl, 2R*-hydroxy-cyclobut-1 S*- yl, 2S*-hydroxy-cyclobut-1 R*-yl, 3-hydroxymethyl-cyclobut-1 -yl, 2,2-dimethyl-3- hydroxy-cyclobut-1 -yl, 2-methyl-3-hydroxy-cyclobut-1 -yl, 3-difluoro-methyl- cyclobut-1 -yl, 3-methoxy-cyclobut-1 -yl, 3-difluoro-methoxy-cyclobut-1 -yl, 2- methoxy-3-hydroxy-cyclobut-1 -yl, 3-methoxy-3-trifluoro-methyl-cyclobut-1 -yl, 3- cyano-methyl-cyclobut-1 -yl, 3-methyl-3-cyano-cyclobut-1 -yl, 3-cyano-3- methoxy-carbonyl-cyclobut-1 -yl, 1 -(tert-butoxy-carbonyl-amino)-cyclobut-l -yl, 2-hydroxy-cyclopent-1 -yl, 3-hydroxy-cyclopent-1 -yl, 2S-(tert-butoxy-carbonyl- amino)-cyclopent-1 -yl, 3,3-difluoro-5-hydroxy-cyclopent-1 -yl, 4-hydroxy- cyclohex-1 -yl, 4-hydroxy-cyclohex-1 -yl, cis-(4-hydroxy-cyclohex-1 -yl), trans-(4- hydroxy-cyclohex-1 -yl), 4-methyl-4-hydroxy-cyclohex-1 -yl, 4-(hydroxy-methyl)- cyclohex-1 -yl, cis-(4-(hydroxy-methyl)-cyclohex-1 -yl), trans-(4-(hydroxy- methyl)-cyclohex-1 -yl), 3-difluoro-methyl-cyclohex-1 -yl, 4-methoxy-cyclohex-1 - yl, 4-methoxy-cyclohex-1-yl, cis-(4-methoxy-cyclohex-1 -yl), trans-(4-m ethoxy- cyclohex-1 -yl), 2S-cyano-cyclohex-1 -yl, 4-cyano-cyclohex-1 -yl, 4-amino- cyclohex-1 -yl, amino-carbonyl-cyclohex-1 -yl, 1 -hydroxy-cycloprop-1 -yl-ethyl, 1 - cyano-cycloprop-1 -yl-methyl, 3-hydroxy-cyclobut-1 -yl-methyl, 1 -hydroxy- cyclobut-1 -yl-methyl, 1 -hydroxy-methyl-cyclobut-1 -yl-methyl, 1 -hydroxy- cyclopent-1 -yl-methyl, 3-hydroxy-cyclopent-1 -yl-methyl, 1 -hydroxy-cyclohex-1 - yl-methyl, 4-hydroxy-cyclohex-1 -yl-methyl, cis-(4-hydroxy-cyclohex-1 -yl- methyl), trans-(4-hydroxy-cyclohex-1 -yl-methyl), 4-(hydroxy-methyl)-cyclohex- 1 -yl-methyl, cis-(4-(hydroxy-methyl)-cyclohex-1 -yl-methyl), trans-(4-(hydroxy- methyl)-cyclohex-1 -yl-methyl), 3-hydroxy-azetidin-1 -yl, 2-hydroxy-methyl- azetin-1 -yl, S-(pyrrolidin-3-yl), 3-hydroxy-pyrrolidin-1 -yl, 4S-methoxy-pyrrolidin- 3R*-yl, 2-oxo-pyrrolidin-1-yl, 2-oxo-pyrrolidin-5-yl, 1 -methyl-2-oxo-pyrrolidin-4- yl, piperidin-4-yl, 2-hydroxy-methyl-piperidin-1 -yl, 3-hydroxy-methyl-piperidin-1 - yl, 2-(ethoxy-carbonyl)-piperidin-4-yl, oxetan-3-yl, 3-hydroxy-oxetan-3-yl, 2- methyl-oxetan-3-yl, tetrahydrofuran-2-yl, tetrahydorfuran-3-yl, 3-hydroxy- tetrahydro-furan-4-yl, 4-fluoro-tetrahydrofuran-3-yl, 4-methoxy-tetrahydrofuran- 3-yl, 4S*-hydroxy-tetrahydro-furan-3R*-yl, 4R*-hydroxy-tetrahydro-furan-3S*-yl, tetrahydropyran-4-yl, 4-hydroxy-tetrahydropyran-3-yl, 4-hydroxy- tetrahydropyran-4-yl, 4,5-dihydroxy-tetrahydropyran-2-yl, 3-cyano- tetrahydropyran-4-yl, morpholin-4-yl, 4-hydroxy-tetrahydrothiophen-3-yl-1 ,1 - dioxide, imidazol-3-yl, oxetan-3-yl-methyl, (2-oxo-3-methyl-oxazolidin-5R-yl)- methyl, 3-hydroxy-tetrahydrofuran-3-yl-methyl, 3-cyano-tetrahydrofuran-3-yl- methyl, 4-hydroxy-tetrahydropyran-3-yl-methyl, 4-hydroxy-tetrahydropyran-4-yl- methyl, 4-methoxy-piperidin-4-yl-methyl, 4R-hydroxy-pyrrolidin-2R-yl-methyl, 2- oxo-4S-hydroxy-pyrrolidin-5R-yl-methyl, 1 -methyl-2-oxo-pyrrolidin-3-yl-methyl, 2-(methoxy-carbonyl)-pyrrolidin-2 -yl-methyl, 1 -tert-butoxy-carbonyl-4S-fluoro- pyrrolidin-4R-yl-methyl, and 1 -(tert-butoxy-carbonyl-3R-hydroxy-pyrrolidin-5S- yl-methyl.

[0064] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of 2-cyclopropyl, 5-cyclopropyl, 4-(1 -(hydroxy-methyl)-cycloprop-l -yl), 4-(1 -(1 -hydroxy-ethyl)- cycloprop-1 -yl), 4-(1 -cyano-cycloprop-1 -yl), 4-(1 -carboxy-cycloprop-1-yl), 4-(1 - (ethoxy-carbonyl)-cycloprop-l -yl), 4-(1 -amino-cycloprop-1 -yl), 4-(1 -amino- carbonyl-cycloprop-1 -yl), 4-(1 -methyl-amino-carbonyl-cycloprop-1 -yl), 4-(1 - (dimethyl-amino-carbonyl)-cycloprop-l -yl), 4-(1 -(methyl-carbonyl-amino)- cycloprop-1 -yl), 4-(1 -(methyl-sulfonyl-amino)-cycloprop-l -yl), 4-(1 -(tert-butoxy- carbonyl-amino)-cycloprop-1 -yl), 1 -cyclobutyl, 4-cyclobutyl, 1 -(3-hydroxy- cyclobut-1 -yl), 4-(3-hydroxy-cyclobut-1 -yl), 4-(1 -hydroxy-cyclobut-1 -yl), 4-(2- hydroxy-cyclobut-1 -yl), 4-(2R*-hydroxy-cyclobut-1 S*-yl), 4-(2S*-hydroxy- cyclobut-1 R*-yl),4-(3-hydroxy-cyclobut-1 -yl), 1 -(3-hydroxymethyl-cyclobut-1 -yl), 4-(2,2-dimethyl-3-hydroxy-cyclobut-1 -yl), 4-(2-methyl-3-hydroxy-cyclobut-1 -yl), 4-(3-difluoro-methyl-cyclobut-1 -yl), 1 -(3-methoxy-cyclobut-1 -yl), 4-(3-difluoro- methoxy-cyclobut-1 -yl), 4-(2-methoxy-3-hydroxy-cyclobut-1 -yl), 4-(3-methoxy-3- trifluoro-methyl-cyclobut-1 -yl), 4-(3-cyano-methyl-cyclobut-1 -yl), 4-(3-methyl-3- cyano-cyclobut-1 -yl), 4-(3-cyano-3-methoxy-carbonyl-cyclobut-1 -yl), 4-( 1 -(tert- butoxy-carbonyl-amino)-cyclobut-1 -yl), 1 -(2-hydroxy-cyclopent-1 -yl), 4-(3- hydroxy-cyclopent-1 -yl), 4R-(2S-(tert-butoxy-carbonyl-amino)-cyclopent-1 -yl), 4-(3,3-difluoro-5-hydroxy-cyclopent-1 -yl), 4-(4-hydroxy-cyclohex-1 -yl), 4-(4- hydroxy-cyclohex-1 -yl), 4-cis-(4-hydroxy-cyclohex-1 -yl), 4-trans-(4-hydroxy- cyclohex-1 -yl), 4-(4-methyl-4-hydroxy-cyclohex-1 -yl), 4-(4-(hydroxy-methyl)- cyclohex-1 -yl), 4-cis-(4-(hydroxy-methyl)-cyclohex-1 -yl), 4-trans-(4-(hydroxy- methyl)-cyclohex-1 -yl), 4-(3-difluoro-methyl-cyclohex-1 -yl), 4-(4-methoxy- cyclohex-1 -yl), 4-(4-methoxy-cyclohex-1 -yl), 4-cis-(4-methoxy-cyclohex-1 -yl), 4- trans-(4-m ethoxy-cyclohex-1 -yl), 4-(2S-cyano-cyclohex-1 -yl), 4-(4-cyano- cyclohex-1 -yl), 4-(4-amino-cyclohex-1 -yl), 4-(amino-carbonyl-cyclohex-1 -yl), 4- (3-(methyl-sulfonyl)-cyclohex-1 -yl), 4-(1 -hydroxy-cycloprop-1 -yl-ethyl), 1 -(1 - cyano-cycloprop-1 -yl-methyl), 1 -(3-hydroxy-cyclobut-1 -yl-methyl), 4-(1 -hydroxy- cyclobut-1 -yl-methyl), 4-(3-hydroxy-cyclobut-1 -yl-methyl), 4-(1 -hydroxy-methyl- cyclobut-1 -yl-methyl), 4-(1 -hydroxy-cyclopent-1 -yl-methyl), 4-(3-hydroxy- cyclopent-1 -yl-methyl), 4-(1 -hydroxy-cyclohex-1 -yl-methyl), 4-(4-hydroxy- cyclohex-1 -yl-methyl), 4-cis-(4-hydroxy-cyclohex-1 -yl-methyl), 4-trans-(4- hydroxy-cyclohex-1 -yl-methyl), 4-(4-hydroxy-methyl-cyclohex-1 -yl-methyl), 4-(4- (hydroxy-methyl)-cyclohex-l -yl-methyl), 4-cis-(4-(hydroxy-methyl)-cyclohex-1 - yl-methyl), 4-trans-(4-(hydroxy-methyl)-cyclohex-1 -yl-methyl), 6-(3-hydroxy- azetidin-1 -yl), 6-(2-hydroxy-methyl-azetin-1 -yl), 1 S-(pyrrolidin-3-yl), 4-(3- hydroxy-pyrrolidin-1 -yl), 4-(4S-methoxy-pyrrolidin-3R*-yl), 3-(2-oxo-pyrrolidin-1 - yl), 4-(2-oxo-pyrrolidin-5-yl), 6-(2-oxo-pyrrolidin-1 -yl), 4-(1 -methyl-2-oxo- pyrrolidin-4-yl), 1 -(piperidin-4-yl), 6-(2-hydroxy-methyl-piperidin-1 -yl), 6-(3- hydroxy-methyl-piperidin-1 -yl), 4-(2-(ethoxy-carbonyl)-piperidin-4-yl), 4-(oxetan- 3-yl), 4-(3-hydroxy-oxetan-3-yl), 4-(2-methyl-oxetan-3-yl), 4-(tetrahydrofuran-2- yl), 1 -(tetrahydorfuran-3-yl), 4-(3-hydroxy-tetrahydro-furan-4-yl), 4-(4-fluoro- tetrahydrofuran-3-yl), 4-(4-methoxy-tetrahydrofuran-3-yl), 4-(4S*-hydroxy- tetrahydro-furan-3R*-yl), 4-(4R*-hydroxy-tetrahydro-furan-3S*-yl), 4- (tetrahydropyran-4-yl), 4-(4-hydroxy-tetrahydropyran-3-yl), 4-(4-hydroxy- tetrahydropyran-4-yl), 4-(4,5-dihydroxy-tetrahydropyran-2-yl), 4-(3-cyano- tetrahydropyran-4-yl), 2-(morpholin-4-yl), 6-(morpholin-4-yl), 4-(4-hydroxy- tetrahydrothiophen-3-yl-1 ,1 -dioxide), 4-(imidazol-3-yl), 1 -(oxetan-3-yl-methyl), 4-(oxetan-3-yl-methyl), 4-((2-oxo-3-methyl-oxazolidin-5R-yl)-methyl), 4-(3- hydroxy-tetrahydrofuran-3-yl-methyl), 4-(3-cyano-tetrahydrofuran-3-yl-methyl), 4-(4-hydroxy-tetrahydropyran-3-yl-methyl), 4-(4-hydroxy-tetrahydropyran-4-yl- methyl), 4-(4-methoxy-piperidin-4-yl-methyl), 4-(4R-hydroxy-pyrrolidin-2R-yl- methyl), 4-(2-oxo-4S-hydroxy-pyrrolidin-5R-yl-methyl), 4-(1 -methyl-2-oxo- pyrrol idi n-3-yl-m ethyl), 4-(2-(methoxy-carbonyl)-pyrrolidin-2-yl-methyl), 4-(1 - tert-butoxy-carbonyl-4S-fluoro-pyrrolidin-4R-yl-methyl), and 4-(1 -(tert-butoxy- carbonyl-3R-hydroxy-pyrrolidin-5S-yl-methyl).

[0065] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of 4-(1 -hydroxy- methyl-cycloprop-1 -yl), 4-(1 -(1 -hydroxy-ethyl)-cycloprop-1 -yl), 4-(1 -cyano- cycloprop-1 -yl), 4-(1 -carboxy-cycloprop-1 -yl), 4-(1 -(tert-butoxy-carbonyl-amino)- cycloprop-1 -yl), 4-(1 -amino-cycloprop-1 -yl), 4-(1 -(methyl-amino-carbonyl)- cycloprop-1 -yl), 4-(1 -(methyl-carbonyl-amino)-cycloprop-l -yl), 4-(1 -(dimethyl- amino-carbonyl)-cycloprop-1yl), 4-(1 -(methyl-sulfonyl-amino)-cycloprop-1 -yl), 4- (1 -hydroxy-cyclobut-1 -yl), 4-(2-hydroxy-cyclobut-1 -yl), 4-(3-hydroxy-cyclobut-1 - yl), 4-(2R*-hydroxy-cyclobut-1 S*-yl), 4-(2S*-hydroxy-cyclobuty-1 R*-yl), 4-(2- methyl-3-hydroxy-cyclobut-1 -yl), 4-(2,2-dimethyl-3-hydroxy-cyclobut-1 -yl), 4-(3- hydroxy-cyclopent-1 -yl), 4-(3,3-difluoro-5-hydroxy-cyclopent-1 -yl), 4R-(2S-(tert- butoxy-carbonyl-amino)-cyclopent-1 -yl), 4-(4-hydroxy-cyclohex-1 -yl), 4-(4- hydroxy-methyl-cyclohex-1 -yl), 4-(4-methoxy-cyclohexyl), 4-(4-cyano- cyclohexy-1 -yl), 4-(2S-cyano-cyclohexyl), 4-(3-cyano-methyl-cyclobut-1 -yl), 4- (3-methyl-3-cyano-cyclobut-1 -yl), 4-(3-cyano-3-methoxy-carbonyl-cyclobut-1 - yl), 4-(1 -(tert-butoxy-carbonyl-amino)-cyclobut-l -yl), 4-(4-amino-cyclohex-1 -yl), 4-(3-(methyl-sulfonyl)-cyclohex-1 -yl), 4-(1 -hydroxy-cycloprop-1 -yl-ethyl), 4-(1 - hydroxy-cyclobut-1 -yl-methyl), 4-(3-hydroxy-cyclobut-1 -yl-methyl), 4-(3- hydroxy-cyclopent-1 -yl-methyl), 4-(oxetan-3-yl), 4-(2-methyl-oxetan-2-yl), 4-(3- hydroxy-pyrrolidin-1 -yl), 4-(1 -methyl-2-oxo-pyrrolidin-4-yl), 6-(2-hydroxy-methyl- piperidin-1 -yl), 4-(tetrahydro-furan-2-yl), 4-(4-fluoro-tetrahydrofuran-3-yl), 4-(3- hydroxy-tetrahydro-furan-3-yl-methyl), 4-(3-hydroxy-tetrahydro-furan-4-yl), 4- (4S*-hydroxy-tetrahydro-furan-3R*-yl), 4-(4R*-hydroxy-tetrahydro-furan-3S*-yl), 4-(tetrahydro-pyran-4-yl), 4-(4-hydroxy-tetrahydropyran-3-yl), 4-(4-hydroxy- tetrahydro-pyran-4-yl), 4-(4,5-dihydroxy-tetrahydro-pyran-2-yl), 4-(3-cyano- tetrahydropyran-4-yl), 4-(4-hydroxy-tetrahydro-thiophen-3-yl-1 ,1 -dioxide), 4- (imidazol-3-yl), 4-(4-hydroxy-tetrahydro-pyran-3-yl-methyl), 4-(4-hydroxy- tetrahydro-pyran-4-yl-methyl), and 4-((2-oxo-3-methyl-oxazolidin-5R-yl)- methyl).

[0066] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of 4-(1 -hydroxy- methyl-cycloprop-1 -yl), 4-(1 -(1 -hydroxy-ethyl)-cycloprop-1 -yl), 4-(1 -amino- cycloprop-1 -yl), 4-(1 -(methyl-carbonyl-amino)-cycloprop-l -yl), 4-(1 -(tert-butoxy- carbonyl-amino)-cycloprop-1 -yl), 4-(1 -(methyl-sulfonyl-amino)-cycloprop-l -yl), 4-(3-hydroxy-cyclobut-1 -yl), 4-(2S*-hydroxy-cyclobuty-1 R*-yl), 4-(2R*-hydroxy- cyclobut-1 S*-yl), 4-(1 -(tert-butoxy-carbonyl-amino)-cyclobut-l -yl), 4-(3-(methyl- sulfonyl)-cyclohex-1 -yl), 4-(4S*-hydroxy-tetrahydro-furan-3R*-yl), and 4-(4R*- hydroxy-tetrahydro-furan-3S*-yl).

[0067] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R1is selected from the group consisting of cycloprop-1 -yl, cyclobut-1 -yl, cyclopent-1 -y I, cyclopent-1 -yl, cyclohex-1 -yl, azetin-1 -yl, oxetan-

[0068] 2-yl, oxetan-3-yl, piperidin-1 -yl, piperidin-4-yl, pyrrolidin-1 -yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolidin-4-yl, pyrrolidin-5-yl, morpholin-4-yl, imidazol-3-yl, tetrahydro-pyran-2-yl, tetrahydro-pyran-3-yl, tetrahydro-pyran-4-yl, tetrahydro- furan-2-yl, tetrahydro-furan-3-yl, tetrahydro-furan-4-yl, and tetrahydro-thiophen-

[0069] 3-y I; and wherein said R1groups may be further optionally substituted as described herein.

[0070] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of hydrogen, Ci- 4alkyl, hydroxy substituted Ci-4alkyl, halogen substituted Ci-4alkyl, -(Ci-2alkyl)- CN, C2-4alkenyl, hydroxy substituted C2-4alkenyl, -(Ci-2alkyl)-O-(Ci-4alkyl), -(C2- 4alkenyl)-O-(Ci-4alkyl), -(C2-4alkenyl)-O-(Ci-4alkyl), Cs-ecycloalkyl, Cs- ecycloalkenyl, and 4 to 6 membered heterocycloalkyl; and wherein the C3- ecycloalkyl, Cs-ecycloalkenyl, phenyl or 4 to 6 membered heterocycloalkyl is optionally substituted one or more substituents independently selected from the group consisting of -OH, oxo, -Ci-4alkyl, -O-(Ci-4alkyl), -C(O)-(Ci-4alkyl), - C(O)OH, and -C(O)O-(Ci-4alkyl).

[0071] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of Ci-4alkyl, C3- ecycloalkyl and 4 to 6 membered heterocycloalkyl; wherein the Ci-4alkyl, C3- ecycloalkyl and 4 to 6 membered heterocycloalkyl may be further optionally substituted as described herein.

[0072] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of Ci-4alkyl, C3- ecycloalkyl and 4 to 6 membered heterocycloalkyl; wherein the 4 to 6 membered heterocyclyl is saturated; and wherein the Ci-4alkyl, Cs-ecycloalkyl and 4 to 6 membered heterocycloalkyl may be further optionally substituted as described herein. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of Ci-4alkyl, Cs-ecycloalkyl and 4 to 6 membered heterocycloalkyl; wherein the 4 to 6 membered heterocyclyl is partially unsaturated; and wherein the Ci-4alkyl, C3- ecycloalkyl and 4 to 6 membered heterocycloalkyl may be further optionally substituted as described herein.

[0073] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of hydrogen, C1- 4alkyl, -(C2-4alkenyl)-O-(Ci-4alkyl), Cs-scycloalkyl, Cs-ecycloalkenyl, and 4 to 6 membered heterocycloalkyl; wherein the Cs-scycloalkyl, Cs-ecycloalkenyl, or 4 to 6 membered heterocycloalkyl is optionally substituted with a substituent selected from the group consisting of -OH, oxo, -Ci-4alkyl, -O-(Ci-2alkyl), -C(O)- (Ci-4alkyl), -C(O)-C3-5cycloalkyl, -C(O)OH, and -C(O)O-(Ci-4alkyl). In certain embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of hydrogen, Ci-4alkyl, -(C2- 4alkenyl)-O-(Ci-4alkyl), Cs-scycloalkyl, Cs-ecycloalkenyl, and 4 to 6 membered heterocycloalkyl; wherein the Cs-scycloalkyl, Cs-ecycloalkenyl, or 4 to 6 membered heterocycloalkyl is optionally substituted with a substituent selected from the group consisting of -OH, oxo, -Ci-4alkyl, -O-(Ci-2alkyl), -C(O)-(Ci-4alkyl), -C(O)OH, and -C(O)O-(Ci-4alkyl).

[0074] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of hydrogen, Ci-4alkyl, -(C2-4alkenyl)-O-(Ci-4alkyl), Cs-ecycloalkenyl, and 4 to 6 membered heterocycloalkyl; wherein the Cecycloalkenyl, or 4 to 6 membered heterocycloalkyl is optionally substituted with a substituent selected from the group consisting of -OH, oxo, -Ci-4alkyl, -O-(Ci-2alkyl), -C(O)-(Ci-4alkyl), -C(O)- Cs-scycloalkyl, -C(O)OH, and -C(O)O-(Ci-4alkyl). In certain embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of hydrogen, Ci-4alkyl, -(C2-4alkenyl)-O-(Ci-4alkyl), Cs- ecycloalkenyl, and 4 to 6 membered heterocycloalkyl; wherein the Cecycloalkenyl, or 4 to 6 membered heterocycloalkyl is optionally substituted with a substituent selected from the group consisting of -OH, oxo, -Ci-4alkyl, -0- (Ci-2alkyl), -C(O)-(Ci-4alkyl), -C(O)OH, and -C(O)O-(Ci-4alkyl).

[0075] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of hydrogen, Ci-4alkyl, and Cs-scycloalkyl.

[0076] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of hydrogen, isopropyl, isobutyl, 3-methoxy-prop-1 -en-2-yl, cyclopropyl, cyclobutyl, 4- hydroxy-cyclohexen-1 -yl, 1 -methoxy-cyclohexen-1 -yl, 4-carboxy-cyclohexen-1 - yl, 3-isopropyl-3-hydroxy-azetidin-1 -yl, pyrrolidin-1 -yl, piperidin-1 -yl, morpholin- 4-yl, 2,5-dihydrofuran-3-yl, 3,4-dihydro-pyran-5-yl, 3,6-dihydro-pyran-5-yl, 1 - (tert-butoxy-carbonyl)-2,5-dihydro-pyrrol-3-yl, 1 ,2,3,6-tetrahydro-pyridin-4-yl, 1 - (tert-butoxy-carbonyl)-l ,2,3,6-tetrahydro-pyridin-4-yl, 1 -(tert-butoxy-carbonyl)- 1 , 2, 3,6-tetrahydro-pyrid in-5-y 1 , 1 -(methyl-carbonyl)-l ,2,3,6-tetrahydro-pyridin-4- yl, 1 -(isopropyl-carbonyl)-l ,2,3,6-tetrahydro-pyridin-4-yl, 1 -(cyclopropyl- carbonyl)-1 ,2,3,6-tetrahydro-pyridin-4-yl, and 3,6-dihydro-2H-thiopyran-4-yl 1 ,1 - dioxide.

[0077] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of hydrogen, isopropyl, isobutyl, 3-methoxy-prop-1 -en-2-yl, cyclopropyl, cyclobutyl, 4- hydroxy-cyclohex-1 -enyl, 4-methoxy-cyclohexen-1 -yl, 4-carboxy-cyclohexen-1 - yl, 3-isopropyl-3-hydroxy-azetidin-1 -yl, piperidin-1 -yl, morpholin-4-yl, 2,5- dihydro-furan-3-yl, 3,4-dihydro-pyran-5-yl, 3,6-dihydro-pyran-5-yl, 1 , 2,3,6- tetrahydro-pyridin-4-yl, 1-(methyl-carbonyl)-1 ,2,3,6-tetrahydro-pyridin-4-yl, 1 - (isopropyl-carbonyl)-l ,2,3,6-tetrahydro-pyridin-4-yl, 1 -(tert-butoxy-carbonyl)-

[0078] 1 .2.3.6-tetrahydro-pyridin-4-yl, 1 -(cyclopropyl-carbonyl)-l ,2,3,6-tetrahydro- pyridin-4-yl, and 3,6-dihydro-2H-thiopyran-4-yl 1 ,1 -dioxide.

[0079] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of hydrogen, isopropyl, 3-methoxy-prop-1 -en-2-yl, 4-hydroxy-cyclohexen-1 -yl, 1 -methoxy- cyclohexen-1 -yl, 4-carboxy-cyclohexen-1 -yl, 3-isopropyl-3-hydroxy-azetidin-1 - yl, pyrrolidin-1 -yl, piperidin-1 -yl, morpholin-4-yl, 2,5-dihydrofuran-3-yl, 3,4- dihydro-pyran-5-yl, 3,6-dihydro-pyran-5-yl, 1 ,2,3,6-tetrahydro-pyridin-4-yl, 1 - (tert-butoxy-carbonyl)-l ,2,3,6-tetrahydro-pyridin-4-yl, 1 -(tert-butoxy-carbonyl)-

[0080] 1 .2.3.6-tetrahydro-pyrid in-5-y 1 , 1 -(methyl-carbonyl)-l ,2,3,6-tetrahydro-pyridin-4- yl, 1 -(isopropyl-carbonyl)-l ,2,3,6-tetrahydro-pyridin-4-yl, 1 -(cyclopropyl- carbonyl)-1 ,2,3,6-tetrahydro-pyridin-4-yl, and 3,6-dihydro-2H-thiopyran-4-yl 1 ,1 - dioxide;

[0081] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of hydrogen, isopropyl, 3-methoxy-prop-1 -en-2-yl, 4-hydroxy-cyclohex-1 -enyl, 4-methoxy- cyclohexen-1 -yl, 4-carboxy-cyclohexen-1 -yl, 3-isopropyl-3-hydroxy-azetidin-1 - yl, piperidin-1 -yl, morpholin-4-yl, 2,5-dihydro-furan-3-yl, 3,4-dihydro-pyran-5-yl,

[0082] 3.6-dihydro-pyran-5-yl, 1 ,2,3,6-tetrahydro-pyridin-4-yl, 1 -(methyl-carbonyl)-

[0083] 1 .2.3.6-tetrahydro-pyridin-4-yl, 1 -(isopropyl-carbonyl)-l ,2,3,6-tetrahydro-pyridin- 4-yl, 1 -(tert-butoxy-carbonyl)-l ,2,3,6-tetrahydro-pyridin-4-yl, 1 -(cyclopropyl- carbonyl)-1 ,2,3,6-tetrahydro-pyridin-4-yl, and 3,6-dihydro-2H-thiopyran-4-yl 1 ,1 - dioxide.

[0084] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of isopropyl, 4- hydroxy-cyclohex-1 -enyl, 4-methoxy-cyclohexen-1 -yl, 4-carboxy-cyclohexen-1 - yl, morpholin-4-yl, 3,4-dihydro-pyran-5-yl, 3,6-dihydro-pyran-5-yl, 1-(methyl- carbonyl)-1 ,2,3,6-tetrahydro-pyridin-4-yl, 1 -(isopropyl-carbonyl)-l ,2,3,6- tetrahydro-pyridin-4-yl, 1 -(cyclopropyl-carbonyl)-l ,2,3,6-tetrahydro-pyridin-4-yl, and 3,6-dihydro-2H-thiopyran-4-yl 1 ,1 -dioxide.

[0085] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of hydrogen, isopropyl, isobutyl, cyclopropyl, and cyclobutyl; wherein said R2groups may be further optionally substituted as described herein. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R2is selected from the group consisting of cycloprop-1 -yl, cyclobut-1 -yl, morpholin-4-yl, piperidin-1 -yl, dihydro-furan-3-yl, dihydro-pyran-5-yl, tetrahydro-pyridin-4-yl, tetrahydro-pyridin-5-yl, cyclohexen-1 -yl, cyclohex-1 -enyl, dihydro-pyrrol-3-yl, pyrrolidin-1 -yl, azetidin-1 -yl, and thiopyran-4-yl; and wherein said R2groups may be further optionally substituted as described herein.

[0086] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R3is selected from the group consisting of Ci-4alkyl, hydroxy substituted Ci-4alkyl, and -(Ci-2alkyl)-O-(Ci-2alkyl). In certain embodiments, the present invention is directed to compounds of formula (I) wherein R3is selected from the group consisting of Ci-4alkyl and hydroxy substituted Ci-4alkyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R3is Cs-ecycloalkyl, preferably cyclopropyl or cyclobutyl.

[0087] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R3is methyl, ethyl or isopropyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R3is methyl or ethyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R3is methyl.

[0088] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting of phenyl, pyridinyl, pyrim idinyl and thiazolyl; wherein the phenyl, pyridinyl, pyrim idinyl and thiazolyl are further optionally substituted as described herein.

[0089] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting of phenyl, and 5 to 6 membered heteroaryl; wherein the phenyl or 5 to 6 membered heteroaryl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, pentafluorothio, Ci-2alkyl, halogen substituted Ci-2alkyl, -O-(halogen substituted Ci-4alkyl), and C3-4cycloalkyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting of phenyl, and 5 to 6 membered heteroaryl; wherein the phenyl or 5 to 6 membered heteroaryl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, pentafluorothio, Ci-2alkyl, halogen substituted Ci-2alkyl, and C3-4cycloalkyl.

