Il-17a inhibitors

Abstract

The invention provides certain tetrahydropyran-imidazotriazine compounds of formula I or II as IL-17A inhibitors, pharmaceutical compositions thereof, and methods of using a compound of formula I or II to treat psoriasis, rheumatoid arthritis, multiple sclerosis, systemic sclerosis, psoriatic arthritis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma, non-infectious uveitis, or COPD.

Description

IL-17A INHIBITORSBACKGROUND OF THE INVENTION

[0001] The invention provides certain imidazotriazine compounds, pharmaceutical compositions thereof, and methods for their use in the treatment of psoriasis, spondyloarthritis, rheumatoid arthritis and multiple sclerosis.

[0002] Immunological functions are critical for the maintenance of homeostasis and effective response to disease, and abnormal immune responses are established contributors to the pathophysiology of autoimmune disease. In certain disease states, some of the critical pathways contributing to these abnormal autoimmune responses have been discovered to be effective approaches for therapeutic intervention. One recent example is the development of interleukin (IL)- 17 inhibitors. IL-17A is well-established as a pro-inflammatory cytokine which plays a key part in chronic inflammation and is a major driver of tissue damage. IL-17A induces normal immune and inflammatory responses to pathogens but can also contribute to chronic autoimmune diseases including psoriasis, spondyloarthritis, rheumatoid arthritis and multiple sclerosis.

[0003] The IL-17 family consists of six cytokines (IL- 17A through IL-17F). IL-17 receptor (IL- 17R) refers to the heterodimer formed by the IL-17RA and IL-17RC subunits. IL-17A is a major pathological cytokine secreted from Thl7 cells which may act as a homodimer or a heterodimer to signal through IL-17R. (Isono, F., et al., Inhibiting RORgt / Thl7 axis for autoimmune disorders, Drug Discovery Today (2014) Vol. 19(8) 1205-1211). Within the skin and joints, IL- 17A acts on cellular targets, including keratinocytes, endothelial cells, fibroblasts, osteoclasts, chondrocytes, and osteoblasts, to stimulate production of various antimicrobial peptides, chemokines, and proinflammatory and proliferative cytokines, which, in turn, promote tissue inflammation and bone remodeling. The critical importance of the IL-23 / IL-17A axis to the pathogenesis of psoriatic disease has resulted in many new biologic treatments targeting these cytokines. These biologies dramatically improve skin and joint symptoms in patients with moderate-to-severe psoriasis and psoriatic arthritis.

[0004] There are currently no highly efficacious orally administered treatments for moderate to severe psoriasis. A small molecule IL-17A inhibitor may provide efficacy comparable to anti-IL-17A antibodies for psoriasis and / or other IL-17A-dependent diseases, such as psoriatic arthritis. While the inhibition of IL-17A could, in some instances, increase susceptibility to opportunistic infections, an orally available small molecule inhibitor which had a relatively short half-life may provide for an improved agent for management of this risk. An oral agent may enable the patient to stop taking the drug, and rapidly clear the inhibitor from thebody, thus enabling more rapid recovery of the ability to respond to an infection. In addition, anti-drug antibodies against anti-IL-17A antibodies may arise in some patients and may reduce the efficacy of antibodies directed to IL-17A over time. This inactivation pathway would not be operative for small molecule IL-17A inhibitors. For some patients with psoriasis, orally administered small molecule inhibitors of interleukin (IL)-17A may represent a convenient alternative to IL-17A-targeting monoclonal antibodies.

[0005] WO2020 / 146194 recites certain compounds as modulators of IL-17 activity and their uses in the treatment of medical conditions such as inflammatory diseases, and other IL-17-associated disorders. Datta-Mannan, A., et al., report a first-in-human study which assessed the safety, tolerability, pharmacokinetics (PKs), and peripherally circulating IL-17A target engagement profile of single or multiple oral doses of the small molecule IL-17A inhibitor LY3509754 (NCT04586920). The authors concluded that despite strong target engagement and a PK profile that supported once- daily administration, this study showed that oral dosing withLY3509754 was poorly tolerated. (See Safety, Tolerability, and Pharmacokinetics of an Oral Small Molecule Inhibitor of IL-17A (LY3509754): A Phase I Randomized Placebo-Controlled Study., Datta- Mannan, A., et a., (2024), Clin Pharmacol Ther, 115: 1152-1161). To date no small molecule IL- 17A inhibitors have been approved for therapeutic use.

[0006] Thus, there remains a need for small molecule IL-17A inhibitors to provide improved and / or orally available treatments for IL-17-mediated diseases. The present invention provides certain novel compounds that are inhibitors of IL-17A and demonstrate an advantageous combination of pharmacological properties, such as potent inhibition of IL-17A and oral bioavailability, for example. As such, compounds of the present invention are believed to be useful in the treatment of psoriasis, rheumatoid arthritis and multiple sclerosis. The compounds of the present invention may provide an alternative treatment for such disorders. The compounds of the present invention may provide inhibitors of IL-17A with an improved combination of efficacy, safety, and / or tolerability for certain patients.SUMMARY OF THE INVENTION

[0007] In certain aspects, the present disclosure provides a compound of Formula (II):wherein:R1is, oR2is, orR3is, or; andR4isor a pharmaceutically acceptable salt thereof.

[0008] In certain aspects, the present disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt thereof.

[0009] Further, the present invention provides a pharmaceutical composition comprising a compound of formula I or II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0010] The present invention provides further embodiments of the above and particular groups of compounds and / or salts of formula I or II.

[0011] The present invention provides a compound of formula I or II, wherein R1is, or a pharmaceutically acceptable salt thereof.

[0012] The present invention provides a compound of formula I or II, wherein R1is, or a pharmaceutically acceptable salt thereof. The present invention provides a compound of formula I or II, wherein R1isa pharmaceutically acceptable salt thereof. The present invention provides a compound of formula I or II, wherein R1isa pharmaceutically acceptable salt thereof.

[0015] The present invention provides further embodiments of any of the above embodiments, and particular groups of compounds and / or salts of formula I or II.

[0016] The present invention provides a compound according to any of the above embodiments, wherein R2isor a pharmaceutically acceptable salt thereof.

[0017] The present invention provides a compound according to any of the above embodiments, whereinpharmaceutically acceptable salt thereof.

[0018] The present invention provides a compound according to any of the above embodiments, wherein R2isor a pharmaceutically acceptable salt thereof.

[0019] The present invention provides a compound according to any of the above embodiments, wherein R2is or a pharmaceutically acceptable salt thereof.

[0020] The present invention provides a compound according to any of the above embodiments, whereinpharmaceutically acceptable salt thereof.

[0021] The present invention provides a compound according to any of the above embodiments, whereinpharmaceutically acceptable salt thereof.

[0022] The present invention provides a compound according to any of the above embodiments, whereinpharmaceutically acceptable salt thereof.

[0023] The present invention provides a compound according to any of the above embodiments, whereinpharmaceutically acceptable salt thereof.

[0024] The present invention provides a compound according to any of the above embodiments, whereinpharmaceutically acceptable salt thereof.

[0025] The present invention provides a compound according to any of the above embodiments, whereinpharmaceutically acceptable salt thereof.

[0026] The present invention provides a compound according to any of the above embodiments, whereinpharmaceutically acceptable salt thereof.

[0027] The present invention provides further embodiments of any of the above embodiments, and particular groups of compounds and / or salts of formula I.

[0028] The present invention provides a compound according to any of the above embodiments, wherein R4is, or a pharmaceutically acceptable salt thereof.

[0029] The present invention provides a compound according to any of the above embodiments, wherein R4is, or a pharmaceutically acceptable salt thereof.

[0030] The present invention provides a compound according to any of the above embodiments, wherein R4is, or a pharmaceutically acceptable salt thereof.

[0031] The present invention provides a compound according to any of the above embodiments, whereinpharmaceutically acceptable salt thereof.

[0032] The present invention provides a compound according to any of the above embodiments, whereinpharmaceutically acceptable salt thereof.

[0033] The present invention provides a compound according to any of the above embodiments, wherein R4 is, or a pharmaceutically acceptable salt thereof.

[0034] The present invention provides a compound according to any of the above embodiments, whereinpharmaceutically acceptable salt thereof.

[0035] The present invention provides a compound according to any of the above embodiments, wherein R4 is, or a pharmaceutically acceptable salt thereof.

[0036] The present invention provides a compound according to any of the above o embodiments, wherein R4 is, or a pharmaceutically acceptable salt thereof.

[0037] The present invention provides a compound according to any of the above embodiments, wherein R4 is, or a pharmaceutically acceptable salt thereof.

[0038] The present invention provides a compound according to any of the above embodiments, wherein R4 is, or a pharmaceutically acceptable salt thereof.

[0039] The present invention provides a compound according to any of the above embodiments, wherein R4 is, or a pharmaceutically acceptable salt thereof.

[0040] The present invention provides a compound according to any of the above embodiments, wherein R4 is, or a pharmaceutically acceptable salt thereof.

[0041] The present invention provides a compound according to any of the above embodiments, wherein R4 is, or a pharmaceutically acceptable salt thereof.

[0042] The present invention provides a compound according to any of the above embodiments, wherein R4 is, or a pharmaceutically acceptable salt thereof.

[0043] The present invention provides a compound according to any of the above embodiments, wherein R4 is, or a pharmaceutically acceptable salt thereof.

[0044] The present invention provides a compound according to any of the above embodiments, wherein R4 is, or a pharmaceutically acceptable salt thereof.

[0045] The present invention provides a compound according to any of the above embodiments, whereinpharmaceutically acceptable salt thereof.

[0046] The present invention provides a compound according to any of the above embodiments, whereinpharmaceutically acceptable salt thereof.

[0047] The present invention provides a compound according to any of the above embodiments, wherein R4 is, or a pharmaceutically acceptable salt thereof.

[0048] The present invention provides a compound according to any of the above embodiments, wherein R4 is, or a pharmaceutically acceptable salt thereof.

[0049] The present invention provides a compound according to any of the above embodiments, wherein R4 is, or a pharmaceutically acceptable salt thereof.

[0050] The present invention provides a compound according to any of the above embodiments, wherein R4 is, or a pharmaceutically acceptable salt thereof.

[0051] The present invention provides a compound according to any of the above embodiments, whereinpharmaceutically acceptable salt thereof.

[0052] The present invention provides a compound according to any of the above embodiments, wherein R4 is, or a pharmaceutically acceptable salt thereof.

[0053] The present invention provides a compound according to any of the above embodiments, wherein R4 is, or a pharmaceutically acceptable salt thereof.

[0054] The present invention provides a compound according to any of the above embodiments, whereinpharmaceutically acceptable salt thereof.

[0055] The present invention provides a compound according to any of the above embodiments, wherein R4 is, or a pharmaceutically acceptable salt thereof.

[0056] The present invention provides a compound according to any of the above embodiments, wherein R4 is, or a pharmaceutically acceptable salt thereof.

[0057] The present invention provides a compound according to any of the above embodiments, wherein R4, or a pharmaceutically acceptable salt thereof.

[0058] The present invention provides a compound according to any of the above embodiments, whereinpharmaceutically acceptable salt thereof.

[0059] The present invention provides further embodiments of any of the above embodiments, and particular groups of compounds and / or salts of formula I or II.

[0060] The present invention provides a compound according to any of the above embodiments, wherein R3 is, or a pharmaceutically acceptable salt thereof.

[0061] The present invention provides a compound according to any of the above embodiments, whereinpharmaceutically acceptable salt thereof.

[0062] The present invention provides a compound according to any of the above embodiments, wherein R3 is, or a pharmaceutically acceptable salt thereof.

[0063] The present invention provides a compound according to any of the above embodiments, whereinpharmaceutically acceptable salt thereof.

[0064] The present invention provides a compound according to any of the above embodiments, wherein R3 is, or a pharmaceutically acceptable salt thereof.

[0065] The present invention provides a compound according to any of the above embodiments, whereinpharmaceutically acceptable salt thereof.

[0066] The present invention provides a compound according to any of the above embodiments, whereinpharmaceutically acceptable salt thereof.

[0067] The present invention provides a compound according to any of the above embodiments, whereinpharmaceutically acceptable salt thereof.

[0068] The present invention provides a compound according to any of the above embodiments, whereinpharmaceutically acceptable salt thereof.

[0069] Further, the present invention provides a compound selected from the group consisting of:N-((S)-(4,4-difluorocyclohexyl)(3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)-2-(((3R,5R)-2-oxo- 5-(trifluoromethyl)piperidin-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -ethyl- 1H- pyrazole-5-carboxamide;N-(( 1 S)-(3 -(3 -cyclopropyl -4-methylpiperazin- 1 -yl)-2-(((3R, 5R)-2-oxo-5 - (trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)(4,4- difluorocyclohexyl)methyl)-l-ethyl-lH-pyrazole-5-carboxamide (isomer 1);N-(( 1 S)-(3 -(3 -cyclopropyl -4-methylpiperazin- 1 -yl)-2-(((3R, 5R)-2-oxo-5 - (trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)(4,4- difluorocyclohexyl)methyl)-l-ethyl-lH-pyrazole-5-carboxamide (isomer 2);N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)-3- (3,3,4-trimethylpiperazin-l-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl-lH-pyrazole-5- carboxamide; l-ethyl-N-((S)-5,5,5-trifluoro-4,4-dimethyl-l-(3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)-2- (((3R,5R)-2-oxo-5-(trifluoromethyl)piperi din-3-yl)methyl)imidazo[l, 2-b][l, 2, 4]tri azin-6- yl)pentyl)-lH-pyrazole-5-carboxamide;N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)-2-((2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-isopropyl-lH-l,2,4- tri azol e- 5 -carb oxami de;N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)-3- ((3S,5S)-3,4,5-trimethylpiperazin-l-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl-lH- pyrazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)-3- ((3R, 5 S)-3 ,4, 5-trimethylpiperazin- 1 -yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -ethyl- 1H- pyrazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)-3- ((3R,5R)-3,4,5-trimethylpiperazin-l-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl-lH- pyrazole-5-carboxamide;1 -ethyl -N-((S)-5, 5, 5-trifluoro-4,4-dimethyl-l-(2-(((3R,5R)-5-methyl-2-oxopiperi din-3- yl)methyl)-3-(4-methylpiperazin-l-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)pentyl)-lH-pyrazole-5- carboxamide; l-ethyl-N-((lS)-5,5,5-trifluoro-4,4-dimethyl-l-(3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)-2-((3- oxo-2-azabicyclo[3.1.1 ]heptan-4-yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)pentyl)- 1H- pyrazole-5-carboxamide;l-ethyl-4-fluoro-N-((S)-5,5,5-trifluoro-4,4-dimethyl-l-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)pentyl)- lH-pyrazole-5-carboxamide; l-ethyl-N-((S)-5,5,5-trifluoro-4,4-dimethyl-l-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3-(3,3,4-trimethylpiperazin-l-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)pentyl)-lH- pyrazole-5-carboxamide; l-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4-methyl-4,7- diazaspiro[2.5]octan-7-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide; l-ethyl-N-((S)-(3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)-2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide; l-methyl-N-((lS)-(3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)-2-((3-oxo-2- azabicyclo[3.1.1]heptan-4-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide; l-methyl-N-((lS)-(3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-lH-pyrazole-5- carboxamide;N-((lS)-(3-((R)-4,5-dimethyl-4,7-diazaspiro[2.5]octan-7-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l-methyl-lH- pyrazole-5-carboxamide; l-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4-methyl-4,7- diazaspiro[2.5]octan-7-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide;N-((S)-cyclohexyl(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4-methyl-4,7- diazaspiro[2.5]octan-7-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-methyl-lH-pyrazole-5- carboxamide; l-(2-fluoroethyl)-N-((S)-l-(2-(((3R,5R)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4-methyl-4,7- diazaspiro[2.5]octan-7-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)-3-(l- (trifluoromethyl)cyclopropyl)propyl)-lH-pyrazole-5-carboxamide;l-methyl-N-((S)-l-(2-(((3R,5R)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4-methyl-4,7- diazaspiro[2.5]octan-7-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)-3-(l- (trifluoromethyl)cyclopropyl)propyl)-lH-pyrazole-5-carboxamide; l-(2-fluoroethyl)-N-((S)-l-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4-methyl-4,7- diazaspiro[2.5]octan-7-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)-3-(l- (trifluoromethyl)cyclopropyl)propyl)-lH-pyrazole-5-carboxamide;4-cyclopropyl-N-((S)-l-(2-(((3R,5R)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4- methylpiperazin- 1 -yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-3 -(1 - (trifluoromethyl)cyclopropyl)propyl)- 1 ,2, 5-oxadiazole-3 -carboxamide; l-ethyl-N-((S)-5,5,5-trifluoro-4,4-dimethyl-l-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3 -(4-methylpiperazin- 1 -yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)pentyl)- lH-pyrazole-5- carboxamide;N-((lS)-(4,4-difluorocyclohexyl)(3-(octahydro-2H-pyrido[l,2-a]pyrazin-2-yl)-2-(((3R,5R)-2- oxo-5-(trifluoromethyl)piperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -ethyl- lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(4,4-difluorocyclohexyl)(3-(octahydro-2H-pyrido[l,2-a]pyrazin-2-yl)-2-(((3R,5R)-2- oxo-5-(trifluoromethyl)piperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -ethyl- lH-pyrazole-5-carboxamide (isomer 2);N-((S)-(4,4-difluorocyclohexyl)(3-(4-(oxetan-3-yl)piperazin-l-yl)-2-(((3R,5R)-2-oxo-5- (trifluoromethyl)piperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -ethyl- 1H- pyrazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)-3- (4-(tetrahydro-2H-pyran-4-yl)piperazin- 1 -yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -ethyl - lH-pyrazole-5-carboxamide;N-((lS)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)- 3 -(tetrahydro- 1 'H-spiro[cyclopropane- 1 ,6'-pyrazino[2, 1 -c] [ 1 ,4]oxazin]-8'(7'H)-yl)imidazo[ 1 ,2- b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -ethyl- lH-pyrazole-5-carboxamide; l-ethyl-N-((S)-5,5,5-trifluoro-l-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2- (((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)-4,4- dimethylpentyl)-lH-pyrazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-((S)-7,7-difluorohexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)-2- (((3R,5R)-2-oxo-5-(trifluoromethyl)piperi din-3-yl)methyl)imidazo[l, 2-b][l, 2, 4]tri azin-6- yl)m ethyl)- 1 -ethyl- lH-pyrazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-(4-methylpiperazin-l-yl)-2-(((3R,5R)-2-oxo-5- (trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-isopropyl- lH-l,2,4-triazole-5-carboxamide; l-ethyl-N-((S)-((lr,4S)-4-methylcyclohexyl)(3-(4-methylpiperazin-l-yl)-2-(((3R,5R)-2-oxo-5- (trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-lH-pyrazole-5- carboxamide; l-isopropyl-N-((lS)-((lr,4S)-4-methylcyclohexyl)(3-(4-methylpiperazin-l-yl)-2-((2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-lH-l,2,4-triazole-5- carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-((R)-7,7-difluorohexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)-2- (((3R,5R)-2-oxo-5-(trifluoromethyl)piperi din-3-yl)methyl)imidazo[l, 2-b][l, 2, 4]tri azin-6- yl)m ethyl)- 1 -ethyl- lH-pyrazole-5-carboxamide; l-ethyl-N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide;N-((lS)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)- 3 -(4-(tetrahydrofuran-3 -yl)piperazin- 1 -yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -ethyl- 1H- py razol e- 5 -carb oxami de;N-((S)-(4,4-difluorocyclohexyl)(3-(4-(2-methoxyethyl)-4,7-diazaspiro[2.5]octan-7-yl)-2- (((3R,5R)-2-oxo-5-(trifluoromethyl)piperi din-3-yl)methyl)imidazo[l, 2-b][l, 2, 4]tri azin-6- yl)methyl)-4-ethyl- 1 ,2, 5-oxadiazole-3 -carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-(4-(2-methoxyethyl)piperazin-l-yl)-2-(((3R,5R)-2-oxo-5- (trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl-lH- pyrazole-5-carboxamide; l-ethyl-N-((S)-5,5,5-trifluoro-4,4-dimethyl-l-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)pentyl)- lH-pyrazole-5-carboxamide;l-ethyl-N-((S)-5,5,5-trifluoro-4,4-dimethyl-l-(3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)-2-((2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)pentyl)-lH-pyrazole-5-carboxamide;1 -ethyl -N-((S)-5, 5, 5-trifluoro-4,4-dimethyl-l-(2-(((3R,5R)-5-methyl-2-oxopiperi din-3- yl)methyl)-3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)pentyl)- lH-pyrazole-5-carboxamide; l-ethyl-N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide;N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide;4-ethyl-N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-l,2,5-oxadiazole-3-carboxamide;N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide;4-ethyl-N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-l,2,5-oxadiazole-3-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2- (((3R,5R)-2-oxo-5-(trifluoromethyl)piperi din-3-yl)methyl)imidazo[l, 2-b][l, 2, 4]tri azin-6- yl)m ethyl)- 1 -isopropyl- 1H- 1 ,2,4-triazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2- (((3R,5R)-2-oxo-5-(trifluoromethyl)piperi din-3 -yl)methyl)imidazo[l, 2-b][ 1 , 2, 4]tri azin-6- yl)methyl)-4-ethyl- 1 ,2, 5-oxadiazole-3 -carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)-2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -isopropyl- lH-l,2,4-triazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-(4-(2-methoxyethyl)piperazin-l-yl)-2-(((3R,5R)-2-oxo-5- (trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl-lH- l,2,4-triazole-5-carboxamide;1-isopropyl-N-((lS)-5,5,5-trifluoro-4,4-dimethyl-l-(3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)-2-((2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)pentyl)- lH-pyrazole-5- carboxamide; l-isopropyl-N-((S)-5,5,5-trifluoro-4,4-dimethyl-l-(2-(((3R,5R)-5-methyl-2-oxopiperidin-3- yl)methyl)-3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)pentyl)- lH-l,2,4-triazole-5-carboxamide; l-isopropyl-N-((S)-5,5,5-trifluoro-4,4-dimethyl-l-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)pentyl)- lH-l,2,4-triazole-5-carboxamide; l-ethyl-N-((S)-((lr,4S)-4-methylcyclohexyl)(3-(4-methylpiperazin-l-yl)-2-(((3R,5R)-2-oxo-5- (trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-lH-l,2,4- triazole-5-carboxamide;N-((lS)-cycloheptyl(3-(4-methylpiperazin-l-yl)-2-((3-oxo-2-azabicyclo[3.1.1]heptan-4- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -ethyl- 1H- 1 ,2,4-triazole-5-carboxamide; l-ethyl-N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-lH-l,2,4-triazole-5-carboxamide;N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-l-isopropyl-lH-l,2,4-triazole-5-carboxamide; l-ethyl-N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-lH-l,2,4-triazole-5-carboxamide;N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-l-isopropyl-lH-l,2,4-triazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4- methylpiperazin-l-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl-lH-pyrazole-5- carboxamide;N-((lS)-(4,4-difluorocyclohexyl)(3-(8-methyloctahydro-2H-pyrazino[l,2-a]pyrazin-2-yl)-2- (((3R,5R)-2-oxo-5-(trifluoromethyl)piperi din-3-yl)methyl)imidazo[l, 2-b][l, 2, 4]tri azin-6- yl)methyl)-l -ethyl- lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(4,4-difluorocyclohexyl)(3-(8-methyloctahydro-2H-pyrazino[l,2-a]pyrazin-2-yl)-2- (((3R,5R)-2-oxo-5-(trifluoromethyl)piperi din-3-yl)methyl)imidazo[l, 2-b][l, 2, 4]tri azin-6- yl)methyl)-l -ethyl- lH-pyrazole-5-carboxamide (isomer 2);N-((S)-((S)-3,3-difluorocyclohexyl)(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2- (((3R,5R)-2-oxo-5-(trifluoromethyl)piperi din-3-yl)methyl)imidazo[l, 2-b][l, 2, 4]tri azin-6- yl)m ethyl)- 1 -ethyl- 1H- 1 ,2,4-triazole-5-carboxamide;N-((S)-((S)-3,3-difluorocyclohexyl)(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2- (((3R,5R)-2-oxo-5-(trifluoromethyl)piperi din-3-yl)methyl)imidazo[l, 2-b][l, 2, 4]tri azin-6- yl)m ethyl)- 1 -isopropyl- 1H- 1 ,2,4-triazole-5-carboxamide; l-ethyl-N-((R)-l-(3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)-2-(((3R,5R)-2-oxo-5- (trifluoromethyl)piperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-2-((l , 1 , 1 -trifluoro-2- methylpropan-2-yl)oxy)ethyl)-lH-pyrazole-5-carboxamide;N-((S)-(3-(2,2-difluoro-5-methyl-5,8-diazaspiro[3.5]nonan-8-yl)-2-(((3R,5R)-2-oxo-5- (trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)(4,4- difluorocyclohexyl)methyl)-l-ethyl-lH-pyrazole-5-carboxamide; l-ethyl-N-((lS)-5,5,5-trifluoro-l-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-((2- oxopiperi din-3 -yl)methyl)imidazo[l,2-b] [1,2, 4]triazin-6-yl)-4,4-dimethylpentyl)-lH- 1,2,4- triazole-5-carboxamide;N-((lS)-(4,4-difluorocyclohexyl)(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-((2- oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -isopropyl- 1H- 1 ,2,4- triazole-5-carboxamide;N-((S)-((S)-3,3-difluorocyclohexyl)(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2- (((3R,5R)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l- ethyl-lH-l,2,4-triazole-5-carboxamide;N-((S)-((S)-3,3-difluorocyclohexyl)(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2- ((2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl-lH-l,2,4- triazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2- (((3R,5R)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l- isopropyl-lH-l,2,4-triazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-((R)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2- (((3R,5R)-2-oxo-5-(trifluoromethyl)piperi din-3-yl)methyl)imidazo[l, 2-b][l, 2, 4]tri azin-6- yl)m ethyl)- 1 -isopropyl- 1H- 1 ,2,4-triazole-5-carboxamide; l-ethyl-N-((lS)-((lr,4S)-4-methylcyclohexyl)(3-(4-methylpiperazin-l-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-lH-l,2,4-triazole-5-carboxamide; l-ethyl-N-((lS)-5,5,5-trifluoro-l-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-((2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)-4,4-dimethylpentyl)-lH-pyrazole-5- carboxamide;N-((lS)-(4,4-difluorocyclohexyl)(3-(4,5-dimethyl-4,7-diazaspiro[2.5]octan-7-yl)-2-(((3R,5R)-2- oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl- lH-pyrazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2- (((3R,5 S)-5-methyl-2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 - isopropyl-lH-l,2,4-triazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-((R)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2- (((3R,5R)-5-methyl-2-oxopiperidin-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 - isopropyl-lH-l,2,4-triazole-5-carboxamide (isomer 1); l-ethyl-N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide;N-((lS)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[l, 2-b][ 1,2, 4]triazin-6-yl)((lr,4S)-4-methylcy cl ohexyl)methyl)-l -methyl- 1H- pyrazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-(4-isopropylpiperazin-l-yl)-2-(((3R,5R)-2-oxo-5- (trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl-lH- pyrazole-5-carboxamide;N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-l-methyl-lH-pyrazole-5-carboxamide;N-((S)- 1 -(3 -((S)-hexahydropyrazino[2, 1 -c] [ 1 ,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)-3-(l- (trifluoromethyl)cyclopropyl)propyl)-l-methyl-lH-pyrazole-5-carboxamide;N-((lS)-l-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-3 -(1 -(trifluoromethyl)cyclopropyl)propyl)- 1 - methyl - 1 H-py razol e- 5 -carb oxami de;N-((S)-(4,4-difluorocyclohexyl)(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-4- ethyl-l,2,5-oxadiazole-3-carboxamide;4-cyclopropyl-N-((S)-l-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5R)-5- methyl-2-oxopiperi din-3 -yl)methyl)imidazo[l,2-b][ 1,2, 4]tri azin-6-yl)-3-(l - (trifluoromethyl)cyclopropyl)propyl)- 1 ,2, 5-oxadiazole-3 -carboxamide;4-cyclopropyl-N-((S)-(4,4-difluorocyclohexyl)(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin- 8(lH)-yl)-2-(((3R,5R)-5-methyl-2-oxopiperi din-3-yl)methyl)imidazo[l, 2-b][l, 2, 4]tri azin-6- yl)methyl)-l,2,5-oxadiazole-3-carboxamide;4-cyclopropyl-N-((R)-l-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5R)-5- methyl-2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-2-((l , 1 , 1 -trifluoro-2- methylpropan-2-yl)oxy)ethyl)-l,2,5-oxadiazole-3-carboxamide;4-cyclopropyl-N-((R)-l-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5- methyl-2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-2-((l , 1 , 1 -trifluoro-2- methylpropan-2-yl)oxy)ethyl)-l,2,5-oxadiazole-3-carboxamide;4-ethyl-N-((R)-l-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl- 2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-2-((l , 1 , 1 -trifluoro-2- methylpropan-2-yl)oxy)ethyl)-l,2,5-oxadiazole-3-carboxamide;4-cyclopropyl-N-((S)-(4,4-difluorocyclohexyl)(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin- 8(lH)-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6- yl)methyl)-l,2,5-oxadiazole-3-carboxamide; l-ethyl-N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-lH-l,2,4-triazole-5-carboxamide; l-ethyl-N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-lH-l,2,4-triazole-5-carboxamide;N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-l-isopropyl-lH-l,2,4-triazole-5-carboxamide;N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-l-isopropyl-lH-l,2,4-triazole-5-carboxamide; l-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((S)-4- oxohexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide; l-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4-(methylsulfonyl)piperazin-l-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide;4-cyclopropyl-N-((S)-5,5,5-trifluoro-l-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)-4,4- dimethylpentyl)-l,2,5-oxadiazole-3-carboxamide;4-cyclopropyl-N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5- methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-l,2,5-oxadiazole-3-carboxamide;4-(6-((S)-(l-ethyl-lH-pyrazole-5-carboxamido)((lr,4S)-4-methylcyclohexyl)methyl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-3-yl)-N- methylpiperazine- 1 -carboxamide;l-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4-sulfamoylpiperazin-l- yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-lH-pyrazole-5- carboxamide;N-((S)-(3-(4-(2-amino-2-oxoethyl)piperazin-l-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[l, 2-b][ 1,2, 4]triazin-6-yl)((lr,4S)-4-methylcy cl ohexyl)methyl)-l -methyl- 1H- pyrazole-5-carboxamide; l-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4-(2-(methylamino)-2- oxoethyl)piperazin- 1 -yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)(( 1 r,4S)-4-methylcyclohexyl)methyl)- lH-pyrazole-5-carboxamide;N-((S)-(3-(4-(2-(dimethylamino)-2-oxoethyl)piperazin-l-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-l-methyl-lH-pyrazole-5-carboxamide;N-((S)-(3-(4-(2-(3,3-difluoroazetidin-l-yl)-2-oxoethyl)piperazin-l-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-l-methyl-lH-pyrazole-5-carboxamide;N-((S)-(3-(4-(2-(dimethylamino)-2-oxoethyl)piperazin-l-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide;4-methyl-N-((lS)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-4'H- spirofcyclopropane- 1 ,3 '-pyrazino[2, 1 -c] [ 1 ,4]oxazin]-8'(l'H)-yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)((lr,4S)-4-methylcyclohexyl)methyl)-l,2,5-oxadiazole-3-carboxamide (isomer 1);4-methyl-N-((lS)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-4'H- spiro[cyclopropane-l,3'-pyrazino[2,l-c][l,4]oxazin]-8'(l'H)-yl)imidazo[l,2-b][l, 2, 4]tri azin-6- yl)((lr,4S)-4-methylcyclohexyl)methyl)-l,2,5-oxadiazole-3-carboxamide (isomer 2);N-((3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)(4- (trifluoromethyl)cyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer 1);N-((3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)(4-(trifluoromethyl)cyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer 2);N-((3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)(4-(trifluoromethyl)cyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer 3);N-((3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)(4-(trifluoromethyl)cyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer 4);4-methyl-N-((lS)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4- methylhexahydropyrazino[2, 1 -c] [ 1 ,4]oxazin-8(lH)-yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)(( 1 r,4S)- 4-methylcyclohexyl)methyl)-l,2,5-oxadiazole-3-carboxamide (isomer 1);4-methyl-N-((lS)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4- methylhexahydropyrazino[2, 1 -c] [ 1 ,4]oxazin-8(lH)-yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)(( 1 r,4S)- 4-methylcyclohexyl)methyl)-l,2,5-oxadiazole-3-carboxamide (isomer 2);4-methyl-N-((lS)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4- methylhexahydropyrazino[2, 1 -c] [ 1 ,4]oxazin-8(lH)-yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)(( 1 r,4S)- 4-methylcyclohexyl)methyl)-l,2,5-oxadiazole-3-carboxamide (isomer 3);4-methyl-N-((lS)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4- methylhexahydropyrazino[2, 1 -c] [ 1 ,4]oxazin-8(lH)-yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)(( 1 r,4S)- 4-methylcyclohexyl)methyl)-l,2,5-oxadiazole-3-carboxamide (isomer 4);N-((S)-((S)-3,3-difluorocyclohexyl)(3-((3S,9aS)-3-(methoxymethyl)hexahydropyrazino[2,l- c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2- b][l,2,4]triazin-6-yl)methyl)-4-ethyl-l,2,5-oxadiazole-3-carboxamide;N-((lS)-(3-(3-(methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl-4,4-d2)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer 1);N-((lS)-(3-(3-(methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl-4,4-d2)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer 2);N-((lS)-(3-(3-(methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl-4,4-d2)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer 3);N-((lS)-(3-(3-(methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl-4,4-d2)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer 4);N-((3-((3S,9aS)-3-(methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)- 5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)(4- (trifluoromethyl)cyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer 1);N-((3-((3S,9aS)-3-(methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)- 5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)(4- (trifluoromethyl)cyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer 2);N-((3-((3S,9aS)-3-(methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)- 5-methyl-2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)(4- (trifluoromethyl)cyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer 3);N-((3-((3S,9aS)-3-(methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)- 5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)(4- (trifluoromethyl)cyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer 4);N-((l,l-difluorospiro[2.5]octan-5-yl)(3-((3S,9aS)-3-(methoxymethyl)hexahydropyrazino[2,l- c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2- b][l,2,4]triazin-6-yl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer 1);N-((l,l-difluorospiro[2.5]octan-5-yl)(3-((3S,9aS)-3-(methoxymethyl)hexahydropyrazino[2,l- c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2- b][l,2,4]triazin-6-yl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer 2);N-((l,l-difluorospiro[2.5]octan-5-yl)(3-((3S,9aS)-3-(methoxymethyl)hexahydropyrazino[2,l- c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2- b][l,2,4]triazin-6-yl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer 3);N-((l,l-difluorospiro[2.5]octan-5-yl)(3-((3S,9aS)-3-(methoxymethyl)hexahydropyrazino[2,l- c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2- b][l,2,4]triazin-6-yl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer 4);N-((l,l-difluorospiro[2.5]octan-5-yl)(3-((3S,9aS)-3-(methoxymethyl)hexahydropyrazino[2,l- c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2- b][l,2,4]triazin-6-yl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer 5);N-((l,l-difluorospiro[2.5]octan-5-yl)(3-((3S,9aS)-3-(methoxymethyl)hexahydropyrazino[2,l- c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2- b][l,2,4]triazin-6-yl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer 6);N-((l,l-difluorospiro[2.5]octan-5-yl)(3-((3S,9aS)-3-(methoxymethyl)hexahydropyrazino[2,l- c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2- b][l,2,4]triazin-6-yl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer 7); andN-((S)-(3-((3S,9aS)-3-(methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide; or a pharmaceutically acceptable salt thereof.

[0070] Further, the present invention provides an embodiment represented by a formula corresponding to each of the compounds listed above, wherein the formula is represented with flat bonds, and wherein the embodiment represents and includes all isomeric forms of the compounds, including all enantiomers, diastereomers, racemic mixtures, and all purified forms and mixtures of isomers.

[0071] Further, the present invention provides a pharmaceutical composition comprising compound and / or salt of one of the particular embodiments of the preceding list immediately above, and a pharmaceutically acceptable carrier, diluent or excipient.DETAILED DESCRIPTION OF THE INVENTION

[0072] Compounds of the present invention are potent inhibitors of IL- 17 A, and upon administration to a patient in need thereof, may provide therapeutic benefits while avoiding certain problems associated with biological IL-17A signaling antagonists, such as IL-17 antibodies. As such, compounds of the present invention are believed to be useful for the treatment of conditions in which excessive IL-17A mediated signaling plays a role, and such as psoriasis, rheumatoid arthritis, spondyloarthritis and multiple sclerosis, including relief of certain immunologically-mediated symptoms. Compounds of the present invention are also believed to be useful in improving disease symptoms in psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, palmoplantar psoriasis, rheumatoid arthritis, multiple sclerosis, systemic sclerosis, psoriatic arthritis, spondyloarthritis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma, non-infectious uveitis, and COPD.

[0073] Further, the present invention provides a compound of formula I or II, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0074] In another embodiment, the present invention provides a pharmaceutical composition comprising the compound of formula I or II, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. Furthermore, this embodiment of the invention provides a pharmaceutical composition for treating psoriasis, comprising the compound of formula I or II, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers, or diluents. In another embodiment the invention provides a pharmaceutical composition for treating rheumatoid arthritis, comprising the compound of formula I or II, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers, or diluents. In another embodiment the invention provides a pharmaceutical composition fortreating multiple sclerosis, comprising the compound of formula I or II, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers, or diluents.