[0090] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting of 4-chloro- phenyl, 4-methyl-phenyl, 4-ethyl-phenyl, 2,4-dimethyl-phenyl, 4-trifluoro-methyl- phenyl, 4-(2,2,2-trifluoro-ethyl)-phenyl, 2-fluoro-4-methyl-phenyl, 2-chloro-4- trifluoro-methyl-phenyl, 2-methyl-4-trifluoro-methyl-phenyl, 4-trifluoro-methoxy- phenyl, 4-pentafluorothio-phenyl, 4-cyclopropyl-phenyl, 6-trifluoro-methyl- pyridin-3-yl, 2-trifluoro-methyl-pyrimidin-5-yl, 4-difluoro-methyl-thiazol-2-yl, and 2-trifluoro-methyl-thiazol-5-yl.

[0091] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting of 4-chloro- phenyl, 4-methyl-phenyl, 4-ethyl-phenyl, 4-trifluoro-methyl-phenyl, 2,4-dimethyl- phenyl, 2-fluoro-4-methyl-phenyl, 2-chloro-4-trifluoro-methyl-phenyl, 2-methyl- 4-trifuoro-methyl-phenyl, 4-trifluoro-methoxy-phenyl, 4-pentafluoro-thio-phenyl,

[0092] 4-cyclopropyl-phenyl, 6-trifluoro-methyl-pyridin-3-yl, 2-trifluoro-methyl-pyrimidin-

[0093] 5-yl, 4-difluoro-methyl-thiazol-2-yl, and 2-trifluoro-methyl-thiazol-5-yl.

[0094] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting of 4-chloro- phenyl, 4-methyl-phenyl, 4-ethyl-phenyl, 4-trifluoro-methyl-phenyl, 4-(2,2,2- trifluoro-ethyl)-phenyl, 2-methyl-4-trifluoro-methyl-phenyl, 4-trifluoro-methoxy- phenyl, 4-pentafluorothio-phenyl, 4-cyclopropyl-phenyl, 6-trifluoro-methyl- pyridin-3-yl, 2-trifluoro-methyl-pyrimidin-5-yl, 4-difluoro-methyl-thiazol-2-yl, and 2-trifluoro-methyl-thiazol-5-yl.

[0095] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting of 4-chloro- phenyl, 4-methyl-phenyl, 4-ethyl-phenyl, 4-trifluoro-methyl-phenyl, 4-trifluoro- methoxy-phenyl, 2-methyl-4-trifuoro-methyl-phenyl, 4-pentafluoro-thio-phenyl, 4-cyclopropyl-phenyl, 6-trifluoro-methyl-pyridin-3-yl, 2-trilfuoro-methyl- pyridimidin-5-yl, 2-trifluoro-methyl-thiazol-5-yl, and 4-difluoro-methyl-thiazol-2- yl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting of 4-chloro-phenyl, 4-methyl-phenyl, 4-trifluoro-methyl-phenyl, 2-methyl-4-trifuoro-methyl-phenyl, 4- trifluoro-methoxy-phenyl, 4-pentafluoro-thio-phenyl, 4-cyclopropyl-phenyl, 6- trifluoro-methyl-pyridin-3-yl, 2-trilfuoro-methyl-pyridimidin-5-yl, and 2-trifluoro- methyl-thiazol-5-yl.

[0096] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting of 4-chloro- phenyl, 4-methyl-phenyl, 4-ethyl-phenyl, 2,4-dimethyl-phenyl, 4-trifluoro-methyl- phenyl, 2-fluoro-4-methyl-phenyl, 2-chloro-4-trifluoro-methyl-phenyl, 2-methyl- 4-trifluoro-methyl-phenyl, 4-pentafluorothio-phenyl, 4-cyclopropyl-phenyl, 6- trifluoro-methyl-pyridin-3-yl, 2-trifluoro-methyl-pyrimidin-5-yl, and 2-trifluoro- methyl-thiazol-5-yl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting of 4- chloro-phenyl, 4-methyl-phenyl, 2,4-dimethyl-phenyl, 4-trifluoro-methyl-phenyl, 2-fluoro-4-methyl-phenyl, 2-chloro-4-trifluoro-methyl-phenyl, 2-methyl-4- trifluoro-methyl-phenyl, 4-pentafluoro-thio-phenyl, 4-cyclopropyl-phenyl, 6- trifluoro-methyl-pyridin-3-yl, 2-trifluoro-methyl-pyrimidin-5-yl, and 2-trifluoro- methyl-thiazol-5-yl.

[0097] In certain embodiments, the present invention is directed to compounds of formula (I) wherein R4is selected from the group consisting of phenyl, pyridin-3-yl, thiazol-5-yl, thiazol-2-yl, and pyridim idin-5-yl; and wherein said R4groups may be further optionally substituted as described herein.

[0098] Additional embodiments of the present invention, include those wherein the substituents selected for one or more of the variables defined herein (i.e. , a, R1, R2, R3, and R4) 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.

[0099] Representative compounds of the present invention are as 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, the S*- and R* designations are intended to indicate that the exact stereo-configuration of the center has not been determined.

[0100] Table 1 : Representative Compounds of Formula (l-A)

[0101]

[0102] Table 2: Representative Compounds of Formula (l-B) aCompound was prepared as either the cis or trans stereoisomer at the stereocenters at the 1 - and 4-positions on the cyclohex-1 -yl. However, the relative orientation was not determined.

[0103] In certain embodiments, the present invention is directed to one or more compounds of formula (I) independently selected from the group consisting of 2-[5-methyl-2-(o-tolyl)-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p- tolyl)acetamide;

[0104] 2-[2-(2,6-dimethylphenyl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin- 4-yl]-N-(p-tolyl)acetam ide;

[0105] 2-[2-(2-methoxy-3-pyridyl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin- 4-yl]-N-(p-tolyl)acetam ide;

[0106] 2-[5-methyl-2-(m-tolyl)-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p- tolyl)acetamide;

[0107] 2-[2-[4-(hydroxymethyl)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0108] 2-[2-(4-chlorophenyl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]- N-(p-tolyl)acetam ide;

[0109] 2-[2-[4-(cyanomethyl)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0110] 2-[2-(3-cyanophenyl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]- N-(p-tolyl)acetam ide;

[0111] 2-[2-(2-hydroxy-4-pyridyl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin- 4-yl]-N-(p-tolyl)acetam ide;

[0112] 2-[2-(2,4-dimethylpyrazol-3-yl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0113] 2-[5-methyl-2-(1 -methylpyrazol-4-yl)-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0114] 2-[5-methyl-7-oxo-2-(p-tolyl)-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p- tolyl)acetamide; 2-[5-methyl-2-(6-methylpyridazin-4-yl)-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0115] 2-[2-[4-(hydroxymethyl)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide;

[0116] 2-[2-[4-(cyanomethyl)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide;

[0117] 2-[2-[4-(cyanomethyl)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(4-ethylphenyl)acetamide;

[0118] 2-[2-(2-cyano-4-pyridyl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4- yl]-N-(p-tolyl)acetamide;

[0119] 2-[2-(2-methoxyphenyl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4- yl]-N-(p-tolyl)acetamide;

[0120] 2-[5-methyl-7-oxo-2-(4-sulfamoylphenyl)-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4- yl]-N-(p-tolyl)acetamide;

[0121] 2-[2-[4-fluoro-3-(hydroxymethyl)phenyl]-5-methyl-7-oxo-

[0122] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0123] 2-[2-(1 -ethyl-5-fluoro-pyrazol-4-yl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0124] 2-[2-[4-(1 -hydroxy- 1 -methyl-ethyl)phenyl]-5-methyl-7-oxo-

[0125] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0126] 2-[2-[4-(1 -hydroxy- 1 -methyl-ethyl)phenyl]-5-methyl-7-oxo-

[0127] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0128] 2-[5-methyl-2-(3-methyl-1 H-pyrazol-5-yl)-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0129] 2-[5-methyl-2-(2-methyl-3-pyridyl)-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4- yl]-N-(p-tolyl)acetamide;

[0130] 2-[2-[4-(hydroxymethyl)-2-methoxy-phenyl]-5-methyl-7-oxo-

[0131] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0132] N-(4-ethylphenyl)-2-[2-[4-(hydroxymethyl)phenyl]-5-methyl-7-oxo-

[0133] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]acetamide;

[0134] 4-[5-methyl-4-[2-(4-methylanilino)-2-oxo-ethyl]-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-2-yl]benzamide; 2-[2-[5-(difluoromethyl)-3-pyridyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0135] 2-[2-(2-methoxy-4-pyridyl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin- 4-yl]-N-(p-tolyl)acetam ide;

[0136] 2-(2-isothiazol-4-yl-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl)-N- (p-tolyl)acetamide;

[0137] 2-(2-isothiazol-4-yl-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl)-N- (p-tolyl)acetamide;

[0138] 2-[2-(5-cyano-3-pyridyl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4- yl]-N-(p-tolyl)acetamide;

[0139] 2-[5-methyl-2-(1 -methylpyrazol-4-yl)-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-[4-(2,2,2-trifluoroethyl)phenyl]acetamide;

[0140] 2-[2-(2-fluorophenyl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]- N-(p-tolyl)acetam ide;

[0141] 2-(5-methyl-2-oxazol-5-yl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl)-N-(p- tolyl)acetamide;

[0142] 2-[2-[4-(1 -hydroxyethyl)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0143] 2-[2-[4-(2-hydroxyethyl)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0144] 2-[5-methyl-2-(1 -methyl-2-oxo-4-pyridyl)-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0145] N-methyl-5-[5-methyl-4-[2-(4-methylanilino)-2-oxo-ethyl]-7-oxo-

[0146] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-2-yl]pyridine-2-carboxamide;

[0147] 2-[2-(6-methoxy-3-pyridyl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin- 4-yl]-N-(p-tolyl)acetam ide;

[0148] 2-[2-[1 -(2-cyanoethyl)pyrazol-4-yl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0149] 2-[5-methyl-7-oxo-2-(1 H-pyrazol-4-yl)-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4- yl]-N-(p-tolyl)acetamide;

[0150] 2-[5-methyl-7-oxo-2-(1 H-pyrazol-4-yl)-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4- yl]-N-(p-tolyl)acetamide; 2-[2-[ 1 -(2-hydroxyethyl)pyrazol-4-yl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0151] 2-[4-[5-methyl-4-[2-(4-methylanilino)-2-oxo-ethyl]-7-oxo-

[0152] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-2-yl]pyrazol-1 -yl]acetamide;

[0153] 2-[2-[1 -(difluoromethyl)pyrazol-4-yl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0154] 2-[2-(4-cyano-2-fluoro-phenyl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0155] 2-[2-[4-(cyanomethoxy)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0156] N-methyl-2-[4-[5-methyl-4-[2-(4-methylanilino)-2-oxo-ethyl]-7-oxo-

[0157] [1 .2.4]triazolo[1 ,5-a]pyrimidin-2-yl]pyrazol-1 -yl]acetamide;

[0158] 2-[2-(4-methoxyphenyl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4- yl]-N-(p-tolyl)acetamide;

[0159] 2-[2-[1 -(2,2-difluoroethyl)pyrazol-4-yl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0160] 2-[2-[4-(2,2-difluoroethoxy)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0161] 2-[5-methyl-2-[4-(methylcarbamoylamino)phenyl]-7-oxo-

[0162] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0163] 2-[2-(3-fluorophenyl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]- N-(p-tolyl)acetam ide;

[0164] 2-[2-[2-fluoro-4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-5-methyl-7-oxo-

[0165] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0166] 3-fluoro-4-[5-methyl-4-[2-(4-methylanilino)-2-oxo-ethyl]-7-oxo-

[0167] [1 .2.4]triazolo[1 ,5-a]pyrimidin-2-yl]benzamide;

[0168] 2-[2-[4-(difluoromethoxy)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0169] 2-[2-[4-(methanesulfonamido)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0170] 2-[4-[5-methyl-4-[2-(4-methylanilino)-2-oxo-ethyl]-7-oxo-

[0171] [1 .2.4]triazolo[1 ,5-a]pyrimidin-2-yl]phenyl]acetamide; 2-[2-[4-(2-hydroxy-1 , 1 -dimethyl-ethyl)phenyl]-5-methyl-7-oxo-

[0172] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0173] 2-[2-(6-amino-3-pyridyl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4- yl]-N-(p-tolyl)acetamide;

[0174] 2-[2-[4-(3-hydroxypropyl)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0175] N-(3-hydroxypropyl)-4-[5-methyl-4-[2-(4-methylanilino)-2-oxo-ethyl]-7- oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-2-yl]benzamide;

[0176] 2-[2-[1 -(2-hydroxypropyl)pyrazol-4-yl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0177] 2-[2-[1 -(2-hydroxyethyl)pyrazol-4-yl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide;

[0178] 2-[2-[1 -(2-hydroxy-1 , 1 -dimethyl-ethyl)pyrazol-4-yl]-5-methyl-7-oxo-

[0179] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0180] 2-[2-(1 ,3-dimethylpyrazol-4-yl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0181] 2-[2-[5-(methoxymethyl)-1-methyl-pyrazol-4-yl]-5-methyl-7-oxo-

[0182] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0183] 2-[5-methyl-7-oxo-2-[4-[rac-(1 S)-1 -methoxyethyl]phenyl]-

[0184] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0185] N-methyl-2-[4-[5-methyl-4-[2-(4-methylanilino)-2-oxo-ethyl]-7-oxo-

[0186] [1 .2.4]triazolo[1 ,5-a]pyrimidin-2-yl]phenyl]acetamide;

[0187] 2-[2-[4-(1 -cyano-1 -methyl-ethyl)phenyl]-5-methyl-7-oxo-

[0188] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0189] 2-[2-[4-(cyanomethyl)-3-fluoro-phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0190] 2-[2-[4-(1 -m ethoxy-1 -methyl-ethyl)phenyl]-5-methyl-7-oxo-

[0191] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0192] 2-[2-[4-(2-methoxyethyl)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0193] 2-[2-[3-fluoro-4-(methoxymethyl)phenyl]-5-methyl-7-oxo-

[0194] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide; 2-[2-[4-(methoxymethyl)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0195] 2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6-isopropyl-5-methyl-7-oxo-

[0196] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0197] 2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6-isopropyl-5-methyl-7-oxo-

[0198] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0199] 2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6-isopropyl-5-methyl-7-oxo-

[0200] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0201] 2-[2-(5-fluoro-1-methyl-pyrazol-4-yl)-6-isopropyl-5-methyl-7-oxo-

[0202] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0203] 2-[2-[6-(hydroxymethyl)-3-pyridyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0204] 2-[2-[4-(3-hydroxy-3-methyl-butyl)phenyl]-5-methyl-7-oxo-

[0205] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide;

[0206] 2-[5-methyl-7-oxo-2-[4-[rac-(2S)-3-ethoxy-2-hydroxy-propyl]phenyl]-

[0207] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide;

[0208] 2-[2-[4-[3-hydroxy-2-(hydroxymethyl)-2-methyl-propyl]phenyl]-5-methyl-

[0209] 7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4- (trifluoromethyl)phenyl]acetamide;

[0210] 2-[5-methyl-2-(4-methylthiazol-5-yl)-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin- 4-yl]-N-(p-tolyl)acetam ide;

[0211] 2-[5-methyl-2-(3-methylimidazol-4-yl)-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0212] 2-[2-(2,3-dimethylimidazol-4-yl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0213] 2-(5-methyl-7-oxo-2-thiazol-5-yl-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl)-N-(p- tolyl)acetamide;

[0214] 2-[2-[5-(hydroxymethyl)-2-furyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0215] 2-[2-[1 -(2-methoxyethyl)pyrazol-4-yl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0216] 2-[2-(2,5-dimethylpyrazol-3-yl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide; 2-[5-methyl-2-(2-methylthiazol-5-yl)-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin- 4-yl]-N-(p-tolyl)acetam ide;

[0217] 2-[2-[5-(hydroxymethyl)-2-thienyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0218] 2-[5-methyl-7-oxo-2-[4-[rac-(1S,3R)-3-hydroxy-1-methyl-butyl]phenyl]-

[0219] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0220] 2-[2-[5-(hydroxymethyl)-3-thienyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0221] 2-[2-(6-cyano-3-pyridyl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4- yl]-N-(p-tolyl)acetamide;

[0222] 2-[5-methyl-2-(3-methyl-1 H-pyrazol-4-yl)-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0223] 2-[5-methyl-2-(4-methylisothiazol-5-yl)-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0224] 2-[5-methyl-7-oxo-2-[4-[rac-(2S)-3-amino-2-hydroxy-2-methyl- propyl]phenyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0225] 2-[5-methyl-7-oxo-2-[4-[2,2,2-trifluoro-1 -hydroxy-1 -

[0226] (trifluoromethyl)ethyl]phenyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p- tolyl)acetamide;

[0227] 2-[2-(5-chloro-1 -methyl-pyrazol-4-yl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0228] 2-[5-methyl-7-oxo-2-[4-[rac-(1 S)-2,2,2-trifluoro-1 -hydroxy-1 -methyl- ethyl]phenyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide; rac-(4R)-N-methyl-4-[4-[5-methyl-4-[2-(4-methylanilino)-2-oxo-ethyl]-7- oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-2-yl]phenyl]pentanamide;

[0229] 2-[2-[1-(2-hydroxyethyl)-3-methyl-pyrazol-4-yl]-5-methyl-7-oxo-

[0230] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0231] 2-[2-[1-(2-hydroxyethyl)-5-methyl-pyrazol-4-yl]-5-methyl-7-oxo-

[0232] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0233] 2-[2-(5-cyano-1 -methyl-pyrazol-4-yl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0234] 2-[2-(3-methoxy-1-methyl-pyrazol-4-yl)-5-methyl-7-oxo-

[0235] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide; 2-[5-methyl-2-(3-methylisoxazol-5-yl)-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0236] 2-[5-methyl-2-(3-methylisoxazol-5-yl)-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0237] 2-[2-(3-cyano-1 -methyl-pyrazol-4-yl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0238] 2-[2-(1 ,5-dimethylpyrazol-4-yl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0239] 2-[2-[2-(2-hydroxyethyl)-4-methyl-pyrazol-3-yl]-5-methyl-7-oxo-

[0240] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0241] 2-[2-[2-(hydroxymethyl)thiazol-5-yl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0242] 2-[5-methyl-2-(2-methyloxazol-5-yl)-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin- 4-yl]-N-(p-tolyl)acetam ide;

[0243] 2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6-isopropyl-5-methyl-7-oxo-

[0244] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide;

[0245] 2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6-isopropyl-5-methyl-7-oxo-

[0246] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[6-(trifluoromethyl)-3-pyridyl]acetamide;

[0247] N-(4-chlorophenyl)-2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6- isopropyl-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]acetamide;

[0248] 2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6-isopropyl-5-methyl-7-oxo-

[0249] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(pentafluoro-λ6- sulfanyl)phenyl]acetamide;

[0250] 2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6-isopropyl-5-methyl-7-oxo-

[0251] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[2-(trifluoromethyl)thiazol-5-yl]acetamide;

[0252] 2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6-isopropyl-5-methyl-7-oxo-

[0253] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[2-(trifluoromethyl)thiazol-5-yl]acetamide;

[0254] 2-[2-[2-(hydroxymethyl)oxazol-5-yl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0255] 2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-5-methyl-6-morpholino-7-oxo-

[0256] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide;

[0257] 2-[2-[4-(1 -hydroxy- 1 -methyl-ethyl)phenyl]-5-methyl-7-oxo-6-(1 -piperidy I)-

[0258] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide; 2-[6-(2,5-dihydrofuran-3-yl)-2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-5- methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide; tert-butyl 4-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-5-methyl-4-[2-(4- methylanilino)-2-oxo-ethyl]-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-6-yl]-3,6- dihydro-2H-pyridine-1 -carboxylate;

[0259] 2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-5-methyl-7-oxo-6-[rac-(4R)-4- hydroxycyclohexen-1 -y l]-[ 1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p- tolyl)acetamide;

[0260] 2-[2-[4-(1 -hydroxy- 1 -methyl-ethyl)phenyl]-5-methyl-7-oxo-6-(1 ,2,3,6- tetrahydropyridin-4-yl)-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0261] 2-[6-(3,4-dihydro-2H-pyran-5-yl)-2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]- 5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0262] 2-[6-(3,4-dihydro-2H-pyran-5-yl)-2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]- 5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0263] 2-[2-[4-(1 -hydroxy- 1 -methyl-ethyl)phenyl]-5-methyl-6-[1 -(2- methylpropanoyl)-3,6-dihydro-2H-pyridin-4-yl]-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0264] 2-[6-(1 , 1 -dioxo-3,6-dihydro-2H-thiopyran-4-yl)-2-[4-(1 -hydroxy- 1 -methyl- ethyl)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p- tolyl)acetamide;

[0265] 2-[6-(3,6-dihydro-2H-pyran-5-yl)-2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]- 5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0266] 2-[2-[4-(1 -hydroxy- 1 -methyl-ethyl)phenyl]-6-[1 -(methoxymethyl)vinyl]-5- methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0267] 2-[6-[1 -(cyclopropanecarbonyl)-3,6-dihydro-2H-pyridin-4-yl]-2-[4-(1 - hydroxy-1 -methyl-ethyl)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4- yl]-N-(p-tolyl)acetamide; rac-(1 S)-4-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-5-methyl-4-[2-(4- methylanilino)-2-oxo-ethyl]-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-6-yl]cyclohex-3- ene-1 -carboxylic acid;

[0268] 2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-5-methyl-7-oxo-6-[rac-(4S)-4- methoxycyclohexen-1 -y l]-[ 1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p- tolyl)acetamide; 2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6-isopropyl-5-methyl-7-oxo-

[0269] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[2-(trifluoromethyl)pyrimidin-5- yl]acetamide;

[0270] 2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6-isopropyl-5-methyl-7-oxo-

[0271] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[2-methyl-4- (trifluoromethyl)phenyl]acetamide;

[0272] 2-[2-[4-(1 -hydroxy- 1 -methyl-ethyl)phenyl]-5-methyl-7-oxo-6-pyrrolidin-1 - yl-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0273] 2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6-isopropyl-5-methyl-7-oxo-

[0274] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(trifluoromethoxy)phenyl]acetamide;

[0275] 2-[6-(1 -acetyl-3,6-dihydro-2H-pyridin-4-yl)-2-[4-(1 -hydroxy-1 -methyl- ethyl)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p- tolyl)acetamide;

[0276] 2-[5-ethyl-2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6-isopropyl-7 -oxo-

[0277] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide; tert-butyl 5-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-5-methyl-4-[2-(4- methylanilino)-2-oxo-ethyl]-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-6-yl]-3,6- dihydro-2H-pyridine-1 -carboxylate;

[0278] 2-[6-(3-hydroxy-3-isopropyl-azetidin-1 -y l)-2-[4-( 1 -hydroxy-1 -methyl- ethyl)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p- tolyl)acetamide;

[0279] N-(4-cyclopropylphenyl)-2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6- isopropyl-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]acetamide; tert-butyl 3-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-5-methyl-4-[2-(4- methylanilino)-2-oxo-ethyl]-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-6-yl]-2,5- dihydropyrrole-1 -carboxylate;

[0280] N-[4-(difluoromethyl)thiazol-2-yl]-2-[2-[4-(1 -hydroxy-1 -methyl- ethyl)phenyl]-6-isopropyl-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4- yl]acetamide; and stereoisomers, and pharmaceutically acceptable salts thereof.

[0281] In certain embodiments, the present invention is directed to one or more compounds of formula (I) independently selected from the group consisting of 2-[2-(4-cyclobutyl-2-fluoro-phenyl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0282] 2-[2-[4-[1 -(hydroxymethyl)cyclopropyl]phenyl]-5-methyl-7-oxo-

[0283] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0284] 2-[2-[4-[1 -(hydroxymethyl)cyclopropyl]phenyl]-5-methyl-7-oxo-

[0285] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0286] 2-[2-[1 -[(1 -cyan°cycl°pr°pyl)methyl]pyrazol-4-yl]-5-methyl-7-oxo-

[0287] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0288] 2-[5-methyl-7-oxo-2-[3-(2-oxopyrrolidin-1 -y l)pheny l]-[ 1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0289] 2-[2-[4-(3-hydroxyoxetan-3-yl)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0290] 2-[5-methyl-2-[1 -(oxetan-3-ylmethyl)pyrazol-4-yl]-7-oxo-

[0291] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0292] 2-[2-[4-[1 -(hydroxymethyl)cyclopropyl]phenyl]-5-methyl-7-oxo-

[0293] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide;

[0294] 2-[5-methyl-7-oxo-2-[1 -(4-piperidyl)pyrazol-4-yl]-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0295] 2-[2-[4-(1 -cyanocyclopropyl)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0296] 2-[5-methyl-7-oxo-2-[4-(5-oxopyrrolidin-2-yl)phenyl]-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0297] 2-[5-methyl-7-oxo-2-[4-(1 H-pyrazol-3-yl)phenyl]-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0298] 2-[2-[4-(3-hydroxypyrrolidin-1 -yl)phenyl]-5-methyl-7-oxo-

[0299] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0300] N-(4-ethylphenyl)-2-[2-[4-[1 -(hydroxymethyl)cyclopropyl]phenyl]-5- methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]acetamide;

[0301] 2-[2-[6-[2-(hydroxymethyl)-1 -piperidyl]-3-pyridyl]-5-methyl-7-oxo-

[0302] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0303] 2-[2-[6-[3-(hydroxymethyl)-1 -piperidyl]-3-pyridyl]-5-methyl-7-oxo-

[0304] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide; 2-[2-[1-(2-hydroxycyclopentyl)pyrazol-4-yl]-5-methyl-7-oxo-

[0305] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0306] 2-[5-methyl-7-oxo-2-[1-[(3S)-pyrrolidin-3-yl]pyrazol-4-yl]-

[0307] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0308] 2-[2-[6-[2-(hydroxymethyl)azetidin-1-yl]-3-pyridyl]-5-methyl-7-oxo-

[0309] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0310] 2-[2-[4-[1-(hydroxymethyl)cyclopropyl]phenyl]-6-isopropyl-5-methyl-7- oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0311] 2-[2-[4-[1-(hydroxymethyl)cyclopropyl]phenyl]-6-isopropyl-5-methyl-7- oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0312] 2-[2-(5-cyclopropyl-1-methyl-pyrazol-4-yl)-5-methyl-7-oxo-

[0313] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0314] 2-[2-[4-[1-(hydroxymethyl)cyclopropyl]phenyl]-6-isopropyl-5-methyl-7- oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide; ethyl 1 -[4-[5-methyl-4-[2-(4-methylanilino)-2-oxo-ethyl]-7-oxo-

[0315] [1 .2.4]triazolo[1 ,5-a]pyrimidin-2-yl]phenyl]cyclopropanecarboxylate;

[0316] 2-[2-[4-[1-(hydroxymethyl)cyclopropyl]phenyl]-5-methyl-7-oxo-

[0317] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(pentafluoro-λ6- sulfanyl)phenyl]acetamide;

[0318] 2-[2-[4-[1-(hydroxymethyl)cyclopropyl]phenyl]-5-methyl-7-oxo-

[0319] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[6-(trifluoromethyl)-3-pyridyl]acetamide;

[0320] 1-[4-[5-methyl-4-[2-(4-methylanilino)-2-oxo-ethyl]-7-oxo-

[0321] [1 .2.4]triazolo[1 ,5-a]pyrimidin-2-yl]phenyl]cyclopropanecarboxylic acid;

[0322] N-methyl-1-[4-[5-methyl-4-[2-(4-methylanilino)-2-oxo-ethyl]-7-oxo-

[0323] [1 .2.4]triazolo[1 ,5-a]pyrimidin-2-yl]phenyl]cyclopropanecarboxamide;

[0324] 1-[4-[5-methyl-4-[2-(4-methylanilino)-2-oxo-ethyl]-7-oxo-

[0325] [1 .2.4]triazolo[1 ,5-a]pyrimidin-2-yl]phenyl]cyclopropanecarboxamide;

[0326] N-(4-cyclopropylphenyl)-2-[2-[4-[1-(hydroxymethyl)cyclopropyl]phenyl]-5- methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]acetamide;

[0327] 2-[2-[4-[1-(hydroxymethyl)cyclopropyl]phenyl]-5-methyl-7-oxo-

[0328] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[2-(trifluoromethyl)thiazol-5-yl]acetamide;

[0329] N,N-dimethyl-1-[4-[5-methyl-4-[2-(4-methylanilino)-2-oxo-ethyl]-7-oxo-

[0330] [1 .2.4]triazolo[1 ,5-a]pyrimidin-2-yl]phenyl]cyclopropanecarboxamide; 2-[2-[4-[1 -(hydroxymethyl)cyclopropyl]phenyl]-6-isobutyl-5-methyl-7-oxo-

[0331] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0332] 2-[2-[4-[1 -(hydroxymethyl)cyclopropyl]phenyl]-6-isopropyl-5-methyl-7- oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(pentafluoro-λ6- sulfanyl)phenyl]acetamide;

[0333] 2-[5-methyl-7-oxo-2-[4-[rac-(2R)-tetrahydropyran-2-yl]phenyl]-

[0334] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0335] 2-[2-[2-fluoro-4-[rac-(2S)-2-methyloxetan-2-yl]phenyl]-5-methyl-7-oxo-

[0336] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0337] 2-[2-[4-(1 -hydroxycyclobutyl)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0338] 2-[5-methyl-7-oxo-2-(4-tetrahydropyran-4-ylphenyl)-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0339] 2-[2-[4-(1 -aminocyclopropyl)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0340] 2-[5-methyl-7-oxo-2-[4-[rac-(3S,4R)-4-hydroxytetrahydrofuran-3- yl]phenyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0341] 2-[5-methyl-2-[4-(oxetan-3-ylmethyl)phenyl]-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0342] 2-[5-methyl-7-oxo-2-[4-[rac-(1 S,3R)-3-hydroxycyclopentyl]phenyl]-

[0343] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0344] 2-[2-[4-[1 -(hydroxymethyl)cyclopropyl]phenyl]-5-methyl-7-oxo-

[0345] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[2-(trifluoromethyl)pyrimidin-5- yl]acetamide;

[0346] 2-[5-methyl-7-oxo-2-[1 -[rac-(3R)-tetrahydrofuran-3-yl]pyrazol-4-yl]-

[0347] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0348] 2-[2-[4-(4-hydroxytetrahydropyran-4-yl)phenyl]-5-methyl-7-oxo-

[0349] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0350] N-(4-chlorophenyl)-2-[2-[4-[1 -(hydroxymethyl)cyclopropyl]phenyl]-5- methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]acetamide;