[0075] Further, the present invention provides a method of treating a disease or disorder selected from the group consisting of psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, palmoplantar psoriasis, rheumatoid arthritis, multiple sclerosis, systemic sclerosis, psoriatic arthritis, spondyloarthritis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma, non-infectious uveitis, and / or COPD, comprising administering to a patient in need thereof an effective amount of a compound of formula I and / or II, or a pharmaceutically acceptable salt thereof. Further, the present invention provides a method of treating psoriasis, comprising administering to a patient in need thereof an effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof. Further, the present invention provides a method of treating spondyloarthritis, comprising administering to a patient in need thereof an effective amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof.

[0076] In one embodiment, the present invention provides a compound of formula I or II, or a pharmaceutically acceptable salt thereof, for use in the treatment of psoriasis. In another particular embodiment the invention provides a compound of formula I or II, or a pharmaceutically acceptable salt thereof, for use in treating spondyloarthritis. In another particular embodiment the invention provides a compound of formula I or II, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder selected from the group consisting of psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, palmoplantar psoriasis, rheumatoid arthritis, multiple sclerosis, psoriatic arthritis, spondyloarthritis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma, non-infectious uveitis, and / or COPD.

[0077] In yet another embodiment, the present invention provides the use of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of psoriasis. In yet another embodiment, the present invention provides the use of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of spondyloarthritis.

[0078] The compounds or salts of the present invention are usually administered in the form of pharmaceutical compositions comprising the compound of formula I or II, or a pharmaceutically acceptable salt thereof, as an active ingredient, and at least one pharmaceutically acceptable carrier, diluent and / or excipient. These compositions can be administered by a variety of routes including oral, sublingual, nasal, subcutaneous, intravenous, and intramuscular. Such pharmaceutical compositions and processes for preparing them are well known in the art. See, e.g., Remington: The Science and Practice of Pharmacy (University of the Sciences in Philadelphia, ed., 21st ed., Lippincott Williams & Wilkins Co., 2005).

[0079] Compositions of compounds of formula I or II, or pharmaceutically acceptable salts thereof, are preferably formulated in a unit dosage forms, each dosage containing from about 0.5 to about 2000 mg of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with at least one suitable pharmaceutically acceptable carrier, diluent and / or excipient. It will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms. It is contemplated that the compound of the invention, as for example in a pharmaceutical composition of the invention, will be used to treat psoriasis, rheumatoid arthritis and / or multiple sclerosis, by chronic administration.

[0080] As used herein, the term “patient” refers to a mammal, preferably a human. As used herein, the terms “treatment”, “treating”, or “mitigating” are intended to refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of an existing disorder and / or a reduction in symptoms thereof, but does not necessarily indicate a total elimination of all symptoms. As used herein, the term “effective amount” of a compound of formula I or II, refers to an amount, that is a dosage, which is effective in inhibiting an IL-17A mediated response in a patient. A preferred “effective amount” is determined as an amount that can treat or eliminate the signs and symptoms of moderate to severe psoriasis in the patient, as compared to the patient when untreated. In determining an effective amount or dose of a compound of formula I or II, a number of factors are considered, including, but not limited to the compound to be administered and its particular formulation; the patients size, age, and general health; the degree of involvement or the severity of the disorder;the response of the individual patient; the mode of administration; and other relevant circumstances.

[0081] "Pharmaceutically acceptable salts" or “a pharmaceutically acceptable salt” refers to the relatively non-toxic, inorganic and organic salt or salts of the compound of the present invention. It will be understood by the skilled artisan that compounds of the present invention are capable of forming salts. The compounds of the present invention contain basic heterocycles, and accordingly react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Such pharmaceutically acceptable acid addition salts and common methodology for preparing them are well known in the art. See, e.g., P. Stahl, et al., HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, (VCHA / Wiley-VCH, 2008); S.M. Berge, et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Sciences, Vol 66, No. 1, January 1977.

[0082] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds described herein are intended to include all Z-, E- and tautomeric forms as well.

[0083] Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. The stereochemistry of pure enantiomers can be specified at each chiral carbon by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiralchromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.

[0084] When stereochemistry is not specified in a chemical structure, for instance when flat bonds are drawn, molecules with stereocenters described herein include isomers, such as enantiomers and diastereomers, mixtures of enantiomers, including racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. In certain embodiments, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates or mixtures of diastereomers. Resolution of the racemates or mixtures of diastereomers, if possible, can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral high-pressure liquid chromatography (HPLC) column. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and / or trituration.

[0085] The compounds of Formula I or II can be used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedures known in the art, for instance as described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs. In certain embodiments, the compounds of Formula I or II have some or all of theJH atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods. Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development . [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. RadioanaL Chem., 1981, 64(1-2), 9-32. Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co. Unless otherwise stated, compounds of Formula I or II are intended to includecompounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure. The compounds of Formula I or II optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), or carbon- 14 (14C).EXAMPLES AND PREPARATIONS

[0086] The following examples are provided for illustration purposes only. The abbreviations used herein are defined according to Aldrichimica Acta, vol. 17, No. 1, 1984. Other abbreviations are defined as follows: “ACN” refers to acetonitrile; “AcOH” refers to acetic acid; “Ag(pyr2)MnO4” refers to bis(l-pyridyl)silver permanganate; “aq” refers to aqueous; “BOC2O” refers to di- / c / 7-butyl dicarbonate; “CbzOSu” refers to benzyl N-succinimidyl carbonate; “CDF’ refers to carbonyldiimidazole; “DBN” refers to l,5-diazabicyclo(4.3.0)non-5-ene; “DCC” refers to 7V,7V-dicyclohexylcarbodiimide; “DCE” refers to dichloroethane; “DCM” refers to dichloromethane; “DDQ” refers to 2,3-dichloro-5,6-dicyano-l,4-benzoquinone; “DIPEA” refers to diisopropylethylamine; “DMAP” refers to 4-dimethylaminopyridine; “DMF” refers to dimethylformamide; “DMP” refers to Dess-Martin periodinane; “DMSO” refers to dimethyl sulfoxide; “EDCI” refers to l-ethyl-3-(3-dimethylaminopropyl)carbodiimide; “EtOAc” refers to ethyl acetate; “EtOH” refers to ethanol; “ES / MS” refers to electron spray - mass spectrometry; “FA” refers to formic acid; “h” refers to hour(s); “zPrOH” refers to isopropanol; “KHMDS” refers to potassium bis(trimethylsilyl)amide; “KOtBu” refers to potassium / crt-butoxide; “LAH” refers to lithium aluminium hydride; “LED” refers to light-emitting diode; “LDA” refers to lithium diisopropylamide; “LiHMDS” refers to lithium bis(trimethylsilyl)amide; “MeOH” refers to methanol; “min” refers to minutes; “NaBEECN” refers to sodium cyanoborohydride; “NBS” refers to N-bromosuccinimide; “PE” refers to petroleum ether; “Prep-HPLC” refers to preparatory high performance liquid chromatography; “Prep-TLC” refers to preparatory thin layer chromatography; “Prep-SFC” refers to preparatory supercritical fluid chromatography; “Py” refers to pyridine; “RT” refers to room temperature; “sat” refers to saturated; “ / BuOH” refers to tert-butanol; “TEA” refers to triethylamine; “TFA” refers to trifluoroacetic acid; “THF” refers to tetrahydrofuran; “THP” refers to 2-tetrahydropyran; “Ti(OEt)4” refers to titanium(IV)ethoxide; “Ti(iPrO)4” refers to titanium isopropoxide; “TMEDA” refers to N,N,N',N'- tetramethylethylenediamine; “TMSC1” refers to trimethyl silyl chloride; “TMSCN” refers to trimethyl silyl cyanide; “TMSI” refers to iodotrimethylsilane; “T4P” refers to 2,4,6-tributyl- 1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide.

[0087] In the schemes below, all substituents unless otherwise indicated, are as previously defined. The reagents and starting materials are either commercially available or may be prepared by methods well known to one of ordinary skill in the art, some of which are presented in the preparations below. Without limiting the scope of the invention, the following schemes, preparations, and examples are provided to further illustrate the invention.Scheme 1

[0088] Scheme 1 depicts the preparation of compounds of the present invention beginning with a suitable aminotriazine (i) and bromoketone (ii). The PG moiety on the amine of the intermediates is a standard amine protecting group well known to the skilled artisan, including carbamate protecting groups. The aminotriazine (i) and bromoketone (ii) are reacted in presence of an appropriate base, such as DIPEA, and trimethyl borate in a suitable solvent, suchas THF, at 70 °C for at least 3 h. The imidazotriazine intermediate (iii) is deprotected under acidic conditions, and include reacting intermediate (iii) in a mixture of appropriate acids, such as aq. HC1 and AcOH, at 60 °C for at least 30 min. Alternatively, intermediate (iii) is reacted with TMSI in a suitable solvent, such as DCM, at 20 °C for 2 h. Alternatively, the deprotection of intermediate (iii) is accomplished in presence of Pd / C and ammonium formate or ammonium acetate in an appropriate solvent, such as MeOH. The deprotected amine (iv) is reacted with a suitable carboxylic acid under standard amide coupling conditions and include an appropriate coupling reagent, such as EDCI or T4P, a suitable base, such as DIPEA or pyridine, in an appropriate solvent, such as DCM, at RT for at least 1 h. The resulting intermediate (v) is reacted with a suitable amine in presence of Ag(pyr2)MnC>4 in an appropriate solvent. Alternatively, intermediate (v) is reacted with a suitable amine in presence of AgNCE and TBAP, in an appropriate solvent, such as THF. Optionally, a protected amine is present on group R5and R6of intermediate (vi) and include a carbamate protecting group. Following the deprotection of the amine under acidic conditions, the amine is functionalized under reductive amination conditions with a suitable carbonyl and include reacting the deprotected amine with an appropriate reducing agent, such as NaBHjCN, in presence of AcOH or NaOAc, in a suitable solvent, such as MeOH. Alternatively, the deprotected amine is reacted with an appropriate acyl chloride, sulfonyl chloride or alkyl chloride, in presence of a suitable base, such as DIPEA or TEA, in an appropriate solvent such as ACN or DCM.Scheme 2

[0089] Scheme 2 depicts the preparation of the triazine intermediate (i) beginning with a suitable triazine amine (vii). The triazine amine (vii) is reacted with methylboronic acid under Suzuki coupling conditions in presence of an appropriate Pd catalyst, such as Pd(dppf)C12, and a suitable base, such as K3PO4, in an appropriate mixture of solvent, such as dioxane and H2O, at 100 °C for 12 h. Following the protection of the amine (viii) under conditions well known to the skilled artisan, intermediate (ix) is reacted with l,3,5-trichloro-l,3,5-triazinane-2,4,6-trione, in a suitable solvent, such as DCE, at 70 °C for 12 h. The triazine (x) and protected lactam (xi) are reacted under standard nucleophilic substitution conditions and include a suitable base, such as CS2CO3, in an appropriate solvent, such as THF. Following the deprotection of the amines of intermediate (xii) under acidic conditions well known to the skilled person, the ester (xiii) ishydrolyzed in presence of a suitable base, such as LiOH, in an appropriate mixture of solvents, such as THF and H2O. The triazine intermediate (i) is generated under decarboxylation conditions and include reacting (xiv) with NaCl in a suitable solvent, such as DMF, at 100 °C for 12 h.

[0090] Scheme 3 depicts an alternative preparation of the triazine intermediate (i) beginning with a suitable piperidone (xv). The piperidone (xv) is reacted in the presence of TMSC1, TMEDA and I2 in an appropriate solvent, such as toluene, at 0 °C for 2 h. The resulting intermediate (xvi) is reacted with a suitable phosphite, such as triethyl phosphite, in an appropriate solvent, such as toluene, at 100 °C for 12 h, under N2 atmosphere. The ylide (xvii) and the aldehyde (xviii) are reacted under Wittig-Homer conditions and include a suitable base, such as KOtBu, in an appropriate solvent, such as THF. The olefin intermediate (xix) is reacted under hydrogenation conditions and include H2, NH3 MeOH and Pd / AhCh, in a suitable mixtureof solvents, such as DCM and MeOH. Following the rearomatization of the triazine (xx) into the intermediate (xxi), which was deprotected under acidic conditions with an appropriate acid, such as TFA, in a suitable solvent, such as DCM, to provide the triazine intermediate (i).PREPARATIONSPreparation 12-chloro- 1 -(3 , 3 -difluoroazetidin- 1 -yl)ethan- 1 -one

[0091] To a solution of 3,3-difluoroazetidine (300 mg, 2.32 mmol, 1.00 eq, HC1) and K2CO3 (960 mg, 6.95 mmol) in DCM (3 mL) was added 2-chloroacetyl chloride (262 mg, 2.32 mmol, 184 pL) at 0 °C and stirred at 25 °C for 1 h, after the reaction was completed, the reaction mixture was partitioned between H2O (10 mL) and DCM (30 mL x 2). The organic phase was separated, the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title product (220 mg, 1.30 mmol, 56%) as a white solid. ES / MS (m / z): 170 (M+H).Preparation 2 tert-butyl ((4-(2-chloroacetyl)morpholin-3-yl)methyl)carbamate

[0092] To a solution of tert-butyl (morpholin-3-ylmethyl)carbamate (5.00 g, 23.1 mmol) in DCM (50 mL) were added DIPEA (5.98 g, 46.2 mmol, 8.05 mL) and 2-chloroacetyl chloride (3.92 g, 34.7 mmol, 2.76 mL). The mixture was stirred at 0 °C for 1 h. The reaction mixture wasdiluted with H2O (60 mL) and extracted with DCM (40 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, PE / EtOAc) to afford the title product (5.00 g, 17.08 mmol, 74%) was obtained as a yellow oil. ES / MS (m / z): 193 (M-99).Preparation 3 tert-butyl 6-oxohexahydropyrazino[2,l-c][l,4]oxazine-8(lH)-carboxylate

[0093] To a solution of tert-butyl ((4-(2-chloroacetyl)morpholin-3-yl)methyl)carbamate (5.00 g, 17.08 mmol) in THF (200 mL) was added NaH (1.37 g, 34.16 mmol, 60% purity) at 0 °C. The mixture was stirred at 40 °C for 1 h under N2 atmosphere. The reaction mixture was quenched by addition H2O (20 mL) at 0 °C, and then diluted with H2O (400 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were dried over anhydrous ISfeSCU, filtered and concentrated under reduced pressure to afford the title product (4.30 g, 16.78 mmol, 98%) as yellow oil. ES / MS (m / z): 201 (M-55).Preparation 4 benzyl (S)-4-oxohexahydropyrazino[2,l-c][l,4]oxazine-8(lH)-carboxylate

[0094] To a solution of (S)-hexahydropyrazino[2,l-c][l,4]oxazin-4(3H)-one hydrogen chloride (480 mg, 2.49 mmol) in THF (4 mL) and H2O (2 mL) were added NaHCCL (628 mg, 7.47 mmol, 291 pL) and CbzOSu (1.24 g, 4.98 mmol) at 0 °C, the reaction mixture was stirred at 25 °C for 2 h. After the reaction was finished, the reaction mixture was diluted with H2O (30 mL) and extracted with a mixture of DCM and MeOH (DCM: MeOH = 10: 1; 30 mL x 3). Then the organic layers were dried over anhydrous ISfeSCU, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge150x25 mm 10 um; mobile phase: [H2O (NH4HCO3) - ACN]; gradient: 20% - 50% B over 10 min) to provide the title product (500 mg, 1.72 mmol, 69%) as a white solid. ES / MS (m / z): 291 (M+H).

[0095] The following was prepared essentially as described in Preparation 4 using the appropriate amine.Preparation 6 hexahydropyrazino[2,l-c][l,4]oxazin-6(lH)-one HC1

[0096] tert-Butyl 6-oxohexahydropyrazino[2,l-c][l,4]oxazine-8(lH)-carboxylate (4.3 g, 16.78 mmol) in HCI (2M in dioxane) (41.9 mL) was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford the title product (3.20 g, 16.6 mmol, 99%, HCI) as a yellow solid. ES / MS (m / z): 157 (M+H).Preparation 7(S)-hexahydropyrazino[2, 1 -c] [ 1 ,4]oxazin-4(3H)-one

[0097] To a solution of benzyl (S)-4-oxohexahydropyrazino[2,l-c][l,4]oxazine-8(lH)- carboxylate (490 mg, 1.69 mmol) in THF (5 mL) was added Pd / C (50.0 mg, 47.0 mol, 10.0% purity) under N2 atmosphere, then degassed and purged with H2 3 times and stirred at 25 °C for 1 h (15 psi). After the reaction finished, the reaction mixture was filtered and washed with MeOH (30 mL), then the filtrate was concentrated under reduced pressure to give the title product (260 mg, 1.66 mmol, 99%) as a colorless oil. ES / MS (m / z): 157 (M+H).

[0098] The following was prepared essentially as described in Preparation 7 using the appropriate protected amine.Preparation 98-benzylhexahydropyrazino[2,l-c][l,4]oxazin-6(lH)-one

[0099] To a solution of hexahydropyrazino[2,l-c][l,4]oxazin-6(lH)-one hydrochloride (3.20 g, 16.61 mmol) in DMF (30 mL) were added anhydrous ISfeCCh (4.59 g, 33.22 mmol) and benzyl bromide (4.26 g, 24.9 mmol, 2.96 mL). The mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with H2O (100 mL x 2), dried over anhydrous ISfeSCU, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, PE:EtOAc) to afford the title product (2.60 g, 10.5 mmol, 64%) was obtained as yellow oil. ES / MS (m / z): 247 (M+H).Preparation 108'-benzylhexahydro- 1 'H-spiro[cyclopropane- 1 ,6'-pyrazino[2, 1 -c] [ 1 ,4]oxazine][000100] To a solution of 8-benzylhexahydropyrazino[2,l-c][l,4]oxazin-6(lH)-one (500 mg, 2.03 mmol) and Ti(zPrO)4 (1.15 g, 4.06 mmol, 1.20 mL) in THF (10 mL) was added ethylmagnesium bromide (3M, 2.03 mL) at -70 °C, then the reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was quenched by addition H2O (20 mL) at 0 °C, and then extracted with EtOAc (20 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150x25 mmx lO um; mobile phase: [H2O (FA) - ACN]; gradient: 0% - 30% B over 10 min) to afford the title product (80.0 mg, 309.65 pmol, 15%) was obtained as colorless oil. ES / MS (m / z): 259 (M+H).Preparation 11 hexahydro- 1 'H-spiro[cyclopropane- 1 ,6'-pyrazino[2, 1 -c] [ 1 ,4]oxazine][000101] A solution of 8'-benzylhexahydro-l'H-spiro[cyclopropane-l,6'-pyrazino[2,l- c][ 1,4] oxazine] (30.0 mg, 116 pmol) and Pd / C (10.0 mg, 15% purity) in THF (2 mL) was degassed and purged with H2 3 times, and then the mixture was stirred at 20 °C for 2 h under H2 (15 Psi) atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to afford the title product (19.0 mg, 112.94 mol, 97%) as yellow oil.JH NMR (400 MHz, CDCI3) 8 3.82-3.78 (m, 1H), 3.62-3.49 (m, 4H), 3.42-3.28 (m, 2H), 3.11-3.00 (m, 2H), 2.48-2.32 (m, 2H), 0.91-0.71 (m, 3H), 0.59-0.54 (m, 1H).Preparation 12 methyl 1 -(( / c77-butoxycarbonyl )(methyl )ami no)-3 ,3 -difluorocyclobutane- 1 -carboxylate[000102] To a solution of l -(( / c / 7-butoxycarbonyl)amino)-3,3-difluorocyclobutane- l - carboxylic acid (5.00 g, 19.9 mmol) in DMF (50 mL) was added NaH (1.99 g, 49.7 mmol, 60% purity) at 0 °C under N2 and stirred at 0 °C for 0.5 h, then ICH3 (8.47 g, 59.7 mmol, 3.72 mL)was added at 0 °C, the mixture was stirred at 25 °C for 2 h under N2 atmosphere. The reaction mixture was diluted with and H2O, extracted with EtOAc, the combined organic layers were washed with H2O, sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column (SiO2, PEZEtOAc) to afford the title product (4.50 g, 16.1 mmol, 81%) as yellow oil.JH NMR (400 MHz, CDCI3) S 3.78 (s, 3H), 3.26 - 3.16 (m, 2H), 2.99 - 2.93 (m, 5H), 1.43 (s, 9H).Preparation 13 methyl 3 ,3 -difluoro- 1 -(methylamino)cyclobutane- 1 -carboxylate[000103] To a solution of methyl l-((terLbutoxycarbonyl)(methyl)amino)-3,3- difluorocy cl obutane-1 -carboxylate (4.50 g, 16.1 mmol) in DCM (40 mL) was added TFA (18.3 g, 161 mmol, 11.9 mL), the mixture was stirred at 25 °C for 4 h. The reaction mixture was diluted with sat. aq. NaHCCL, extracted with EtOAc, the combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title product (2.20 g, 12.2 mmol, 76%) as yellow oil.1H NMR (400 MHz, CDCI3) d 3.80 (s, 3H), 3.08 - 2.99 (m, 2H), 2.69 - 2.60 (m, 3H), 2.32 (s, 3H).Preparation 14 methyl l-(2-(((benzyloxy)carbonyl)amino)-N-methylacetamido)-3,3-difluorocyclobutane-l- carb oxy late[000104] To a solution of methyl 3, 3 -difluoro- l-(methylamino)cy cl obutane-1 -carboxylate (2.10 g, 11.7 mmol) and ((benzyloxy)carbonyl)glycine (2.94 g, 14.0 mmol) in DCM (20 mL) were added DIPEA (7.57 g, 58.6 mmol, 10.2 mL) and T4P (50% EtOAc solution, 16.8 g, 23.4 mmol). The reaction mixture was stirred at RT for 1 h. The reaction mixture was then diluted with H2O and extracted with EtOAc. The combined organic layers were washed with H2O then sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reducedpressure to give a residue, and the residue was purified by Prep-HPLC (column: Phenomenex luna C18 (250^70 mm, 10 um); mobile phase: [H2O (FA) - ACN]; gradient: 40% - 70% B over 20 min) to afford the title product (2.10 g, 5.67 mmol, 48%) as yellow oil. ES / MS (m / z): 371 (M+H).Preparation 152, 2-difluoro-5-methyl-5,8-diazaspiro[3.5]nonane-6, 9-dione[000105] To a solution of methyl l-(2-(((benzyloxy)carbonyl)amino)-N-methylacetamido)- 3,3-difluorocyclobutane-l-carboxylate (2.10 g, 5.67 mmol) in MeOH (30 mL) was added Pd / C (0.500 g, 469 pmol, 10% purity) under N2 atmosphere, then degassed and purged with H2 3 times, the mixture was stirred at 25 °C for 12 h under H2 (50 psi). The mixture was filtered and concentrated to afford the title product (1.00 g, 4.90 mmol, 86%) as white solid. ’H NMR (400 MHz, CDC13) <5 7.17 (s, 1H), 4.05 (d, J = 1.6 Hz, 2H), 3.57 - 3.50 (m, 2H), 3.15 (s, 3H), 3.11 - 3.02 (m, 2H).Preparation 16 2,2-difluoro-5-methyl-5,8-diazaspiro[3.5]nonane[000106] To a solution of 2, 2-difluoro-5-methyl-5,8-diazaspiro[3.5]nonane-6, 9-dione (900 mg, 4.41 mmol) in THF (10 mL) was added LAH (2.5 M, 7.05 mL) at 0 °C under N2 atmosphere, the mixture was stirred at 70 °C for 1 h under N2 atmosphere. The mixture was quenched by addition 0.67 mL H2O, 0.67 mL 15% aq. NaOH, 2.01 mL H2O at 0 °C, then was added MgSCh and stirred for 0.5 h. The mixture was filtered and concentrated to afford the title product (600 mg, 3.41 mmol, 77%) as yellow oil. 'HNMR (400 MHz, CDCI3) d 2.76 - 2.72 (m, 4H), 2.36 - 2.33 (m, 2H), 2.29 - 2.27 (m, 1H), 2.25 (s, 3H), 2.23 - 2.19 (m, 1H).Preparation 17benzyl (R)-7,7-difluorohexahydropyrrolo[l,2-a]pyrazine-2(lH)-carboxylate[000107] To a solution of (R)-7,7-difluorooctahydropyrrolo[l,2-a]pyrazine HC1 (900 mg, 4.53 mmol) in THF (9 mL) and H2O (9 mL) were added K2CO3 (1.88 g, 13.6 mmol), benzyl (2,5- dioxopyrrolidin-l-yl) carbonate (1.69 g, 6.80 mmol), the mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, which was purified by Prep-HPLC (column: Waters xbridge 150x25 mm 10 um; mobile phase: [H2O (NH4OH v / v) - ACN]; gradient: 40% - 70% B over 9 min) to afford the title product (900 mg, 3.04 mmol, 67%) as yellow oil. ES / MS (m / z): 297 (M+H).Preparation 18 benzyl (S)-7,7-difluorohexahydropyrrolo[l,2-a]pyrazine-2(lH)-carboxylate[000108] To a solution of (S)-7,7-difluorooctahydropyrrolo[l,2-a]pyrazine HC1 (900 mg, 4.53 mmol) in THF (9 mL), H2O (9 mL) were added K2CO3 (1.88 g, 13.6 mmol), benzyl (2,5- dioxopyrrolidin-l-yl) carbonate (1.69 g, 6.80 mmol), the mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by Prep-HPLC (column: Waters xbridge 150x25 mm 10 um; mobile phase: [H2O (NH4OH v / v) - ACN]; gradient: 40% - 70% B over 9 min) to afford the title product (900 mg, 3.04 mmol, 67%) as yellow oil. ES / MS (m / z): 297 (M+H).Preparation 19 (S)-7,7-difluorooctahydropyrrolo[l,2-a]pyrazine[000109] To a solution of benzyl (S)-7,7-difluorohexahydropyrrolo[l,2-a]pyrazine-2(lH)- carboxylate (900 mg, 3.04 mmol) in THF (9 mL) was added Pd / C (323 mg, 304 pmol, 10.0%purity) under N2 atmosphere, then degassed and purged with H2 three times, the mixture was stirred at 25 °C for 2 h (15 psi). The reaction mixture was filtered with THF (10 mL) and the filtrate was concentrated under reduced pressure to afford the title product (410 mg, 2.53 mmol, 83%) as a yellow solid. ES / MS (m / z): 163 (M+H).Preparation 20 (R)-7,7-difluorooctahydropyrrolo[l,2-a]pyrazine[000110] To a solution of benzyl (R)-7,7-difluorohexahydropyrrolo[l,2-a]pyrazine-2(lH)- carboxylate (900 mg, 3.04 mmol) in THF (9 mL) was added Pd / C (323 mg, 304 mol, 10.0% purity) under N2 atmosphere, then degassed and purged with H2 three times, the mixture was stirred at 25 °C for 2 h (15 psi). The reaction mixture was filtered with THF (10 mL) and the filtrate was concentrated under reduced pressure to afford the title product (412 mg, 2.54 mmol, 84%) as a yellow solid. ES / MS (m / z): 163 (M+H).Preparation 21 benzyl (R)-5-methyl-4,7-diazaspiro[2.5]octane-7-carboxylate[000111] A solution of (R)-5-methyl-4,7-diazaspiro[2.5]octane dihydrochloride (800 mg, 4.02 mmol) in THF (8 mL) and H2O (4 mL) were added NaHCCL (675 mg, 8.04 mmol, 313 pL) and benzyl (2,5-dioxopyrrolidin-l-yl) carbonate (1.00 g, 4.02 mmol) at 0 °C, the reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with H2O (30 mL) and extracted with a mixture of DCM and MeOH (DCM: MeOH = 10: 1; 30 mL x 3). Then the organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by Prep-TLC (SiCh, DCM: MeOH = 10: 1) to the title product (750 mg, 2.88 mmol, 72%) as yellow oil. ES / MS (m / z): 261 (M+H).Preparation 227-benzyl 4-( / c / 7-butyl) (R)-5-methyl-4,7-diazaspiro[2.5]octane-4,7-dicarboxylate[000112] A solution of benzyl (R)-5-methyl-4,7-diazaspiro[2.5]octane-7-carboxylate (560 mg, 2.15 mmol) in DCM (5 mL) was added BOC2O (4.69 g, 21.5 mmol, 4.94 mL) and DIPEA (2.78 g, 21.5 mmol, 3.75 mL), the reaction mixture was stirred at 25 °C for 4 h. filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCh, PE: EtOAc = 3 : 1) to afford the title product (760 mg, 2.11 mmol, 98%) as yellow oil. ES / MS (m / z): 361 (M+H).Preparation 23 ter -butyl (R)-5-methyl-4,7-diazaspiro[2.5]octane-4-carboxylate[000113] To a solution of 7-benzyl 4-(tert-butyl) (R)-5-methyl-4,7-diazaspiro[2.5]octane- 4,7-dicarboxylate (730 mg, 2.03 mmol) in THF (8 mL) was added Pd / C (70.0 mg, 65.8 mol, 10.0% purity) under N2 atmosphere, then degassed and purged with H2 three times, the mixture was stirred at 25 °C for 1 h (15 psi). The reaction mixture was filtered, and concentrated under reduced pressure to afford the title product (450 mg, 1.99 mmol, 98%) as yellow oil. ES / MS (m / z): 227 (M+H).Preparation 24 methyl (l-(((tert-butoxycarbonyl)amino)methyl)cyclopropyl)alaninate[000114] To a solution of methyl 2-hydroxypropanoate (2.91 g, 27.9 mmol, 2.66 mL) in DCM (40 mL) were added trifluoromethanesulfonic anhydride (7.88 g, 27.9 mmol, 4.61 mL) and 2,6-lutidine (2.99 g, 27.9 mmol, 3.25 mL), the mixture was stirred at 0 °C for 10 min. Next, the mixture was added a solution of terLbutyl ((l-aminocyclopropyl)methyl)carbamate (4.00 g, 21.4 mmol) and TEA (2.93 g, 28.9 mmol, 4.04 mL) in DCM (20 mL) and furtherly stirred at 25 °C for 6 h. The reaction mixture was concentrated under reduced pressure to give a residue, which waspurified by column chromatography (SiO2, PE: EtOAc = 1 : 1) to afford the title product (3.00 g, crude) as a white solid.Preparation 25 methyl N-(l-(((tert-butoxycarbonyl)amino)methyl)cyclopropyl)-N-methylalaninate[000115] To a solution of methyl ( l -((( / c / 7- butoxycarbonyl)amino)methyl)cyclopropyl)alaninate (2.80 g, 10.2 mmol) in MeOH (30 mL) were added formaldehyde (9.08 g, 102 mmol, 8.33 mL, 34.0% purity), AcOH (617 mg, 10.2 mmol, 588 pL) and NaBJLCN (1.29 g, 20.5 mmol). The mixture was stirred at 25 °C for 5 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCL, PE: EtOAc = 1 : 1) to afford the title product (1.00 g, crude) as a white solid. ‘H NMR (400 MHz, CDCI3). 3 5.14 (brs, 1H), 3.72 (s, 3H), 3.67 (q, J = 6.4 Hz, 1H), 3.18 - 3.14 (m, 2H), 2.45 (s, 3H), 1.44 (s, 9H), 1.28 (d, J = 6.4 Hz, 3H), 0.61 - 0.67 (m, 4H).Preparation 26 methyl N-(l -(aminomethyl)cyclopropyl)-N-methylalaninate[000116] To a solution of methyl N-(l-(((terLbutoxycarbonyl)amino)methyl)cyclopropyl)- N-methylalaninate (0.500 g, 1.75 mmol) in DCM (2 mL) was added TFA (3.07 g, 26.9 mmol, 2 mL). The mixture was stirred at 35 °C for 1.5 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was to afford the title product (0.500 g, crude, TFA) as a white solid.Preparation 274,5-dimethyl-4,7-diazaspiro[2.5]octan-6-one[000117] To a solution of methyl N-(l-(aminomethyl)cyclopropyl)-N-methylalaninate (0.500 g, 1.67 mmol, TFA) in DCM (5 mL) was added NaOH (5M, 3.64 mL) and stirred at 25 °C for 0.5 h. Then the mixture was added K2CO3 (5.00 g, 36.1 mmol) and futher stirred at 25 °C for 0.5 h. The reaction mixture was added MgSCU (5.00 g), filtered and concentrated under reduced pressure to the title product (0.400 g, crude) as a white solid.JH NMR (400 MHz, CDCI3). <5 3.89 - 3.80 (m, 2H), 3.19 - 3.09 (m, 2H), 2.79 - 2.67 (m, 2H), 1.40 (s, 9H), 1.25 (d, J = 8.0 Hz, 6H).Preparation 28 4,5-dimethyl-4,7-diazaspiro[2.5]octane[000118] To a solution of 4,5-dimethyl-4,7-diazaspiro[2.5]octan-6-one (385 mg, 2.50 mmol) in THF (5 mL) was added LAH (2.5M, 2 mL) and stirred at 40 °C for 1 h under N2 atmosphere. After the reaction finished, to the reaction mixture was added H2O (200 mg), NaOH (15%, 200 mg) and H2O (600 mg) in turn at 0 °C, followed by the addition of anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title product (0.330 g, crude) as a white solid. ES / MS (m / z): 141 (M+H).Preparation 29( 1 -(tri fluoromethyl)cy cl opropyl)m ethanolEW53 192-100[000119] To the flow reactor 1 was added a solution of 1- (trifluoromethyl)cyclopropanecarboxylic acid (500 g, 3.24 mol) in THF (1000 mL) and BH3 THF complex (IM, 6.49 L). The temperature of flow reactor 1 was set at 80 °C. The flow rate of pump 1 was adjusted to 15 mL / min for solution 1. The mixture was collected with a bottle contained aq. NH4CI solution. The reaction mixture was collected after running 180 min. The reaction mixture was diluted with H2O and extracted with EtOAc, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (250 g, 1.78 mol, 55%) as a yellow oil. 'HNMR (400 MHz, CDCI3) d 3.72 (s, 2H), 1.10 - 0.95 (m, 2H), 0.83 - 0.70 (m, 2 H).Preparation 303 , 3 ,3 -trifluoro-2,2-dimethylpropan- 1 -ol[000120] A first solution of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (280 g, 1.79 mol) in THF (2800 mL) was pumped by Pump 1 {SI, Pl, 20 mL / min} to a flow reactor {FLR1, GL, CSTRs, 90 mL, 25 °C}. A second solution of LAH (2.5 M, 1.43 L) was pumped by Pump 2 {S2,P2,10 mL / min } to the flow reactor {FLR1,GL, CSTRs, 90 mL,25 °C}. The residence time of flow reactor 1 was {FLR1, 3 min}. The mixture was collected with a bottle. The Pump 1 and Pump 2 was started at the same time. The mixture was quenched by H2O (137 mL), 15% aq. NaOH solution (137 mL), H2O (411 mL) at 0 °C. Then 800 g anhydrous ISfeSCU was added to the mixture. After stirring at 25 °C for 15 min, the mixture was filtered and the filtrate was concentrated under reduced pressure to afford the title product (170 g, 1.20 mol, 67%) as colorless oil. 'HNMR (400 MHz, CDCI3) 8 3.60 (s, 2H), 1.73 (s, 1H), 1.14 (s, 6H).Preparation 31 l-(trifluoromethyl)cyclopropane-l-carbaldehyde[000121] To a solution of methyl sulfmylmethane (87.0 g, 1.11 mol, 87 mL) in DCM (9 mL) was added oxalyl dichloride (70.6 g, 556 mmol, 48.7 mL). The mixture was stirred at -70 °C for 0.5 h. Then l-(trifluoromethyl)cyclopropyl)methanol (60.0 g, 428 mmol) in DCM (1 mL) was added and the mixture was stirred at -70 °C for 0.5 h. To the mixture was then added TEA (212 g, 2.10 mol, 292 mL). The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was diluted with H2O and washed with sat. aq. NaCl solution, the combined organic layers were dried over anhydrous ISfeSCU to afford the title product (59.0 g, crude) as a yellow oil.1H NMR (400 MHz, CDCI3) d 9.68 (s, 1H), 1.28 - 1.15 (m, 2H), 0.83 - 0.80 (m, 2H).[000122] The following was prepared essentially as described in Preparation 31 using the appropriate alcohol.Preparation 33 ethyl 3-(l-(trifluoromethyl)cyclopropyl)acrylate[000123] A mixture of l-(trifluoromethyl)cyclopropane-l-carbaldehyde (59.0 g, 427 mmol), ethyl 2-(dimethoxyphosphoryl)acetate (92.1 g, 469 mmol), DBN (58.3 g, 469 mmol, 56.2 mL), LiCl (19.9 g, 469 mmol, 9.63 mL) in DCM (600 mL) was stirred at 20 °C for 4 h. The reaction mixture was diluted with H2O and extracted with EtOAc, dried over anhydrous ISfeSCU, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCh, PEZEtOAc) to afford the title product (43.0 g, 206 mmol, 48%) as a yellow oil.XH NMR (400 MHz, CDCI3) 3 6.70, (d, J= 16.0 Hz, 1H), 5.88 (d, J= 16.0 Hz, 1H), 4.21 (q, J= 6.8 Hz, 2H), 1.43 - 1.37 (m, 2H), 1.30 (t, J= 7.2 Hz, 3H), 1.07 - 1.01 (m, 2H).