[0351] N-(4-chlorophenyl)-2-[2-[4-[1 -(hydroxymethyl)cyclopropyl]phenyl]-5- methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]acetamide; 2-[5-methyl-2-[4-(oxetan-3-yl)phenyl]-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0352] 2-[2-[4-(4-hydroxycyclohexyl)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0353] 2-[5-methyl-2-[4-[[(5R)-3-methyl-2-oxo-oxazolidin-5-yl]methyl]phenyl]-7- oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide;

[0354] 2-[5-methyl-7-oxo-2-[4-[rac-(1 S,3R)-3-hydroxycyclohexyl]phenyl]-

[0355] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide;

[0356] 2-[6-cyclopropyl-2-[4-[1 -(hydroxymethyl)cyclopropyl]phenyl]-5-methyl-7- oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide; tert-butyl N-[(1 S,2R)-2-[4-[5-methyl-7-oxo-4-[2-oxo-2-[4- (trifluoromethyl)anilino]ethyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-2- yl]phenyl]cyclopentyl]carbamate; tert-butyl (2R,4S)-4-fluoro-2-[[4-[5-methyl-7-oxo-4-[2-oxo-2-[4- (trifluoromethyl)anilino]ethyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-2- yl]phenyl]methyl]pyrrolidine-1 -carboxylate;

[0357] 2-[2-[4-(3-hydroxycyclobutyl)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide;

[0358] 2-[5-methyl-7-oxo-2-[4-[[rac-(3S)-3-hydroxytetrahydrofuran-3- yl]methyl]phenyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4- (trifluoromethyl)phenyl]acetamide;

[0359] 2-[5-m ethy l-7-oxo-2-[4-[[rac-( 1 S , 3S)-3- hydroxycyclopentyl]methyl]phenyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4- (trifluoromethyl)phenyl]acetamide;

[0360] 2-[5-methyl-7-oxo-2-[4-[rac-(1 S,3S)-3-hydroxy-2,2-dimethyl- cyclobutyl]phenyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4- (trifluoromethyl)phenyl]acetamide;

[0361] 2-[2-[4-[(4-hydroxytetrahydropyran-4-yl)methyl]phenyl]-5-methyl-7-oxo-

[0362] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide;

[0363] 2-[2-[4-[(1 -hydroxycyclohexyl)methyl]phenyl]-5-methyl-7-oxo-

[0364] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide;

[0365] 2-[2-[4-[(3-hydroxycyclobutyl)methyl]phenyl]-5-methyl-7-oxo-

[0366] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide; 2-[2-[4-[2-(1-hydroxycyclopropyl)ethyl]phenyl]-5-methyl-7-oxo-

[0367] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide; tert-butyl (2S,4R)-4-hydroxy-2-[[4-[5-methyl-7-oxo-4-[2-oxo-2-[4- (trifluoromethyl)anilino]ethyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-2- yl]phenyl]methyl]pyrrolidine-1 -carboxylate;

[0368] 2-[2-[4-(4-cyanocyclohexyl)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide;

[0369] 2-[5-methyl-7-oxo-2-[4-[rac-(2R)-tetrahydrofuran-2-yl]phenyl]-

[0370] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide;

[0371] 2-[2-[4-[1-(hydroxymethyl)cyclopropyl]phenyl]-6-isopropyl-5-methyl-7- oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[6-(trifluoromethyl)-3- pyridyl]acetamide;

[0372] 2-[2-[4-[1-(hydroxymethyl)cyclopropyl]phenyl]-6-isopropyl-5-methyl-7- oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[6-(trifluoromethyl)-3- pyridyl]acetamide;

[0373] 2-[2-[4-[1-(hydroxymethyl)cyclopropyl]phenyl]-6-isopropyl-5-methyl-7- oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[6-(trifluoromethyl)-3- pyridyl]acetamide;

[0374] 2-[2-[4-[1-(hydroxymethyl)cyclopropyl]phenyl]-6-isopropyl-5-methyl-7- oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[2-(trifluoromethyl)thiazol-5- yl]acetamide;

[0375] N-(4-cyclopropylphenyl)-2-[2-[4-[1-(hydroxymethyl)cyclopropyl]phenyl]-6- isopropyl-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]acetamide;

[0376] 2-[2-[4-[[1-(hydroxymethyl)cyclobutyl]methyl]phenyl]-5-methyl-7-oxo-

[0377] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0378] 2-[2-[4-[(1-hydroxycyclopentyl)methyl]phenyl]-5-methyl-7-oxo-

[0379] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0380] 2-[2-[4-[(1-hydroxycyclobutyl)methyl]phenyl]-5-methyl-7-oxo-

[0381] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0382] 2-[5-m ethy l-7-oxo-2-[4-[rac-( 1 S , 3S)-3-[(R)- methylsulfinyl]cyclohexyl]phenyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p- tolyl)acetamide; 2-[5-methyl-7-oxo-2-[4-[[rac-(3S,4S)-4-hydroxytetrahydropyran-3- yl]methyl]phenyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0383] 2-[2-[4-[(1 SR,2S)-2-cyanocyclohexyl]phenyl]-5-methyl-7-oxo-

[0384] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0385] 2-[5-methyl-7-oxo-2-[4-[rac-(1 R,2S)-4,4-difluoro-2-hydroxy- cyclopentyl]phenyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0386] 2-[5-methyl-7-oxo-2-[4-[[rac-(3R)-3-cyanotetrahydrofuran-3- yl]methyl]phenyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0387] 2-[5-methyl-7-oxo-2-[4-[[rac-(3R)-1-methyl-2-oxo-pyrrolidin-3- yl]methyl]phenyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0388] 2-[5-methyl-2-(2-morpholinothiazol-4-yl)-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0389] 2-[2-(1 -cyclobutylpyrazol-4-yl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0390] 2-[5-methyl-2-(6-morpholino-3-pyridyl)-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0391] 2-[2-[4-[[(2R,4R)-4-hydroxypyrrolidin-2-yl]methyl]phenyl]-5-methyl-7-oxo-

[0392] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide; ethyl rac-(3R,4S)-4-[4-[5-methyl-4-[2-(4-methylanilino)-2-oxo-ethyl]-7- oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-2-yl]phenyl]piperidine-3-carboxylate;

[0393] N-(4-chlorophenyl)-2-[2-[4-[1-(hydroxymethyl)cyclopropyl]phenyl]-6- isopropyl-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]acetamide;

[0394] N-(4-chlorophenyl)-2-[2-[4-[1-(hydroxymethyl)cyclopropyl]phenyl]-6- isopropyl-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]acetamide;

[0395] 2-[2-[4-[[4-(hydroxymethyl)cyclohexyl]methyl]phenyl]-5-methyl-7-oxo-

[0396] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0397] 2-[2-[4-(4-hydroxy-4-methyl-cyclohexyl)phenyl]-5-methyl-7-oxo-

[0398] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0399] 2-[2-[4-[[4-(hydroxymethyl)cyclohexyl]methyl]phenyl]-5-methyl-7-oxo-

[0400] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0401] 2-[2-[4-[[(2R,3S)-3-hydroxy-5-oxo-tetrahydrofuran-2-yl]methyl]phenyl]-5- methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide; 2-[5-methyl-7-oxo-2-[4-[rac-(3S)-1 -methyl-5-oxo-pyrrolidin-3-yl]phenyl]-

[0402] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0403] 2-[2-[4-(4-methoxycyclohexyl)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0404] 2-[2-[4-(4-hydroxy-4-methyl-cyclohexyl)phenyl]-5-methyl-7-oxo-

[0405] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0406] 2-[2-[4-(4-hydroxy-4-methyl-cyclohexyl)phenyl]-5-methyl-7-oxo-

[0407] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0408] 2-[2-[4-(4-methoxycyclohexyl)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0409] 2-[2-[4-[(4-hydroxycyclohexyl)methyl]phenyl]-5-methyl-7-oxo-

[0410] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide; methyl rac-(2S)-2-[[4-[5-methyl-4-[2-(4-methylanilino)-2-oxo-ethyl]-7-oxo-

[0411] [1 .2.4]triazolo[1 ,5-a]pyrimidin-2-yl]phenyl]methyl]pyrrolidine-2 -carboxylate;

[0412] 2-[2-[4-(4-aminocyclohexyl)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0413] 2-[2-[4-[(4-methoxy-4-piperidyl)methyl]phenyl]-5-methyl-7-oxo-

[0414] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0415] 2-[2-[4-[(3R* 4S)-4-methoxypyrrolidin-3-yl]phenyl]-5-methyl-7-oxo-

[0416] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0417] N-(2,4-dimethylphenyl)-2-[2-[4-[1 -(hydroxymethyl)cyclopropyl]phenyl]-6- isopropyl-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]acetamide;

[0418] 2-[5-methyl-7-oxo-2-[6-(2-oxopyrrolidin-1 -y l)-3-pyridy l]-[ 1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0419] 2-[5-methyl-7-oxo-2-[6-(2-oxopyrrolidin-1 -y l)-3-pyridy l]-[ 1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0420] N-(2-fluoro-4-methyl-phenyl)-2-[2-[4-[1 -

[0421] (hydroxymethyl)cyclopropyl]phenyl]-6-isopropyl-5-methyl-7-oxo-

[0422] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]acetamide;

[0423] 2-[2-[4-[1 -(hydroxymethyl)cyclopropyl]phenyl]-6-isopropyl-5-methyl-7- oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[2-(trifluoromethyl)pyrimidin-5- yl]acetamide; 2-[2-(2-cyclopropyloxazol-5-yl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0424] 2-[5-methyl-7-oxo-2-[4-[rac-(2R,4S,5R)-4,5-dihydroxytetrahydropyran-2- yl]phenyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0425] 2-[5-methyl-7-oxo-2-[4-[rac-(2R,4S,5R)-4,5-dihydroxytetrahydropyran-2- yl]phenyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0426] 2-[2-[4-(3-hydroxycyclobutyl)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0427] 2-[2-[4-(3-hydroxycyclobutyl)phenyl]-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0428] 2-[5-methyl-7-oxo-2-[4-[rac-(3S)-4-hydroxy-1 , 1 -dioxo-thiolan-3- yl]phenyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0429] 4-[4-[5-methyl-4-[2-(4-methylanilino)-2-oxo-ethyl]-7-oxo-

[0430] [1 .2.4]triazolo[1 ,5-a]pyrimidin-2-yl]phenyl]cyclohexanecarboxamide;

[0431] 2-[2-[1 -[(3-hydroxycyclobutyl)methyl]pyrazol-4-yl]-5-methyl-7-oxo-

[0432] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0433] 2-[2-[1 -(3-methoxycyclobutyl)pyrazol-4-yl]-5-methyl-7-oxo-

[0434] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0435] 2-[2-[1 -[3-(hydroxymethyl)cyclobutyl]pyrazol-4-yl]-5-methyl-7-oxo-

[0436] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0437] 2-[2-[6-(3-hydroxyazetidin-1 -yl)-3-pyridyl]-5-methyl-7-oxo-

[0438] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide; rac-(2R)-2-[2-[4-[1-(hydroxymethyl)cyclopropyl]phenyl]-5-methyl-7-oxo-

[0439] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)propanamide;

[0440] 2-[6-cyclobutyl-2-[4-[1 -(hydroxymethyl)cyclopropyl]phenyl]-5-methyl-7- oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0441] 2-[2-[1 -(3-hydroxycyclobutyl)pyrazol-4-yl]-5-methyl-7-oxo-

[0442] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0443] 2-[2-[4-[3-(difluoromethyl)cyclobutyl]phenyl]-5-methyl-7-oxo-

[0444] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0445] 2-[2-[4-[3-(2,2-difluoroethoxy)cyclobutyl]phenyl]-5-methyl-7-oxo-

[0446] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide; 2-[2-[4-[4-(difluoromethyl)cyclohexyl]phenyl]-5-methyl-7-oxo-

[0447] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0448] 2-[5-methyl-7-oxo-2-[4-[rac-(1 S,2R)-2-hydroxycyclobutyl]phenyl]-

[0449] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0450] 2-[2-[4-[3-(cyanomethyl)cyclobutyl]phenyl]-5-methyl-7-oxo-

[0451] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0452] 2-[5-methyl-7-oxo-2-[4-[rac-(3S,4R)-4-fluorotetrahydrofuran-3-yl]phenyl]-

[0453] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0454] 2-[5-methyl-7-oxo-2-[4-[rac-(1 R,2S,3S)-3-hydroxy-2-methyl- cyclobutyl]phenyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0455] 2-[5-methyl-7-oxo-2-[4-[rac-(3S,4S)-4-hydroxytetrahydropyran-3- yl]phenyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0456] 2-[2-[4-(3-cyano-3-methyl-cyclobutyl)phenyl]-5-methyl-7-oxo-

[0457] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0458] 2-[5-methyl-7-oxo-2-[4-[rac-(1 S,2S,3S)-3-hydroxy-2-methoxy- cyclobutyl]phenyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0459] 2-[5-methyl-7-oxo-2-[4-[rac-(3S)-3-cyanotetrahydropyran-4-yl]phenyl]-

[0460] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0461] 2-[5-methyl-7-oxo-2-[4-[rac-(3S)-3-cyanotetrahydropyran-4-yl]phenyl]-

[0462] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0463] 2-[5-methyl-7-oxo-2-[4-[rac-(1 S,3S)-3-hydroxy-2,2-dimethyl- cyclobutyl]phenyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide; methyl 1 -cyano-3-[4-[5-methyl-4-[2-(4-methylanilino)-2-oxo-ethyl]-7-oxo-

[0464] [1 .2.4]triazolo[1 ,5-a]pyrimidin-2-yl]phenyl]cyclobutanecarboxylate;

[0465] 2-[5-methyl-7-oxo-2-[4-[rac-(4S)-4-methoxytetrahydrofuran-3-yl]phenyl]-

[0466] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0467] 2-[2-[4-[3-methoxy-3-(trifluoromethyl)cyclobutyl]phenyl]-5-methyl-7-oxo-

[0468] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0469] 2-[2-[4-[1 -(hydroxymethyl)cyclopropyl]phenyl]-6-isopropyl-5-methyl-7- oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[2-methyl-4- (trifluoromethyl)phenyl]acetamide; N-[2-chloro-4-(trifluoromethyl)phenyl]-2-[2-[4-[1 - (hydroxymethyl)cyclopropyl]phenyl]-6-isopropyl-5-methyl-7-oxo-

[0470] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]acetamide;

[0471] 2-[6-isopropyl-5-methyl-7-oxo-2-[4-[1 -[rac-(1 S)-1 - hydroxyethyl]cyclopropyl]phenyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[2- (trifluoromethyl)thiazol-5-yl]acetamide;

[0472] 2-[6-isopropyl-5-methyl-7-oxo-2-[4-[rel-(3R,4S)-4- hydroxytetrahydrofuran-3-yl]phenyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p- tolyl)acetamide;

[0473] 2-[6-isopropyl-5-methyl-7-oxo-2-[4-[rel-(3S,4R)-4- hydroxytetrahydrofuran-3-yl]phenyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p- tolyl)acetamide;

[0474] 2-[2-[4-(3-hydroxycyclobutyl)phenyl]-6-isopropyl-5-methyl-7-oxo-

[0475] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0476] 2-[6-isopropyl-5-methyl-7-oxo-2-[4-[rel-(1 S,2R)-2- hydroxycyclobutyl]phenyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p- tolyl)acetamide;

[0477] 2-[6-isopropyl-5-methyl-7-oxo-2-[4-[rel-(1 R,2S)-2- hydroxycyclobutyl]phenyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p- tolyl)acetamide;

[0478] 2-[6-isopropyl-2-[4-[1 -(methanesulfonamido)cyclopropyl]phenyl]-5- methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4- (trifluoromethyl)phenyl]acetamide;

[0479] 2-[2-[4-(1 -aminocyclobutyl)phenyl]-6-isopropyl-5-methyl-7-oxo-

[0480] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide; tert-butyl N-[1 -[4-[6-isopropyl-5-methyl-7-oxo-4-[2-oxo-2-[4- (trifluoromethyl)anilino]ethyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-2- yl]phenyl]cyclobutyl]carbamate;

[0481] 2-[2-[4-(1 -acetamidocyclopropyl)phenyl]-6-isopropyl-5-methyl-7-oxo-

[0482] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide; tert-butyl N-[1 -[4-[6-isopropyl-5-methyl-7-oxo-4-[2-oxo-2-[4- (trifluoromethyl)anilino]ethyl]-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-2- yl]phenyl]cyclopropyl]carbamate; 2-[2-[4-(1 -aminocyclopropyl)phenyl]-6-isopropyl-5-methyl-7-oxo-

[0483] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide; and stereoisomers, and pharmaceutically acceptable salts thereof.

[0484] In certain embodiments, the present invention is directed to one or more compounds of formula (I) independently selected from the group consisting of 2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6-isopropyl-5-methyl-7-oxo-

[0485] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;

[0486] 2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6-isopropyl-5-methyl-7-oxo-

[0487] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide;

[0488] 2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6-isopropyl-5-methyl-7-oxo-

[0489] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[6-(trifluoromethyl)-3-pyndyl]acetamide;

[0490] 2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6-isopropyl-5-methyl-7-oxo-

[0491] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[2-(trifluoromethyl)thiazol-5-yl]acetamide;

[0492] 2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-5-methyl-6-morpholino-7-oxo-

[0493] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide;

[0494] 2-[2-[4-[1 -(hydroxymethyl)cyclopropyl]phenyl]-6-isopropyl-5-methyl-7- oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[6-(trifluoromethyl)-3- pyridyl]acetamide;

[0495] 2-[2-[4-[1 -(hydroxymethyl)cyclopropyl]phenyl]-6-isopropyl-5-methyl-7- oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[2-(trifluoromethyl)thiazol-5- yl]acetamide;

[0496] 2-[2-[4-[1 -(hydroxymethyl)cyclopropyl]phenyl]-6-isopropyl-5-methyl-7- oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[2-(trifluoromethyl)pyrimidin-5- yl]acetamide;

[0497] 2-[2-[4-[1 -(hydroxymethyl)cyclopropyl]phenyl]-6-isopropyl-5-methyl-7- oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[2-methyl-4- (trifluoromethyl)phenyl]acetamide;

[0498] 2-[2-[4-(1 -acetamidocyclopropyl)phenyl]-6-isopropyl-5-methyl-7-oxo-

[0499] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide;

[0500] 2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6-isopropyl-5-methyl-7-oxo-

[0501] [1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[2-methyl-4- (trifluoromethyl)phenyl]acetamide; and stereoisomers, and pharmaceutically acceptable salts thereof.

[0502] In certain embodiments, the present invention is directed to compounds of formula (I) which, when tested for WRN inhibition according to the procedure as described in Biological Example 1 , which follows hereinafter, exhibit an ICso of less than or equal to about 10 pM, preferably less than or equal to about 5 pM, more preferably less than or equal to about 2 pM, more preferably less than or equal to about 1 pM.

[0503] In certain embodiments, the present invention is directed to compounds of formula (I) which, when tested for WRN inhibition according to the procedure as described in Biological Example 1 , which follows hereinafter, exhibit an ICso of less than or equal to about 0.5 pM, 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.

[0504] Definitions

[0505] As used herein, “halogen” shall mean chlorine, bromine, fluorine and iodine, preferably chloro, fluoro or bromo, more preferably chloro or fluoro, more preferably fluoro.

[0506] As used herein, unless otherwise noted, the term “oxo” shall denote a substituent group of the formula =0 (i.e an oxygen atom bound through a double bond). One skilled in the art will recognize, that wherein an oxo substituent is bound to a ring nitrogen atom, the resulting structure is a N-oxide of the formula >N+-O-).

[0507] 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).

[0508] One skilled in the art will recognize that the term “-(Cx-yalkyl)-” wherein X and Y are integers shall denote any Cx-yalkyl carbon chain as herein defined, wherein said Cx-yalkyl chain is divalent and is bound through two points of attachment, preferably through two terminal carbon atoms.

[0509] As used herein, unless otherwise noted, the term “halogen substituted Cx-yalkyl” wherein X and Y are integers, shall mean any Cx-yalkyl group as defined above substituted with at least one halogen atom, preferably substituted with a least one fluoro atom. For example, -CF3, -CH2-CF3, -CF2- CF2-CF2-CF3, CCI3, -CH2-CCI3, and the like. Similarly, the term “fluoro substituted Cx-yalkyl” wherein X and Y are integers, shall mean any Cx-yalkyl group as defined above substituted with at least one fluoro atom, preferably one to five fluoro atoms, more preferably one to three fluoro atoms. For example, -CF3, -CH2-CF3, -CF2-CF2-CF2-CF3, -CF2-CF3, and the like.

[0510] As used herein, unless otherwise noted, the term “hydroxy substituted Cx-yalkyl” wherein X and Y are integers, shall mean any Cx-yalkyl group as defined above substituted with at least one hydroxy (-OH) group, preferably one to three, more preferably one to two hydroxy groups. For example, - CH2OH, -CH2CH2-OH, -CH2-CH(OH)-CH3, -CH(CH2CH2OH)2, and the like.

[0511] As used herein, unless otherwise noted, the term “Cx-yalkenyl” wherein X and Y are integers, shall denote any straight or branched chain containing between X and Y carbon atoms, further containing at least one, preferably one to three, more preferably one to two, unsaturated double bond. For example - CH=CH2, -CH2-CH=CH2, -CH=CH=CH2-CH=CH2, -CH2-C(=CH2)-CH3, - C(=CH2)-CH3, and the like.

[0512] As used herein, unless otherwise noted, the term “hydroxy substituted Cx-yalkenyl” wherein X and Y are integers, shall mean any Cx-yalkenyl group as defined above substituted with at least one hydroxy (-OH) group, preferably one to three, more preferably one to two hydroxy groups. For example, - CH=CH-OH, -CH2-C(OH)=CH2, -CH2-C(OH)=CH-OH, -CH=CH=C(OH)- CH=CH2, -CH=CH=CH-CH=CH-OH, -CH2-C(=CH2)-CH2-OH, -CH2-C(=CH- OH)-CH2-OH, -C(=CH2)-CH2-OH, and the like.

[0513] As used herein, unless otherwise noted, the term “Cx-ycycloalkyl” wherein X and Y are integers shall mean any stable saturated monocyclic, bicyclic, or polycyclic, containing between X and Y carbon atoms. For example, Cs-scycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0514] As used herein, unless otherwise noted, the term “Cx-ycycloalkenyl” wherein X and Y are integers shall mean any stable saturated monocyclic, bicyclic, or polycyclic, containing between X and Y carbon atoms, further containing at least one unsaturated ring double bond. For example, cyclopentenyl, cyclohexenyl, and the like.

[0515] As used herein, unless otherwise noted, the term “heterocyclyl” shall denote any monocyclic, saturated, partially unsaturated or aromatic ring structure containing at least one heteroatom selected from the group consisting of 0, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of 0, N and S; or any saturated, partially unsaturated, partially aromatic or aromatic bicyclic, fused, bridged or spiro-cyclic ring system containing at least one heteroatom selected from the group consisting of 0, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of 0, N and S. Suitable examples include, but are not limited to, pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, indolinyl, chromenyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzo[b][1 ,4]dioxinyl, benzo[d][1 ,3]dioxolyl, 2H-benzo[d][1 ,2,3]triazol-5-yl, and the like.

[0516] As used herein, unless otherwise noted, the term “4 to 6 membered heterocyclyl” shall denote any four to six membered monocyclic, saturated, partially unsaturated or aromatic ring structure containing at least on heteroatom selected from the group consisting of 0, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of 0, N and S, as described above. The 4 to 6 membered heterocyclyl may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.

[0517] In certain embodiments of the present invention, the 4 to 6 membered heterocyclyl is selected from the group consisting of azetidinyl, oxetanyl, piperidinyl, pyrrolidinyl, morpholinyl, dihydrofuranyl, dihydropyrrolyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydropyridinyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and thiopyranyl.

[0518] As used herein, the term “heterocycloalkyl” shall denote any four to eight, preferably four to six, membered monocyclic, saturated or partially unsaturated ring structure containing at least one heteroatom selected from the group consisting of 0, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of 0, N and S; or any seven to twelve, preferably seven to ten, membered saturated, partially unsaturated or partially aromatic bicyclic ring system containing at least one heteroatom selected from the group consisting of 0, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of 0, N and S. The heterocycloalkyl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure. In certain embodiments, the heterocycloalkyl ring system is fully saturated. In certain embodiments, the heterocycloalkyl ring system is partially unsaturated (i.e. contains at least one unsaturated double bond). In certain embodiments, the heterocycloalkyl ring system is partially aromatic (e.g. benzofused). Examples of suitable heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, indolinyl, chromenyl, 3,4- methylenedioxyphenyl, dihydrobenzofuryl, dihydrofuranyl, dihydropyrrolyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydropyridinyl, and the like.

[0519] As used herein, the term “4 to 6 membered heterocycloalkyl” shall denote any four to six membered monocyclic, saturated or partially unsaturated ring structure containing at least one heteroatom selected from the group consisting of 0, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of 0, N and S; as defined above. The 4 to 6 membered heterocycloalkyl may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.

[0520] In certain embodiments, the present invention is directed to compounds of formula (I) wherein the 4 to 6 membered heterocycloalkyl is selected from the group consisting of azetidinyl, oxetanyl, pyrrolid iny I, piperid iny I, morpholinyl, dihydrofuranyl, dihydropyrrolyl, tetrahydropyranyl, tetrahydrothiophenyl, and tetrahydropyridinyl.

[0521] As used herein, unless otherwise noted, “heteroaryl” shall denote any five or six membered monocyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of 0, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of 0, N and S; or a nine or ten membered bicyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of 0, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of 0, N and S. The heteroaryl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure. Examples of suitable heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, thiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, thiopyranyl, furazanyl, indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, and the like.

[0522] As used herein, unless otherwise noted, “5 to 6 membered heteroaryl” shall denote any five or six membered monocyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of 0, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of 0, N and S; as described above The 5 to 6 membered heteroaryl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.

[0523] In certain embodiments, the present invention is directed to compounds of formula (I) wherein the 5 to 6 membered heteroaryl is selected from the group consisting of furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and thiopyranyl. In certain embodiments, the present invention is directed to compounds of formula (I) wherein the 5 to 6 membered heteroaryl is selected from the group consisting of furanyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and thiopyranyl.

[0524] When a particular group is “substituted” (e.g., alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, 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.

[0525] 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.

[0526] As used herein, the notation shall denote the presence of a stereogenic center.

[0527] 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. Preferably, wherein the compound is present as an enantiomer, the enantiomer is 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 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%.

[0528] 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.

[0529] 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 “phenylC-i- CealkylaminocarbonylCi-Cealkyl” substituent refers to a group of the formula

[0530] Abbreviations used in the specification, particularly the Schemes and Examples, are as follows:

[0531]

[0532] 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.

[0533] 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.

[0534] As used herein, unless otherwise noted, the term “substantially free of a corresponding salt form(s)” when used to described the compound of formula (I) shall mean that mole percent of the corresponding salt form(s) in the isolated base of formula (I) is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably less than about 0.1 mole percent. In an embodiment of the present invention, the compound of formula (I) is present in a form which is substantially free of corresponding salt form(s).

[0535] 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.

[0536] As used herein, unless otherwise noted, the term “prevention” shall include (a) reduction in the frequency of one or more symptoms; (b) reduction in the severity of one or more symptoms; (c) the delay or avoidance of the development of additional symptoms; and I or (d) delay or avoidance of the development of the disorder or condition.

[0537] One skilled in the art will recognize that wherein the present invention is directed to methods of prevention, a subject in need of thereof (i.e. a subject in need of prevention) shall include any subject or patient (preferably a mammal, more preferably a human) who has experienced or exhibited at least one symptom of the disorder, disease or condition to be prevented. Further, a subject in need thereof may additionally be a subject (preferably a mammal, more preferably a human) who has not exhibited any symptoms of the disorder, disease or condition to be prevented, but who has been deemed by a physician, clinician or other medical profession to be at risk of developing said disorder, disease or condition. For example, the subject may be deemed at risk of developing a disorder, disease or condition (and therefore in need of prevention or preventive treatment) as a consequence of the subject’s medical history, including, but not limited to, family history, pre-disposition, co-existing (comorbid) disorders or conditions, genetic testing, and the like.

[0538] The term “subject” as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. Preferably, the subject has experienced and I or exhibited at least one symptom of the disease or disorder to be treated and I or prevented.

[0539] The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent 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.

[0540] 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.

[0541] The present invention is further directed to method of treating disorders and I or diseases mediated by or modulated by inhibition of WRN comprising administering a compound of Formula (I) to a subject in need thereof. The present invention is further directed to the use of any of the compounds as described herein in the preparation of a medicament for the treatment of disorders and / or diseases mediated by or modulated by inhibition of WRN. In certain embodiments, the present invention is directed to methods of treating disorders and I or diseases mediated by or modulated by inhibition of WRN which include, but are not limited to, cancer comprising administering a compound of Formula (I) to a subject in need thereof.

[0542] In certain embodiments, the present invention is directed to methods of treating cancers (preferably cancers characterized as microsatellite instability (MSI) or mismatch repair deficient (dMMR)) comprising administering a compound of Formula (I) to a subject in need thereof. In certain 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 administering a compound of Formula (I) to a subject in need thereof.

[0543] In certain embodiments, the present invention is directed to methods of treating a cancer 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.

[0544] In certain 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 administering a compound of Formula (I) to a subject in need thereof.

[0545] In certain 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. Preferably, the cancer is selected from the group consisting of colonic, gastric, rectal, endometrial, adrenocortical, uterine, cervical, ovarian, and small bowel, comprising administering a compound of Formula (I) to a subject in need thereof.

[0546] 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.

[0547] 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 of 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.

[0548] 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.

[0549] 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.

[0550] 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.

[0551] 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.

[0552] 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.

[0553] 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 .

[0554] As used herein, unless otherwise noted, the term “oxygen protecting group” shall mean a group which may be attached to a 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.

[0555] Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional technigues 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 technigues, 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.

[0556] Additionally, chiral HPLC against a standard may be used to determine percent enantiomeric excess (%ee). The enantiomeric excess may be calculated as follows

[0557] [ (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 = ([a-obs] / [a-max]) X 100. 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 (d2O 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 d218O.

[0558] 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 (R)-CH3CHDOH and (S)-CH3CHDOH or (Z)-CH3CH=CHD and (E)-CH3CH=CHD are examples of isotopic stereoisomers of ethanol and n-propene, respectively.

[0559] In certain embodiments of the present invention, any one or more element(s), in particular when mentioned in relation to a compound of formula (I), shall comprise all isotopes and isotopic mixtures of said element(s), either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. In certain embodiments of the present invention, the compounds of formula (I) 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) may comprise one or more radioactive isotope(s) selected from the group of3H,11C,18F,122l,123l,125l,131l,75Br,76Br,77Br and82Br. Preferably, the radioactive isotope is selected from the group of3H,11C and18F.