[000124] The following was prepared essentially as described in Preparation 33 using the appropriate aldehyde.Preparation 35 ethyl 3-(l-(trifluoromethyl)cyclopropyl)propanoate[000125] To a solution of Pd / C (5.11 g, 4.80 mmol, 10.0 % purity) in THF (200 mL) was added ethyl 3-(l-(trifluoromethyl)cyclopropyl)acrylate (20.0 g, 96.0 mmol). The mixture was stirred at 20 °C under H2 atmosphere for 3 h. The reaction mixture was filtered and the cake was washed with MeOH. The filtrate was concentrated under reduced pressure to afford the title product (12.0 g, 57.0 mmol, 59%) as a white oil. 'HNMR (400 MHz, CDCI3) d 4.14 (q, J= 7.2 Hz, 2 H), 2.49 (t, J= 7.6 Hz, 2H), 1.90 (t, J= 8.0 Hz, 2H), 1.27 (t, J= 7.2 Hz, 3H), 1.00 - 0.96 (m, 2H), 0.65 - 0.62 (m, 2H).Preparation 36 ethyl 5,5,5-trifluoro-4,4-dimethylpentanoate[000126] To a solution of PtCh (24.6 g, 108 mmol) in THF (1800 mL) was added ethyl 5,5,5-trifluoro-4,4-dimethylpent-2-enoate (190 g, 903 mmol). The reaction mixture was stirred at 35 °C under H2 (15 psi) for 20 h. The residue was filtered and concentrated under reduced pressure to afford the title product (170 g, 801 mmol, 89%) as yellow oil.1H NMR (400 MHz, CDCI3) 8 6.97 (d, J = 16.0 Hz, 1H), 5.98 (d, J = 16.0 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 1.34 - 1.28 (m, 9H).Preparation 373 -( 1 -(trifluoromethyl)cy clopropyl)propan- 1 -ol[000127] Ethyl 3-(l-(trifluoromethyl)cyclopropyl)propanoate (20.0 g) was dissolved in THF (240 mL) (solution 1). LAH (2.50 M, 7.22 g) (solution 2). The solution 1 was pumped by pump 1 {SI, Pl, 22.5 mL / min} to flow reactor 1 {FLR1, PF A, Coils reactor, 3.175 (1 / 8”) mm, 60 mL, 25 °C}. The solution 2 was pumped by pump 2 {S2, P2, 7.492 mL / min} to flow reactor 1 {FLR1, PF A, Coils reactor, 3.175 (1 / 8”) mm, 60 mL, 25 °C}. The residence time of flow reactor 1 was 2 min. The mixture was collected with a bottle contained ISfeSCU . 10 FEO. The Pump 2 was started, after 2 min Pump 1 was started, the reaction time was 30 min. The reaction mixture was filtered and the cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to afford the title product (15.0 g, 89.2 mmol, 94%) as a white oil.JH NMR (400 MHz, CDC13) d 3.65 (t, J= 6.0 Hz, 2H), 1.75 - 1.63 (m, 4H), 0.98 - 0.92 (m, 2H), 0.65 - 0.58 (m, 2H). [000128] The following was prepared essentially as described in Preparation 37 using the appropriate ester.Preparation 393-(l-(trifluoromethyl)cyclopropyl)propanal[000129] To a solution of methyl sulfinylmethane (19.3 g, 247 mmol, 19.3 mL) in DCM(160 mL) was added oxalyl dichloride (15.7 g, 123 mmol, 10.8 mL) at -70 °C and stirred at -70°C for 0.5 h. Then added a solution of 3-(l-(trifluoromethyl)cyclopropyl)propan-l-ol (16.0 g, 95.1 mmol) in DCM (40 mL) at -70 °C and the mixture was stirred for 0.5 h. Finally, TEA was added (47.1 g, 466 mmol, 64.8 mL) at -70 °C and the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was diluted with H2O. The organic layers were washed with H2O, dried over anhydrous Na2SO4 to afford the title product (15.8 g, 95.1 mmol, 100%) as a yellow oil. ’H NMR (400 MHz, CDCI3) d 9.80 (s, 1H), 2.68 (t, J= 7.6 Hz, 2H), 1.92 - 1.88 (m, 2H), 1.00 - 0.97 (m, 2H), 0.63 - 0.52 (m, 2H).[000130] The following was prepared essentially as described in Preparation 39 using the appropriate alcohol.Preparation 41(S,E)-2-methyl-N-(3-(l-(trifluoromethyl)cyclopropyl)propylidene)propane-2-sulfinamide[000131] To a solution of 3-(l-(trifluoromethyl)cyclopropyl)propanal (15.0 g, 90.2 mmol) in DCE (150 mL) and DCM (150 mL) were added CuSCL (43.2 g, 270 mmol, 41.5 mL) and (S)- 2-methylpropane-2-sulfinamide (21.8 g, 180 mmol). The mixture was stirred at 60 °C for 8 h.The reaction mixture was filtered and washed with EtOAc. The filtrate was diluted with H2O and extracted with EtOAc, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PEZEtOAc) to afford the title product (13.0 g, 48.2 mmol, 53%) as a yellow oil. 'H NMR (400 MHz, CDCI3) d8.08 (t, J = 4.0 Hz, 1H), 2.74 - 2.67 (m, 2H), 1.93 - 1.87 (m, 2H), 1.20 - 1.17 (m, 9H), 1.03 - 0.99 (m, 2H), 0.66 - 0.56 (m, 2H).Preparation 42(S,Z)-2-methyl-N-(5,5,5-trifluoro-4,4-dimethylpentylidene)propane-2-sulfmamide[000132] To a solution of 5,5,5-trifluoro-4,4-dimethylpentanal (30.0 g, 178 mmol) in THF (300 mL) were added Ti(OEt)4 (109 g, 481 mmol, 99.8 mL) and (S)-2-methylpropane-2- sulfinamide (54.0 g, 446 mmol). The reaction mixture was stirred at 25 °C for 10 h. The reaction mixture was diluted with EtOAc and H2O. Then anhydrous MgSCh was added to the mixture. The mixture was stirred at 25 °C for 0.5 h. Then the mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCh, PEZEtOAc) to afford the title product (32.0 g, 117 mmol, 66%) as a yellow solid. ES / MS (m / z): 272 (M+H).Preparation 43(S)-N-((S)- 1 -cyano-3 -( 1 -(trifluoromethyl)cyclopropyl)propyl)-2-methylpropane-2-sulfmamide[000133] A mixture of (S,E)-2-methyl-N-(3-(l- (trifluoromethyl)cyclopropyl)propylidene)propane-2-sulfmamide (13.0 g, 48.2 mmol), TMSCN (19.1 g, 193 mmol, 24.1 mL), H2O (1.74 g, 96.5 mmol, 1.74 mL) and CsF (1.47 g, 9.65 mmol) in DCM (130 mL) was degassed and purged with N2 3 times at 0 °C, and then the mixture was stirred at 25 °C under N2 atmosphere for 12 h. The reaction mixture was diluted with H2O and extracted with EtOAc, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PEZEtOAc) to afford the title product (10.0 g, 31.1 mmol, 65%) as a yellow oil. H NMR (400 MHz, CDCI3) d4.22 - 4.21 (m, 1H), 4.18 (d, J= 7.2 Hz, 1H), 2.14 - 2.06 (m, 2H), 1.83 - 1.70 (m, 2H), 1.26 - 1.25 (m, 9H), 1.03 (s, 2H), 0.67 - 0.60 (m, 2H).[000134] The following was prepared essentially as described in Preparation 43 using the appropriate sulfinamide.Preparation 45(S)-2-amino-4-( l -(tri 11 uoromethyl)cyclopropyl (butanoic acid[000135] To a solution of (S)-N-((S)-l-cyano-3-(l-(trifluoromethyl)cyclopropyl)propyl)-2- methylpropane-2-sulfmamide (10.0 g, 31.1 mmol) in HC1 (1 mL) and AcOH (10 mL). The mixture was stirred at 80 °C for 3.5 h. The reaction mixture was concentrated under reduced pressure to afford the title product (7.00 g, crude, HC1) as a yellow oil. ES / MS (m / z): 212 (M+H).[000136] The following was prepared essentially as described in Preparation 45 using the appropriate sulfinamide.Preparation 49(S)-2-(((benzyloxy)carbonyl)amino)-4-(l-(trifluoromethyl)cyclopropyl)butanoic acid[000137] A mixture of (S)-2-amino-4-(l-(trifluoromethyl)cyclopropyl)butanoic acid (6.40 g, 30.3 mmol), benzyl (2,5-dioxopyrrolidin-l-yl) carbonate (11.3 g, 45.4 mmol), K2CO3 (12.5 g, 90.9 mmol) and H2O (20 mL) in THF (100 mL) was stirred at 20 °C under N2 atmosphere for 1 h. The reaction mixture was quenched by IM aq. HC1 (50 mL) at 0 °C, and then diluted with H2O and extracted with EtOAc. The combined organic layer was dried over anhydrous ISfeSCU, filtered and concentrated under reduced pressure to give a residue, which was purified by prep- HPLC (column: Phenomenex luna C18 (250^70 mm, 10 um); mobile phase: [H2O (FA) - ACN];gradient: 34% - 64% B over 20 min) to afford the title product (8.00 g, 22.5 mmol, 78% yield) as a yellow solid. ES / MS (m / z): 346 (M+H)[000138] The following was prepared essentially as described in Preparation 49 using the appropriate amine.Preparation 53 benzyl (S)-(l-(dimethyl(oxo)-16-sulfaneylidene)-2-oxo-5-(l-(trifluoromethyl)cyclopropyl)pentan-3-yl)carbamate[000139] Trimethylsulfoxonium iodide (2.78 g, 12.6 mmol) in THF (30 mL) was added to a solution of KO / Bu (IM, 12.6 mL) and the resulting mixture was stirred at 25 °C for 1 h to obtain a first mixture. To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-4-(l- (trifluoromethyl)cyclopropyl)butanoic acid (3.00 g, 8.44 mmol) in THF (30 mL) was added CDI (1.78 g, 10.9 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for 1 h. The suspension was then filtered and the filtrate was cooled to 25 °C to obtain a second mixture. The second mixture was added to the first at 25 °C. The resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over anhydrous ISfeSCU, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (Si O2, PEZEtOAc) and then was purified by prep-HPLC (column: Phenomenex luna C 18 (250^70 mm, 10 um); mobile phase: [H2O (FA) - ACN]; gradient: 40% - 70% B over 30 min). Then residue was purified by prep-SFC (column: DAICEL CHIRALPAK AD (250 mmx30 mm, 10 um); mobile phase: [CO2- EtOH (0.1% NH3H2O)]; B%:45%, isocratic elution mode) to afford the title product (2.80 g, 6.43 mmol, 61%) as a yellow solid. ES / MS (m / z): 420 (M+H).[000140] The following was prepared essentially as described in Preparation 53 using the appropriate carboxylic acid.Preparation 57 tert-butyl (S)-4-(((benzyloxy)carbonyl)amino)-4-cycloheptyl-3-oxobutanoate[000141] A solution of (S)-2-(((benzyloxy)carbonyl)amino)-2-cycloheptylacetic acid (56.0 g, 183 mmol) and CDI (32.7 g, 201 mmol) in THF (600 mL) was stirred at 0 °C for 2 h.Meanwhile, to a solution of tert-butyl acetate (63.9 g, 550 mmol, 73.7 mL) in THF (500 mL) was added a solution of LDA (2M, 275 mL) and the reaction mixture was stirred at -78 °C for 2 h.The two reaction mixtures were mixed and stirred at -78 °C for 2 h. The reaction mixture was quenched by the addition of sat. aq. NH4CI solution and extracted with EtOAc, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiCL, PE / EtOAc) to afford the title product (36.0 g, 89.2 mmol, 49%) as a white solid. ES / MS (m / z): 426 (M+Na).Preparation 58 tert-butyl (4S)-4-(((benzyloxy)carbonyl)amino)-2-bromo-4-cycloheptyl-3-oxobutanoate[000142] To a solution of tert-butyl (S)-4-(((benzyloxy)carbonyl)amino)-4-cycloheptyl-3- oxobutanoate (36.0 g, 89.2 mmol) in MeOH (400 mL) was added NBS (13.5 g, 75.8 mmol) and 2,6-dimethylpyridine (771 mg, 7.14 mmol) at 0 °C. The reaction mixture was stirred at 15 °C for 2 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with sat. aq. NaHCCh solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title product (40.0 g, 82.9 mmol, 93%) as a yellow oil. ES / MS (m / z): 426 (M-55)Preparation 59 benzyl (S)-(3 -bromo- 1 -cycloheptyl -2-oxopropyl)carbamate[000143] To a solution of tert-butyl (4S)-4-(((benzyloxy)carbonyl)amino)-2-bromo-4- cycloheptyl-3-oxobutanoate (40.0 g, 82.9 mmol) in toluene (400 mL) was added TFA (56.7 g, 497 mmol, 36.8 mL) at 0 °C. The reaction mixture was stirred at 75 °C for 2 h. The reaction mixture was diluted with H2O and sat. aq. NaHCCh solution was added to adjust the pH = 9. The reaction mixture was extracted with DCM and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by prep-HPLC (basic condition; column: Kromasil Eternity XT (250 mm x 80 mm, 10 um); mobile phase: [H2O (NH4OH)-ACN]; B%: 55%-85%, 20 min) to afford a mixture of stereoisomers. The title compound was isolated as the first eluting, single stereoisomer by chiralprep-SFC purification (column: Daicel Chiralcel OJ (250 mm x 30 mm, 10 um); mobile phase: [0.1% NH3H2O in zPrOH]; B%: 20%-20%, 3 min); (11.3 g, 29.5 mmol, 36%) and was obtained as a white solid. ES / MS (m / z): 384 (M+H).Preparation 60 benzyl (S)-(l-bromo-2-oxo-5-(l-(trifluoromethyl)cyclopropyl)pentan-3-yl)carbamate[000144] To a solution of benzyl (S)-(l-(dimethyl(oxo)-16-sulfaneylidene)-2-oxo-5-(l- (trifluoromethyl)cyclopropyl)pentan-3-yl)carbamate (1.80 g, 4.13 mmol) in THF (20 mL) was added HBr (1.01 g, 4.13 mmol, 680 pL, 33.0% purity). The mixture was stirred at 55 °C for 2 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layer was dried over anhydrous ISfeSCU, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCE, PEZEtOAc)to afford the title product as a yellow solid. ES / MS (m / z): 422 (M+H).[000145] The compounds in the following table were prepared essentially as described in Preparation 60 using the appropriate sulfaneylidene.Preparation 63 benzyl ((S)-3-bromo-l-((lr,4S)-4-methylcyclohexyl)-2-oxopropyl)carbamate[000146] To a solution of benzyl ((S)-3-(dimethyl(oxo)-16-sulfaneylidene)-l-((lR,4S)-4- methylcyclohexyl)-2-oxopropyl)carbamate (150 g, 395 mmol) in THF (1500 mL) was added LiBr (34.3 g, 395 mmol) followed by MsOH (38.0 g, 395 mmol, 28.1 mL). The reaction mixture was stirred at 45 °C for 12 h. The reaction mixture was quenched by the addition of H2O and then extracted twice with EtOAc. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Phenomenex luna C18 250^ 100 mmx lO mm; mobile phase: [H2O (FA) - ACN]; B%: 60%-80%) to afford the title product (18.2 g, 47.8 mmol, 12%) as a white solid. ES / MS (m / z): 382 (M+H).Preparation 642-((l , 1 , 1 -trifluoro-2-methylpropan-2-yl)oxy)acetic acid[000147] To a solution of l,l,l-trifhioro-2-methylpropan-2-ol (38.4 g, 299 mmol, 32.8 mL) in THF (600 mL) was added NaH (23.9 g, 599 mmol, 60.0% purity) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. A solution of 2-bromoacetic acid (50.0 g, 359 mmol, 25.8mL) was added. The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was quenched by addition NH4CI at 0 °C, and then diluted with H2O and extracted with EtOAc. The combined organic layers were dried over by anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCh, PEZEtOAc) to afford the title product (34.0 g, 182 mmol, 61%) as a yellow oil.JH NMR (400 MHz, CDCI3) 8 10.4 (s, 1H), 4.23 (s, 2H), 1.41 (s, 6H).Preparation 65N-methoxy-N-methyl-2-((l , 1 , 1 -trifluoro-2-methylpropan-2-yl)oxy)acetamide[000148] To a solution of 2-((l,l,l-trifluoro-2-methylpropan-2-yl)oxy)acetic acid (32.0 g, 171 mmol), HATU (130 g, 343 mmol) and DIPEA (88.8 g, 687 mmol, 119 mL) in DCM (600 mL) was added N,O-dimethylhydroxylamine (20.1 g, 206 mmol, HC1 salt) at RT. The reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with H2O and extracted withEtOAc. The combined organic layers were dried over by anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PEZEtOAc) to afford the title product (27.0 g, 117 mmol, 69%) as a colorless oil. ESZMS (m / z): 230 (M+H).Preparation 662-((l , 1 , 1 -trifluoro-2-methylpropan-2-yl)oxy)acetaldehyde[000149] To a solution of N-methoxy-N-methyl-2-((l,l,l-trifluoro-2-methylpropan-2- yl)oxy)acetamide (27.0 g, 117 mmol) in THF (100 mL) was added DIBAL-H (1 M, 236 mL) at - 75 °C. The reaction mixture was stirred at -75 °C for 2 h. The reaction mixture was quenched by addition of H2O at 0 °C, and then diluted with H2O and extracted with EtOAc. The combined organic layers were dried over by anhydrous Na2SO4, filtered, and concentrated under reducedpressure to afford the title product (22.0 g, crude) as a yellow oil.1H NMR (400 MHz, CDCh) 8 9.67 (s, 1H), 4.10 (s, 2H), 1.36 (s, 6H).Preparation 67 ethyl 3,3-difluorocyclohexane-l-carboxylate[000150] To a solution of N,N-diethylamino-S,S-difluorosulfinium tetrafluoroborate (5.05 kg, 22.0 mol) and TEA 3 HF (2.13 kg, 13.2 mol, 2.15 L) in DCE (25.0 L) was added dropwise ethyl 3-oxocyclohexane-l-carboxylate (1.50 kg, 8.81 mol) over a period of 30 min. The reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was poured into sat. aq. NaHCCh solution (15.0 L) at 20 °C and the organic phase was separated. The aq. phase was extracted with DCM, the combined organic phases were washed with a 10% aq. solution of citric acid and NaCl. Upon concentration under reduced pressure to give a residue, a distillation under vacuum (80 °C, -0.095 MPa) was performed to afford the title product (1.26 kg, 6.56 mol, 74%) as a yellow oil.XH NMR (400 MHz, CDCh) 6 4.15 (q , J = 7.2 Hz, 2H), 2.57- 2.64 (m, 1H), 2.30-2.37 (m, 1H), 1.99-2.12 (m, 2H), 1.78-1.94 (m, 2H), 1.53-1.73 (m, 2H), 1.35-1.45 (m,l H), 1.26 (t, J = 7.2 Hz, 3H).Preparation 68 3,3-difluorocyclohexane-l-carboxylic acid[000151] To a solution of ethyl 3, 3 -difluorocy cl ohexane-1 -carboxylate (1.26 kg, 6.56 mol, 1.00 eq) in EtOH (7.56 L) and H2O (5.04 L) was added portionwise LiOH H2O (330 g, 7.88 mol, 1.20 eq) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with a 3M HC1. aq. adjust pH = 3 and extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was stirred in PE at RT for 5 h to afford the title product (655 g, 3.99 mol) as a white solid. 'H NMR (400 MHz, CDCh) 6 2.66-2.72 (m, 1H), 2.33-2.41 (m, 1H), 2.06- 2.14 (m, 2H), 1.81-1.97 (m, 2H), 1.57-1.76 (s, 2H), 1.40-1.49 (m, 1H).Preparation 69(3,3-difluorocyclohexyl)methanol[000152] To a solution of 3,3-difluorocyclohexane-l-carboxylic acid (50.0 g, 305 mmol) in THF (600 mL) was added portionwise NaBP (12.7 g, 335 mmol) at 0 °C followed by a dropwise addition of BF3 OEt2 (43.2 g, 305 mmol, 37.5 mL). The reaction mixture was stirred at RT for 3 h. The reaction mixture was quenched by the addition of sat. aq. NH4CI solution and extracted with EtOAc, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to afford the title product (45.0 g, 300 mmol, 98%) as a yellow oil.JH NMR (400 MHz, DMSO-d6) 5 4.56 (t, J = 6.4 Hz, 1H), 3.22-3.32 (m, 2H), 2.00-2.07 (m, 1H), 1.93-1.98 (m, 1H), 1.58-1.79 (m, 4H), 1.35-1.51 (m, 2H), 0.95-1.02 (m, 1H).Preparation 70 3,3-difluorocyclohexane-l-carbaldehyde[000153] To a solution of (3,3-difluorocyclohexyl)methanol (40.0 g, 266 mmol) in DCM (1.00 L) was added DMP (124 g, 293 mmol, 90.8 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by re-crystallization from PE at 20 °C to afford the title product (39.0 g, 263 mmol, 99%) as a yellow oil. 'H NMR (400 MHz, CDCI3) 8 9.67 (d, J = 1.6 Hz, 1H), 2.62-2.71 (m, 1H), 2.31-2.40 (m, 1H), 1.97-2.06 (m, 2H), 1.75-1.92 (m, 4H), 1.51-1.57 (m, 1H).Preparation 71 (S,E)-2-methyl-N-(2-((l,l,l-trifluoro-2-methylpropan-2-yl)oxy)ethylidene)propane-2- sulfmamide[000154] To a solution of 2-((l,l,l-trifluoro-2-methylpropan-2-yl)oxy)acetaldehyde (22.0 g, 129 mmol) and (S)-2-methylpropane-2-sulfinamide (18.8 g, 155 mmol) in DCM (300 mL) was added CuSCU (41.2 g, 258 mmol, 39.6 mL) at RT. The reaction mixture was stirred at RT for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCh, PE / EtOAc) to afford the title product (6.00 g, 18.6 mmol, 14%) as a colorless oil. ES / MS (m / z): 274 (M+H).[000155] The compound in the following table was prepared essentially as described in Preparation 71 using the appropriate aldehyde.Preparation 73(R)-N-((S)- 1 -cyano-2-((l , 1 , 1 -trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2- sulfinamide[000156] To a solution of (S,E)-2-methyl-N-(2-((l,l,l-trifluoro-2-methylpropan-2- yl)oxy)ethylidene)propane-2-sulfinamide (5.00 g, 18.2 mmol) in DCM (50.0 mL) was added CsF (555 mg, 3.66 mmol, 135 pL), H2O (659 mg, 36.5 mmol, 659 pL) and TMSCN (3.63 g, 36.5 mmol, 4.58 mL). The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with H2O and extracted with PE. The combined organic layers were dried over by anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PEZEtOAc) to afford the title product (3.00 g, 9.77 mmol, 53%) as a yellow oil. ES / MS (m / z): 301 (M+H).[000157] The compound in the following table was prepared essentially as described in Preparation 73 using the appropriate sulfinamide.Preparation 750-( 1,1,1 -trifluoro-2-methylpropan-2-yl)-L-serine[000158] To a solution of (R)-N-((S)-l-cyano-2-((l,l,l-trifluoro-2-methylpropan-2- yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (3.00 g, 9.99 mmol) in AcOH (15.7 g, 262 mmol, 15.0 mL) was added HC1 (12 M, 15.0 mL). The reaction mixture was stirred at 110 °C for 12 h. The reaction mixture was concentrated under reduced pressure to afford the title product (2.50 g, 9.94 mmol, 99%, HC1 salt) as a brown solid. ES / MS (m / z): 216 (M+H).Preparation 76N-((benzyloxy)carbonyl)-O-(l,l,l-trifluoro-2-methylpropan-2-yl)-L-serine[000159] To a solution of O-(l,l,l-trifluoro-2-methylpropan-2-yl)-L-serine (2.50 g, 9.94 mmol, HC1 salt), CbzOSu (2.48 g, 9.94 mmol) and K2CO3 (4.12 g, 29.8 mmol) in THF (15.0 mL) was added H2O (15.0 mL). The reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCL, PEZEtOAc = 100: 1 to 1 : 1) to afford the title product (2.50 g, 7.16 mmol, 72%) as a yellow oil. ES / MS (m / z): 350 (M+H).Preparation 77 benzyl (S)-(4-(dimethyl(oxo)-16-sulfaneylidene)-3 -oxo- 1 -((1 , 1 , 1 -trifluoro-2-methylpropan-2- yl)oxy)butan-2-yl)carbamate[000160] To trimethyl sulfoxonium iodide (4.44 g, 20.1 mmol) was added to a solution of KO / Bu (2.26 g, 20.1 mmol) in THF (30.0 mL) and the reaction mixture was stirred at 65 °C for 2 h under N2 atmosphere. After that time, the solution was cooled to 0 °C to obtain the first mixture. To a solution of N-((benzyloxy)carbonyl)-O-(l,l,l-trifluoro-2-methylpropan-2-yl)-L- serine (2.35 g, 6.73 mmol) in THF (30.0 mL) was added TEA (1.36 g, 13.4 mmol, 1.87 mL) and HATU (5.12 g, 13.4 mmol) at RT. The reaction mixture was stirred at RT for 2 h. The suspension was then filtered, and the filtrate was cooled to 0 °C to obtain the second mixture. The second mixture was added to the first mixture at 0 °C. The resulting mixture was stirred at RT for 1 h. The reaction mixture was quenched by the addition of H2O at RT, and extracted with EtOAc. The combined organic layers were dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, which was purified by prep-TLC (SiCL, DCM / MeOH) to afford the title product (850 mg, 1.85 mmol, 27%) as a white solid. ES / MS (m / z): 424 (M+H).Preparation 78 benzyl (S)-(4-bromo-3 -oxo- 1 -((1 , 1 , 1 -trifluoro-2-methylpropan-2-yl)oxy)butan-2-yl)carbamate[000161] To a solution benzyl (S)-(4-(dimethyl(oxo)-16-sulfaneylidene)-3-oxo-l-((l,l,l- trifluoro-2-methylpropan-2-yl)oxy)butan-2-yl)carbamate (600 mg, 1.42 mmol) in THF (5.00 mL) was added LiBr (246 mg, 2.83 mmol, 71.1 pL) and MsOH (408 mg, 4.25 mmol, 303 pL) at 0 °C. The reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered,and concentrated under reduced pressure to afford the title product (600 mg, crude) as a black oil.ES / MS (m / z): 426 (M+H).Preparation 79 tert-butyl (S)-2-((diphenylmethylene)amino)-2-((S)-3-oxocyclohexyl)acetate[000162] To a solution of tert-butyl 2-((diphenylmethylene)amino)acetate (250 g, 846 mmol) in DCM (17.0 L) was added 4-[(R)-allyloxy-[(2S,4S,5R)-l-(9-anthrylmethyl)-5-vinyl- quinuclidin-l-ium-2-yl]methyl]quinoline; bromide (51.2 g, 84.6 mmol), followed by CsOH H2O (1.42 kg, 8.46 mol) under N2 atmosphere. The mixture was cooled to -70 °C. A solution of cyclohex-2-en-l-one (244 g, 2.54 mol, 246 mL) in DCM (450 mL) was added dropwise over 30 min at -70 °C under N2 atmosphere. The mixture was stirred at -70 °C under N2 atmosphere for 6 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (Si O2, PEZEtOAc) to afford the title product (352 g, 53%) as a white solid. ES / MS (m / z): 392 (M+H).Preparation 80 tert-butyl (S)-2-((diphenylmethylene)amino)-2-((S)-3-methylenecyclohexyl)acetate[000163] To a solution of methyltriphenylphosphonium iodide (186 g, 459 mmol) in THF (1000 mL) was added potassium 2-methylpropan-2-olate (IM, 460 mL) at -30 °C and stirred for 0.5 h. Then a solution of tert-butyl (S)-2-((diphenylmethylene)amino)-2-((S)-3- oxocyclohexyl)acetate (100 g, 255 mmol) in THF (2000 mL) was dropwise added at 0 °C, the reaction mixture was stirred at 0 °C for 2 h. The mixture was diluted with H2O and extracted with EtOAc, the combined organic layers were washed with sat. aq. NaCl solution, dried overanhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCL, PEZEtOAc) to afford the title product (160 g, 323 mmol, 29%) as a yellow oil. ES / MS (m / z): 390 (M+H).Preparation 81 tert-butyl (S)-2-amino-2-((S)-3-methylenecyclohexyl)acetate[000164] To a solution of tert-butyl (S)-2-((diphenylmethylene)amino)-2-((S)-3- methylenecyclohexyl)acetate (100 g, 257 mmol) in THF (1000 mL) was added citric acid (0.5 M, 2.57 L). The mixture was diluted with H2O and extracted with EtOAc, the combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue to afford the title product (50.0 g, 215 mmol, 84%) as a white solid. ES / MS (m / z): 226 (M+H).Preparation 82 tert-butyl (S)-2-amino-2-((l S,3R)-3-methylcyclohexyl)acetate[000165] tert-butyl (S)-2-amino-2-((S)-3-methylenecyclohexyl)acetate (50.0 g, 222 mmol) was dissolved in MeOH (1000 mL). The fixed bed (50 mL) was completely packed with granular catalyst Pd / C (5%). The H2 back pressure regulator was adjusted to 1 MPa, and the flow rate of H2 was 95 mL / min. Then the reaction mixture was pumped by Pump 1 (SI, Pl, 3.003 mL / min) to fixed bed {FLR1, SS, Fixed bed, 12.70 (1 / 2”) mm, 10 mL, 50 °C}. The reaction mixture was flowing through the fixed bed to leave the reactor zone, then the reaction mixture was collected from the reactor output. The mixture was filtered and concentrated under reduced pressure to give a residue to afford the title product (50.0 g, 210 mmol, 95%) as white solid. ES / MS (m / z): 228 (M+H).Preparation 83 tert-butyl (S)-2-(((benzyloxy)carbonyl)amino)-2-((lS,3R)-3-methylcyclohexyl)acetate[000166] A solution of tert-butyl (S)-2-amino-2-((lS,3R)-3-methylcyclohexyl)acetate (50.0 g, 220 mmol) in THF (500 mL) and H2O (250 mL) was added NaHCO3(27.7 g, 330 mmol, 12.8 mL) and benzyl (2,5-dioxopyrrolidin-l-yl) carbonate (82.2 g, 330 mmol) at 0 °C, the reaction mixture was stirred at 25 °C for 12 h. The mixture was diluted with H2O and extracted with EtOAc, the combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PE / EtOAc) to afford the title product (72.0 g, 199 mmol, 91%) as a yellow solid. ES / MS (m / z): 384 (M+Na).Preparation 84(S)-2-(((benzyloxy)carbonyl)amino)-2-((lS,3R)-3-methylcyclohexyl)acetic acid[000167] To a solution of tert-butyl (S)-2-(((benzyloxy)carbonyl)amino)-2-((lS,3R)-3- methylcyclohexyl)acetate (72.0 g, 199 mmol) in DCM (720 mL) was dropwise added TFA (332 g, 2.91 mol, 216 mL) at 0 °C. The mixture was stirred at 20 °C for 12 h. The mixture was diluted with H2O and extracted with EtOAc, the combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue to afford the title product (60.0 g, 179 mmol, 90%) as a white solid. ES / MS (m / z): 328 (M+Na).Preparation 85 (2S)-2-amino-2-(3,3-difluorocyclohexyl)acetic acid[000168] To a solution of (S)-N-(cyano(3,3-difluorocyclohexyl)methyl)-2-methylpropane- 2-sulfinamide (49.0 g, 176 mmol, 1.00 eq) in AcOH (250 mL) was added hydrochloric acid (12 M, 250 mL, 17.0 eq). The reaction mixture was stirred at 110 °C for 12h. The reaction mixture was concentrated under reduced pressure to afford the title product (31.0 g, 160 mmol, 91.1% yield) as a brown solid. ES / MS (m / z): 194 (M+H).Preparation 86 (2S)-2-(((benzyloxy)carbonyl)amino)-2-(3,3-difluorocyclohexyl)acetic acid[000169] To a solution of (2S)-2-amino-2-(3,3-difhrorocyclohexyl)acetic acid (31.0 g, 160 mmol, 1.00 eq) in THF (250 mL) and H2O (250 mL) was added potassium carbonate (66.5 g, 481 mmol, 3.00 eq) followed by N-(benzyloxycarbonyloxy)succinimide (44.0 g, 176 mmol, 1.10 eq). The reaction mixture was stirred at 20 °C for 10 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with a IM HC1 aq. to adjust pH = 3, then extracted with DCM. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue which was purified by prep-HPLC (0.1% FA condition) to afford the title product (40.0 g, 122 mmol, 76.1% yield) as a white solid. ES / MS (m / z): 328 (M+H).Preparation 87 benzyl ((S)-3-(dimethyl(oxo)-16-sulfaneylidene)-l-((lS,3R)-3-methylcyclohexyl)-2- oxopropyl)carbamate[000170] To a solution of trimethyl sulfoxonium iodide (29.7 g, 135 mmol) in THF (275 mL) was added to a solution of potassium 2-methylpropan-2-olate (IM, 144 mL, 1) at 0 °C and the resulting mixture was stirred at 20 °C for 3 h to obtain a first mixture. To a flask was added (S)-2-(((benzyloxy)carbonyl)amino)-2-((lS,3R)-3-methylcyclohexyl)acetic acid (27.5 g, 90.1 mmol) in THF (275 mL) was added CDI (18.9 g, 117 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 3 h. The suspension was then filtered and the filtrate was cooled to 0 °C to obtain a second mixture. The mixture was diluted with H2O and extracted with EtOAc, the combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCL, DCM / MeOH) to afford the title product (13.0 g, 35.2 mmol) as a white solid. ES / MS (m / z): 380 (M+H).Preparation 88 benzyl ((lS)-l-(3,3-difluorocyclohexyl)-3-(dimethyl(oxo)-16-sulfaneylidene)-2- oxopropyl)carbamate[000171] To a solution of trimethyl sulfoxonium iodide (66.6 g, 302 mmol) in THF (400 mL) was added a solution of KO / Bu (33.9 g, 302 mmol) in THF (400 mL). The reaction mixture was stirred at 65 °C for 2 h and then cooled down to 0 °C (Reaction 1). In parallel, to a solution of (2S)-2-(((benzyloxy)carbonyl)amino)-2-(3,3-difluorocyclohexyl)acetic acid (33.0 g, 101 mmol) in THF (300 mL) was added TEA (13.3 g, 131 mmol, 18.2 mL) followed by HATU (49.8 g, 131 mmol) at 0 °C. The reaction mixture was stirred at RT for 2 h. The suspension was thenfiltered, and the filtrate was cooled down to 0 °C (Reaction 2). The content of the Reaction 2 was slowly added to the Reaction 1 at 0 °C and the resulting mixture was further stirred at 0 °C for 2 h. The reaction mixture was quenched by the addition of H2O and then diluted with EtOAc. An extraction was performed with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (0.1% FA condition) to afford the title product (20.0 g, 49.2 mmol, 49%) as a white solid. ES / MS (m / z): 402 (M+H).Preparation 89 benzyl ((S)-3-bromo-l-((lS,3R)-3-methylcyclohexyl)-2-oxopropyl)carbamate[000172] To a solution of benzyl ((S)-3-(dimethyl(oxo)-16-sulfaneylidene)-l-((lS,3R)-3- methylcyclohexyl)-2-oxopropyl)carbamate (30.5 g, 80.4 mmol) in THF (600 mL) was added HBr in AcOH (29.6 g, 120 mmol, 19.8 mL, 33% purity) at 0 °C under N2 atmosphere. The mixture was stirred at 45 °C for 3 h under N2. The mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Phenomenex luna cl8 250 mm x 100 mm x 10 um; mobile phase: [H2O (FA) - ACN]; gradient: 65% - 85% B over 20 min) and prep- SFC (column: DAICEL CHIRALCEL OJ (250 mm x 50 mm, 10 um); mobile phase: [CCE / zPrOH (0.1%NH3H2O)]; B%: 15%, isocratic elution mode) to afford the title product (13.0 g, 34.0 mmol, 52%) as off-white solid. ES / MS (m / z): 382 (M+H).Preparation 90 / c / 7-butyl (S)-4-(((benzyloxy)carbonyl)amino)-4-(4,4-difluorocyclohexyl)-3-oxobutanoate-n-[000173] A solution of (S)-2-(((benzyloxy)carbonyl)amino)-2-(4,4- difluorocyclohexyl)acetic acid (30.0 g, 91.6 mmol) in THF (320 mL) and CDI (16.3 g, 100 mmol) was stirred at 0 °C for 2 h. Meanwhile, a solution of tert-butyl acetate (31.9 g, 274 mmol, 36.8 mL) in THF (200 mL) was added a solution of LDA (2 M, 160 mL), and the mixture was stirred at -70 °C for 1 h. The two reaction mixtures were combined and stirred at -70 °C for 1 h. The resulting mixture was diluted with sat. aq. NH4CI solution, extracted with EtOAc, washed with sat. aq. NaCl solution, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCL, PE / EtOAc) to afford the title product (30.0 g, 70.5 mmol, 77%) as a yellow oil. ES / MS (m / z): 448 (M+Na).Preparation 91 tert-butyl (4S)-4-(((benzyloxy)carbonyl)amino)-2-bromo-4-(4,4-difluorocyclohexyl)-3- oxobutanoate[000174] To a solution of tert-butyl (5)-4-(((benzyloxy)carbonyl)amino)-4-(4,4- difluorocyclohexyl)-3-oxobutanoate (30.0 g, 70.5 mmol) in MeOH (300 mL) was added NBS (10.0 g, 56.4 mmol) and 2,6-dimethylpyridine (610 mg, 5.64 mmol) at 0 °C. The mixture was stirred at RT for 2 h. The reaction was diluted with sat. aq. NaHCCh solution, extracted with EtOAc, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title product (20.0 g, 39.6 mmol, 56%) as a yellow solid. ES / MS (m / z): 450 (M-55).Preparation 92 benzyl (S)-(3 -bromo- 1 -(4,4-difluorocyclohexyl)-2-oxopropyl)carbamate[000175] To a solution of tert-butyl (4S)-4-(((benzyloxy)carbonyl)amino)-2-bromo-4-(4,4- difluorocyclohexyl)-3-oxobutanoate (20.0 g, 39.6 mmol) in toluene (300 mL) was added TFA (27.1 g, 237 mmol, 17.6 mL). The reaction mixture was stirred at 75 °C for 2 h. The reaction mixture was diluted with sat. aq. NaHCCL solution, and extracted with EtOAc, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, which was purified by Prep-HPLC (basic condition; column: Kromasil Eternity XT (250 mm x 80 mm, 10 mm); mobile phase: [H2O (NFLHCOs^ACN]; B%: 45%-70%) to afford a mixture of stereoisomers. The title compound was isolated as the first eluting, single stereoisomer by chiral SFC purification (column: Daicel Chiralcel OJ (250 mm x 50 mm, 10 mm); mobile phase: [Neu- MeOH]; B%: 20%); (12.0 g, 26.4 mmol, 67%) as a white solid. ES / MS (m / z): 404 m / z (M+H)Preparation 93 benzyl ((S)-l-((S)-3,3-difluorocyclohexyl)-3-(dimethyl(oxo)-16-sulfaneylidene)-2- oxopropyl)carbamate[000176] Benzyl ((S)-l-((S)-3,3-difluorocyclohexyl)-3-(dimethyl(oxo)-16-sulfaneylidene)- 2-oxopropyl)carbamate was isolated as the second eluting, single stereoisomer by chiral SFC purification (column: Daicel Chiralpak IF (250 mm x 30 mm, 10 mm); mobile phase: [CO2 -0.1% NH3»H2O in EtOH]; B%: 35%); (9.00 g, 22.4 mmol, 47.3% yield) and was obtained as a white solid. ES / MS (m / z): 402 (M+H).Preparation 94 benzyl ((S)-3-bromo-l-((S)-3,3-difluorocyclohexyl)-2-oxopropyl)carbamate[000177] To a solution of benzyl ((S)-l-((S)-3,3-difhiorocyclohexyl)-3-(dimethyl(oxo)-16- sulfaneylidene)-2-oxopropyl)carbamate (4.00 g, 9.96 mmol) in THF (15 mL) was added lithium bromide (1.30 g, 14.9 mmol, 375 pL) followed by methanesulfonic acid (1.44 g, 14.9 mmol, 1.07 mL, 1.50 eq). The reaction mixture was stirred at 45 °C for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PEZEtOAc) to afford the title product (3.30 g, 8.16 mmol, 81.9% yield) as a white solid. *H NMR (400 MHz, CDCI3) 57.27-7.41 (m, 5H), 5.34-5.42 (m, 1H), 5.12 (s, 2H), 4.71-4.79 (m, 1H), 3.99-4.08 (m, 1H), 3.77 (s, 1H), 2.12-2.15 (m, 2H), 1.75-1.84 (m, 2H), 1.59-1.67 (m, 1H), 1.38-1.55 (m, 2H), 0.82-1.29 (m, 2H).Preparation 95 tert-butyl (R)-2-oxo-5-(trifluoromethyl)piperidine- 1 -carboxylate[000178] To a solution of (R)-5-(trifluoromethyl)piperidin-2-one (6.60 g, 39.5 mmol) in ACN (50 mL) was added successively BOC2O (10.3 g, 47.4 mmol, 10.9 mL) and DMAP (965 mg, 7.90 mmol). The reaction mixture was stirred at RT for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCh, PE:EtOAc) to afford the title product (8.00 g, 29.9 mmol, 76%) as a white solid. ES / MS (m / z): 290 m / z (M+Na).