[0560] In certain embodiments, the present invention is directed to compounds of formula (I) wherein one or more atoms (preferably, one or more hydrogen, carbon, oxygen, nitrogen or fluorine atom) are replaced with a radioactive or non-radioactive isotope.

[0561] The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

[0562] For use in medicine, the salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salts.” Other salts may, however, be useful in the 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.

[0563] 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, a-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, nicotine 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.

[0564] 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.

[0565] General Synthesis Schemes:

[0566] Compounds of formula (I) of the present invention may be prepared as described in the general schemes and examples which follow herein.

[0567] Compounds of formula (I) may be prepared as described in Scheme 1 , below.

[0568] Scheme 1

[0569] Accordingly, 5-nitro-1 H-1 ,2,4-triazole, a known compound, is reacted with a suitably selected halogenating agent such as NBS, NCS, NIS, Br2, and the like, preferably a suitably selected brominating agent, such as Br2, NBS,, and the like; in the presence of a suitably selected base such as NaOH, KOH, and the like; in a suitably selected solvent such as water, ACN, DMF, AcOH, and the like; at a temperature in the range of from about 25 °C to about 100 °C, preferably at about 80 °C; to yield the corresponding compound of formula (V), wherein Hal1is the corresponding halogen (for example, when the halogenating agent is Br2, the corresponding Hal1group is Br).

[0570] The compound of formula (V) is reacted with a suitably selected reducing agent, such as a metal such as Fe, Zn, and the like; in the presence of a suitably selected additive such as NH4CI, AcOH, and the like; in a suitably selected solvent or mixture of solvents, such as EtOH, H2O, THF, a mixture of THF and water, a mixture of EtOH and water, and the like; at a temperature in the range of from about 25 °C to about 100 °C, preferably at about 80 °C; to yield the corresponding compound of formula (VI).

[0571] The compound of formula (VI) is reacted with a suitably substituted compound of formula (VII), wherein A1is Ci-4alkyl, preferably methyl or ethyl, a known compound or compound prepared by known methods; in the presence of an acid such as TsOH, AcOH, H3PO4, and the like; neat or in a suitably selected organic solvent such as toluene, EtOH, and the like; at a temperature greater than about 100 °C, preferably at about 110 °C; to yield the corresponding compound of formula (VIII).

[0572] The compound of formula (VIII) is reacted with a suitably substituted compound of formula (IX), wherein Hal2is a suitably selected halogen such as Br, Cl or I, preferably Br or I, a known compound or compound prepared by known method; in the presence of a suitably selected inorganic base such as CS2CO3, K2CO3, EtsN, DIPEA and the like; in a suitably selected solvent such as DMF, DMSO and the like; at a temperature in the range of from about room temperature to about 65 °C, preferably at about 60 °C; to yield a compound of formula (X).

[0573] The compound of formula (X) is reacted with a suitably substituted compound of formula (XI), wherein BI2 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

[0574] > / 0- _rB\ the boron atom to which they are bound to formanc| the like; a known compound or compound prepared by known methods; in the presence of a suitably selected palladium catalyst such as Xphos Pd G3, Pd-PEPPSITM- Ipent, Pd(dppf) G4, cataCXium®Pd G4, and the like; in the presence of a suitably selected base such a CS2CO3, K2CO3, Na2COs, 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 a temperature greater than about 80 °C, preferably at about 100 °C; to yield the corresponding compound of formula (I).

[0575] Compounds of formula (I) may alternatively be prepared as described in Scheme 2, below.

[0576] Scheme 2

[0577] Accordingly, a compound of formula (VIII), prepared for example as described in Scheme 1 above, is reacted with a suitably substituted compound of formula (XII), wherein Hal3is a suitably selected halogen such as Br, Cl or I, preferably Br or I, and wherein A2is Ci-4alkyl, preferably tert-butyl, a known compound or compound prepared by known methods; in the presence of a suitably selected base such as CS2CO3, K2CO3, EtsN, DIPEA and the like; in a suitably selected solvent such as DMF, DMSO, MeCN, 1 ,4-dioxane and the like; at a temperature in the range of from about room temperature to about 65 °C, preferably at about room temperature; to yield the corresponding compound of formula (XIII).

[0578] The compound of formula (XIII) is reacted with a suitably substituted compound of formula (XI), wherein BI2 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 oA /

[0579] A '' the boron atom to which they are bound to form O" x , and the like; a known compound or compound prepared by known methods; in the presence of a suitably selected palladium catalyst such as Xphos Pd G3, Pd-PEPPSI™- Ipent, Pd(dppf) G4, cataCXium®Pd G4, and the like; in the presence of a suitably selected base such a CS2CO3, K2CO3, Na2COs, 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 a temperature greater than about 80 °C, preferably at about 100 °C; to yield the corresponding compound of formula

[0580] (XIV).

[0581] The compound of formula (XIV) is reacted in the presence of a suitably selected acid, such as HCI, TFA, and the like or a suitably selected base such as NaOH, LiOH, KOH and the like; in a suitably selected solvent or mixture of solvents, such as 1 ,4-dioxane, DCM, water, EtOH and the like; at a temperature in the range of from about 0 °C to about room temperature, preferably at about 25 °C; to yield the corresponding compound of formula

[0582] (XV).

[0583] The compound of formula (XV) is reacted with a suitably substituted compound of formula (XVI), a known compound or compound prepared by known methods; in the presence of a suitably selected amide coupling reagent such as HATLI, HBTII, Mukaiyama’s reagent (2-chloro-1 -methylpyridinium iodide, CMPI), and the like; in the presence of a suitably selected base such as EtsN, DIPEA and the like; in a suitably selected solvent such as DMF, DMSO, MeCN, and the like; at room temperature; to yield the corresponding compound of formula (I).

[0584] Compounds of formula (I) may alternatively be prepared as described in Scheme 3, below.

[0585]

[0586] Scheme 3 Accordingly, a suitably substituted compound of formula (XVII) wherein

[0587] Hal4is a suitably selected halogen such as Br, Cl or I, preferably Br, a known compound or compound prepared by known methods is reacted with a suitably substituted compound of formula (VII), wherein A1is Ci-4alkyl, preferably methyl or ethyl, a known compound or compound prepared by known methods; in the presence of an acid such as TsOH, AcOH, H3PO4, and the like; neat or in a suitably selected organic solvent such as toluene, EtOH, butan-1 -ol, DMF, and the like; at a temperature greater than about 80 °C, preferably at about 100 °C; to yield the corresponding compound of formula (XVIII).

[0588] The compound of formula (XVIII) is reacted with a suitably substituted compound of formula (IX), wherein Hal2is a suitably selected halogen such as Br, Cl or I, preferably Br or I, a known compound or compound prepared by known method; in the presence of a suitably selected inorganic base such as CS2CO3, K2CO3, EtsN, DIPEA, EtsN and the like; in a suitably selected solvent such as DMF, DMSO, 1 ,4-dioxane, MeCN and the like; at a temperature in the range of from about room temperature to about 65 °C, preferably at about 50 °C; to yield the corresponding compound of formula (XIX).

[0589] The compound of formula (XIX) 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 catalyst such as a mixture of NiBr2*dtbbpy and [lr((dtbbpy)ppy)2]PFe, and the like; in a suitably selected solvent such as DMA, MTBE, 1 ,4-dioxane and the like; at a temperature in the range of from about 25 °C to about 40 °C, preferably at about 25 °C; under blue light (450 nm) irradiation; to yield the corresponding compound of formula (la).

[0590] Compounds of formula (I) may alternatively be prepared as described in Scheme 4, below.

[0591] Scheme 4

[0592] Accordingly, a suitably substituted compound of formula (lb), prepared for example as described herein, is reacted with a suitably selected halogenating agent such as NBS, NCS, NIS, Br2, and the like, preferably NBS; in the presence of a suitably selected acid such as AcOH, TsOH, and the like; in a suitably selected solvent such as water, DMF, MeCN, and the like; at a temperature in the range of from about 0 °C to about 65 °C , preferably at about 25 °C; to yield the corresponding compound of formula (XXI), wherein Hal5is the corresponding halogen (for example, when the halogenating agent is Br2, the corresponding Hal5group is Br).

[0593] The compound of formula (XXI) is reacted with a suitably substituted compound of formula (XXII), wherein BI2 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; 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, Na2COs, 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 a temperature greater than about 80 °C, preferably at about 100 °C; to yield the corresponding compound of formula (I). (DONG, Z., et al., Nature 2021 , pp 451 -456, Vol. 598)

[0594] Pharmaceutical Compositions

[0595] The present invention further comprises pharmaceutical compositions containing one or more compounds of formula (I) with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately 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.

[0596] 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 seventy of the condition being treated and the compound being employed. The use of either daily administration or periodic dosing may be employed.

[0597] 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 preformulation 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 preformulation 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.

[0598] 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 flavoured syrups, aqueous or oil suspensions, and flavoured 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, polyvinyl-pyrrolidone or gelatin.

[0599] The method of treating disorders mediated by 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, elixers, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.

[0600] 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.

[0601] 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 betalactose, 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.

[0602] The liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methylcellulose 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.

[0603] To prepare a pharmaceutical composition of the present invention, a compound of formula (I) as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral). Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

[0604] Methods of formulating pharmaceutical compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1 -3, edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1 -2, edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1 -2, edited by Lieberman et al; published by Marcel Dekker, Inc. Compounds of this 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.

[0605] 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.

[0606] Synthesis Examples

[0607] 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.

[0608] 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, and the like.

[0609] Intermediate Example 1 : 3-Bromo-1 / - / -1 ,2,4-triazol-5-amine

[0610] Step A: 3-Bromo-5-nitro-1 / - / -1 ,2,4-triazole. To a solution of 5-nitro-1 H- 1 ,2,4-triazole (250 g, 2.19 mol) in H2O (2500 mL) was added NaOH (87.7 g, 2.19 mol) and Br2 (420 g, 2.63 mol, 136 mL). The mixture was stirred at 80 °C for 16 hours. The solution was cooled to 25 °C, acidified to pH=3 with 1 M HCI, and then extracted with EtOAc (2000 mL x 3). The combined organic layers were washed with brine (2000 mL x 1 ), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a yellow solid. The yellow solid was used in the next step without further purification.1H NMR (400 MHz, D2O) 5 8.61 (s, 1 H).

[0611] Step B: 3-Bromo-1 / - / -1 ,2,4-triazol-5-amine. To a solution of 3-bromo-5- nitro-1 / - / -1 ,2,4-triazole (100 g, 518 mmol) and NH4CI (139 g, 2.59 mol) in EtOH (1000 mL) and H2O (500 mL) was added Fe (145 g, 2.59 mol) in portions at 60 °C. The mixture was stirred at 80 °C for 2 hours. The reaction mixture was filtered through Celite® and the filtrate was concentrated to remove EtOH. The residue was diluted with ethyl acetate and sat. aq. NaHCOs. The aqueous layer was separated and extracted with ethyl acetate (1500 mL x 15) and 2- methyltetrahydrofuran (1000 mL x 5). The combined organic layers were washed with brine (5000 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a white solid. The white solid was used in the next step without further purification.1H NMR (400 MHz, DMSO-cfe) 5 12.27 (br s, 1 H), 6.30 (s, 2H).

[0612] Intermediate Example 2: 2-Bromo-5-methyl-[1 ,2,4]triazolo[1 ,5-alpyrimidin- 7(4H)-one

[0613] To a solution of 3-bromo-1 / - / -1 ,2,4-triazol-5-amine (Intermediate 1 ) (50.0 g, 307 mmol) and ethyl 3-oxobutanoate (95.8 g, 736 mmol) in toluene (500 mL) was added TsOH*H2O (10.5 g, 55.2 mmol). The mixture was stirred at 120 °C for 12 hours. The reaction mixture was filtered and the residue was then triturated with MeOH at 25 °C for 1 hour to yield the title compound as a white solid.1H NMR (400 MHz, DMSO-cfe) 5 13.37 (br s, 1 H), 5.87 (s, 1 H), 2.30 (s, 3H).

[0614] Intermediate Example 3: 2-Bromo-6-isopropyl-5-methyl-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-7(4H)-one

[0615] A mixture of 3-bromo-1 / - / -1 ,2,4-triazol-5-amine (Intermediate 1 ) (2.0 g, 12.27 mmol) and ethyl 2-acetyl-3- methylbutanoate (5.1 g, 14.8 mmol, 50% purity) in AcOH (20 mL) was stirred at 120 °C for 16 hours. The reaction mixture was concentrated to dryness in vacuo. The mixture was filtered, and the filter cake was rinsed with ethyl acetate (40 mL). The solid was collected, dried in vacuo to yield a yellow solid. The yellow solid was purified by prep- HPLC (Column: Phenomenex luna C18, 15 pm, 250 x 70 mm; Mobile Phase: 75% MeCN / water (0.225% FA); Flow rate: 25 mL / min) to yield the title

[0616] To a 100 mL round bottom flask was added 5-(4-bromophenyl)-4 / - / - 1 ,2,4-triazol-3-amine (1 g, 4.18 mmol) and TsOH*H2O (195 mg, 1 .0 mmol). Toluene (30 mL) was added followed by ethyl-2-acetyl-3-methylbutanoate (3.0 mL, 15.1 mmol). The reaction was heated at 120 °C for 24 hours with a Dean- Stark apparatus. EtOAc (50 mL) was added and the precipitate was collected by filtration. After drying in a vacuum oven, the title compound was obtained as the tosylate salt, as a white solid. MS (ESI): mass calculated for CisH-isBrlSkO, 346.0; m / z measured, 347.0 [M+H]+.1H NMR (400 MHz, DMSO-de) 5 13.00 (s, 1 H), 8.03 (d, J = 8.6 Hz, 2H), 7.73 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 7.8 Hz, 2H), 3.03 (q, J = 7.0 Hz, 1 H), 2.39 (s, 3H), 2.29 (s, 4H), 1.30 (d, J = 6.9 Hz, 6H).

[0617] Intermediate Example 5: 2-Bromo-6-cvclopropyl-5-methyl-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-7(4 / - / )-one

[0618] A mixture of 5-Bromo-1 / - / -1 ,2,4-triazole-3-amine (Intermediate 1 ) (400 mg, 2.45 mmol) and ethyl 2-cyclopropyl-3-oxobutanoate (500 mg, 2.94 mmol) in AcOH (1 mL) was stirred at 100 °C. The solution was cooled to room temperature and the solids were filtered. The resulting tan solids were used in the next step without further purification. MS (ESI): mass calculated for C9H9BrN4O, 268.0; m / z measured, 269.0, 271.0 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 5 13.20 (br s, 1 H), 2.43 (s, 3H), 1 .53 - 1 .41 (m, 1 H), 0.92 - 0.82 (m, 2H), 0.69 - 0.59 (m, 2H).

[0619] Intermediate Example 6: 2-(2-Bromo-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4(7 / - / )-yl)- / \ / -(p-tolyl)acetamide

[0620] To a solution of 2-bromo-5-methyl-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-7(4 / - / )- one (Intermediate 2) (38.0 g, 166 mmol) and 2-chloro- / V-(p-tolyl)acetamide (42.1 g, 229 mmol) in DMF (380 mL) was added Nal (109 g, 730 mmol) and K2CO3 (122 g, 879 mmol). The mixture was stirred at 65 °C for 8 hours and then cooled to 25 °C, filtered, and diluted with EtOAc and water. The organic phase was extracted with EtOAc (500 mL x 3) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with DCM at 25 °C for 1 hour twice to yield the title compound as a pink solid.1H NMR (400 MHz, DMSO-cfe) 5 10.42 (s, 1 H), 7.45 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 6.13 (s, 1 H), 5.08 (s, 2H), 2.41 (s, 3H), 2.25 (s, 3H).

[0621] Intermediate Example 7: te / Y-Butyl 2-(2-bromo-6-isopropyl-5-methyl-7-oxo- [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)acetate

[0622] To a solution of 2-bromo-6-isopropyl-5-methyl-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-7(4 / - / )-one (Intermediate 3) (850 mg, 3.13 mmol) in DMF (8 mL) was added te / Y-butyl 2-bromoacetate (0.62 mL, 3.58 mmol) and K2CO3 (255 mg, 1 .84 mmol) at room temperature for 2 hours. Water (15 mL) was added to the mixture and a white solid precipitated. The mixture was filtered and the filter cake was rinsed with H2O (10 mL). The solid was collected and dried in vacuo to yield the title compound as a white solid. MS (ESI): mass calculated for Ci5H2iBrN4O3, 384.0; m / z measured, 385.1 [M+H]+.1H NMR (400 MHz, CDCI3) 5 4.96 - 4.87 (m, 2H), 3.18 (br s, 1 H), 2.38 - 2.33 (m, 3H), 1 .52 - 1 .47 (m, 9H), 1.42 - 1.36 (m, 6H).

[0623] Intermediate Example 8: 2-(2-Bromo-6-isopropyl-5-methyl-7-oxo- [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)- / \ / -(p-tolyl)acetamide.

[0624] A mixture of 2-bromo-6-isopropyl-5-methyl-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-7(4H)-one (Intermediate 3) (120 mg, 0.44 mmol), 2-chloro- / V-(4- methylphenyl)acetamide (105.7 mg, 0.58 mmol), K2CO3 (305.9 mg, 2.21 mmol), and Nal (200.0 mg, 1 .33 mmol) in DMF (2.5mL) was stirred at 65 °C overnight. The mixture was cooled to room temperature, filtered over Celite® and concentrated. EtOAc was added and the solid was filtered. The filtrate was concentrated and purified by column chromatography (SiC>2, 40-100% EtOAc / Heptane) to yield the title compound as a pink solid. MS (ESI): mass calculated for Ci8H2oBrN502, 417.1 ; m / z measured, 418.1 , 420.1 [M+H]+.1H NMR (400 MHz, DMSO-de) 5 10.39 (s, 1 H), 7.45 (d, J = 8.8 Hz, 2H), 7.13 (d, J

[0625] = 8.3 Hz, 2H), 5.14 (s, 2H), 3.27 - 3.15 (m, 1 H), 2.42 (s, 3H), 2.26 (s, 3H), 1.30 (d, J = 7.3 Hz, 6H).

[0626] Intermediate Example 9: 2-(2-Bromo-6-isopropyl-5-methyl-7-oxo- [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)- / \ / -(4-(pentafluoro-l6- sulfaneyl)phenyl)acetamide.

[0627] A mixture of 2-bromo-6-isopropyl-5-methyl-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-7(4 / - / )-one (Intermediate 3) (75 mg, 0.28 mmol), 2-chloro-N-(4- (pentafluoro-l6-sulfaneyl)phenyl)acetamide (98 mg, 0.33 mmol), K2CO3 (115 mg, 0.83 mmol), and Nal (125 mg, 0.83 mmol) was dissolved in DMF then placed in a heating block at 50 °C and stirred for 17 hours. Additional 2-chloro- N-(4-(pentafluoro-l6-sulfonyl)phenyl)acetamide (50 mg), K2CO3 (58 mg) and Nal (63 mg) were added and stirred for an additional 5 hours. The reaction mixture was filtered through Celite® and the filtrate was concentrated. EtOAc was added and the solid was filtered. The filtrate was adsorbed onto silica and purified by column chromatography (SiC>2, 40-100% EtOAc / heptane) to yield a brown oil. MS (ESI): mass calculated for C-iyH-iyBrFsNsC S, 529.0; m / z measured, 530.1 [M+H]+.

[0628] Intermediate Example 10: 2-(2-Bromo-6-isopropyl-5-methyl-7-oxo- [1 ,2,4]triazolo[1 ,5-alpyrimidin-4(7H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide To a mixture of 2-bromo-6-isopropyl-5-methyl-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-7(4 / - / )-one (Intermediate 3) (157 mg, 0.58 mmol) and K2COs (339 mg, 2.45 mmol) in DMF (4.17 mL) was added 2-bromo-4’- (trifluoromethyl)acetanilide (205 mg, 0.73 mmol) and stirred at 60°C for 4 hours. The mixture was cooled to room temperature and quenched with water (1 mL). The organic phase was extracted with EtOAc (10 mL x 3). The combined organic layers were then washed with brine, dried over magnesium sulfate, filtered, and concentrated to yield an oil. The oil was purified by reverse phase prep-HPLC (Column: Kinetex EVO C18, 5 pm, 100 x 30 mm; Mobile Phase: 40 - 60% MeCN / 10 mM aq. NH4OH water; Flow Rate: 30 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for Ci8Hi?BrF3N5O2, 471.0; m / z measured, 474.0 [M+H]+.1H NMR (400 MHz, DMSO-de) 5 10.87 (s, 1 H), 7.8-7.8 (m, 2H), 7.7-7.7 (m, 2H), 5.20 (s, 2H), 3.2-3.3 (m, 1 H), 2.43 (s, 3H), 1 .31 (d, 6H, J = 6.8 Hz).19F NMR (376 MHz, DMSO- ds) 5 -60.4.

[0629] Intermediate Example 11 : 2-(2-(4-Bromophenyl)-6-isopropyl-5-methyl-7-oxo- [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)- / \ / -(p-tolyl)acetamide

[0630] To a 100 mL round bottom flask was added 2-(4-bromophenyl)-6- isopropyl-5-methyl-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-7(4 / - / )-one (Intermediate 4) (1.5 g, 2.9 mmol), 2-chloro-N-(4-methylphenyl)acetamide (0.64 g, 3.5 mmol), Nal (1 .74 g, 11 .6 mmol) and K2CO3 (2.0 g, 14.4 mmol) followed by DMF (20 mL) and then the reaction mixture was stirred at 65 °C overnight. The flask was cooled to room temperature and water (100 mL) was added, which led to a white suspension. After filtration, the collected solid was washed with water and small amounts of EtOAc. After drying overnight in a vacuum oven, the title compound was obtained as a white solid. MS (ESI): mass calculated for C24H24BrN5O2, 493.1 ; m / z measured, 494.1 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 5 10.45 (s, 1 H), 8.03 (d, J = 8.6 Hz, 2H), 7.73 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.3 Hz, 3H), 5.26 (s, 2H), 3.32 (s, 3H), 3.25 (p, J = 7.0 Hz, 1 H), 2.44 (s, 3H), 2.25 (s, 4H), 1 .34 (d, J = 7.0 Hz, 7H). Intermediate Example 12: 2-(2-(4-(2-Hvdroxypropan-2-yl)phenyl)-6-isopropyl-5- methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)acetic acid

[0631] Step A. te / t-Butyl 2-(2-(4-(2-hydroxypropan-2-yl)phenyl)-6-isopropyl-5- methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7H)-yl)acetate. To a solution of te / t-butyl 2-(2-bromo-6-isopropyl-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a] pyrimidin- 4(7 / - / )-yl)acetate (Intermediate 7) (400 mg, 1.04 mmol), Xphos Pd G3 (88 mg, 0.10 mmol) and CS2CO3 (1.02 g, 3.1 mmol) in DMF / water (4 mL, v / v = 6 / 1 ) was added (4-(2-hydroxypropan-2-yl)phenyl)boronic acid (269 mg, 1 .2 mmol) and stirred at 100 °C for 12 hours under N2. The reaction mixture was poured into H2O (20 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield a residue. The residue was purified by column chromatography (SiC>2, 0 - 9% EtOAc / petroleum ether) to yield the title compound as a pale yellow solid. MS (ESI): mass calculated for C24H32N4O4, 440.2; m / z measured, 441 .2 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.27 - 8.20 (m, 2H), 7.61 - 7.55 (m, 2H), 5.03 (s, 2H), 3.34 - 3.14 (m, 1 H), 2.39 (s, 3H), 1 .62 (s, 6H), 1 .52 - 1.49 (m, 9H), 1.44 - 1.40 (m, 6H).

[0632] Step B. 2-(2-(4-(2-Hydroxypropan-2-yl)phenyl)-6-isopropyl-5-methyl-7- oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)acetic acid.

[0633] HCI in 1 ,4-dioxane (5 mL, 4N) was added to te / t-butyl 2-(2-(4-(2- hydroxypropan-2-yl)phenyl) -6-isopropyl-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4(7 / - / )-yl)acetate (354 mg, 0.80 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The solids were washed with EtOAc / petroleum ether to yield the title compound as a pale yellow solid. MS (ESI): mass calculated for C20H24N4O4, 384.2; m / z measured, 385.0 [M+H]+.1H NMR (400 MHz, DMSO-de) 5 13.74 - 13.52 (m, 1 H), 8.06 - 7.98 (m, 2H), 7.64 - 7.57 (m, 2H), 5.18 - 5.15 (m, 2H), 3.26 - 3.19 (m, 1 H), 2.45 - 2.40 (m, 3H), 1 ,45(s, 6H), 1 .32 (d, J = 6.9 Hz, 6H).

[0634] Intermediate Example 13: 2-(2-(4-(1 -(Hvdroxymethyl)cvclopropyl)phenyl)-6- isopropyl-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)acetic acid

[0635] Step A. te / t-Butyl 2-(2-(4-(1 -(hydroxymethyl)cyclopropyl)phenyl)- 6-isopropyl-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-alpyrimidin-4(7 / - / )- yl)acetate. To a mixture of te / Y-butyl 2-(2-bromo-6-isopropyl-5-methyl-7- oxo-[1 ,2,4]triazolo[1 ,5-a] pyrimidin-4(7 / - / )-yl)acetate (Intermediate 7) (800 mg, 2.0 mmol) in DMF / H2O (10 mL) was added (1 -(4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)methanol (690 mg, 2.5 mmol), CS2CO3 (2.0 g, 6.1 mmol) and Xphos Pd G3 (180 mg, 0.2 mmol) under N2. The vessel containing the resulting mixture was charged with N2, heated at 100 °C and stirred for 16 hours. The suspension was filtered through a pad of Celite® and the filter cake was washed with ethyl acetate (100 mL x 2). The combined filtrates were concentrated to dryness and the residue was purified by column chromatography (SiC>2, 0-90% EtOAc / petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C25H32N4O4, 452.2; m / z measured, 453.0 [M+H]+.1H NMR (400 MHz, CDCI3) 5 8.24 - 8.13 (m, 2H), 7.43 (br d, J = 7.4 Hz, 2H), 5.02 (s, 2H), 3.73 (s, 2H), 3.30 - 3.17 (m, 1 H), 2.98 - 2.84 (m, 1 H), 2.38 (s, 3H), 1.49 (s, 9H), 1.41 (d, J = 7.0 Hz, 6H), 0.98 - 0.87 (m, 4H).

[0636] Step B. 2-(2-(4-(1 -(Hydroxymethyl)cyclopropyl)phenyl)-6- isopropyl-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)acetic acid. A solution of te / t-butyl 2-(2-(4-(1 - (hydroxymethyl)cyclopropyl)phenyl) -6-isopropyl- 5-methyl-7-oxo- [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)acetate (509 mg, 1.1 mmol) in 4M HCI / 1 ,4-dioxane (5 mL, 4M) was stirred at room temperature for 12 hours. The mixture was concentrated to dryness in vacuo and the residue was purified by flash column chromatography (S iC>2, 0-80% EtOAc / petroleum ether) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C21H24N4O4, 396.1 ; m / z measured, 397.0 [M+H]+.1H NMR (400 MHz, DMSO- , mixture was stirred at 100 °C for 30 minutes under argon. The reaction mixture was poured into a separatory funnel containing H2O (300 mL) and the aqueous layer was extracted with ethyl acetate (3 x 300 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield a beige solid. This residue was used in the next step without further purification. MS (ESI): mass calculated for C24H25N5O3, 431.2; m / z measured, 432.2 [M+H]+.1H NMR (400 MHz, DMSO-de) 5 10.46 (s, 1 H), 8.03 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H), 6.09 (d, J = 0.9 Hz, 1 H), 5.19 (s, 2H), 5.12 (s, 1 H), 2.42 (s, 3H), 2.25 (s, 3H), 1.44 (s, 6H).

[0637] Step B. 2-(6-Bromo-2-(4-(2-hvdroxypropan-2-yl)phenyl)-5-methyl-7-oxo- [1 ,2,4]triazolo[1 ,5-alpyrimidin-4(7H)-yl)- / V-(p-tolyl)acetamide. To a suspension of 2-(2-(4-(2-hydroxypropan-2-yl)phenyl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4(7 / - / )-yl)-A / -(p-tolyl)acetamide (1.67 g, 3.87 mmol) in MeCN (19 mL) was added NBS (894 mg, 5.03 mmol) and AcOH (221 pL, 3.87 mmol). The reaction was stirred for 1 hour at room temperature. The reaction was then diluted with ethyl acetate (200 mL) and transferred to a separatory funnel containing sat. aq. NaHCOs. The aqueous layer was extracted with ethyl acetate (3 x 200 mL) and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. This residue was purified by column chromatography (SiC>2, 50%-100% EtOAc / heptanes) to yield the title compound as a white solid. MS (ESI): mass calculated for C24H24BrN50s, 509.1 ; m / z measured, 510.1 [M+H]+.1H NMR (400 MHz, DMSO-de) 5 10.46 (s, 1 H), 8.04 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 5.35 (s, 2H), 5.13 (s, 1 H), 2.67 (s, 3H), 2.25 (s, 3H), 1.45 (s, 6H).

[0638] Example 1 : 2-(2-(4-(2-Hvdroxypropan-2-yl)phenyl)-6-isopropyl-5-methyl-7-oxo-

[0639] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)- / \ / -(p-tolyl)acetamide

[0640] To a solution of 2-(2-(4-(2-hydroxypropan-2-yl)phenyl)-6- isopropyl-5-methyl-7-oxo- [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)acetic acid (Intermediate 12) (200 mg, 0.52 mmol) in DMF (2 mL) was added p- toluidine (80 mg, 0.75 mmol), TEA (0.28 mL, 2.0 mmol), DMAP (128 mg, 0.23 mmol) and Mukaiyama reagent (2-chloro-1 -methylpyridinium iodide, 280 mg, 1.1 mmol). The mixture was stirred at room temperature for 3 hours. The residue was diluted with H2O (25 mL) and extracted with ethyl acetate (25 mL x 2). The combined organic layers were washed with brine 30 mL, dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by reverse phase prep-HPLC (Column: Phenomenex luna C18, 10 pm, 150 x 25 mm; Mobile Phase: 25 - 100%

[0641] MeCN / water (0.225% FA); Flow rate: 25 mL / min) to yield the title compound as a yellow solid. MS (ESI): mass calculated for C27H31N5O3, 473.2; m / z measured, 474.3 [M+H]+.1H NMR (400 MHz, DMSO-de) 5 10.48 - 10.39 , 2 hours and then poured into H2O and extracted with EtOAc. The organic layer was separated, dried over MgSCM, filtered and evaporated. The residue was purified by reverse phase HPLC (Column: Waters Xselect CSH C18, 5 pm, 150 x 19 mm; Mobile Phase: 45 - 80% MeCN / water (0.16% TFA); Flow Rate: 25 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C27H28F3N5O3, 527.2; m / z measured, 528.2 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 5 10.92 (s, 1 H) 7.96 - 8.09 (m, 2H) 7.81 (br d, J = 8.80 Hz, 2H) 7.71 (br d, J = 8.80 Hz, 2H) 7.53 - 7.68 (m, 2H) 5.33 (s, 2H) 3.07 - 3.31 (m, 1 H) 2.42 - 2.47 (m, 3H) 1 .44 (s, 6H) 1 .35 (d, J = 6.85 Hz, 6H).