[000179] The compound in the following table was prepared essentially as described in Preparation 95 using the appropriate lactam.Preparation 971 -(tert-butyl) 3-methyl (5R)-2-oxo-5-(trifluoromethyl)piperidine-l,3-dicarboxylate[000180] To a solution of tert-butyl (R)-2-oxo-5-(trifluoromethyl)piperidine-l-carboxylate (8.00 g, 29.9 mmol) in THF (100 mL) was added a solution of LiHMDS (IM, 59.9 mL) at -78 °C. The reaction mixture was stirred at -78 °C for 1 h and methyl chloroformate (5.45 g, 57.7 mmol, 4.47 mL) was then added. The reaction mixture was stirred at -78 °C for 2 h. The reaction mixture was quenched by the addition of sat. aq. NH4CI solution at 0 °C and then extracted with EtOAc. The combined organic layers were dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCh, PE:EtOAc) to afford the title product (7.00 g, 21.5 mmol, 72%) as a white solid. ES / MS (m / z): 673 (2M+Na).[000181] The compound in the following table was prepared essentially as described in Preparation 97 using the appropriate lactam.Preparation 99 6-vinyl- 1 , 2, 4-tri azin-3 -amine[000182] To a solution of 6-bromo-l,2,4-triazin-3-amine (200 g, 1.14 mol) and 4, 4,5,5- tetramethyl-2-vinyl-l,3,2-dioxaborolane (193 g, 1.26 mol, 213 mL) in dioxane (1200 mL) and H2O (62 mL) was added Pd(dppf)C12 (41.8 g, 57.1 mmol) and K3PO4 (509 g, 2.40 mol). The mixture was stirred at 80 °C for 3 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCh, PE / EtOAc) to afford the title product (139 g, crude) as a white solid.JH NMR (400 MHz, CDCI3) 8 8.34 (s, 1H), 6.99 - 6.77 (m, 1H), 6.08 (d, J = 16.0 Hz, 1H), 5.71 - 5.41 (m, 3H).[000183] The compound in the following table was prepared essentially as described in Preparation 99 using the appropriate triazine.Preparation 101 tert-butyl (tert-butoxycarbonyl)(6-methyl-l,2,4-triazin-3-yl)carbamate[000184] To a solution of 6-methyl-l,2,4-triazin-3-amine (60.0 g, 544 mmol) in DCM (400 mL) was added BOC2O (297 g, 1.36 mol, 312 mL) and DMAP (53.2 g, 435 mmol). The mixture was stirred at 25 °C for 12 h. The mixture was concentrated to afford the title product (40.0 g, 128 mmol, 24%) as a yellow solid. ES / MS (m / z): 643 m / z (2M+Na).Preparation 102 tert-butyl (6-vinyl-l,2,4-triazin-3-yl)carbamate[000185] To a solution of 6-vinyl-l,2,4-triazin-3-amine (100 g, 818 mmol) in THF (300 mL) was added LiHMDS (1.00 M, 1.15 L) at -65 °C for 1 h. Then Boc2O (232 g, 1.06 mol, 244 mL) in THF (200 mL) was added at -65 °C for 1 h. The mixture was stirred at -65 °C for 1 h under N2 atmosphere. The reaction mixture was diluted with sat. aq. NH4CI and extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCL, PEZEtOAc) to afford the title product (100 g, crude) as a white solid. ES / MS (m / z): 123 (M-99).Preparation 103 tert-butyl (6-formyl-l,2,4-triazin-3-yl)carbamate[000186] To a solution of tert-butyl (6-vinyl-l,2,4-triazin-3-yl)carbamate (100 g, 449 mmol) in THF (1750 mL) and H2O (1150 mL) was added OsCL (3.50 g, 13.7 mmol, 714 pL) at 0 °C and stirred for 10 min. Then NalCh was added (240 g, 1.12 mol, 62.3 mL) at 0 °C in four portions, the reaction mixture was stirred at 0 °C for another 4 h under N2 atmosphere. Thereaction mixture was filtered, and then filtrate was quenched by FeCh solution, then stirred for another 0.5 h. The mixture was extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PEZEtOAc) to afford tert-butyl (6-formyl-l,2,4-triazin-3-yl)carbamate (80.0 g, 338 mmol, 75.3% yield) was obtained as a yellow oil. ES / MS (m / z): 223 (M-H).Preparation 104 tert-butyl (tert-butoxycarbonyl)(6-(chloromethyl)-l,2,4-triazin-3-yl)carbamate[000187] To a solution of tert-butyl A-tert-butoxycarbonyl-N-(6-methyl-l,2,4-triazin-3- yl)carbamate (40.0 g, 128 mmol) in DCE (400 mL) was added l,3,5-trichloro-l,3,5-triazinane- 2, 4, 6-trione (20.9 g, 90.2 mmol). The mixture was stirred at 70 °C for 12 h. The mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiCh, PEZEtOAc) to afford the title product (16.0 g, 46.4 mmol, 36%) as yellow oil. ES / MS (m / z): 245 (M-99)Preparation 1052-(tert-butyl) 4-methyl 4-((3-(bis(tert-butoxycarbonyl)amino)-l,2,4-triazin-6-yl)methyl)-3-oxo-2-azabicyclo[3.1.1 ]heptane-2,4-dicarboxylate[000188] To a solution of 2-(tert-butyl) 4-methyl 3-oxo-2-azabicyclo[3.1.1]heptane-2,4- dicarboxylate (10.3 g, 38.2 mmol) in THF (150 mL) was added CS2CO3 (22.6 g, 69.6 mmol) at 0°C under N2. The mixture was stirred at 0 °C for 1 h, then was added tert-butyl (tert- butoxycarbonyl)(6-(chloromethyl)-l,2,4-triazin-3-yl)carbamate (12.0 g, 34.8 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was partitioned between H2O and EtOAc. The organic phase was separated, washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, PEZEtOAc) to afford the title product (18.0 g, 31.1 mmol, 90%) as yellow oil. ES / MS (m / z): 578 (M+H).[000189] The compounds in the following table were prepared essentially as described in Preparation 105 using the appropriate triazine and carbonyl.Preparation 108 methyl 4-((3-amino-l,2,4-triazin-6-yl)methyl)-3-oxo-2-azabicyclo[3.1.1]heptane-4-carboxylate;TFA[000190] To a solution of 2-( / c 7-butyl) 4-methyl 4-((3-(bis(tert-butoxycarbonyl)amino)- l,2,4-triazin-6-yl)methyl)-3-oxo-2-azabicyclo[3.1.1]heptane-2,4-dicarboxylate (18.0 g, 31.1 mmol) in DCM (180 mL) was added TFA (35.5 g, 311 mmol, 23.1 mL). The mixture was stirred at 25 °C for 12 h. The residue was concentrated to afford the title product (12.0 g, 30.6 mmol, 98%, TFA) as yellow oil. ES / MS (m / z): 278 (M+H).[000191] The compounds in the following table were prepared essentially as described in Preparation 108 using the appropriate triazine.Preparation 1114-((3-amino-l,2,4-triazin-6-yl)methyl)-3-oxo-2-azabicyclo[3.1.1]heptane-4-carboxylic acid[000192] To a solution of methyl 4-((3-amino-l,2,4-triazin-6-yl)methyl)-3-oxo-2- azabicyclo[3.1.1]heptane-4-carboxylate; TFA (12.0 g, 30.6 mmol) in THF (120 mL) and H2O (20.0 mL) was added LiOH FEO (3.86 g, 92.0 mmol). The mixture was stirred at 25 °C for 12 h. The residue was adjusted with IM aq. HC1 to pH = 6, the mixture was concentrated to the title product (8.00 g, 30.3 mmol, 99%) as yellow oil. ES / MS (m / z): 264 (M+H).[000193] The compounds in the following table were prepared essentially as described in Preparation 111 using the appropriate triazine.Preparation 1144-((3-amino-l,2,4-triazin-6-yl)methyl)-2-azabicyclo[3.1.1]heptan-3-one[000194] To a solution of 4-((3-amino-l,2,4-triazin-6-yl)methyl)-3-oxo-2- azabicyclo[3.1.1]heptane-4-carboxylic acid (4.00 g, 10.6 mmol) in DMF (50.0 mL) was added NaCl (1.24 g, 21.2 mmol). The mixture was stirred at 100 °C for 12 h. The mixture was filtered and concentrated to give a residue. The residue was purified by reversed-phase HPLC (column: Welch Ultimate XB > C18 20 - 40pm; 120 A; mobile phase: [H2O (NH4HCO3) - ACN]; B%: 30 - 50% 45min; % min) to afford the title product (1.20 g, 5.47 mmol, 52%) as a yellow solid. ES / MS (m / z): 220 (M+H).[000195] The compounds in the following table were prepared essentially as described in Preparation 114 using the appropriate triazine.* This isomer was isolated as the second eluting, single stereoisomer by prep-SFC (column: DAICEL CHIRALPAK AD (250 mm*50 mm, 10 um);mobile phase: [CO2-EtOH];B%:50%, isocratic elution mode) to afford the title product (23.0 g, 83.3 mmol, 100% purity) as yellow solid.Preparation 1174-((3 -amino- 1 ,2,4-triazin-6-yl)methyl)-2-azabicyclo[3.1.1 ]heptan-3 -one (isomer 1 ) Preparation 1184-((3 -amino- 1 ,2,4-triazin-6-yl)methyl)-2-azabicyclo[3.1.1 ]heptan-3 -one (isomer 2)[000196] The mixture of stereoisomers of 4-((3-amino-l,2,4-triazin-6-yl)methyl)-2- azabicyclo[3.1.1]heptan-3-one was purified by prep-SFC (column: DAICEL CHIRALPAK IG (250 mm * 30 mm, 10 urn); mobile phase: [CO2- ACN / EtOH (0.1% NH3H2O)]; B%: 70%, isocratic elution mode). The first eluting isomer (1.20 g, 5.47 mmol, 55%) was obtained asyellow solid. ES / MS (m / z): 220 (M+H). The second eluting isomer (1.30 g, 5.93 mmol, 59%) was obtained as yellow solid. ES / MS (m / z): 220 (M+H).Preparation 119 3 -iodopiperidin-2-one[000197] TMSC1 (219 g, 2.02 mol, 256 mL) was added dropwise to a solution cooled to 0 °C of piperidin-2-one (100 g, 1.01 mol) and TMEDA (351 g, 3.03 mol, 456 mL) in toluene (1000 mL) under N2 atmosphere, the mixture was stirred at 0 °C for 0.5 h, then molecular iodine (307 g, 1.21 mol, 243 mL) was introduced in three portions. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched by addition sat. aq. NaHCCL at 0 °C. The reaction mixture was diluted with H2O and extracted with DCM. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCL, PEZEtOAc) to afford the title product (177 g, crude) as a white solid.1H NMR (400 MHz, CDCI3) 8 7.32 (s, 1H), 4.76 (t, J = 4.0 Hz, 1H), 3.30 - 3.20 (m, 2H), 2.17 - 1.99 (m, 2H), 1.94 - 1.80 (m, 1H), 1.75 - 1.73 (m, 1H).[000198] The compounds in the following table were prepared essentially as described in Preparation 119 using the appropriate piperidone.Preparation 122 di ethyl (2-oxopiperi din-3 -yl)phosphonate[000199] To a solution of 3-iodopiperidin-2-one (177 g, 786 mmol) and triethyl phosphite (653 g, 3.93 mol, 674 mL) in toluene (600 mL) was stirred at 100 °C for 12 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography ( Si O2, PEZEtOAc then DCM / MeOH) to afford the title product (150 g, crude) as a white solid. 'H NMR (400 MHz, CDCI3) 5 6.47 (s, 1H), 4.34 - 4.00 (m, 4H), 3.44 - 3.26 (m, 2H), 3.11 - 2.88 (m, 1H), 2.30 - 1.96 (m, 3H), 1.88 - 1.66 (m, 1H), 1.41 - 1.28 (m, 6H).[000200] The compounds in the following table were prepared essentially as described in Preparation 122 using the appropriate iodopiperidone.Preparation 125 tert-butyl (E)-(6-((2-oxopiperi din-3 -ylidene)m ethyl)- 1, 2, 4-triazin-3-yl)carbamate[000201] To a solution of diethyl (2-oxopiperidin-3-yl)phosphonate (55.9 g, 237 mmol) in THF (500 mL) was added potassium 2-methylpropan-2-olate (IM, 246 mL) at 0 °C for 1 h. tert- Butyl (6-formyl-l,2,4-triazin-3-yl)carbamate (41.0 g, 182 mmol) in THF (250 mL) was added. The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCh, DCM / MeOH) to afford the title product (45.0 g, 147 mmol, 81%) as a white solid. ES / MS (m / z): 250 (M-55).[000202] The compounds in the following table were prepared essentially as described in Preparation 125 using the appropriate piperidone phosphonate.Preparation 128 tert-butyl (6-((2-oxopiperi din-3 -yl)m ethyl)- 1,6-dihydro-l, 2, 4-triazin-3-yl)carbamate[000203] To a mixture of tert-butyl (E)-(6-((2-oxopiperi din-3 -ylidene)methyl)- 1,2, 4-triazin- 3-yl)carbamate (45.0 g, 147 mmol) and NHLMeOH (7M, 63.1 mL) in MeOH (2000 mL) was stirred at 20 °C until becoming clear solution. The H2 back pressure regulator was adjusted to 0 MPa, the flow rate of H2 to 95 mL / min, heated the fixed bed Pd / AhCL (30.0 g, 147 mmol, 5% purity) to 20 °C. Then the solution was pumped into the reactor at a flow rate of 3 mL / min, for 25 h in total. After the reaction was finished, the tubing was washed with MeOH (400 mL), all the reaction solution was collected for analysis. The reaction mixture was concentrated under reduced pressure to give a residue, which was triturated with DCM at 25 °C for 10 min to afford the title product (40.0 g, crude) as a white solid. ES / MS (m / z): 310 (M+H).[000204] The compounds in the following table were prepared essentially as described in Preparation 128 using the appropriate piperidone triazine.Preparation 131 tert-butyl (6-((2-oxopiperidin-3-yl)methyl)-l,2,4-triazin-3-yl)carbamate[000205] To a solution of tert-butyl (6-((2-oxopiperi din-3 -yl)m ethyl)- 1,6-dihydro- 1,2,4- triazin-3-yl)carbamate (49.0 g, 158 mmol) in THF (500 mL) was added DDQ (35.9 g, 158 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by addition sat. aq. NaHCCh at 0 °C, and then extracted with DCM / MeOH (10: 1). The combined organic layers were washed with aq. NaHCCh, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, which was triturated with PEZEtOAc (1 : 1) at 25 °C for 20 min to afford the title product (40.0 g, crude) as a white solid. ES / MS (m / z): 308 (M+H).[000206] The compounds in the following table were prepared essentially as described in Preparation 131 using the appropriate piperidone triazine.Preparation 134 3-((3-amino-l,2,4-triazin-6-yl)methyl)piperidin-2-one (isomer 2)[000207] To a solution of tert-butyl (6-((2-oxopiperi din-3 -yl)m ethyl)- 1, 2, 4-triazin-3- yl)carbamate (40.0 g, 130 mmol) in DCM (300 mL) was added TFA (230 g, 2.02 mol, 150 mL) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue, then the residue was adjusted to 8 by addition of NHLMeOH (7M) and concentrated under reduced pressure to give a residue. The title compound was isolated as the second eluting, single stereoisomer by chiral SFC purification (column: DAICEL CHIRALPAK AY (250 mm * 50 mm, 10 um); mobile phase: [CCh-ACN / zPrOH (0.1% NH3H2O)]; B%:50%, isocratic elution mode) and reversed-phase HPLC (column: Welch Ultimate XB-NH2 250 * 50 * 10 um; mobile phase: [Hexane-EtOH 0.1% NH3H2O ]; gradient: 25%-65% B over 15 min. The title product (8.00 g, 34.7 mmol, 26.6% yield, 89.9% purity) was obtained as a white solid. ES / MS (m / z): 208 (M+H).[000208] The compound in the following table was prepared essentially as described in Preparation 134 using the appropriate protected triazine.[000209] The compound in the following table was prepared essentially as described in Preparation 134 using the appropriate protected triazine.*This was isolated as the second eluting, single stereoisomer by Prep-SFC (column: DAICELCHIRALPAK AD (250 mmx30 mm, 10 urn); mobile phase: [CO2- EtOH (0.1% NH3«H2O)]; B%:40%, isocratic elution mode). The title product (8.00 g, 35.1 mmol, 65%, 97.0% purity) was obtained as a yellow solid.Preparation 137 benzyl ((lS)-((S)-3,3-difluorocyclohexyl)(2-((2-oxopiperidin-3-yl)methyl)imidazo[l,2- b] [ 1 ,2,4]triazin-6-yl)methyl)carbamate[000210] To a solution of 3-((3-amino-l,2,4-triazin-6-yl)methyl)piperidin-2-one (0.300 g, 1.45 mmol), benzyl ((S)-3-bromo-l-((S)-3,3-difluorocyclohexyl)-2-oxopropyl)carbamate (877 mg, 2.17 mmol) in THF (5 mL) was added trimethyl borate (752 mg, 7.24 mmol, 817 pL) and DIPEA (935 mg, 7.24 mmol, 1.26 mL). The mixture was stirred at 75 °C for 4 h. The residue was diluted with H2O and extracted with EtOAc, the combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, which was purified by column (SiCh, DCM / MeOH) to afford the title product (300 mg, 585 pmol, 40%) as a yellow solid. ES / MS (m / z): 513 (M+H).