[0642] Example 3: 2-(2-(4-(2-Hvdroxypropan-2-yl)phenyl)-6-isopropyl-5-methyl-7-oxo- [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)- / \ / -(6-(trifluoromethyl)pyridin-3- vDacetamide

[0643] The title compound was prepared according to the procedure described in Example 2, substituting 3-amino-6-(trifluoromethyl)pyridine for 4-aminobenzotrifluoride. The resulting residue was purified by reverse phase prep-HPLC (Column: Waters Xselect CSH C18, 5 pm, 150 x 19 mm; Mobile Phase: 40 - 75% MeCN / water (0.16% TFA); Flow Rate: 25 mL / min) to yield the title compound. MS (ESI): mass calculated for C26H27F3N6O3, 528.2; m / z measured, 529.1 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 5 11 .20 (s, 1 H) 8.90 (s, 1 H) 8.31 (br d, J = 9.29 Hz, 1 H) 8.02 (d, J = 7.83 Hz, 2 H) 7.84 - 7.96 (m, 2 H) 7.60 (d, J = 8.31 Hz, 2 H) 5.36 (s, 2 H) 3.18 - 3.28 (m, 2 H) 2.45 (s, 3 H) 2.14 (s, 2 H) 1 .44 (s, 6 H) 1.35 (d, J = 6.85 Hz, 6 H).

[0644] Example 4: / V-(4-Chlorophenyl)-2-(2-(4-(2-hvdroxypropan-2-yl)phenyl)-6- isopropyl-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)acetamide

[0645] The title compound was prepared according to procedure as described in Example 2 substituting 4-chloroaniline for 4- aminobenzotrifluoride. The residue was purified by reverse phase prep- HPLC (Column: Waters Xselect CSH C18, 5 pm, 150 x 19 mm; Mobile Phase: 40 - 75% MeCN / water (0.16% TFA); Flow Rate: 25 mL / min) to yield the title compound. MS (ESI): mass calculated for C26H28CIN5O3, 493.2; m / z measured, 494.2 [M+H]+ 1H NMR (400 MHz, DMSO-de) 5 10.68 (s, 1 H) 8.02 (d, J = 8.80 Hz, 2 H) 7.58 - 7.64 (m, 3 H) 7.37 - 7.42 (m, 2

[0646] H) 5.28 (s, 2 H) 3.25 (br s, 2 H) 2.41 - 2.46 (m, 3 H) 1 .44 (s, 6 H) 1 .29 - 1 .40 (m, 6 H).

[0647] Example 5: 2-(2-(4-(2-hydroxypropan-2-yl)phenyl)-6-isopropyl-5-methyl-7-oxo-

[0648] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)- / \ / -(4-(pentafluoro-l6- sulfaneyl)phenyl)acetamide

[0649] The title compound was prepared according to procedure as described in Example 2, substituting 4-aminophenylsulfur pentafluoride for 4- aminobenzotrifluoride. The residue was purified by reverse phase prep-HPLC (Column: Waters Xselect CSH C18, 5 pm, 150 x 19 mm; Mobile Phase: 45 - 80% MeCN / water (0.16% TFA); Flow Rate: 25 mL / min) to yield the title compound. MS (ESI): mass calculated for C26H28F5N5O3S, 585.2; m / z measured, 586.2 [M+H]+.1H NMR (400 MHz, DMSO-de) 5 11.00 (s, 1 H) 8.02 (d, J = 8.31 Hz, 2 H) 7.87 - 7.93 (m, 2 H) 7.80 (br d, J = 9.29 Hz, 2 H) 7.60 (d, J = 8.31 Hz, 2 H) 5.33 (s, 2 H) 3.21 - 3.33 (m, 2 H) 2.44 (s, 3 H) 1 .44 (s, 5 H) 1.34 (d, J = 6.85 Hz, 6 H).

[0650] Example 6: 2-(2-(4-(2-hydroxypropan-2-yl)phenyl)-6-isopropyl-5-methyl-7-oxo- [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7H)-yl)-N-(2-(trifluoromethyl)thiazol-5- vDacetamide The title compound was prepared according to procedure as described in Example 2 substituting 2-(trifluoromethyl)thiazol-5-amine for 4-aminobenzotrifluoride. The residue was purified by reverse phase prep-HPLC (Column: Waters Xbridge BEH C18, 5 pm, 150 x 19 mm; , , , tolyl)acetamide (Intermediate 8) (67.6 mg, 0.16 mmol), 4-(1 - (hydroxylmethyl)cyclopropyl)phenylboronic acid (38 mg, 0.2 mmol), K3PO4(107 mg, 0.53 mmol), and Pd-PEPPSITM-lpent (20 mg, 0.025 mmol). The vial was capped then evacuated and backfilled with argon three times. A mixture of DMF / H2O (1.21 mL, v / v = 10:1 ) was added and stirred at 95 °C overnight. The reaction mixture was cooled to room temperature and purified by reverse phase prep-HPLC (Column: Kinetex EVO C18, 5 pm, 100 x 30 mm; Mobile Phase: 35 - 53% MeCN / 10 mM NH4OH in water; Flow Rate: 30 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C28H31N5O3, 485.2; m / z measured, 486.3 [M+H]+.1H NMR (400 MHz, DMSO-de) 5 10.44 (s, 1 H), 7.99 (d, 2H, J = 8.3 Hz), 7.4-7.5 (m, 2H), 7.42 (d, 2H, J = 8.3 Hz), 7.13

[0651] (d, 2H, J = 8.3 Hz), 5.26 (s, 2H), 4.72 (t, 1 H, J = 5.6 Hz), 3.57 (d, 2H, J = 5.4 Hz), 3.2-3.3 (m, 1 H), 2.43 (s, 3H), 2.25 (s, 3H), 1 .34 (d, 6H, J = 6.8 Hz), 0.9-0.9 (m, 2H), 0.8-0.8 (m, 2H).

[0652] Example 8: 2-(2-(4-(1 -(Hydroxymethyl)cyclopropyl)phenyl)-6-isopropyl-5- methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)- / \ / -(4- (trifluoromethyl)phenyl)acetamide

[0653] The title compound was prepared according to procedure as described in Example 7 substituting Intermediate 10 for Intermediate 8. The residue was purified by reverse phase prep-HPLC (Column: Kinetex EVO C18, 5 pm, 100 x 30 mm; Mobile Phase: 50 - 70% MeCN / 10 mM aq NH4OH water; Flow Rate: 30 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C28H28F3N5O3, 539.2; m / z measured, 540.1 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 5 10.93 (s, 1 H), 7.99 (d, 2H, J = 8.3 Hz), 7.80 (d, 2H, J = 1 .0 Hz), 7.71 (d, 2H, J = 1 .0 Hz), 7.42 (d, 2H, J = 8.3 Hz), 5.32 (s, 2H), 4.72 (t, 1 H, J = 5.6 Hz), 3.57 (d, 2H, J = 5.4 Hz), 3.2-3.3 (m, 1 H), 2.44 (s, 3H), 1 .34 (d, 6H, J = 6.8 Hz), 0.9-0.9 (m, 2H), 0.8-0.8 (m, 2H).19F NMR (376 MHz, DMSO- ds,) 5 -60.4.

[0654] Example 9: 2-(2-(4-(1 -(Hydroxymethyl)cyclopropyl)phenyl)-6-isopropyl-5- methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)- / \ / -(6- (trifluoromethyl)pyridin-3-yl)acetamide The title compound was prepared according to procedure as described in Example 1 , substituting 6-(trifluoromethyl)pyridin-3-amine for p-toluidine and Intermediate 13 for Intermediate 12. The residue was purified by prep-HPLC (Column: Phenomenex luna C18, 10 pm, 150 x 25 mm; Mobile Phase: 40 - 70% MeCN / water (0.225% FA); Flow Rate: 30 mL / min) to yield the title compound as an off white powder. MS (ESI): mass calculated For C27H27F3N6O3, 540.2; m / z measured, 541.2 [M+H]+.1H NMR (400 MHz, DMSO-de) 5 11 .31 - 11.11 (m, 1 H), 8.97 - 8.84 (m, 1 H), 8.35 - 8.27 (m, 1 H), 8.03 - 7.96 (m, 2H), 7.93 - 7.87 (m, 1 H), 7.48 - 7.40 (m, 2H), 5.42 - 5.27 (m, 2H), 4.78 - 4.68 (m, 1 H), 3.62 - 3.55 (m, 2H), 3.26 (br s, 1 H), 2.47 - 2.43 (m, 3H), 1 .39 - 1 .30 (m, 6H), 0.92 - 0.85 (m, 2H), 0.83 - 0.77 (m, 2H).19F NMR (377 MHz, DMSO-de) 5 - 65.7.

[0655] Example 10: / V-(4-Chlorophenyl)-2-(2-(4-(1 - (hydroxymethyl)cyclopropyl)phenyl)-6-isopropyl-5-methyl-7-oxo- [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)acetamide

[0656] The title compound was prepared according to procedure as described in Example 1 , substituting 4-chloroaniline for p-toluidine and Intermediate 13 for Intermediate 12. The residue was purified by reverse phase prep-HPLC (Column: Phenomenex C18, 3 pm, 80 x 40 mm; Mobile Phase: 10 - 72% MeCN / 10 mM NH4OH in water; Flow Rate: 25 mL / min) to yield the title compound as a white powder. MS (ESI): mass calculated for C27H28CIN5O3, 505.2; m / z measured, 506.2 [M+H]+.1H NMR (400 MHz, DMSO-de) 5 10.68 (s, 1 H), 7.99 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.9 Hz, 2H), 7.40 (dd, J = 8.8, 11 .3 Hz, 4H), 5.28 (s, 2H), 4.71 (t, J = 5.6 Hz, 1 H), 3.57 (d, J = 5.4 Hz, 2H), 2.43 (s, 3H), 1 .34 (d, J = 6.9 Hz, 6H), 0.91 - 0.85 (m, 2H), 0.82 - 0.75 (m, 2H). Example 11 : 2-(2-(4-(1-(Hvdroxymethyl)cvclopropyl)phenyl)-6-isopropyl-5- methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7H)-yl)-N-(4-(pentafluoro-l6- sulfaneyl)phenyl)acetamide

[0657] The title compound was prepared according to procedure as described in Example 7 substituting Intermediate 9 for Intermediate 8. The residue was purified by reverse phase HPLC (Column: Kinetex EVO C18, 5 pm, 100 x 30 mm; Mobile Phase: 10 - 100% MeCN / 10 mM NH4OH in water; Flow Rate: 30 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C27H28F5N5O3S, 597.2; m / z measured, 598.1 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 5 11 .00 (br s, 1 H), 7.99 (d, J = 8.8 Hz, 2H), 7.91 - 7.86 (m, 2H), 7.79 (d, J = 9.3 Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H), 5.32 (s, 2H), 4.72 (t, J = 5.6 Hz, 1 H), 3.57 (d, J = 5.4 Hz, 2H), 3.30 - 3.20 (m, 1 H), 2.44 (s, 3H), 1 .34 (d, J = 6.8 Hz, 6H), 0.93 - 0.86 (m, 2H), 0.81 - 0.74 (m, 2H).

[0658] Example 12: 2-(2-(4-(1-(Hydroxymethyl)cyclopropyl)phenyl)-6-isopropyl-5- methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)- / \ / -(2- (trifluoromethyl)thiazol-5-yl)acetamide

[0659] The title compound was prepared according to procedure as described in Example 1 , substituting 2-(trifluoromethyl)thiazol-5-amine for p-toluidine and Intermediate 13 for Intermediate 12. The residue was purified by reverse phase prep-HPLC: (Column: Phenomenex luna C18, 10 pm, 150 x 25 mm; Mobile Phase: 40 - 70% MeCN / water (0.225% FA); Flow Rate: 25 mL / min) to yield the title compound as a light yellow solid. MS (ESI): mass calculated for C25H25F3N6O3S, 546.2; m / z measured, 547.3 [M+H]+.1H NMR (400 MHz, DMSO-de) 5 12.81 - 12.30 (m, 1 H), 7.97 (d, J = 8.4 Hz, 2H), 7.84 (s, 1 H), 7.41 (d, J = 8.4 Hz, 2H), 5.39 (s, 2H), 4.71 (t, J = 5.6 Hz, 1 H), 3.57 (d, J = 5.6 Hz, 2H), 3.24 - 3.20 (m, 1 H), 2.43 (s, 3H), 1 .35 (s, 3H), 1 .33 (s, 3H), 0.90 - 0.86 (m, 2H), 0.81 - 0.76 (m, 2H).19F NMR (376 MHz, DMSO-cfe) 5 -59.4.

[0660] Example 13: / V-(4-Cyclopropylphenyl)-2-(2-(4-(1 - (hydroxymethyl)cyclopropyl)phenyl)-6-isopropyl-5-methyl-7-oxo- [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)acetamide

[0661] The title compound was prepared according to procedure as described in Example 1 , substituting 4-cyclopropylaniline for p-toluidine and Intermediate 13 for Intermediate 12. The residue was purified by reverse phase prep-HPLC (Column: Phenomenex luna C18, 10 pm, 150 x 25 mm; Mobile Phase: 45 - 75% MeCN / water (0.225% FA); Flow Rate: 30 mL / min) to yield the title compound as a white powder. MS (ESI): mass calculated for C30H33N5O3, 511.3; m / z measured, 512.4 [M+H]+.1H NMR (400 MHz, DMSO-de) 5 10.42 (s, 1 H), 7.99 (d, J = 8.4 Hz, 2H), 7.43 (dd, J = 8.5, 13.3 Hz, 4H), 7.03 (d, J = 8.6 Hz, 2H), 5.28 -

[0662] 5.21 (m, 2H), 4.71 (t, J = 5.6 Hz, 1 H), 3.57 (d, J = 5.5 Hz, 2H), 3.25 -

[0663] 3.21 (m, 1 H), 2.42 (s, 3H), 1.82 (s, 1 H), 1.34 (s, 3H), 1.32 (s, 3H), 0.92 - 0.86 (m, 4H), 0.81 - 0.77 (m, 2H), 0.64 - 0.56 (m, 2H).

[0664] Example 14: / V-(2-Chloro-4-(trifluoromethyl)phenyl)-2-(2-(4-(1 - (hydroxymethyl)cyclopropyl)phenyl)-6-isopropyl-5-methyl-7-oxo- [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)acetamide

[0665] A mixture of 2-(2-(4-(1 -(hydroxymethyl)cyclopropyl)phenyl)-6-isopropyl- 5-methyl-7 -oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)acetic acid (Intermediate 13) (120 mg, 303 pmol), 2-chloro-4-(trifluoromethyl)aniline (75 mg, 384 pmol), and Mukaiyama reagent (123 mg, 482 pmol) was added to a 40 mL thread vial equipped with magnetic stirrer. Then TEA (134 pL, 963 pmol) in DMF (2 mL) was added to the mixture. The mixture was stirred at room temperature for 2 hours. To the reaction mixture was added H2O (5 mL) and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuum to dryness. The residue was purified by prep-HPLC (Column: Welch Xtimate C18, 5 pm, 150 x 25 mm; Mobile Phase: 45 - 75% MeCN / water (0.225% FA); Flow Rate: 30 mL / min) to yield the title compound as a white powder. MS (ESI): mass calculated for C28H27CIF3N5O3, 573.2; m / z measured, 574.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 10.46 - 10.38 (m, 1 H), 8.10 - 7.93 (m, 4H), 7.74 - 7.67 (m, 1 H), 7.43 (d, J = 8.5 Hz, 2H), 5.46 - 5.37 (m, 2H), 4.76 - 4.68 (m, 1 H), 3.58 (d, J = 5.6 Hz, 2H), 3.27 - 3.21 (m, 1 H), 2.46 (s, 3H), 1 .34 (d, J = 7.0 Hz, 6H), 0.91 - 0.87 (m, 2H), 0.83 - 0.78 (m, 2H).

[0666] Example 15: / V-(2-Fluoro-4-methylphenyl)-2-(2-(4-(1 - (hvdroxymethyl)cvclopropyl)phenyl)-6-isopropyl-5-methyl-7-oxo- [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)acetamide The title compound was prepared according to procedure as described in Example 14 substituting 2-fluoro-4-methylaniline for 2- chloro-4-(trifluoromethyl)aniline. The residue was purified by prep-HPLC (Column: Phenomenex luna C18, 10 pm, 150 x 25 mm; Mobile Phase: 40 - 70% MeCN / water (0.225% FA); Flow Rate: 25 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C28H30FN5O3, 503.2; m / z measured, 504.3 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 5 10.31 - 10.24 (m, 1 H), 8.05 - 7.98 (m, 2H), 7.68 (t, J = 8.3 Hz, 1 H), 7.47 - 7.40 (m, 2H), 7.16 - 7.09 (m, 1 H), 6.97 (br d, J = 7.8 Hz, 1 H), 5.33 (s, 2H), 4.73 (t, J = 5.6 Hz, 1 H), 3.58 (d, J = 5.6 Hz, 2H), 3.27 - 3.21 (m, 1 H), 2.43 (s, 3H), 2.29 (s, 3H), 1 .33 (d, J = 7.0 Hz, 6H), 0.92 - 0.87 (m, 2H), 0.83 - 0.78 (m, 2H).19F NMR (376 MHz, DMSO-de) 5 - 125.0.

[0667] Example 16: 2-(2-(4-(1-(hydroxymethyl)cyclopropyl)phenyl)-6-isopropyl-5- methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)- / \ / -(2- (trifluoromethyl)pyrimidin-5-yl)acetamide

[0668] The title compound was prepared according to procedure as described in Example 14 substituting 2-(trifluoromethyl)pyrimidin-5- amine for 2-chloro-4-(trifluoromethyl)aniline. The residue was purified by prep-HPLC (Column: Phenomenex luna C18, 10 pm, 150 x 25 mm; Mobile Phase: 35 - 65% MeCN / water (0.225% FA); Flow Rate: 25 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C26H26F3N7O3, 541.2; m / z measured, 542.3 [M+H]+.1H NMR (400 MHz, DMSO-de) 5 11 .54 - 11 .32 (m, 1 H), 9.24 - 9.16 (m, 2H), 8.02 - 7.95 (m, 2H), 7.41 (d, J = 8.5 Hz, 2H), 5.39 - 5.34 (m, 2H), 4.71 (t, J = 5.6 Hz, 1 H), 3.59 - 3.55 (m, 2H), 3.24 (br d, J = 7.1 Hz, 1 H), 2.45 (s, 3H), 1.37 - 1 .31 (m, 6H), 0.91 - 0.86 (m, 2H), 0.82 - 0.76 (m, 2H).19F NMR (376 MHz, DMSO-de) 5 -68.2.

[0669] Example 17: / V-(2,4-dimethylphenyl)-2-(2-(4-(1 -

[0670] (hydroxymethyl)cyclopropyl)phenyl)-6-isopropyl-5-methyl-7-oxo-

[0671] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)acetamide

[0672] The title compound was prepared according to procedure as described in Example 1 , substituting 2,4-dimethylaniline for p-toluidine and Intermediate 13 for Intermediate 12. The residue was purified by prep-HPLC (Column: Phenomenex luna C18, 10 pm, 150 x 25 mm; Mobile Phase: 40 - 70% MeCN / water (0.225% FA); Flow Rate: 25 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C29H33N5O3, 499.3; m / z measured, 500.2 [M+H]+.1H NMR (400 MHz, DMSO-de) 5 9.80 (s, 1 H), 8.02 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 8.1 Hz, 1 H), 7.04 (s, 1 H), 6.96 (br d, J = 8.1 Hz, 1 H), 5.27 (s, 2H), 4.74 (t, J = 5.6 Hz, 1 H), 3.58 (d, J = 5.5 Hz, 2H), 3.28 - 3.20 (m, 1 H), 2.46 (s, 3H), 2.24 (s, 3H), 2.20 (s, 3H), 1 .33 (d, J = 6.9 Hz, 6H), 0.92 - 0.87 (m, 2H), 0.84 - 0.79 (m, 2H).

[0673] Example 18: 2-(2-(4-(1-(hydroxymethyl)cyclopropyl)phenyl)-6-isopropyl-5- methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)- / \ / -(2-methyl-4- (trifluoromethyl)phenyl)acetamide The title compound was prepared according to procedure as described in Example 14, substituting 2-methyl-4-(trifluoromethyl)aniline for 2-chloro-4-(trifluoromethyl)aniline. The residue was purified by prep- HPLC (Column: Phenomenex luna C18, 10 pm, 150 x 25 mm; Mobile , , , , , , , , Hz, 2H), 5.21 (s, 2H), 3.77 (s, 3H), 3.28 - 3.18 (m, 1 H), 2.41 (s, 3H), 2.25 (s, 3H), 1 .32 (d, J = 6.8 Hz, 6H).19F NMR (376 MHz, DMSO-de) 5 - 133.1. Example 20: 2-(6-Cvclopropyl-2-(4-(1 -(hvdroxymethyl)cvclopropyl)phenyl)-5- methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)- / \ / -(p-tolyl)acetamide

[0674] Step A. 2-(2-Bromo-6-cyclopropyl-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- ide. A mixture of 2-bromo-6-cyclopropyl-

[0675] 5-methyl-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-7(4 / - / )-one (Intermediate 5) (101 mg, 0.38 mmol), 2-chloro- / V-(4-methylphenyl)acetamide (87 mg, 0.47 mmol), K2CO3 (273 mg, 1.98 mmol), and Nal (226 mg, 1.5 mmol) in DMF (3 mL) was stirred at 60 °C overnight. The mixture was cooled to room temperature and quenched with water (1 mL). A pink solid precipitated. The solid was filtered, washed with EtOAc and dried to yield the title compound as a light pink solid. Used in the next step without further purification. MS (ESI): mass calculated for Ci8Hi8BrN5O2, 415.1 ; m / z measured, 416.0 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 5 10.39 (s, 1 H), 7.44 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 8.3 Hz, 2H), 5.11 (s, 2H), 2.54 (s, 3H), 2.25 (s, 3H), 1 .62 - 1 .53 (m, 1 H), 1 .01 - 0.94 (m, 2H), 0.60 - 0.55 (m, 2H).

[0676] Step B. 2-(6-Cyclopropyl-2-(4-(1 -(hvdroxymethyl)cvclopropyl)phenyl)-5- methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)- / \ / -(p-tolyl)acetamide. The title compound was prepared according to procedure as described in Example 7 substituting 2-(2-bromo-6-cyclopropyl-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-4(7 / - / )-yl)- / V-(p-tolyl)acetamide for Intermediate 8. The residue was purified by reverse phase prep-HPLC (Column: Waters Xbridge BEH C18, 5 pm, 150 x 19 mm; Mobile Phase: 30 - 65% MeCN / 10 mM NH4OH in water; Flow Rate: 25 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C28H29N5O3, 483.2; m / z measured, 484.2 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 5 10.44 (s, 1 H), 7.99 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 1 .0 Hz, 2H), 7.41 (d, J = 1 .0 Hz, 2H), 7.13 (d, J = 8.3 Hz, 2H), 5.23 (s, 2H), 4.73 (t, J = 5.4 Hz, 1 H), 3.57 (d, J = 5.4 Hz, 2H), 2.55 (s, 3H), 2.25 (s, 3H), 1 .63 - 1 .55 (m, 1 H), 1 .02 - 0.96 (m, J = 8.3 Hz, 2H), 0.91 - 0.86 (m, 2H), 0.82 -

[0677] 0.76 (m, 2H), 0.62 - 0.56 (m, J = 3.9 Hz, 2H).

[0678] Example 21 : te / Y-Butyl 4-(2-(4-(2-hvdroxypropan-2-yl)phenyl)-5-methyl-7-oxo-4-

[0679] (2-oxo-2-(p-tolylamino)ethyl)-4,7-dihydro-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-6-yl)-

[0680] 3,6-dihydropyridine-1 (2 / - / )-carboxylate

[0681] To a suspension of 2-(6-bromo-2-(4-(2-hydroxypropan-2- yl)phenyl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)-A / -(p- tolyl)acetamide (Intermediate 14) (25 mg, 0.05 mmol), (1 -tert- butoxycarbonyl-1 ,2,3,6-tetrahydropyridin-4-yl)boronic acid pinacol ester (30.3 mg, 0.1 mmol), and CS2CO3 (48.4 mg, 0.15 mmol) in DMF / H2O (0.5 mL, v / v = 10:1 ) was added cataCXium®Pd G4 (5.5 mg, 0.07 mmol). The mixture was placed in a heating block at 95 °C for 30 minutes. The mixture was cooled to room temperature and metal scavenger, Si-Thiol, was added and the mixture was stirred for an additional 30 mins. The suspension was filtered over Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (Column: Kinetex EVO C18, 5 pm, 100 x 30 mm; Mobile Phase: 15 - 65% MeCN / 10 mM NH4OH in water; Flow Rate: 30 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C34H40N6O5, 612.3; m / z measured, 557.2 [M-fBu+2H]+.1H NMR (400 MHz, CDCI3) 5 8.85 (br s, 1 H), 8.18 (d, 2H, J = 8.3 Hz), 7.54 (br d, 2H, J = 8.3 Hz), 7.3-7.4 (m, 2H), 7.10 (br d, 2H, J = 8.3 Hz), 5.66 (br s, 1 H), 5.09 (br s, 2H), 4.04 (br s, 2H), 3.5-3.8 (m, 2H), 2.4-2.5 (m, 3H), 2.3-2.3 (m, 3H), 1.9-2.1 (m, 1 H), 1.6-1 .6 (m, 7H), 1.50 (s, 9H). Example 22: 2-(2-(4-(2-Hydroxypropan-2-yl)phenyl)-5-methyl-7-oxo-6-(1 ,2,3,6- tetrahydropyridin-4-yl)-[1 ,2,4ltriazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)- / \ / -(p- tolyl)acetamide

[0682] To a suspension of te / Y-butyl 4-(2-(4-(2-hydroxypropan-2-yl)phenyl)-5- methyl-7-oxo-4-(2-oxo-2-(p-tolylamino)ethyl)-4,7-dihydro-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-6-yl)-3,6-dihydropyridine-1 (2 / - / )-carboxylate (Example 21 ) (100 mg, 0.13 mmol) in 1 mL DCM was added TFA (0.02 mL, 0.26 mmol). The reaction was stirred for 5 minutes before being neutralized with aq. NaHCOs. The mixture was then transferred to a separatory funnel and diluted with DCM. The layers were separated and the aqueous layers was extracted 3x with DCM / / PrOH (3:1 ). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (Column: Kinetex EVO C18, 5 pm, 100 x 30 mm; Mobile Phase: 10 - 95% MeCN / water (0.1 % TFA); Flow Rate: 30 mL / min) to yield the title compound. MS (ESI): mass calculated for C29H32N6O3, 512.2; m / z measured, 513.3 [M+H]+.1H NMR (400 MHz, DMSO-de) 5 10.48 (s, 1 H), 8.86 (br s, 2H), 8.03 (d, 2H, J = 8.3 Hz), 7.61 (d, 2H, J = 8.8 Hz), 7.47 (d, 2H, J = 8.3 Hz), 7.14 (d, 2H, J = 8.3 Hz), 5.7-5.7 (m, 1 H), 5.27 (s, 2H), 5.0-5.2 (m, 1 H), 3.7-3.8 (m, 4H), 2.4-2.5 (m, 3H), 2.2-2.3 (m, 3H), 1.4-1.5 (m, 6H).

[0683] Example 23: 2-(6-(1 -(Cyclopropanecarbonyl)-1 ,2,3,6-tetrahydropyridin-4-yl)-2- (4-(2-hydroxypropan-2-yl)phenyl)-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-alpyrimidin-

[0684] 4(7H)-yl)- / V-(p-tolyl)acetamide

[0685] The title compound was prepared according to procedure as described in Example 21 substituting cyclopropyl(4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1 (2 / - / )-yl)methanone for (1 - tert-butoxycarbonyl-1 ,2,3,6-tetrahydropyridin-4-yl)boronic acid pinacol ester. The residue was purified by reverse phase HPLC (Column: Kinetex EVO C18, 5 pm, 100 x 30 mm; Mobile Phase: 20 - 80% MeCN / 10 mM NH4OH in water; Flow Rate: 30 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C33H36N6O4, 580.3; m / z measured, 581 .3 [M+H]+.1H NMR (400 MHz, Methanol-^) 5

[0686] 8.06 (d, 2H, J = 8.3 Hz), 7.50 (d, 2H, J = 8.8 Hz), 7.36 (d, 2H, J = 8.3 Hz), 7.04 (d, 2H, J = 8.3 Hz), 5.73 (br d, 1 H, J = 12.2 Hz), 5.23 (s, 2H), 4.3-4.4 (m, 1 H), 3.7-4.2 (m, 3H), 2.4-2.5 (m, 1 H), 2.4-2.4 (m, 3H), 2.3- 2.3 (m, 1 H), 22-2.2 (m, 3H), 1.8-2.0 (m, 1 H), 1.45 (s, 6H), 1.1 -1.2 (m, 1 H), 0.83 (br s, 2H), 0.7-0.8 (m, 2H).

[0687] Example 24: 2-(2-(4-(2-hydroxypropan-2-yl)phenyl)-6-( 1 -isobutyryl-1 ,2,3,6- tetrahydropyridin-4-yl)-5-methyl-7-oxo-[1 ,2,4ltriazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)- / V-(p-tolyl)acetamide The title compound was prepared according to procedure as described in Example 21 , substituting 2-methyl-1 -(4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3,6-dihydropyridin-1 (2 / - / )-yl)propan-1 -one for (1 -tert- Butoxycarbonyl-1 ,2,3,6-tetrahydropyridin-4-yl)boronic acid pinacol ester. The residue was purified by reverse phase HPLC (Column: Kinetex EVO C18, 5 pm, 100 x 30 mm; Mobile Phase: 20 - 80% MeCN / 10 mM NH4OH in water; Flow Rate: 30 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C33H38N6O4, 582.3; m / z measured, 583.2 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 5 10.45 (s, 1 H), 8.03 (d, 2H, J = 8.3 Hz), 7.60 (d, 2H, J = 8.3 Hz), 7.47 (d, 2H, J = 8.8 Hz), 7.14 (d, 2H, J = 8.3 Hz), 5.70 (br s, 1 H), 5.25 (s, 2H), 5.12 (s, 1 H), 4.2-4.3 (m, 1 H), 4.1 -4.1 (m, 1 H), 3.6-3.8 (m, 2H), 2.9-3.0 (m, 1 H), 2.4-2.4 (m, 4H), 2.25 (s, 4H), 1.4-1.5 (m, 6H), 1.0-1.1 (m, 6H).

[0688] Example 25: 2-(2-(4-(2-Hydroxypropan-2-yl)phenyl)-6-(3-methoxyprop-1 -en-2- yl)-5-methyl-7-oxo-[1 ,2,4ltriazolo[1 ,5-a]pyrimidin-4(7H)-yl)- / \ / -(p-tolyl)acetamide

[0689] The title compound was prepared according to procedure as described in Example 21 substituting 2-(3-methoxyprop-1 -en-2-yl)-4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolane for (1 -tert-butoxycarbonyl-1 ,2,3,6-tetrahydropyridin-4- yl)boronic acid pinacol ester. The residue was purified by reverse phase HPLC (Column: Kinetex EVO C18, 5 pm, 100 x 30 mm; Mobile Phase: 10 - 100% MeCN / 10 mM NH4OH in water; Flow Rate: 30 mL / min) to yield a white solid. MS (ESI): mass calculated for C28H31N5O4, 501.2; m / z measured, 502.2 [M+H]+.1H NMR (400 MHz, DMSO-de) 5 10.49 (s, 1 H), 8.04 (d, J = 8.2 Hz, 2H), 7.61 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 8.1 Hz, 2H), 5.63 (s, 1 H), 5.27 (s, 2H), 5.17 (s, 1 H), 5.12 (s, 1 H), 4.07 (s, 2H), 3.32 (s, 3H), 2.41 (s, 3H), 2.25 (s, 3H), 1.45 (s, 6H). Example 26: 6-(1 , 1 -Dioxido-3,6-dihydro-2 / - / -thiopyran-4-yl)-2-(4-(2- hydroxypropan-2-yl)phenyl)-5-methyl-4-(2-oxo-2-(p-tolyl)ethyl)-

[0690] [1 ,2,4]triazolo[1 ,5-a]pyrimidin-7(4 / - / )-one

[0691] The title compound was prepared according to procedure as described in Example 21 , substituting 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3,6-dihydro-2 / - / -thiopyran 1 ,1 -dioxide for (1 -tert- butoxycarbonyl-1 ,2,3,6-tetrahydropyridin-4-yl)boronic acid pinacol ester. The residue was purified by reverse phase HPLC (Column: Kinetex EVO C18, 5 pm, 100 x 30 mm; Mobile Phase: 10 - 100% MeCN / 10 mM NH4OH in water; Flow Rate: 30 mL / min) to yield a white solid. MS (ESI): mass calculated for C29H31 N5O5S, 561.2; m / z measured, 562.2 [M+H]+.1H NMR (400 MHz, DMSO-de) 5 10.45 (s, 1 H), 8.04 (d, J = 8.5 Hz, 1 H), 7.61 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 5.66 - 5.59 (m, 1 H), 5.26 (s, 2H), 5.12 (s, 1 H), 4.09 - 3.95 (m, 1 H),

[0692] 3.93 - 3.75 (m, 1 H), 3.46 - 3.34 (m, 3H), 3.11 - 2.93 (m, 1 H), 2.64 -

[0693] 2.54 (m, 1 H), 2.41 (s, 3H), 2.25 (s, 3H), 1.45 (s, 6H).

[0694] Example 27: 6-(3,4-Dihydro-2 / - / -pyran-5-yl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-

[0695] 5-methyl-4-(2-oxo-2-(p-tolyl)ethyl)-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-7(4 / - / )-one The title compound was prepared according to procedure as described in Example 21 substituting 2-(3,4-dihydro-2H-pyran-5-yl)-4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolane for (1-tert-butoxycarbonyl-1 ,2,3,6-tetrahydropyridin-4- yl)boronic acid pinacol ester. The residue was purified by reverse phase HPLC , , , , , , , Example 29: 4-(2-(4-(2-Hydroxypropan-2-yl)phenyl)-5-methyl-7-oxo-4-(2-oxo-2-

[0696] (p-tolyl)ethyl)-4,7-dihydro-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-6-yl)cyclohex-3-ene-1 - carboxylic acid

[0697] The title compound was prepared according to procedure as described in Example 21 substituting 4-(4, 4,5, 5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)cyclohex-3-ene-1 -carboxylic acid for (1 -tert- butoxycarbonyl-1 ,2,3,6-tetrahydropyridin-4-yl)boronic acid pinacol ester. The residue was purified by reverse phase HPLC (Column: Kinetex EVO C18, 5 pm, 100 x 30 mm; Mobile Phase: 10 - 100% MeCN / 10 mM NH4OH in water; Flow Rate: 30 mL / min) to yield a white solid. MS (ESI): mass calculated for C31H33N5O5, 555.2; m / z measured, 556.2 [M+H]+.1H NMR (400 MHz, DMSO-de) 5 10.28 (s, 1 H), 8.02 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 7.9 Hz, 2H), 7.44 (d, J = 7.9 Hz, 2H), 7.10 (d, J = 7.9 Hz, 2H), 5.63 (br s, 1 H), 5.23 (s, 2H), 2.44 (m, 1 H), 2.37 (s, 3H), 2.34 (br s, 2H), 2.25 (s, 3H), 2.20 (m, 2H), 2.00 (m, 1 H), 1.7-1.8 (m, 1 H), 1.47 (s, 6H).

[0698] Example 30: 2-(4-(2-Hydroxypropan-2-yl)phenyl)-6-(4-methoxycyclohex-1 -en-1 - yl)-5-methyl-4-(2-oxo-2-(p-tolyl)ethyl)-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-7(4 / - / )-one The title compound was prepared according to procedure as described in Example 21 substituting 2-(4-methoxycyclohex-1 -en-1 -yl)-4,4,5,5- tetramethyl-1 ,3,2-dioxaborolane for (1 -tert-butoxycarbonyl-1 ,2,3,6- tetrahydropyridin-4-yl)boronic acid pinacol ester. The residue was purified by , resulting solution was stirred at room temperature for 10 minutes. To another 4 mL vial was placed [4,4'-B / s(1 , 1 -dimethylethyl)-2,2'-bipyridine- / 1 , A / 1 ']b / s[2-(2- pyridinyl- / V)phenyl-C]iridium(lll) hexafluorophosphate (1.37 mg, 0.0015 mmol), [4,4'-Bis(1 , 1 -dimethylethyl)-2,2'-bipyridine] nickel (II) dibromide tetrahydrate (4.2 mg, 0.0075 mmol), quinuclidine (22.2 mg, 0.2 mmol), phthalimide (3.31 mg, 0.0225 mmol), 2-(2-(4-bromophenyl)-6-isopropyl-5-methyl-7-oxo- [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7H)-yl)- / V-(p-tolyl)acetamide (Intermediate 11 ) (49.4 mg, 0.1 mmol) and a magnetic stir bar. DMA (1 mL) was then added to this vial.

[0699] The MTBE solution from the first vial was transferred to a 2 mL syringe. Then a syringe filter and a new needle were installed on the syringe before the MTBE solution was injected through the syringe filter into the DMA solution. The reaction mixture was capped and removed from the glovebox. The vial was stirred at 1500 rpm stir rate and irradiated under 450 nm LED modules at 100% light intensity with a fan speed of 5200 rpm in a Penn Integrated Photoreactor for 2 hours. The reaction mixture was then filtered through Celite® and diluted with DMSO / H2O (5:1 , 1 mL). The residue was purified by reserve phase HPLC (Waters Xselect CSH C18, 5 pm, 19 x 150 mm; Mobile Phase: 35 - 70% MeCN / water (0.16% TFA); Flow Rate: 25 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C28H31N5O3, 485.2; m / z measured, 486.0 [M+H]+.1H NMR (400 MHz, DMSO-de) 5 10.46 (s, 1 H), 8.03 (d, 2H, J = 8.3 Hz), 7.47 (d, 2H, J = 8.3 Hz), 7.3-7.4 (m, 2H, J = 8.3 Hz), 7.14 (d, 2H, J = 8.3 Hz), 5.26 (s, 2H), 4.05 (quin, 1 H, J = 7.5 Hz), 3.25 (m, 1 H), 2.9-3.0 (m, 1 H), 2.6-2.7 (m, 2H), 2.43 (s, 3H), 2.25 (s, 3H), 1 .9-2.0 (m, 2H), 1 .34 (d, 6H, J = 6.8 Hz).

[0700] Example 32: 2-(2-(4-((3*R,4*S)-4-Hydroxytetrahvdrofuran-3-yl)phenyl)-6- isopropyl-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)- / \ / -(p- tolvDacetamide

[0701] The title compound was prepared according to procedure as described in Example 31 substituting 1 ,4-anhydroerythritol for cyclobutane-1 ,3-diol. The residue was purified by reserve phase HPLC (Column: Waters Xselect CSH C18, 5 pm, 19 x 150 mm; Mobile Phase: 30 - 65% MeCN / water (0.16% TFA); Flow Rate: 25 mL / min). The pure fractions were further purified by chiral SFC (Column: Cell-B 21 x 250 mm ID, 5 pm; Mobile Phase: 30% MeOH; Flow Rate: 65 mL / min). The first-eluting fractions were collected and concentrated in vacuo to yield the title compound as a white solid. MS (ESI): mass calculated for C28H31N5O4, 501 .2; m / z measured, 502.3 [M+H]+.1H NMR (400 MHz, DMSO-de) 5 10.46 (s, 1 H), 8.0- 8.1 (m, 2H), 7.47 (d, 2H, J = 8.3 Hz), 7.4-7.4 (m, 2H), 7.1 -7.2 (m, 2H), 5.26 (s, 2H), 4.25 (q, 1 H, J = 4.4 Hz), 4.17 (dd, 1 H, J = 7.2, 8.7 Hz), 3.98 (dd, 1 H, J = 5.6, 9.2 Hz), 3.75 (dd, 1 H, J = 6.1 , 8.6 Hz), 3.5-3.7 (m, 1 H), 3.2-3.3 (m, 2H), 2.43 (s, 3H), 2.25 (s, 3H), 1 .34 (d, 6H, J = 6.8 Hz).

[0702] Example 33: 2-(2-(4-((3*S,4*R)-4-Hydroxytetrahydrofuran-3-yl)phenyl)-6- isopropyl-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)- / \ / -(p- tolvDacetamide

[0703] The title compound was obtained via chiral SFC purification of the material prepared in Example 32, collecting the second-eluting fractions and concentrating in vacuo to yield the title compound as a white solid. MS (ESI): mass calculated for C28H31N5O4, 501.2; m / z measured, 502.4 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 5 10.46 (s, 1 H), 8.0-8.1 (m, 2H), 7.47 (d, 2H, J = 8.3 Hz), 7.4-7.4 (m, 2H), 7.1 -7.2 (m, 2H), 5.26 (s, 2H), 4.25 (q, 1 H, J = 4.4 Hz), 4.17 (dd, 1 H, J = 7.2, 8.7 Hz), 3.98 (dd, 1 H, J = 5.6, 9.2 Hz), 3.75 (dd, 1 H, J = 6.1 , 8.6 Hz), 3.5-3.7 (m, 1 H), 3.2-3.3 (m, 2H), 2.43 (s, 3H), 2.25 (s, 3H), 1 .34 (d, 6H, J = 6.8 Hz).

[0704] Example 34: 2-(2-(4-(2-Hvdroxypropan-2-yl)phenyl)-5-methyl-6-morpholino-7- oxo-[1 ,2,4]triazolo[1 ,5-alpyrimidin-4(7 / - / )-yl)- / \ / -(4-

[0705] (trifluoromethyl)phenyl)acetamide

[0706] Step A: Methyl 2-morpholino-3-oxobutanoate. Triethvlamine (5.21 mL, 37 mmol) was added to a mixture of methyl 2 -chloroacetoacetate (1 .5 mL, 12 mmol) in MeCN (8 mL). Then a solution of morpholine (1 .09 mL, 12 mmol) in MeCN (8 mL) was added. The reaction mixture was stirred at 60 °C overnight. The reaction mixture was filtered, then the filtrate was diluted with EtOAc and water. The layers were separated, and the organic layer was washed with water, brine, dried over MgSCM, filtered, and concentrated in vacuo. The residue was purified by column chromatography (S iC>2, 0 - 60% EtOAc / heptane) to yield the title compound as a light-yellow oil. MS (ESI): mass calculated for C9H15NO4, 201.1 ; m / z measured, 202.0 [M+H]+.

[0707] Step B: 2-Bromo-5-methyl-6-morpholino-[1 ,2,4]triazolo[1 ,5- a]pyrimidin-7(4 / - / )-one. To a microwave vial was added 3-bromo-1 / - / - 1 ,2,4-triazol-5-amine (Intermediate 1 ) (200 mg, 1.23 mmol), TsOH*H2O (64 mg, 0.33 mmol) in toluene (2 mL), and methyl 2-morpholino-3- oxobutanoate (296 mg, 1.47 mmol). The reaction mixture was capped and stirred at 90 °C overnight. Toluene was evaporated to yield a sticky gum, to which was then added MeCN. The resulting precipitate was filtered and washed with Et20 to yield the title compound as a white solid. MS (ESI): mass calculated for C Hi2BrN5O2, 313.0; m / z measured: 314.0 [M+H]+.

[0708] Step C: 2-(2-Bromo-5-methyl-6-morpholino-7-oxo-

[0709] [1 ,2,4]triazolo[1 ,5-a]pvrimidin-4(7H)-vl)- / V-(4- (trifluoromethyl)phenyl)acetamide. To a 40 mL vial was added 2-bromo- 5-methyl-6-morpholino-[1 , 2, 4]triazolo[ 1 ,5-a]pyrimidin-7(4 / - / )-one (175 mg, 0.56 mmol), Nal (336 mg, 2.2 mmol), 2-chloro- / V-[4- (trifluoromethyl)phenyl]acetamide (159 mg, 0.67 mmol) and K2CO3 (385 mg, 2.8 mmol). DMF (3.8 mL) was then added and the reaction mixture was stirred at 65 °C overnight. The reaction mixture was cooled to room temperature, and water was added. The organic phase was washed with water and brine, dried over MgSO4, filtered, and evaporated. The residue was purified by reverse phase HPLC (Column: Phenomenex Gemini-NX C18, 5 pm, 150 x 30 mm; Mobile Phase: 20 - 80% MeCN / 10 mM NH4OH in water; Flow Rate: 30 mL / min) to yield the title compound. MS (ESI): mass calculated for CigHisBrFsNeOs, 514.1 ; m / z measured, 515.1 [M+H]+.

[0710] Step D: 2-(2-(4-(2-Hvdroxypropan-2-yl)phenyl)-5-methyl-6-morpholino-7- oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)- / \ / -(4- (trifluoromethyl)phenyl)acetamide. The title compound was prepared according to procedure as described in Example 7 substituting 2-(2-bromo-5-methyl-6- morpholino-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrim idin-4(7 / - / )-yl)- / V-(4- (trifluoromethyl)phenyl)acetamide (55 mg, 0.11 mmol) for 2-(2-bromo-6- isopropyl-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)- / V-(p- tolyl)acetamide and further substituting (4-(2-hydroxypropan-2- yl)phenyl)boronic acid (25.0 mg, 0.139 mmol) for 4-(1 - (hydroxylmethyl)cyclopropyl)phenylboronic acid. The residue was purified by reverse phase HPLC (Column: Kinetex EVO C18, 5 pm, 100 x 30 mm; Mobile Phase: 30 - 85% MeCN / 10 mM aq NH4OH water; Flow Rate: 30 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C28H29F3N6O4, 570.2; m / z measured, 571.2 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 5 10.83 - 10.99 (m, 2 H) 8.02 (d, J = 8.31 Hz, 2 H) 7.77 - 7.83 (m, 2 H) 7.68 - 7.75 (m, 2 H) 7.60 (d, J = 8.31 Hz, 2 H) 5.29 (s, 2 H) 5.11 (s, 1 H) 3.82 (br d, J = 6.85 Hz, 2 H) 3.51 - 3.67 (m, 5 H) 2.59 (s, 3 H) 2.07 (s, 1 H) 1.44 (s, 6 H).

[0711] Example 35: 2-[2-[4-(1-Acetamidocvclopropyl)phenyll-6-isopropyl-5-methyl-7- oxo-[1 ,2,4]triazolo[1 ,5-alpyrimidin-4-yll-N-[4-(trifluoromethyl)phenyl]acetamide

[0712] The title compound was prepared according to procedure as described in Example 7 substituting Intermediate 10 for 2-(2-bromo-6-isopropyl-5-methyl- 7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)- / V-(p-tolyl)acetamide and further substituting A / -(1 -(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)cyclopropyl)acetamide for 4-(1 -(hydroxylmethyl)cyclopropyl)phenyl boronic acid. The resulting residue was purified by reverse phase prep-HPLC (Column: Waters Xbridge BEH C18, 5 pm, 150 x 19 mm; Mobile Phase: 40 - 75% MeCN / 10 mM NH4OH in water; Flow Rate: 25 mL / min) to yield title compound as a white powder. MS (ESI): mass calculated for C29H29F3N6O3, 566.2; m / z measured, 567.3 [M+H]+.1H NMR (400 MHz, DMSO-de) 5 10.91 (s, 1 H), 8.60 (s, 1 H), 7.97 (d, J = 8.3 Hz, 2H), 7.80 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 1 .0 Hz, 2H), 7.23 (d, J = 8.3 Hz, 2H), 5.31 (s, 2H), 3.27 - 3.21 (m, 1 H), 2.44 (s, 3H), 1.86 (s, 3H), 1.34 (d, J = 6.8 Hz, 6H), 1.25 - 1.20 (m, 2H), 1.18 - 1.14 (m, 2H).19F NMR (DMSO-cfe, 376 MHz) 5 -60.4.

[0713] Example 36: 2-(6-lsopropyl-5-methyl-2-(4-(1 -

[0714] (methylsulfonamido)cyclopropyl)phenyl)-7-oxo-[1 ,2,4]triazolo[1 ,5-alpyrimidin-

[0715] 4(7H)-yl)- / V-(4-(trifluoromethyl)phenyl)acetamide

[0716] The title compound was prepared according to procedure as described in Example 7 substituting Intermediate 10 for Intermediate 8 and further substituting A / -(1 -(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)cyclopropyl)methanesulfonamide for 4-(1 -

[0717] (hydroxylmethyl)cyclopropyl)phenyl boromc acid. The resulting residue was purified by reverse phase prep-HPLC (Column: Waters Xbridge BEH C18, 5 pm, 150 x 19 mm; Mobile Phase: 40 - 75% MeCN / 10 mM NH4OH in water; Flow Rate: 25 mL / min) to yield the title compound. MS (ESI): mass calculated for C28H29F3N6O4S, 602.2; m / z measured, 603.0 [M+H]+.1H NMR (401 MHz, DMSO-cfe) 5 8.09 (d, J = 8.3 Hz, 2H), 7.86 (d, J = 1 .0 Hz, 2H), 7.77 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.3 Hz, 2H), 5.38 (s, 2H), 3.33 - 3.28 (m, 1 H), 2.68 (s, 3H), 2.50 (s, 3H), 1 .40 (d, J = 6.8 Hz, 8H), 1 .27 - 1 .21 (m, 2H).19F NMR (DMSO-cfe, 376 MHz) 5 -60.4.

[0718] Example 37 : 2-(2-(4-(2-Hydroxypropan-2-yl)phenyl)-6-isopropyl-5- methyl-7-oxo-[1 ,2,4ltriazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)- / \ / -(2-methyl-4-

[0719] (trifluoromethyl)phenyl)acetamide

[0720] The title compound was prepared according to procedure as described in Example 14 substituting 2-methyl-4-(trifluoromethyl)aniline for 2-chloro-4- (trifluoromethyl)aniline and further substituting Intermediate 12 for Intermediate 13. The residue was purified by prep-HPLC (Column: Phenomenex Gemini-NX C18, 5 pm, 150 x 30 mm; Mobile Phase: 20 - 80% MeCN / 10 mM NH4OH in water; Flow Rate: 30 mL / min) to yield the title compound as a white solid. MS (ESI): mass calculated for C28H30F3N5O3, 541.2; m / z measured, 542.3 [M+H]+.1HNMR (400 MHz, DMSO-de) 5 ppm 10.07 (s, 1 H) 7.95 - 8.15 (m, 3 H) 7.76 (d, J = 8.31 Hz, 2 H) 7.59 - 7.66 (m, 3 H) 7.48 - 7.59 (m, 1 H) 5.37 (s, 2 H) 5.12 (s, 1 H) 2.46 - 2.48 (m, 3 H) 2.31 - 2.44 (m, 3 H) 1 .46 (s, 6 H) 1.34 (d, J = 6.85 Hz, 6 H).19F NMR (376 MHz, DMSO-de) 5 -60.6.

[0721] Example 38: 2-(2-(4-(2-Hydroxypropan-2-yl)phenyl)-6-isopropyl-5- methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4(7 / - / )-yl)- / \ / -(2- (trifluoromethyl)pyrimidin-5-yl)acetamide (ID No. 435)

[0722] The title compound was prepared according to the procedure described in Example 2, substituting 2-(trifluoromethyl)pyrimidin-5-amine for 4- aminobenzotrifluoride. The resulting residue was purified by reverse phase prep-HPLC (Column: Waters Xselect CSH C18, 5 pm, 150 x 19 mm; Mobile Phase: 40 - 75% MeCN / water (0.16% TFA); Flow Rate: 25 mL / min) to yield the title compound. MS (ESI): mass calculated for C25H26F3N7O3, 529.2; m / z measured, 530.3 [M+H]+.1HNMR (400 MHz, DMSO-de) 5 ppm 11.44 (s, 1 H) 9.22 (s, 2 H) 7.97 - 8.15 (m, 2 H) 7.55 - 7.72 (m, 2 H) 5.38 (s, 2 H) 3.18 - 3.29 (m, 1 H) 2.44 - 2.47 (m, 3 H) 1 .44 (s, 6 H) 1 .35 (d, J = 6.85 Hz, 6 H).19F NMR (376 MHz, DMSO-cfe) 5 -68.2.

[0723] Biological Examples

[0724] WRN Protein Expression and Purification

[0725] 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%.

[0726] 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 ZnCI2, 5 mM MgCI2, 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 ZnCl2, 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 ZnCl2, 0.1 % NP-40) and another 5 CVs buffer A. The purified protein was then eluted with buffer C (20 mM HEPES pH 7.5, 500 mM 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 ZnCI2, 0.01 % NP- 40) and loaded onto a heparin column (HiTrap Heparin HP, Cytiva) preequilibrated 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 ZnCI2, 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.

[0727] Biological Example 1 : WRN ATPase Activity Assay ADP-Glo Assay Format and Reagents

[0728] 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.

[0729] Forked dsDNA Preparation

[0730] A forked double-stranded DNA (dsDNA) substrate was designed to stimulate ATPase activity using the synthetic oligonucleotide sequences outlined below (Integrated DNA Technologies). The oligos were resuspended upon receipt at 0.2 mM in IDT Duplex Buffer and stored at -20°C. As needed, OLIGO-A and OLIGO-B were annealed at 0.05 mM in 10 mM Tris buffer pH 8.0, 1 mM EDTA, 10 mM MgCl2 and 50 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.

[0731] OLIGO-A

[0732] 5’- TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCGTACCCGATGTGTTCGTTC-3’ OLIGO-B

[0733] 5’- GAACGAACACATCGGGTACGTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT-3’ Activity Assay Assembly

[0734] 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).

[0735] 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:

[0736] 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 Coming cyclic olefin copolymer (COC) assay plates.

[0737] 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.

[0738] Compound Data Analysis

[0739] 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, ICso is the compound concentration at the inflection point of the dose-response, H is the Hill coefficient, and [I] is the compound concentration.

[0740] 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.

[0741] Biological Example 2: WRN Cellular Viability Assays

[0742] HCT-116 Cell Proliferation Assay

[0743] Effect of compound treatment on cell proliferation was determined using the CellTiter-Glo Luminescent Cell Viability Assay (Promega #G8461 ). HCT- 116 (ATCC #CCL-247TM) were maintained in McCoy’s 5A+Glumax (Thermo Fisher #36600021 ) supplemented with 10% heat inactivated fetal bovine serum (FBS; Invitrogen #16140). 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 IxPenStrep (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.

[0744] SW-620 Cell Proliferation Assay

[0745] Effect of compound treatment on cell proliferation was determined using the CellTiter-Glo Luminescent Cell Viability Assay (Promega #G8461 ). SW- 620 (ATCC #CCL-227TM) 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 IxPenStrep (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.

[0746] Representative compounds of the present invention were tested according to the procedure described in Example B1 , B2, B3 and B4 above, with results as listed in Table BIO-1 below. The values presented in Table BIO- 1 below represent the average of between 1 and 6 individual measurements, as noted in the parenthetical (#) which follows the reported average.

[0747] Table BIO-1: Measured WRN Activity

[0748]

[0749] NT indicates that the compound was not tested. 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.

[0750] 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.

Claims

What is Claimed:whereinis selected from the group consisting of unsubstituted or substituted phenyl, unsubstituted or substituted 5 membered heteroaryl, and unsubstituted or substituted 6 membered heteroaryl; wherein the substituted phenyl, substituted 5 membered heteroaryl or substituted 6 membered heteroaryl is substituted with one or more independently selected from the group consisting of halogen, -OH, oxo, CN, Ci- 4alkyl, halogen substituted Ci-4alkyl, hydroxy substituted Ci-ealkyl, (fluoro substituted Ci-4alkyl)-OH, -(Ci-4alkyl)-CN, -(Ci-4alkyl)-O-(Ci-4alkyl), -(hydroxy substituted Ci-4alkyl)-O-(Ci-2alkyl), -O-(Ci-4alkyl), -O-(halogen substituted Ci-4alkyl), -O-(Ci-4alkyl)-CN, -C(O)-NRARB, -(Ci-4alkyl)-C(O)-NRARB, -NRARB, - (hydroxy substituted Ci-4alkyl)-NRARB, -NH-C(O)-NRARB, -NRA-SO2-(Ci-4alkyl), and -SO2-NRARB; and wherein RAand RBare each independently selected from the group consisting of hydrogen, Ci-4alkyl and hydroxy substituted Ci- 4alkyl; provided that whenis unsubstituted phenyl, methylphenyl, chlorophenyl, thiophenyl, or unsubstituted 6 membered heteroaryl, then a is 1 ; a is an integer from 0 to 1 ;R1is selected from the group consisting of Cs-ecycloalkyl, -(Ci-2alkyl)-C3- scycloalkyl, 4 to 6 membered heterocyclyl and -(Ci-2alkyl)-(4 to 6 membered heterocyclyl); wherein the Cs-ecycloalkyl or 4 to 6 membered heterocyclyl, whether alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of halogen,-OH, oxo, -CN, Ci-4alkyl, hydroxy substituted Ci-4alkyl, halogen substituted Ci- 4alkyl, -(Ci-4alkyl)-CN, -O-Ci-4alkyl, -O-(halogen substituted Ci-4alkyl), -C(0)- (Ci-4alkyl), -C(O)OH, -C(O)-O-(Ci-4alkyl), -NRCRD, -C(O)-NRCRD, -NRc-C(O)- (Ci-4alkyl), -NRc-C(O)-O-(Ci-4alkyl), -NRc-SO2-(Ci-4alkyl) and -SO2-(Ci-4alkyl); and wherein Rcand RDare each independently selected from the group consisting of hydrogen and Ci-4alkyl;R2is selected from the group consisting of hydrogen, Ci-4alkyl, hydroxy substituted Ci-4alkyl, halogen substituted Ci-4alkyl, -(Ci-2alkyl)-CN, C2-4alkenyl, hydroxy substituted C2-4alkenyl, -(Ci-2alkyl)-O-(Ci-4alkyl), -(C2-4alkenyl)-O-(Ci- 4alkyl), -(C2-4alkenyl)-O-(Ci-4alkyl), Cs-ecycloalkyl, Cs-ecycloalkenyl, and 4 to 6 membered heterocycloalkyl; wherein the Cs-ecycloalkyl, Cs-ecycloalkenyl, phenyl or 4 to 6 membered heterocycloalkyl is optionally substituted one or more substituents independently selected from the group consisting of -OH, oxo, -Ci-4alkyl, -0- (Ci-4alkyl), -C(O)-(Ci-4alkyl), -C(O)-C3-6cycloalkyl, -C(O)OH, and -C(O)O-(Ci- 4alkyl);R3is selected from the group consisting of Ci-4alkyl, hydroxy substituted Ci-4alkyl, -(Ci-2alkyl)-O-(Ci-4alkyl), and Cs-ecycloalkyl;R4is selected from the group consisting of phenyl, and 5 to 6 membered heteroaryl; wherein the phenyl or 5 to 6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, pentafluorothio, Ci-4alkyl, halogen substituted Ci- 4alkyl, -O-Ci-4alkyl, -O-(halogen substituted Ci-4alkyl), and Cs-scycloalkyl; or a stereoisomer or pharmaceutically acceptable salt thereof.

2. A compound as in Claim 1 , whereinis selected from the group consisting of unsubstituted or substituted phenyl, unsubstituted or substituted 5 membered heteroaryl, substituted 5 membered heteroaryl, and unsubstituted or substituted 6 membered heteroaryl;wherein the substituted phenyl, substituted 5 membered heteroaryl or substituted 6 membered heteroaryl is substituted with one to three substituents independently selected from the group consisting of halogen, -OH, oxo, CN, Ci- 2alkyl, halogen substituted Ci-4alkyl, hydroxy substituted Ci-ealkyl, (fluoro substituted Ci-4alkyl)-OH, -(Ci-3alkyl)-CN, -(hydroxy substituted Ci-4alkyl)-O-(Ci- 2alkyl), -O-(Ci-2alkyl), -O-(halogen substituted Ci-2alkyl), O-(Ci-4alkyl)-CN, -(Ci-4alkyl)-O-(Ci-2alkyl), -C(O)-NRARB, -(Ci-2alkyl)-C(O)-NRARB, -NRARB, -(hydroxy substituted Ci-4alkyl)-NRARB, -NH-C(O)-NRARB, -NRA-SO2-(Ci-4alkyl), and - SO2-NRARB;and wherein RAand RBare each independently selected from the group consisting of hydrogen, Ci-2alkyl and hydroxy substituted Ci-salkyl; provided that whenis unsubstituted phenyl, methylphenyl, chlorophenyl, thiophenyl, or unsubstituted 6 membered heteroaryl, then a is 1 ; a is an integer from 0 to 1 ;R1is selected from the group consisting of Cs-ecycloalkyl, -(Ci-2alkyl)-C3- scycloalkyl, 4 to 6 membered heterocyclyl and -(Ci-2alkyl)-(4 to 6 membered heterocyclyl); wherein the Cs-ecycloalkyl or 4 to 6 membered heterocyclyl, whether alone or as part of a substituent group, is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, oxo, -CN, Ci-2alkyl, hydroxy substituted Ci salkyl, halogen substituted Ci- 2alkyl, -(Ci-2alkyl)-CN, -O-Ci-2alkyl, -O-(halogen substituted Ci-2alkyl), -C(0)- (Ci-2alkyl), -C(O)OH, -C(O)-O-(Ci-4alkyl), -NRCRD, -C(O)-NRCRD, -NRc-C(0)- (Ci-2alkyl), -NRc-C(O)-O-(Ci-4alkyl), -NRc-SO2-(Ci-4alkyl) and -SO2-(Ci-2alkyl); and wherein Rcand RDare each independently selected from the group consisting of hydrogen, and Ci-2alkyl;R2is selected from the group consisting of hydrogen, Ci-4alkyl, -(C2- 4alkenyl)-O-(Ci-4alkyl), Cs-scycloalkyl, Cs-ecycloalkenyl, and 4 to 6 membered heterocycloalkyl; wherein the Cs-scycloalkyl, Cs-ecycloalkenyl, or 4 to 6 membered heterocycloalkyl is optionally substituted with a substituent selected from the group consisting of -OH, oxo, -Ci-4alkyl, -0-(Ci-2alkyl), -C(0)-(Ci-4alkyl), -C(0)- C3-5cycloalkyl, -C(O)OH, and -C(0)0-(Ci-4alkyl);R3is Ci-2alkyl;R4is selected from the group consisting of phenyl, and 5 to 6 membered heteroaryl; wherein the phenyl or 5 to 6 membered heteroaryl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, pentafluorothio, Ci-2alkyl, halogen substituted Ci-2alkyl, - O-(halogen substituted Ci-4alkyl), and C3-4cycloalkyl; or a stereoisomer or pharmaceutically acceptable salt thereof.

3. A compound as in Claim 1 or Claim 2, wherein(?A!) is selected from the group consisting of phenyl, 2-fluoro-phenyl, 3- fluoro-phenyl, 4-chloro-phenyl, 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl- phenyl, 2,6-dimethyl-phenyl, 4-hydroxy-methyl-phenyl, 4-(1 -hydroxy-ethyl)- phenyl, 4-(2-hydroxy-ethyl)-phenyl, 4-(1 -hydroxy-isopropyl)-phenyl, 2-fluoro-4- (1 -hydroxy-isopropyl)-phenyl, 4-(2-hydroxy-1 , 1 -dimethyl)-phenyl, 4-(3-hydroxy- n-propyl)-phenyl, 4-(2-hydroxy-3-methoxy-n-propyl)-phenyl, 4-(3-hydroxy-3- methyl-n-butyl)-phenyl, 4-(1 -methyl-3-hydroxy-n-butyl)-phenyl, 4-(2-methyl-2- hydroxy-methyl-3-hydroxy-n-propyl)-phenyl, 4-(1 ,1 ,1 ,3,3,3-hexafluoro-2- hydroxy-isopropyl)-phenyl, 4-(3,3,3-trifluoro-2-hydroxy-isopropyl)-phenyl, 2- methoxy-phenyl, 4-methoxy-phenyl, 2-methoxy-4-hydroxy-methyl-phenyl, 3- hydroxy-methyl-4-fluoro-phenyl, 4-difluoro-methoxy-phenyl, 4-(2,2-difluoro- ethoxy)-phenyl, 4-(methoxy-methyl)-phenyl, 4-(1 -methoxy-ethyl)-phenyl, 4-(2- methoxy-ethyl)-phenyl, 4-(2-methoxy-isopropyl)-phenyl, 3-fluoro-4-(methoxy- methyl)-phenyl, 3-cyano-phenyl, 2-fluoro-4-cyano-phenyl, 3-fluoro-4-cyano- methyl-phenyl, 4-cyano-methyl-phenyl, 4-(2-cyano-isopropyl)-phenyl, 4-(cyano- methoxy)-phenyl, 4-(amino-carbonyl)-phenyl, 2-fluoro-4-(amino-carbonyl)- phenyl, 4-(methyl-amino-carbonyl-amino)-phenyl, 4-(amino-carbonyl-methyl)- phenyl, 4-(3-hydroxy-n-propyl-amino-carbonyl)-phenyl, 4-(methyl-amino- carbonyl-methyl)-phenyl, 4-(3-amino-2-methyl-2-hydroxy-n-propyl)-phenyl, 4-(1 - methyl-3-(methyl-amino-carbonyl)-n-propyl)-phenyl, 4-(amino-sulfonyl)-phenyl, 4-(methyl-sulfonyl-amino)-phenyl, pyridin-3-yl, 2-methyl-pyridin-3-yl, 5- difluoromethyl-pyridin-3-yl, 6-hydroxy-methyl-pyridin-3-yl, 2-hydroxy-pyridin-4-yl, 2-methoxy-pyridin-4-yl, 6-methoxy-pyridin-3-yl, 2-cyano-pyridin-4-yl, 5- cyano-pyridin-3-yl, 6-cyano-pyridin-3-yl, 1 -methyl-2-oxo-pyridin-4-yl, 6-amino- pyridin-3-yl, 6-(methyl-amino-carbonyl)-pyridin-3-yl, pyrazol-4-yl, 3-methyl- pyrazo-4-yl, 3-methyl-pyrazol-5-yl, 1 -methyl-pyrazol-4-yl, 1 ,3-dimethyl-pyrazol- 4-yl, 1 ,3-dimethyl-pyrazol-5-yl, 1 ,4-dimethyl-pyrazol-5-yl, 1 ,5-dimethyl-pyrazol-4-yl, 1 -(difluoro-methyl)-pyrazol-4-yl, 1 -ethyl-5-fluoro-pyrazol-4-yl, 1 -(2,2- difluoro-ethyl)-pyrazol-4-yl, 1 -methyl-5-fluoro-pyrazol-4-yl, 1 -methyl-5-chloro- pyrazol-4-yl, 1 -methyl-3-methoxy-pyrazol-4-yl, 1 -(2-methoxy-ethyl)-pyrazol-4-yl, 1 -methyl-5-(methoxy-methyl)-pyrazol-4-yl, 1 -(2,2-difluoro-ethoxy)-pyrazol-4-yl,1 -(2-hydroxy-ethyl)-pyrazol-4-yl, 1 -(2-hydroxy-n-propyl)-pyrazol-4-yl, 1 -hydroxy- ethyl-5-methyl-pyrazol-4-yl, 1 -(2-hydroxy-ethyl)-5-methyl-pyrazol-4-yl, 1 - hydroxy-ethyl-4-methyl-pyrazol-5-yl, 1 -(2-hydroxy-1 , 1 -dimethyl-ethyl)-pyrazol-4- yl, 1 -(2-cyano-ethyl)-pyrazol-4-yl, 1 -methyl-5-cyano-pyrazol-4-yl, 1 -methyl-3- cyano-pyrazol-4-yl, 1 -(amino-carbonyl-methyl)-pyrazol-4-yl, 1 -(methyl-amino- carbonyl-methyl)-pyrazol-4-yl, 6-methyl-pyridazin-4-yl, 1 -methyl-imidazol-5-yl, 1 ,2-dimethyl-imidazol-5-yl, thiazol-4-yl, thiazol-5-yl, 2-methyl-thiazol-5-yl, 4- methyl-thiazol-5-yl, 2-hydroxy-methyl-thiazol-5-yl, oxazol-5-yl, 2-methyl-oxazol-5-yl, 2-(hydroxy-methyl)-oxazol-5-yl, 4-methyl-isothiazol-5-yl, 3-methyl-isoxazol- 5-yl, 5-hydroxy-methyl-furan-5-yl, 5-hydroxy-methyl-thiophen-3-yl, and 5- hydroxy-methyl-thiophen-5-yl; provided that whenmethyl-phenyl, 4-chloro-phenyl, or pyrid in-3-y I , then a is 1 ; a is an integer from 0 to 1 ;R1is selected from the group consisting of 2-cyclopropyl, 5-cyclopropyl, 4-(1 -(hydroxy-methyl)-cycloprop-l -yl), 4-(1 -(1 -hydroxy-ethyl)-cycloprop-1 -yl), 4- (1 -cyano-cycloprop-1 -yl), 4-(1 -carboxy-cycloprop-1 -yl), 4-(1 -(ethoxy-carbonyl)- cycloprop-1 -yl), 4-(1 -amino-cycloprop-1 -yl), 4-(1 -amino-carbonyl-cycloprop-1 - yl), 4-(1 -methyl-amino-carbonyl-cycloprop-1 -yl), 4-(1 -(dimethyl-amino- carbonyl)-cycloprop-1 -yl), 4-(1 -(methyl-carbonyl-amino)-cycloprop-l -yl), 4-(1 - (methyl-sulfonyl-amino)-cycloprop-l -yl), 4-(1 -(tert-butoxy-carbonyl-amino)- cycloprop-1 -yl),1 -cyclobutyl, 4-cyclobutyl, 1 -(3-hydroxy-cyclobut-1 -yl), 4-(3- hydroxy-cyclobut-1 -yl), 4-(1 -hydroxy-cyclobut-1 -yl), 4-(2-hydroxy-cyclobut-1 -yl),4-(2R*-hydroxy-cyclobut-1 S*-yl), 4-(2S*-hydroxy-cyclobut-1 R*-yl),4-(3-hydroxy- cyclobut-1 -y I), 1 -(3-hydroxymethyl-cyclobut-1 -y I), 4-(2,2-dimethyl-3-hydroxy- cyclobut-1 -y I), 4-(2-methyl-3-hydroxy-cyclobut-1 -y I) , 4-(3-difluoro-methyl- cyclobut-1 -y I), 1 -(3-methoxy-cyclobut-1 -y I) , 4-(3-difluoro-methoxy-cyclobut-1 - y I), 4-(2-methoxy-3-hydroxy-cyclobut-1 -y I) , 4-(3-methoxy-3-trifluoro-methyl- cyclobut-1 -y I), 4-(3-cyano-methyl-cyclobut-1 -y I), 4-(3-methyl-3-cyano-cyclobut- 1 -y I) , 4-(3-cyano-3-methoxy-carbonyl-cyclobut-1 -y I) , 4-(1 -(tert-butoxy-carbonyl- amino)-cyclobut-1 -y I) , 1 -(2-hydroxy-cyclopent-1 -y I) , 4-(3-hydroxy-cyclopent-1 - y I), 4R-(2S-(tert-butoxy-carbonyl-amino)-cyclopent-1 -y I) , 4-(3,3-difluoro-5- hydroxy-cyclopent-1 -y I), 4-(4-hydroxy-cyclohex-1 -y I), 4-(4-hydroxy-cyclohex-1 - yl), 4-cis-(4-hydroxy-cyclohex-1 -yl), 4-trans-(4-hydroxy-cyclohex-1 -yl), 4-(4- methyl-4-hydroxy-cyclohex-1 -yl), 4-(4-(hydroxy-methyl)-cyclohex-1 -yl), 4-cis-(4- (hydroxy-methyl)-cyclohex-l -yl), 4-trans-(4-(hydroxy-methyl)-cyclohex-1 -yl), 4- (3-difluoro-methyl-cyclohex-1 -yl), 4-(4-methoxy-cyclohex-1 -yl), 4-(4-methoxy- cyclohex-1 -yl), 4-cis-(4-methoxy-cyclohex-1 -yl), 4-trans-(4-methoxy-cyclohex-1 - yl), 4-(2S-cyano-cyclohex-1 -yl), 4-(4-cyano-cyclohex-1 -yl), 4-(4-amino- cyclohex-1 -yl), 4-(amino-carbonyl-cyclohex-1 -yl), 4-(3-(methyl-sulfonyl)- cyclohex-1 -yl), 4-(1 -hydroxy-cycloprop-1 -yl-ethyl), 1 -(1 -cyano-cycloprop-1 -yl- methyl), 1 -(3-hydroxy-cyclobut-1 -yl-methyl), 4-(1 -hydroxy-cyclobut-1 -yl-methyl), 4-(3-hydroxy-cyclobut-1 -yl-methyl), 4-(1 -hydroxy-methyl-cyclobut-1 -yl-methyl), 4-(1 -hydroxy-cyclopent- 1 -yl-methyl), 4-(3-hydroxy-cyclopent-1 -yl-methyl), 4-(1 - hydroxy-cyclohex-1 -yl-methyl), 4-(4-hydroxy-cyclohex-1 -yl-methyl), 4-cis-(4- hydroxy-cyclohex-1 -yl-methyl), 4-trans-(4-hydroxy-cyclohex-1 -yl-methyl), 4-(4- hydroxy-methyl-cyclohex-1 -yl-methyl), 4-(4-(hydroxy-methyl)-cyclohex-1 -yl- methyl), 4-cis-(4-(hydroxy-methyl)-cyclohex-1 -yl-methyl), 4-trans-(4-(hydroxy- methyl)-cyclohex-1 -yl-methyl), 6-(3-hydroxy-azetidin-1 -yl), 6-(2-hydroxy-methyl- azetin-1 -yl), 1 S-(pyrrolidin-3-yl), 4-(3-hydroxy-pyrrolidin-1 -yl), 4-(4S-methoxy- pyrrolidin-3R*-yl), 3-(2-oxo-pyrrolidin-1 -yl), 4-(2-oxo-pyrrolidin-5-yl), 6-(2-oxo- pyrrolidin-1 -yl), 4-(1 -methyl-2-oxo-pyrrolidin-4-yl), 1 -(piperidin-4-yl), 6-(2- hydroxy-methyl-piperidin-1 -yl), 6-(3-hydroxy-methyl-piperidin-1 -yl), 4-(2- (ethoxy-carbonyl)-piperidin-4-yl), 4-(oxetan-3-yl), 4-(3-hydroxy-oxetan-3-yl), 4- (2-methyl-oxetan-3-yl), 4-(tetrahydrofuran-2-yl), 1 -(tetrahydorfuran-3-yl), 4-(3- hydroxy-tetrahydro-furan-4-yl), 4-(4-fluoro-tetrahydrofuran-3-yl), 4-(4-methoxy-tetrahydrofuran-3-yl), 4-(4S*-hydroxy-tetrahydro-furan-3R*-yl), 4-(4R*-hydroxy- tetrahydro-furan-3S*-yl), 4-(tetrahydropyran-4-yl), 4-(4-hydroxy- tetrahydropyran-3-yl), 4-(4-hydroxy-tetrahydropyran-4-yl), 4-(4,5-dihydroxy- tetrahydropyran-2-yl), 4-(3-cyano-tetrahydropyran-4-yl), 2-(morpholin-4-yl), 6- (morpholin-4-yl), 4-(4-hydroxy-tetrahydrothiophen-3-yl-1 ,1 -dioxide), 4-(imidazol-3-yl), 1 -(oxetan-3-yl-methyl), 4-(oxetan-3-yl-methyl), 4-((2-oxo-3-methyl- oxazolidin-5R-yl)-methyl), 4-(3-hydroxy-tetrahydrofuran-3-yl-methyl), 4-(3- cyano-tetrahydrofuran-3-yl-methyl), 4-(4-hydroxy-tetrahydropyran-3-yl-methyl),4-(4-hydroxy-tetrahydropyran-4-yl-methyl), 4-(4-methoxy-piperidin-4-yl-methyl), 4-(4R-hydroxy-pyrrolidin-2R-yl-methyl), 4-(2-oxo-4S-hydroxy-pyrrolidin-5R-yl- methyl), 4-(1 -methyl-2-oxo-pyrrolidin-3-yl-methyl), 4-(2-(methoxy-carbonyl)- pyrrolidin-2-yl-methyl), 4-(1 -tert-butoxy-carbonyl-4S-fluoro-pyrrolidin-4R-yl- methyl), and 4-(1 -(tert-butoxy-carbonyl-3R-hydroxy-pyrrolidin-5S-yl-methyl);R2is selected from the group consisting of hydrogen, isopropyl, isobutyl, 3-methoxy-prop-1 -en-2-yl, cyclopropyl, cyclobutyl, 4-hydroxy-cyclohexen-1 -yl, 1 -methoxy-cyclohexen-1 -yl, 4-carboxy-cyclohexen-1 -yl, 3-isopropyl-3-hydroxy- azetidin-1 -yl, pyrrolidin-1 -yl, piperidin-1 -yl, morpholin-4-yl, 2,5-dihydrofuran-3-yl, 3,4-dihydro-pyran-5-yl, 3,6-dihydro-pyran-5-yl, 1 -(tert-butoxy-carbonyl)-2,5- dihydro-pyrrol-3-yl, 1 ,2,3,6-tetrahydro-pyridin-4-yl, 1 -(tert-butoxy-carbonyl)- 1 ,2,3,6-tetrahydro-pyridin-4-yl, 1 -(tert-butoxy-carbonyl)-l ,2,3,6-tetrahydro- pyridin-5-yl, 1 -(methyl-carbonyl)-1 ,2,3,6-tetrahydro-pyridin-4-yl, 1 -(isopropyl- carbonyl)-1 ,2,3,6-tetrahydro-pyridin-4-yl, 1 -(cyclopropyl-carbonyl)-l ,2,3,6- tetrahydro-pyridin-4-yl, and 3,6-dihydro-2H-thiopyran-4-yl 1 ,1 -dioxide;R3is methyl or ethyl;R4is selected from the group consisting of 4-chloro-phenyl, 4-methyl- phenyl, 4-ethyl-phenyl, 2,4-dimethyl-phenyl, 4-trifluoro-methyl-phenyl, 4-(2,2,2- trifluoro-ethyl)-phenyl, 2-fluoro-4-methyl-phenyl, 2-chloro-4-trifluoro-methyl- phenyl, 2-methyl-4-trifluoro-methyl-phenyl, 4-trifluoro-methoxy-phenyl, 4- pentafluorothio-phenyl, 4-cyclopropyl-phenyl, 6-trifluoro-methyl-pyridin-3-yl, 2- trifluoro-methyl-pyrimidin-5-yl, 4-difluoro-methyl-thiazol-2-yl, and 2-trifluoro- methyl-thiazol-5-yl; or a stereoisomer or pharmaceutically acceptable salt thereof.

4. A compound as in Claim 3, whereinis selected from the group consisting of phenyl, 2-fluoro-phenyl, 4-(hydroxy-methyl)-phenyl, 4-(1 -hydroxy-ethyl)-phenyl, 4-(2-hydroxy-ethyl)- phenyl, 4-(1 -hydroxy-isopropyl)-phenyl, 4-cyano-methyl-phenyl, 4-(2-hydroxy- 1 , 1 -dimethyl)-phenyl, 4-(2-methyl-2-hydroxy-methyl-3-hydroxy-n-propyl)- phenyl, 4-difluoro-methoxy-phenyl, 4-(2,2-difluoro-ethoxy)-phenyl, 4-(cyano- methoxy)-phenyl, 4-(2-hydroxy-3-methoxy-n-propyl)-phenyl, 4-(3-hydroxy-3- methyl-n-butyl)-phenyl, 2-fluoro-4-(1 -hydroxy-isopropyl)-phenyl, 4-(3,3,3- trifluoro-2-hydroxy-isopropyl)-phenyl, 4-methoxy-methyl-phenyl, 4-(3-hydroxy-n- propyl-amino-carbonyl)-phenyl, 4-(amino-sulfonyl)-phenyl, 4-(methyl-sulfonyl- amino)-phenyl, 4-(methyl-amino-carbonyl-amino)-phenyl, 1 -methyl-5-fluoro- pyrazol-4-yl, and pyridin-3-yl; provided that whenis phenyl or pyrid in-3-y I, then a is 1 ; a is an integer from 0 to 1 ;R1is selected from the group consisting of 4-(1 -(hydroxy-methyl)- cycloprop-1 -yl), 4-(1 -(1 -hydroxy-ethyl)-cycloprop-1 -yl), 4-(1 -carboxy-cycloprop- 1 -yl), 4-(1 -(tert-butoxy-carbonyl-amino)-cycloprop-l -yl), 4-(1 -cyano-cycloprop- 1 -yl), 4-(1 -amino-cycloprop-1 -yl), 4-(1 -(methyl-carbonyl-amino)-cycloprop-l -yl), 4-(1 -(methyl-amino-carbonyl)-cycloprop-l -yl), 4-(1 -(dimethyl-amino-carbonyl)- cycloprop-1 -yl), 4-(1 -(methyl-sulfonyl-amino)-cycloprop-l -yl), 4-(2R*-hydroxy- cyclobut-1 S*-yl), 4-(2S*-hydroxy-cyclobuty-1 R*-yl), 4-(3-hydroxy-cyclobut-1 -yl), 4-(2-hydroxy-cyclobut-1 -yl), 4-(1 -hydroxy-cyclobut-1 -yl), 4-(4-hydroxy-cyclohex- 1 -yl), 4-(2,2-dimethyl-3-hydroxy-cyclobut-1 -yl), 4-(2-methyl-3-hydroxy-cyclobut- 1 -yl), 4-(3-cyano-methyl-cyclobut-1 -yl), 4-(3-methyl-3-cyano-cyclobut-1 -yl), 4- (3-cyano-3-methoxy-carbonyl-cyclobut-1 -yl), 4-(1 -(tert-butoxy-carbonyl-amino)- cyclobut-1 -yl), 4-(3-hydroxy-cyclopent-1 -yl), 4-(3,3-difluoro-5-hydroxy- cyclopent-1 -yl), 4-(4-hydroxy-methyl-cyclohex-1 -yl), 4-(4-m ethoxy-cyclohex-1 - yl), 4-(4-cyano-cyclohex-1 -yl), 4-(2S-cyano-cyclohex-1 -yl), 4R-(2S-(tert-butoxy- carbonyl-amino)-cyclopent-1 -yl), 4-(4-amino-cyclohex-1 -yl), 4-(3-(methyl- sulfonyl)-cyclohex-1 -yl), 4-(1 -hydroxy-cycloprop-1 -yl-ethyl), 4-(1 -hydroxy- cyclobut-1 -yl-methyl), 4-(3-hydroxy-cyclobut-1 -yl-methyl), 4-(3-hydroxy-cyclopent-1 -yl-methyl), 4-(oxetan-3-yl), 4-(2-methyl-oxetan-2-yl), 4-(3-hydroxy- tetrahydro-furan-4-yl), 4-(3-hydroxy-pyrrolidin-1 -yl), 4-(1 -methyl-2-oxo- pyrrolidin-4-yl), 4-(tetrahydro-furan-2-yl), 4-(4S*-hydroxy-tetrahydro-furan-3R*- yl), 4-(4R*-hydroxy-tetrahydro-furan-3S*-yl), 4-(4-fluoro-tetrahydrofuran-3-yl), 4- (3-hydroxy-tetrahydro-furan-3-yl-methyl), 4-(4-hydroxy-tetrahydro-pyran-4-yl- methyl), 4-(tetrahydro-pyran-4-yl), 4-(4-hydroxy-tetrahydropyran-3-yl), 4-(4- hydroxy-tetrahydro-pyran-4-yl), 4-(3-cyano-tetrahydropyran-4-yl), 4-(4,5- dihydroxy-tetrahydro-pyran-2-yl), 4-(4-hydroxy-tetrahydro-pyran-3-yl-methyl), 6- (2-hydroxy-methyl-piperidin-1 -yl), 4-(4-hydroxy-tetrahydro-thiophen-3-yl-1 , 1 - dioxide), 4-(imidazol-3-yl), and 4-((2-oxo-3-methyl-oxazolidin-5R-yl)-methyl);R2is selected from the group consisting of hydrogen, isopropyl, isobutyl,3-methoxy-prop-1 -en-2-yl, cyclopropyl, cyclobutyl, 4-hydroxy-cyclohex-1 -enyl,4-methoxy-cyclohexen-1 -yl, 4-carboxy-cyclohexen-1 -yl, 3-isopropyl-3-hydroxy- azetidin-1 -yl, piperidin-1 -yl, morpholin-4-yl, 2,5-dihydro-furan-3-yl, 3,4-dihydro- pyran-5-yl, 3,6-dihydro-pyran-5-yl, 1 ,2,3,6-tetrahydro-pyridin-4-yl, 1 -(methyl- carbonyl)-1 ,2,3,6-tetrahydro-pyridin-4-yl, 1 -(isopropyl-carbonyl)-l ,2,3,6- tetrahydro-pyridin-4-yl, 1 -(tert-butoxy-carbonyl)-l ,2,3,6-tetrahydro-pyridin-4-yl,1 -(cyclopropyl-carbonyl)-l ,2,3,6-tetrahydro-pyridin-4-yl, and 3,6-dihydro-2H- thiopyran-4-yl 1 ,1 -dioxide;R3is methyl or ethyl;R4is selected from the group consisting of 4-chloro-phenyl, 4-methyl- phenyl, 4-ethyl-phenyl, 4-trifluoro-methyl-phenyl, 2,4-dimethyl-phenyl, 2-fluoro- 4-methyl-phenyl, 2-chloro-4-trifluoro-methyl-phenyl, 2-methyl-4-trifuoro-methyl- phenyl, 4-trifluoro-methoxy-phenyl, 4-pentafluoro-thio-phenyl, 4-cyclopropyl- phenyl, 6-trifluoro-methyl-pyridin-3-yl, 2-trifluoro-methyl-pyrimidin-5-yl, 4- difluoro-methyl-thiazol-2-yl, and 2-trifluoro-methyl-thiazol-5-yl; or a stereoisomer or pharmaceutically acceptable salt thereof.

5. A compound as in Claim 1 , whereinis selected from the group consisting of substituted phenyl, unsubstituted or substituted 5 membered heteroaryl, and substituted 6 membered heteroaryl;wherein the substituted phenyl, substituted 5 membered heteroaryl or substituted 6 membered heteroaryl is substituted with one to three substituents independently selected from the group consisting of halogen, -OH, oxo, CN, Ci- 2alkyl, halogen substituted Ci-4alkyl, hydroxy substituted Ci-ealkyl, (fluoro substituted Ci-4alkyl)-OH, -(Ci-3alkyl)-CN, -(hydroxy substituted Ci-4alkyl)-O-(Ci- 2alkyl), -O-(Ci-2alkyl), -O-(halogen substituted Ci-2alkyl), O-(Ci-4alkyl)-CN, -(Ci-4alkyl)-O-(Ci-2alkyl), -C(O)-NRARB, -(Ci-2alkyl)-C(O)-NRARB, -NRARB, -(hydroxy substituted Ci-4alkyl)-NRARB, -NH-C(O)-NRARB, -NRA-SO2-(Ci-4alkyl), and - SO2-NRARB;and wherein RAand RBare each independently selected from the group consisting of hydrogen, Ci-2alkyl and hydroxy substituted Ci-salkyl; provided thatis other than methylphenyl or chlorophenyl; a is 0;R2is selected from the group consisting of hydrogen, Ci-4alkyl, -(C2- 4alkenyl)-O-(Ci-4alkyl), Cs-ecycloalkenyl, and 4 to 6 membered heterocycloalkyl; wherein the Cecycloalkenyl, or 4 to 6 membered heterocycloalkyl is optionally substituted with -OH, oxo, -Ci-4alkyl, -O-(Ci-2alkyl), -C(O)-(Ci-4alkyl), -C(O)-C3-5cycloalkyl, -C(O)OH, and -C(O)O-(Ci-4alkyl);R3is Ci-2alkyl;R4is selected from the group consisting of phenyl, and 5 to 6 membered heteroaryl; wherein the phenyl or 5 to 6 membered heteroaryl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, pentafluorothio, C 1 -2alky I, halogen substituted C 1 -2alky I, - O-(halogen substituted Ci-4alkyl), and C3-4cycloalkyl; or a stereoisomer or pharmaceutically acceptable salt thereof.

6. A compound as in Claim 5, whereinis selected from the group consisting of 2-fluoro-phenyl, 3-fluoro- phenyl, 2,6-dimethyl-phenyl, 4-hydroxy-methyl-phenyl, 4-(1 -hydroxy-ethyl)- phenyl, 4-(2-hydroxy-ethyl)-phenyl, 4-(1 -hydroxy-isopropyl)-phenyl, 2-fluoro-4- (1 -hydroxy-isopropyl)-phenyl, 4-(2-hydroxy-1 , 1 -dimethyl)-phenyl, 4-(3-hydroxy-n-propyl)-phenyl, 4-(2-hydroxy-3-methoxy-n-propyl)-phenyl, 4-(3-hydroxy-3- methyl-n-butyl)-phenyl, 4-(1 -methyl-3-hydroxy-n-butyl)-phenyl, 4-(2-methyl-2- hydroxy-methyl-3-hydroxy-n-propyl)-phenyl, 4-(1 ,1 ,1 ,3,3,3-hexafluoro-2- hydroxy-isopropyl)-phenyl, 4-(3,3,3-trifluoro-2-hydroxy-isopropyl)-phenyl, 2- methoxy-phenyl, 4-methoxy-phenyl, 2-methoxy-4-hydroxy-methyl-phenyl, 3- hydroxy-methyl-4-fluoro-phenyl, 4-difluoro-methoxy-phenyl, 4-(2,2-difluoro- ethoxy)-phenyl, 4-(methoxy-methyl)-phenyl, 4-(1 -methoxy-ethyl)-phenyl, 4-(2- methoxy-ethyl)-phenyl, 4-(2-methoxy-isopropyl)-phenyl, 3-fluoro-4-(methoxy- methyl)-phenyl, 3-cyano-phenyl, 2-fluoro-4-cyano-phenyl, 3-fluoro-4-cyano- methyl-phenyl, 4-cyano-methyl-phenyl, 4-(2-cyano-isopropyl)-phenyl, 4-(cyano- methoxy)-phenyl, 4-(amino-carbonyl)-phenyl, 2-fluoro-4-(amino-carbonyl)- phenyl, 4-(methyl-amino-carbonyl-amino)-phenyl, 4-(amino-carbonyl-methyl)- phenyl, 4-(3-hydroxy-n-propyl-amino-carbonyl)-phenyl, 4-(methyl-amino- carbonyl-methyl)-phenyl, 4-(3-amino-2-methyl-2-hydroxy-n-propyl)-phenyl, 4-(1 - methyl-3-(methyl-amino-carbonyl)-n-propyl)-phenyl, 4-(amino-sulfonyl)-phenyl,4-(methyl-sulfonyl-amino)-phenyl, 2-methyl-pyridin-3-yl, 5-difluoromethyl- pyridin-3-yl, 6-hydroxy-methyl-pyridin-3-yl, 2-hydroxy-pyridin-4-yl, 2-methoxy- pyridin-4-yl, 6-methoxy-pyridin-3-yl, 2-cyano-pyridin-4-yl, 5-cyano-pyridin-3-yl, 6-cyano-pyridin-3-yl, 1 -methyl-2-oxo-pyridin-4-yl, 6-amino-pyridin-3-yl, 6- (methyl-amino-carbonyl)-pyridin-3-yl, pyrazol-4-yl, 3-methyl-pyrazo-4-yl, 3- methyl-pyrazol-5-yl, 1 -methyl-pyrazol-4-yl, 1 ,3-dimethyl-pyrazol-4-yl, 1 ,3- dimethyl-pyrazol-5-yl, 1 ,4-dimethyl-pyrazol-5-yl, 1 ,5-dimethyl-pyrazol-4-yl, 1- (difluoro-methyl)-pyrazol-4-yl, 1 -ethyl-5-fluoro-pyrazol-4-yl, 1 -(2,2-difluoro- ethyl)-pyrazol-4-yl, 1 -methyl-5-fluoro-pyrazol-4-yl, 1 -methyl-5-chloro-pyrazol-4- yl, 1 -methyl-3-methoxy-pyrazol-4-yl, 1 -(2-methoxy-ethyl)-pyrazol-4-yl, 1 -methyl-5-(methoxy-methyl)-pyrazol-4-yl, 1 -(2,2-difluoro-ethoxy)-pyrazol-4-yl, 1 -(2- hydroxy-ethyl)-pyrazol-4-yl, 1 -(2-hydroxy-n-propyl)-pyrazol-4-yl, 1 -hydroxy- ethyl-5-methyl-pyrazol-4-yl, 1 -(2-hydroxy-ethyl)-5-methyl-pyrazol-4-yl, 1 - hydroxy-ethyl-4-methyl-pyrazol-5-yl, 1 -(2-hydroxy-1 , 1 -dimethyl-ethyl)-pyrazol-4- yl, 1 -(2-cyano-ethyl)-pyrazol-4-yl, 1 -methyl-5-cyano-pyrazol-4-yl, 1 -(amino- carbonyl-methyl)-pyrazol-4-yl, 1 -(methyl-amino-carbonyl-methyl)-pyrazol-4-yl,6-methyl-pyridazin-4-yl, 1 -methyl-imidazol-5-yl, 1 ,2-dimethyl-imidazol-5-yl, thiazol-4-yl, thiazol-5-yl, 2-methyl-thiazol-5-yl, 4-methyl-thiazol-5-yl, 2-hydroxy-methyl-thiazol-5-yl, oxazol-5-yl, 2-methyl-oxazol-5-yl, 2-(hydroxy-methyl)- oxazol-5-yl, 4-methyl-isothiazol-5-yl, 3-methyl-isoxazol-5-yl, 5-hydroxy-methyl- furan-5-yl, 5-hydroxy-methyl-thiophen-3-yl, and 5-hydroxy-methyl-thiophen-5-yl; a is 0;R2is selected from the group consisting of hydrogen, isopropyl, 3- m ethoxy-prop-1 -en-2-yl, 4-hydroxy-cyclohexen-1 -yl, 1 -methoxy-cyclohexen-1 - yl, 4-carboxy-cyclohexen-1 -yl, 3-isopropyl-3-hydroxy-azetidin-1 -yl, pyrrolidin-1 - yl, piperidin-1 -yl, morpholin-4-yl, 2,5-dihydrofuran-3-yl, 3,4-dihydro-pyran-5-yl,3.6-dihydro-pyran-5-yl, 1 ,2,3,6-tetrahydro-pyridin-4-yl, 1 -(tert-butoxy-carbonyl)-1 .2.3.6-tetrahydro-pyridin-4-yl, 1 -(tert-butoxy-carbonyl)-l ,2,3,6-tetrahydro- pyridin-5-yl, 1 -(methyl-carbonyl)-1 ,2,3,6-tetrahydro-pyridin-4-yl, 1 -(isopropyl- carbonyl)-1 ,2,3,6-tetrahydro-pyridin-4-yl, 1 -(cyclopropyl-carbonyl)-l ,2,3,6- tetrahydro-pyridin-4-yl, and 3,6-dihydro-2H-thiopyran-4-yl 1 ,1 -dioxide;R3is methyl or ethyl;R4is selected from the group consisting of 4-chloro-phenyl, 4-methyl- phenyl, 4-ethyl-phenyl, 4-trifluoro-methyl-phenyl, 4-(2,2,2-trifluoro-ethyl)-phenyl, 2-methyl-4-trifluoro-methyl-phenyl, 4-trifluoro-methoxy-phenyl, 4- pentafluorothio-phenyl, 4-cyclopropyl-phenyl, 6-trifluoro-methyl-pyridin-3-yl, 2- trifluoro-methyl-pyrimidin-5-yl, 4-difluoro-methyl-thiazol-2-yl, and 2-trifluoro- methyl-thiazol-5-yl; or a stereoisomer or pharmaceutically acceptable salt thereof.

7. A compound as in Claim 6, whereinis selected from the group consisting of 4-hydroxy-methyl-phenyl,4-(2-hydroxy-1 ,1 -dimethyl)-phenyl, 4-(1 -hydroxy-ethyl)-phenyl, 4-(2-hydroxy- ethyl)-phenyl, 4-(1 -hydroxy-isopropyl)-phenyl, 4-(2-methyl-2-hydroxy-methyl-3- hydroxy-n-propyl)-phenyl, 4-(2-hydroxy-3-methoxy-n-propyl)-phenyl, 4-(3- hydroxy-3-methyl-n-butyl)-phenyl, 4-(3,3,3-trifluoro-2-hydroxy-isopropyl)- phenyl, 2-fluoro-4-(1 -hydroxy-isopropyl)-phenyl, 4-difluoro-methoxy-phenyl, 4- (2,2-difluoro-ethoxy)-phenyl, 4-methoxy-methyl-phenyl, 4-cyano-methyl-phenyl, 4-(cyano-methoxy)-phenyl, 4-(3-hydroxy-n-propyl-amino-carbonyl)-phenyl, 4-(methyl-amino-carbonyl-amino)-phenyl, 4-(amino-sulfonyl)-phenyl, 4-(methyl- sulfonyl-amino)-phenyl, and 1 -methyl-5-fluoro-pyrazol-4-yl; a is 0;R2is selected from the group consisting of hydrogen, isopropyl, 3- m ethoxy-prop-1 -en-2-yl, 4-hydroxy-cyclohex-1 -enyl, 4-methoxy-cyclohexen-1 - yl, 4-carboxy-cyclohexen-1 -yl, 3-isopropyl-3-hydroxy-azetidin-1 -yl, piperidin-1 - yl, morpholin-4-yl, 2,5-dihydro-furan-3-yl, 3,4-dihydro-pyran-5-yl, 3,6-dihydro- pyran-5-yl, 1 ,2,3,6-tetrahydro-pyridin-4-yl, 1 -(methyl-carbonyl)-1 ,2,3,6- tetrahydro-pyridin-4-yl, 1-(isopropyl-carbonyl)-1 ,2,3,6-tetrahydro-pyridin-4-yl, 1 - (tert-butoxy-carbonyl)-l ,2,3,6-tetrahydro-pyridin-4-yl, 1 -(cyclopropyl-carbonyl)- 1 ,2,3,6-tetrahydro-pyridin-4-yl, and 3,6-dihydro-2H-thiopyran-4-yl 1 ,1 -dioxide;R3is methyl or ethyl;R4is selected from the group consisting of 4-chloro-phenyl, 4-methyl- phenyl, 4-ethyl-phenyl, 4-trifluoro-methyl-phenyl, 4-trifluoro-methoxy-phenyl, 2- methyl-4-trifuoro-methyl-phenyl, 4-pentafluoro-thio-phenyl, 4-cyclopropyl- phenyl, 6-trifluoro-methyl-pyridin-3-yl, 2-trilfuoro-methyl-pyridimidin-5-yl, 2- trifluoro-methyl-thiazol-5-yl, and 4-difluoro-methyl-thiazol-2-yl; or a stereoisomer or pharmaceutically acceptable salt thereof.

8. A compound as in Claim 6, whereinis 4-(1 -hydroxy-isopropyl)-phenyl; a is 0;R2is selected from the group consisting of isopropyl, 4-hydroxy- cyclohex-1 -enyl, 4-methoxy-cyclohexen-1 -yl, 4-carboxy-cyclohexen-1 -yl, morpholin-4-yl, 3,4-dihydro-pyran-5-yl, 3,6-dihydro-pyran-5-yl, 1 -(methyl- carbonyl)-1 ,2,3,6-tetrahydro-pyridin-4-yl, 1 -(isopropyl-carbonyl)-l ,2,3,6- tetrahydro-pyridin-4-yl, 1 -(cyclopropyl-carbonyl)-l ,2,3,6-tetrahydro-pyridin-4-yl, and 3,6-dihydro-2H-thiopyran-4-yl 1 ,1 -dioxide;R3is methyl or ethyl;R4is selected from the group consisting of 4-chloro-phenyl, 4-methyl- phenyl, 4-trifluoro-methyl-phenyl, 2-methyl-4-trifuoro-methyl-phenyl, 4-trifluoro- methoxy-phenyl, 4-pentafluoro-thio-phenyl, 4-cyclopropyl-phenyl, 6-trifluoro-methyl-pyridin-3-yl, 2-trilfuoro-methyl-pyridimidin-5-yl, and 2-trifluoro-methyl- thiazol-5-yl; or a stereoisomer or pharmaceutically acceptable salt thereof.

9. A compound as in Claim 1 , whereinis selected from the group consisting of unsubstituted or substituted phenyl, unsubstituted or substituted 5 membered heteroaryl, and unsubstituted or substituted 6 membered heteroaryl; wherein the substituted phenyl, substituted 5 membered heteroaryl or substituted 6 membered heteroaryl is substituted with halogen or Ci-2alkyl; a is 1 ;R1is selected from the group consisting of Cs-ecycloalkyl, -(Ci-2alkyl)-C3- scycloalkyl, 4 to 6 membered heterocyclyl and -(Ci-2alkyl)-(4 to 6 membered heterocyclyl); wherein the Cs-ecycloalkyl or 4 to 6 membered heterocyclyl, whether alone or as part of a substituent group, is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OH, oxo, -CN, Ci-2alkyl, hydroxy substituted Ci salkyl, halogen substituted Ci- 2alkyl, -(Ci-2alkyl)-CN, -O-Ci-2alkyl, -O-(halogen substituted Ci-2alkyl), -C(0)- (Ci-2alkyl), -C(O)OH, -C(O)-O-(Ci-4alkyl), -NRCRD, -C(O)-NRCRD, -NRC-C(O)- (Ci-2alkyl), -NRc-C(O)-O-(Ci-4alkyl), -NRc-SO2-(Ci-4alkyl) and -SO2-(Ci-2alkyl); and wherein Rcand RDare each independently selected from the group consisting of hydrogen, and Ci-2alkyl;R2is selected from the group consisting of hydrogen, Ci-4alkyl, and C3- scycloalkyl;R3is Ci-2alkyl;R4is selected from the group consisting of phenyl, and 5 to 6 membered heteroaryl; wherein the phenyl or 5 to 6 membered heteroaryl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, pentafluorothio, C 1 -2alky I, halogen substituted C 1 -2alky I, and C3-4cycloalkyl;or a stereoisomer or pharmaceutically acceptable salt thereof.

10. A compound as in Claim 9, whereinis selected from the group consisting of phenyl, 2-fluoro-phenyl, pyridin-3-yl, pyrazol-4-yl, 1 -methyl-pyrazol-4-yl, thiazol-4-yl, and oxazol-5-yl; a is 1 ;R1is selected from the group consisting of 2-cyclopropyl, 5-cyclopropyl, 4-(1 -(hydroxy-methyl)-cycloprop-l -yl), 4-(1 -(1 -hydroxy-ethyl)-cycloprop-1 -yl), 4- (1 -cyano-cycloprop-1 -yl), 4-(1 -carboxy-cycloprop-1 -yl), 4-(1 -(ethoxy-carbonyl)- cycloprop-1 -yl), 4-(1 -amino-cycloprop-1 -yl), 4-(1 -amino-carbonyl-cycloprop-1 - yl), 4-(1 -methyl-amino-carbonyl-cycloprop-1 -yl), 4-(1 -(dimethyl-amino- carbonyl)-cycloprop-1 -yl), 4-(1 -(methyl-carbonyl-amino)-cycloprop-1-yl), 4-(1 - (methyl-sulfonyl-amino)-cycloprop-l -yl), 4-(1 -(tert-butoxy-carbonyl-amino)- cycloprop-1 -yl),1 -cyclobutyl, 4-cyclobutyl, 1 -(3-hydroxy-cyclobut-1 -yl), 4-(3- hydroxy-cyclobut-1 -yl), 4-(1 -hydroxy-cyclobut-1 -yl), 4-(2-hydroxy-cyclobut-1 -yl), 4-(2R*-hydroxy-cyclobut-1 S*-yl), 4-(2S*-hydroxy-cyclobut-1 R*-yl),4-(3-hydroxy- cyclobut-1 -yl), 1 -(3-hydroxymethyl-cyclobut-1 -yl), 4-(2,2-dimethyl-3-hydroxy- cyclobut-1 -yl), 4-(2-methyl-3-hydroxy-cyclobut-1 -yl), 4-(3-difluoro-methyl- cyclobut-1 -yl), 1 -(3-methoxy-cyclobut-1 -yl), 4-(3-difluoro-methoxy-cyclobut-1 - yl), 4-(2-methoxy-3-hydroxy-cyclobut-1 -yl), 4-(3-methoxy-3-trifluoro-methyl- cyclobut-1 -yl), 4-(3-cyano-methyl-cyclobut-1 -yl), 4-(3-methyl-3-cyano-cyclobut- 1 -yl), 4-(3-cyano-3-methoxy-carbonyl-cyclobut-1 -yl), 4-(1 -(tert-butoxy-carbonyl- amino)-cyclobut-1 -yl), 1 -(2-hydroxy-cyclopent-1 -yl), 4-(3-hydroxy-cyclopent-1 - yl), 4R-(2S-(tert-butoxy-carbonyl-amino)-cyclopent-1 -yl), 4-(3,3-difluoro-5- hydroxy-cyclopent-1 -yl), 4-(4-hydroxy-cyclohex-1 -yl), 4-(4-hydroxy-cyclohex-1 - yl), 4-cis-(4-hydroxy-cyclohex-1 -yl), 4-trans-(4-hydroxy-cyclohex-1 -yl), 4-(4- methyl-4-hydroxy-cyclohex-1 -yl), 4-(4-(hydroxy-methyl)-cyclohex-1 -yl), 4-cis-(4- (hydroxy-methyl)-cyclohex-l -yl), 4-trans-(4-(hydroxy-methyl)-cyclohex-1 -yl), 4- (3-difluoro-methyl-cyclohex-1 -yl), 4-(4-methoxy-cyclohex-1 -yl), 4-(4-methoxy- cyclohex-1 -yl), 4-cis-(4-methoxy-cyclohex-1 -yl), 4-trans-(4-methoxy-cyclohex-1 - yl), 4-(2S-cyano-cyclohex-1 -yl), 4-(4-cyano-cyclohex-1 -yl), 4-(4-amino- cyclohex-1 -yl), 4-(amino-carbonyl-cyclohex-1 -yl), 4-(3-(methyl-sulfonyl)-cyclohex-1 -yl), 4-(1 -hydroxy-cycloprop-1 -yl-ethyl), 1 -(1 -cyano-cycloprop-1 -yl- methyl), 1 -(3-hydroxy-cyclobut-1 -yl-methyl), 4-(1 -hydroxy-cyclobut-1 -yl-methyl), 4-(3-hydroxy-cyclobut-1 -yl-methyl), 4-(1 -hydroxy-methyl-cyclobut-1 -yl-methyl), 4-(1 -hydroxy-cyclopent- 1 -yl-methyl), 4-(3-hydroxy-cyclopent-1 -yl-methyl), 4-(1 - hydroxy-cyclohex-1 -yl-methyl), 4-(4-hydroxy-cyclohex-1 -yl-methyl), 4-cis-(4- hydroxy-cyclohex-1 -yl-methyl), 4-trans-(4-hydroxy-cyclohex-1 -yl-methyl), 4-(4- hydroxy-methyl-cyclohex-1 -yl-methyl), 4-(4-(hydroxy-methyl)-cyclohex-1 -yl- methyl), 4-cis-(4-(hydroxy-methyl)-cyclohex-1 -yl-methyl), 4-trans-(4-(hydroxy- methyl)-cyclohex-1 -yl-methyl), 6-(3-hydroxy-azetidin-1 -yl), 6-(2-hydroxy-methyl- azetin-1 -yl), 1 S-(pyrrolidin-3-yl), 4-(3-hydroxy-pyrrolidin-1 -yl), 4-(4S-methoxy- pyrrolidin-3R*-yl), 3-(2-oxo-pyrrolidin-1 -yl), 4-(2-oxo-pyrrolidin-5-yl), 6-(2-oxo- pyrrolidin-1 -yl), 4-(1 -methyl-2-oxo-pyrrolidin-4-yl), 1 -(piperidin-4-yl), 6-(2- hydroxy-methyl-piperidin-1 -yl), 6-(3-hydroxy-methyl-piperidin-1 -yl), 4-(2- (ethoxy-carbonyl)-piperidin-4-yl), 4-(oxetan-3-yl), 4-(3-hydroxy-oxetan-3-yl), 4- (2-methyl-oxetan-3-yl), 4-(tetrahydrofuran-2-yl), 1 -(tetrahydorfuran-3-yl), 4-(3- hydroxy-tetrahydro-furan-4-yl), 4-(4-fluoro-tetrahydrofuran-3-yl), 4-(4-methoxy- tetrahydrofuran-3-yl), 4-(4S*-hydroxy-tetrahydro-furan-3R*-yl), 4-(4R*-hydroxy- tetrahydro-furan-3S*-yl), 4-(tetrahydropyran-4-yl), 4-(4-hydroxy- tetrahydropyran-3-yl), 4-(4-hydroxy-tetrahydropyran-4-yl), 4-(4,5-dihydroxy- tetrahydropyran-2-yl), 4-(3-cyano-tetrahydropyran-4-yl), 2-(morpholin-4-yl), 6- (morpholin-4-yl), 4-(4-hydroxy-tetrahydrothiophen-3-yl-1 ,1 -dioxide), 4-(imidazol-3-yl), 1 -(oxetan-3-yl-methyl), 4-(oxetan-3-yl-methyl), 4-((2-oxo-3-methyl- oxazolidin-5R-yl)-methyl), 4-(3-hydroxy-tetrahydrofuran-3-yl-methyl), 4-(3- cyano-tetrahydrofuran-3-yl-methyl), 4-(4-hydroxy-tetrahydropyran-3-yl-methyl),4-(4-hydroxy-tetrahydropyran-4-yl-methyl), 4-(4-methoxy-piperidin-4-yl-methyl), 4-(4R-hydroxy-pyrrolidin-2R-yl-methyl), 4-(2-oxo-4S-hydroxy-pyrrolidin-5R-yl- methyl), 4-(1 -methyl-2-oxo-pyrrolidin-3-yl-methyl), 4-(2-(methoxy-carbonyl)- pyrrolidin-2 -yl-methyl), 4-(1 -tert-butoxy-carbonyl-4S-fluoro-pyrrolidin-4R-yl- methyl), and 4-(1 -(tert-butoxy-carbonyl-3R-hydroxy-pyrrolidin-5S-yl-methyl);R2is selected from the group consisting of hydrogen, isopropyl, isobutyl, cyclopropyl, and cyclobutyl;R3is methyl;R4is selected from the group consisting of 4-chloro-phenyl, 4-methyl- phenyl, 4-ethyl-phenyl, 2,4-dimethyl-phenyl, 4-trifluoro-methyl-phenyl, 2-fluoro- 4-methyl-phenyl, 2-chloro-4-trifluoro-methyl-phenyl, 2-methyl-4-trifluoro-methyl- phenyl, 4-pentafluorothio-phenyl, 4-cyclopropyl-phenyl, 6-trifluoro-methyl- pyridin-3-yl, 2-trifluoro-methyl-pyrimidin-5-yl, and 2-trifluoro-methyl-thiazol-5-yl; or a stereoisomer or pharmaceutically acceptable salt thereof.

11. A compound as in Claim 10, whereinis selected from the group consisting of phenyl, 2-fluoro-phenyl and pyridin-3-yl; a is 1R1is selected from the group consisting of 4-(1 -hydroxy-methyl- cycloprop-1 -yl), 4-(1 -(1 -hydroxy-ethyl)-cycloprop-1 -yl), 4-(1 -cyano-cycloprop-1 - yl), 4-(1 -carboxy-cycloprop-1 -yl), 4-(1 -(tert-butoxy-carbonyl-amino)-cycloprop-l - yl), 4-(1 -amino-cycloprop-1 -yl), 4-(1 -(methyl-amino-carbonyl)-cycloprop-1 -yl), 4- (1 -(methyl-carbonyl-amino)-cycloprop-l -yl), 4-(1 -(dimethyl-amino-carbonyl)- cycloprop-1 yl), 4-(1 -(methyl-sulfonyl-amino)-cycloprop-l -yl), 4-(1 -hydroxy- cyclobut-1 -yl), 4-(2-hydroxy-cyclobut-1 -yl), 4-(3-hydroxy-cyclobut-1 -yl), 4-(2R*- hydroxy-cyclobut-1 S*-yl), 4-(2S*-hydroxy-cyclobuty-1 R*-yl), 4-(2-methyl-3- hydroxy-cyclobut-1 -yl), 4-(2,2-dimethyl-3-hydroxy-cyclobut-1 -yl), 4-(3-hydroxy- cyclopent-1 -yl), 4-(3,3-difluoro-5-hydroxy-cyclopent-1 -yl), 4R-(2S-(tert-butoxy- carbonyl-amino)-cyclopent-1 -yl), 4-(4-hydroxy-cyclohex-1 -yl), 4-(4-hydroxy- methyl-cyclohex-1 -yl), 4-(4-methoxy-cyclohexyl), 4-(4-cyano-cyclohexy-1 -yl), 4- (2S-cyano-cyclohexyl), 4-(3-cyano-methyl-cyclobut-1 -yl), 4-(3-methyl-3-cyano- cyclobut-1 -yl), 4-(3-cyano-3-methoxy-carbonyl-cyclobut-1 -yl), 4-(1 -(tert-butoxy- carbonyl-amino)-cyclobut-1 -yl), 4-(4-amino-cyclohex-1 -yl), 4-(3-(methyl- sulfonyl)-cyclohex-1 -yl), 4-(1 -hydroxy-cycloprop-1 -yl-ethyl), 4-(1 -hydroxy- cyclobut-1 -yl-methyl), 4-(3-hydroxy-cyclobut-1 -yl-methyl), 4-(3-hydroxy- cyclopent-1 -yl-methyl), 4-(oxetan-3-yl), 4-(2-methyl-oxetan-2-yl), 4-(3-hydroxy- pyrrolidin-1 -yl), 4-(1 -methyl-2-oxo-pyrrolidin-4-yl), 6-(2-hydroxy-methyl- piperidin-1 -yl), 4-(tetrahydro-furan-2-yl), 4-(4-fluoro-tetrahydrofuran-3-yl), 4-(3- hydroxy-tetrahydro-furan-3-yl-methyl), 4-(3-hydroxy-tetrahydro-furan-4-yl), 4-(4S*-hydroxy-tetrahydro-furan-3R*-yl), 4-(4R*-hydroxy-tetrahydro-furan-3S*-yl), 4-(tetrahydro-pyran-4-yl), 4-(4-hydroxy-tetrahydropyran-3-yl), 4-(4-hydroxy- tetrahydro-pyran-4-yl), 4-(4,5-dihydroxy-tetrahydro-pyran-2-yl), 4-(3-cyano- tetrahydropyran-4-yl), 4-(4-hydroxy-tetrahydro-thiophen-3-yl-1 ,1 -dioxide), 4- (imidazol-3-yl), 4-(4-hydroxy-tetrahydro-pyran-3-yl-methyl), 4-(4-hydroxy- tetrahydro-pyran-4-yl-methyl), and 4-((2-oxo-3-methyl-oxazolidin-5R-yl)- methyl);R2is selected from the group consisting of hydrogen, isopropyl, isobutyl, cyclopropyl, and cyclobutyl;R3is methyl;R4is selected from the group consisting of 4-chloro-phenyl, 4-methyl- phenyl, 4-ethyl-phenyl, 2,4-dimethyl-phenyl, 4-trifluoro-methyl-phenyl, 2-fluoro- 4-methyl-phenyl, 2-chloro-4-trifluoro-methyl-phenyl, 2-methyl-4-trifluoro-methyl- phenyl, 4-pentafluoro-thio-phenyl, 4-cyclopropyl-phenyl, 6-trifluoro-methyl- pyridin-3-yl, 2-trifluoro-methyl-pyrimidin-5-yl, and 2-trifluoro-methyl-thiazol-5-yl; or a stereoisomer or pharmaceutically acceptable salt thereof.

12. A compound as in Claim 10, whereinphenyl; a is 1 ;R1is selected from the group consisting of 4-(1 -hydroxy-methyl- cycloprop-1 -yl), 4-(1 -(1 -hydroxy-ethyl)-cycloprop-1 -yl), 4-(1 -amino-cycloprop-1 - yl), 4-(1 -(methyl-carbonyl-amino)-cycloprop-l -yl), 4-(1 -(tert-butoxy-carbonyl- amino)-cycloprop-1 -yl), 4-(1 -(methyl-sulfonyl-amino)-cycloprop-l -yl), 4-(3- hydroxy-cyclobut-1 -yl), 4-(2S*-hydroxy-cyclobuty-1 R*-yl), 4-(2R*-hydroxy- cyclobut-1 S*-yl), 4-(1 -(tert-butoxy-carbonyl-amino)-cyclobut-l -yl), 4-(3-(methyl- sulfonyl)-cyclohex-1 -yl), 4-(4S*-hydroxy-tetrahydro-furan-3R*-yl), and 4-(4R*- hydroxy-tetrahydro-furan-3S*-yl);R2is selected from the group consisting of hydrogen, isopropyl, isobutyl, cyclopropyl and cyclobutyl;R3is methyl;R4is selected from the group consisting of 4-chloro-phenyl, 4-methyl- phenyl, 2,4-dimethyl-phenyl, 4-trifluoro-methyl-phenyl, 2-fluoro-4-methyl- phenyl, 2-chloro-4-trifluoro-methyl-phenyl, 2-methyl-4-trifluoro-methyl-phenyl, 4- pentafluoro-thio-phenyl, 4-cyclopropyl-phenyl, 6-trifluoro-methyl-pyridin-3-yl, 2- trifluoro-methyl-pyrimidin-5-yl, and 2-trifluoro-methyl-thiazol-5-yl; or a stereoisomer or pharmaceutically acceptable salt thereof.

13. A compound as in Claim 1 , selected from the group consisting of 2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6-isopropyl-5-methyl-7-oxo-[1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-(p-tolyl)acetamide;2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6-isopropyl-5-methyl-7-oxo-[1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide;2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6-isopropyl-5-methyl-7-oxo-[1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[6-(trifluoromethyl)-3-pyndyl]acetamide;2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6-isopropyl-5-methyl-7-oxo-[1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[2-(trifluoromethyl)thiazol-5-yl]acetamide;2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-5-methyl-6-morpholino-7-oxo-[1 .2.4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide;2-[2-[4-[1-(hydroxymethyl)cyclopropyl]phenyl]-6-isopropyl-5-methyl-7- oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[6-(trifluoromethyl)-3- pyridyl]acetamide;2-[2-[4-[1-(hydroxymethyl)cyclopropyl]phenyl]-6-isopropyl-5-methyl-7- oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[2-(trifluoromethyl)thiazol-5- yl]acetamide;2-[2-[4-[1-(hydroxymethyl)cyclopropyl]phenyl]-6-isopropyl-5-methyl-7- oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[2-(trifluoromethyl)pyrimidin-5- yl]acetamide;2-[2-[4-[1-(hydroxymethyl)cyclopropyl]phenyl]-6-isopropyl-5-methyl-7- oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[2-methyl-4- (trifluoromethyl)phenyl]acetamide;2-[2-[4-(1-acetamidocyclopropyl)phenyl]-6-isopropyl-5-methyl-7-oxo-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[4-(trifluoromethyl)phenyl]acetamide;2-[2-[4-(1 -hydroxy-1 -methyl-ethyl)phenyl]-6-isopropyl-5-methyl-7-oxo- [1 ,2,4]triazolo[1 ,5-a]pyrimidin-4-yl]-N-[2-methyl-4- (trifluoromethyl)phenyl]acetamide; and stereoisomers and pharmaceutically acceptable salts thereof.

14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Claim 1 .

15. A pharmaceutical composition made by mixing a compound of Claim 1 and a pharmaceutically acceptable carrier.

16. A process for making a pharmaceutical composition comprising mixing a compound of Claim 1 and a pharmaceutically acceptable carrier.

17. 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 the compound of Claim 1 .

18. The method of Claim 17, wherein the disorder mediated by or modulated by inhibition of WRN is a cancer.

19. The method of Claim 17, wherein the disorder mediated by or modulated by inhibition of WRN is a cancer characterized as microsatellite instability (MSI) or mismatch repair deficient (dMMR).

20. The method of Claim 17, 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.21 . 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 of Claim 1.

22. 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 14.

23. A method of treating a cancer mediated by or modulated by inhibition of WRN 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 14.

24. 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 14.

25. The use of a compound as in Claim 1 for the preparation of a medicament for treating: (a) colonic, (b) gastric, (c) rectal, (d) endometrial, (e) adrenocortical, (f) uterine, (g) cervical, (h) mesothelial, (i) esophageal, (j) breast, (k) kidney, (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.

26. The use of a compound as in Claim 1 , 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.

27. A compound as in Claim 1 for use as a medicament.

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

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

30. A compound as in Claim 1 for use in the treatment of a cancer characterized as microsatellite instability (MSI) or mismatch repair deficient (dMMR) selected from the group consisting of colonic, gastric, rectal, endometrial, adrenocortical, uterine, cervical, mesothelial, esophageal, breast, kidney, prostate, ovarian, pancreatic, germ cell, liver, lung, biliary tract / gallbladder, head / neck, thyroid, thymic, small bowel, bladder, skin, prostate, brain, neuroendocrine, soft tissue, appendiceal, leukemia, lymphoma, and myeloma cancers.31 . A composition comprising a compound as in Claim 1 for use in the treatment of a disorder mediated by or modulated by inhibition of WRN.

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

33. A composition comprising a compound as in Claim 1 for use in the treatment of a cancer characterized as microsatellite instability (MSI) or mismatch repair deficient (dMMR) selected from the group consisting of colonic, gastric, rectal, endometrial, adrenocortical, uterine, cervical, mesothelial, esophageal, breast, kidney, prostate, 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.

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

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