[000211] The compounds in the following table were prepared essentially as described in Preparation 137 using the appropriate triazine and bromoketone.[000212]Preparation 160 3-((6-((S)-amino((S)-3,3-difluorocyclohexyl)methyl)imidazo[l,2-b][l,2,4]triazin-2- yl)methyl)piperidin-2-one[000213] A solution of benzyl ((1 S)-((S)-3, 3 -difluorocycloh exyl)(2-((2-oxopiperi din-3 - yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)carbamate (300 mg, 585 pmol) in HC1 (12M, 937 pL) and AcOH (98.3 mg, 1.64 mmol, 93.7 pL) was stirred at 50 °C for 1 h. The residue was diluted with H2O and extracted with EtOAc, then the aq. phase was adjusted to pH = 8 with a sat. aq. NaHCCh solution and extracted with DCM, the combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title product (220 mg, 581 pmol, 99%) as a white solid. ES / MS (m / z): 379 (M+H).[000214] The compounds in the following table were prepared essentially as described in Preparation 160 using the appropriate protected amine.Preparation 179(3R, 5R)-3 -((6-((R)- 1 -amino-2-((l , 1 , 1 -trifluoro-2-methylpropan-2-yl)oxy)ethyl)imidazo[ 1 ,2- b][l,2,4]triazin-2-yl)methyl)-5-(trifluoromethyl)piperidin-2-one[000215] To a solution of benzyl ((R)-l-(2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-2-((l , 1 , 1 -trifluoro-2-methylpropan-2- yl)oxy)ethyl)carbamate (120 mg, 199 pmol) in MeOH (2 mL) was added NH4COOH (87.9 mg, 1.39 mmol), Pd / C (21.1 mg, 19.9 pmol, 10% purity) under nitrogen. The mixture was stirred under nitrogen at 25 °C for 1 h. The reaction mixture was filtered and the cake was washed withMeOH, then concentrated under reduced pressure to afford (3R,5R)-3-((6-((R)-l-amino-2- ((1,1,1 -trifluoro-2-methylpropan-2-yl)oxy)ethyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-2-yl)methyl)-5- (trifluoromethyl)piperidin-2-one (80.0 mg, 170 pmol, 85.7% yield) as a white solid. ES / MS (m / z): 469 (M+H).[000216] The compound in the following table was prepared essentially as described in Preparation 179 using the appropriate protected amine.Preparation 181 l-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6- yl)((lr,4S)-4-methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide[000217] To a solution of (3R,5S)-3-[[6-[amino-(4-methylcyclohexyl)methyl]imidazo[l,2- b][l,2,4]triazin-2-yl]methyl]-5-methyl-piperidin-2-one (0.800 g, 2.16 mmol) and 2- ethylpyrazole-3 -carboxylic acid (363 mg, 2.59 mmol) in pyridine (10 mL) was added EDCI (827 mg, 4.32 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was partitionedbetween H2O and EtOAc. The organic phase was separated, washed with sat. aq. NaCl solution, and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCh, DCM / MeOH = 1 / 0 to 10 / 1) to afford the title product (1.00 g, 94.3%) as yellow solid. ES / MS (m / z): 493 (M+H).[000218] The compounds in the following table were prepared essentially as described in Preparation 181 using the appropriate amine and carboxylic acid.Preparation 206N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -isopropyl- 1H- 1 ,2,4-triazole-5- carb oxami de[000219] To a solution of (3R,5R)-3-((6-((S)-amino(4,4- difluorocyclohexyl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-2-yl)methyl)-5- (trifluoromethyl)piperidin-2-one (150 mg, 336 pmol) and lithium l-isopropyl-lH-l,2,4-triazole- 5-carboxylate (81.1 mg, 504 pmol) in DCM (3 mL) were added T4P (50.0% EtOAc solution , 242 mg, 672 pmol) and DIPEA (130 mg, 1.01 mmol). The mixture was stirred at 20 °C for 4 h. The residue was diluted with H2O and extracted with DCM, the combined organic layers were washed with sat. aq. NaCl solution dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by Prep-HPLC (column: Phenomenex luna C 18 150^25 mmx lO um; mobile phase: [H2O (FA) - ACN]; gradient: 44% - 64% B over 10 min) to afford the title product (65.0 mg, 111 pmol, 33%) as a white solid. ES / MS (m / z): 584 (M+H).[000220] The compounds in the following table were prepared essentially as described in Preparation 206 using the appropriate amine and lithium carboxylate.Preparation 218 tert-butyl 7-(6-((S)-(4,4-difluorocyclohexyl)(l-ethyl-lH-pyrazole-5-carboxamido)methyl)-2- (((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-3-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate[000221] To a solution of N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-2-oxo-5- (trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl-lH- pyrazole-5-carboxamide (150 mg, 264 pmol), tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (560 mg, 2.64 mmol) in THF (2 mL) at 0-5 °C was added Ag(pyr2)MnC>4 (153 mg, 396 pmol) insmall portions over the course of 15 min. The reaction mixture was then diluted with DCM and filtered through packed MgSC atop diatomaceous earth with DCMZEtOAc washes. The residue was purified by prep-TLC (PE / EtOAc = 0: 1) to afford the title product (78.0 mg, 100 pmol, 38%) as a yellow solid. ES / MS (m / z): 779 (M+H).[000222] The compounds in the following table were prepared essentially as described in Preparation 218 using the appropriate protected amine and imidazotriazine.Preparation 251 tert-butyl 2-cyclopropyl-4-(6-((S)-(4,4-difluorocyclohexyl)(l-ethyl-lH-pyrazole-5- carboxamido)methyl)-2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2- b][l, 2, 4]tri azin-3 -yl)piperazine-l -carboxylate[000223] To a solution of N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-2-oxo-5- (trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl-lH- pyrazole-5-carboxamide (120 mg, 211 pmol) and tert-butyl 2-cyclopropylpiperazine-l- carboxylate (573 mg, 2.53 mmol) in THF (2 mL) were added AgNCh (107 mg, 633 pmol) and TBAP (457 mg, 1.27 mmol). The mixture was stirred at 0 °C for 1 h. The reaction mixture was filtered with EtOAc (150 mL) and the filter was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCL, PE / EtOAc = 0: 1) to afford the title product (107 mg, 134 pmol, 64%) as a yellow solid. ES / MS (m / z): 793 (M+H).[000224] The compounds in the following table were prepared essentially as described in Preparation 251 using the appropriate protected amine and imidazotriazine.Preparation 256N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)-3-(4,7-diazaspiro[2.5]octan-7-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl-lH-pyrazole-5- carboxamide[000225] To a tert-butyl 7-(6-((S)-(4,4-difluorocyclohexyl)(l-ethyl-lH-pyrazole-5- carboxamido)methyl)-2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2- b][l,2,4]triazin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (78.0 mg, 100 pmol) in DCM (1.50 mL) was added HC1 (2M in dioxane) (1.22 mL). The mixture was stirred at 25 °C for 1 h. The mixture was filtered and concentrated to afford the title product (60.0 mg, 88.4 pmol, 88%) as a yellow solid. ES / MS (m / z): 679 (M+H).[000226] The compounds in the following table were prepared essentially as described in Preparation 256 using the appropriate protected amine.Preparation 274N-((lS)-(3-(3-cyclopropylpiperazin-l-yl)-2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)(4,4-difluorocyclohexyl)methyl)-l-ethyl-lH- pyrazole-5-carboxamide[000227] To a solution of tert-butyl 2-cyclopropyl-4-(6-((S)-(4,4-difluorocyclohexyl)(l- ethyl-lH-pyrazole-5-carboxamido)methyl)-2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperi din-3- yl)methyl)imidazo[l,2-b][l, 2, 4]triazin-3-yl)piperazine-l -carboxylate (102 mg, 128 pmol) in DCM (3 mL) was added ZnBr2 (173 mg, 771 pmol, 38.6 pL). The mixture was stirred at 25 °C for 18 h. The reaction mixture was filtered and concentrated under reduced pressure to afford the title product (80.0 mg, 115 pmol, 90%) as a yellow solid. ES / MS (m / z): 693 (M+H).[000228] The com pounds in the following table were prepared essentially as described in Preparation 274 using the appropriate protected amine.Preparation 286 l-(2-fluoroethyl)-N-((S)-l-(2-(((3R,5R)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4,7- diazaspiro[2.5]octan-7-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)-3-(l- (trifluoromethyl)cyclopropyl)propyl)-lH-pyrazole-5-carboxamide[000229] To a solution of tert-butyl 7-(6-((S)-l-(l-(2-fluoroethyl)-lH-pyrazole-5- carboxamido)-3-(l-(trifluoromethyl)cyclopropyl)propyl)-2-(((3R,5R)-5-methyl-2-oxopiperidin- 3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (70.0 mg, 92.0 pmol) in DCM (1.50 mL) was added TMSOTf (30.6 mg, 138 pmol, 24.9 pL) at 0 °C and stirred at 0 °C for 1 h. Then the reaction mixture was diluted with H2O and adjusted the pH of thesolution to 8 with sat. aq. NaHCCh solution, then was extracted with DCM. The combined organic layers were dried over anhydrous anhydrous Na2SO4, filtered and concentrated to afford the title product (60.0 mg, 80.8 pmol, 88%, 89% purity) as a yellow solid. ES / MS (m / z): 661 (M+H).[000230] The compound in the following table was prepared essentially as described in Preparation 286 using the appropriate protected amine.Preparation 288 benzyl ((l S)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3- yl)methyl)-3-(4-(tetrahydrofuran-3-yl)piperazin-l -yl)imidazo[l,2-b][l, 2, 4]tri azin-6- yl)methyl)carbamate[000231] To a solution of benzyl ((S)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-2-oxo-5- (trifluoromethyl)piperi din-3 -yl)methyl)-3 -(piperazin- 1 -yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)methyl)carbamate hydrochloride (60.0 mg, 85.5 pmol, HC1) and dihydrofuran-3(2H)-one (36.8 mg, 427 pmol) in MeOH (1 mL) were added NaBHjCN (10.7 mg, 171 pmol) and NaOAc(28.0 mg, 342 pmol) at 25 °C. The mixture was stirred at 25 °C for 0.5 h. The residue was diluted with H2O (20 mL) and extracted with EtOAc 45 mL (15 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO2, DCM: MeOH= 10: 1) to afford the title product (55.0 mg, 74.8 pmol, 87%) as a yellow solid. ES / MS (m / z): 735 (M+H).Preparation 289 benzyl ((S)-(4,4-difluorocyclohexyl)(3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)-2-(((3R,5R)-2- oxo-5-(trifluoromethyl)piperi din-3-yl)methyl)imidazo[l,2-b][l, 2, 4]tri azin-6- yl)methyl)carbamate[000232] To a solution of benzyl ((S)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-2-oxo-5- (trifluoromethyl)piperidin-3-yl)methyl)-3-(4,7-diazaspiro[2.5]octan-7-yl)imidazo[l,2- b][l,2,4]triazin-6-yl)methyl)carbamate (70.0 mg, 101 pmol) in MeOH(l mL) was added formaldehyde (109 mg, 1.34 mmol, 0.1 mL, 37% purity), NaBHjCN (19.1 mg, 304 pmol), the mixture was stirred at 25 °C for 0.5 h. The reaction mixture was diluted with sat. aq. NaHCCh solution (5 mL) and H2O (5 mL), extracted with EtOAc (5 mL x 3), the combined organic layers were washed with sat. aq. NaCl solution (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiCL, DCM: MeOH = 10: 1) to afford the title product (40.0 mg, 56.7 pmol, 56%) as yellow solid. ES / MS (m / z): 705 (M+H).[000233] The compounds in the following table were prepared essentially as described in Preparation 289 using the appropriate amine.Preparation 292 benzyl ((S)-5,5,5-trifluoro-4,4-dimethyl-l-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)pentyl)carbamate[000234] A mixture of benzyl ((S)-5,5,5-trifhroro-4,4-dimethyl-l-(2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)-3-(4,7-diazaspiro[2.5]octan-7-yl)imidazo[l,2-b][l, 2, 4]tri azin-6- yl)pentyl)carbamate (115 mg, 165 pmol, HC1), formaldehyde (545 mg, 6.72 mmol, 500 pL,37.0% purity), NaBHsCN (31.2 mg, 497 pmol) and AcOH (9.96 mg, 165 pmol, 9.50 pL) in MeOH (1 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 25 °C for 1 h under N2 atmosphere. The residue was purified by Prep-HPLC (FA Condition : column: Phenomenex luna C18 150^25 mmx lO um; mobile phase: [H2O (FA)-ACN]; gradient:20%-40% B over 10 min) to afford the title product (33.0 mg, 49.2 pmol, 30%) as a yellow solid. ES / MS (m / z): 671 (M+H).Preparation 293 benzyl ((S)-(4,4-difluorocyclohexyl)(3-(4-(2-methoxyethyl)-4,7-diazaspiro[2.5]octan-7-yl)-2- (((3R, 5R)-2-oxo-5-(trifluoromethyl)piperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)methyl)carbamate[000235] To a solution of benzyl ((S)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-2-oxo-5- (trifluoromethyl)piperidin-3-yl)methyl)-3-(4,7-diazaspiro[2.5]octan-7-yl)imidazo[l,2- b][l,2,4]triazin-6-yl)methyl)carbamate (85.0 mg, 123 pmol), l-bromo-2-methoxy ethane (34.2 mg, 246 pmol, 23.1 pL) in DMF (1 mL) was added DIPEA (79.5 mg, 615 pmol, 107 pL), the mixture was stirred at 70 °C for 4 h. The reaction mixture was diluted with H2O (5 mL), extracted with EtOAc (5 mL x 3), the combined organic layers were washed with H2O (10 mL x 2), sat. aq. NaCl solution (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiCh, DCM: MeOH = 10: 1) to afford the title product (45.0 mg, 60.1 pmol, 49%) as a yellow solid. ES / MS (m / z): 749 (M+H).Preparation 294 tert-butyl ((4-(6-((S)-(l-ethyl-lH-pyrazole-5-carboxamido)((lr,4S)-4-methylcyclohexyl)methyl)- 2-(((3R, 5 S)-5-m ethyl -2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 , 2, 4]tri azin-3 -yl)piperazin- 1 - yl)sulfonyl)carbamate[000236] To a solution of l-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3 -(piperazin- 1 -yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)(( 1 r,4S)-4- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide (50.0 mg, 86.7 pmol) and tert-butyl N- chlorosulfonylcarbamate (37.4 mg, 173 pmol) in DCM (1 mL) was added TEA (26.3 mg, 260 pmol, 36.2 pL). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was diluted with H2O and extracted with DCM, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (SiO2, DCM: MeOH= 10: 1) to afford the title product (30.0 mg, 39.6 pmol, 46%) as yellow solid. ES / MS (m / z): 756 (M+H).Preparation 295 (3R,5R)-3-((6-((S)-amino(4,4-difluorocyclohexyl)methyl)-3-(4-(tetrahydrofuran-3-yl)piperazin- 1 -yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-2-yl)methyl)-5-(trifluoromethyl)piperidin-2-one[000237] To a solution of benzyl ((lS)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-2-oxo-5- (trifluoromethyl)piperi din-3 -yl)methyl)-3-(4-(tetrahydrofuran-3-yl)piperazin-l-yl)imidazo[ 1,2- b][l,2,4]triazin-6-yl)methyl)carbamate (50.0 mg, 68.0 pmol) in DCM (0.5 mL) was added TMSI (40.8 mg, 204 pmol, 27.7 pL) at 0 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with IM aq. HC1 solution and washed with EtOAc. The aqueous phase was adjusted to pH = 8-9 with sat. aq. NaHCCh solution and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reducedpressure to afford the title product (35.0 mg, 58.2 pmol, 86%) as a yellow solid. ES / MS (m / z): 601 (M+H).[000238] The compounds in the following table were prepared essentially as described in Preparation 295 using the appropriate amine.Preparation 299 (3R,5R)-3-((6-((S)-amino(4,4-difluorocyclohexyl)methyl)-3-(4-(2-methoxyethyl)piperazin-l- yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-2-yl)methyl)-5-(trifluoromethyl)piperidin-2-one[000239] To a solution of benzyl ((S)-(4,4-difluorocyclohexyl)(3-(4-(2- methoxyethyl)piperazin-l-yl)-2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperi din-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)carbamate (110 mg, 152 pmol) in MeOH (2 mL) was added Pd / C (50.0 mg, 10% purity) and NH4COOH (47.9 mg, 760 pmol) under N2 atmosphere. The suspension was degassed and purged with N2 3 times. The mixture was stirred at 25 °C for 0.5 h. The mixture was filtered and concentrated to give a residue. The residue was diluted with H2O (20 mL) and adjusted pH to 8 with sat. aq. NaHCCh solution and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title product (110 mg, crude) as a white solid. ES / MS (m / z): 589 (M+H).Preparation 300 (3R,5R)-3-((6-((S)-amino((lr,4S)-4-methylcyclohexyl)methyl)-3-(4-methylpiperazin-l- yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-2-yl)methyl)-5-(trifluoromethyl)piperidin-2-one[000240] To a solution of benzyl ((S)-((lr,4S)-4-methylcyclohexyl)(3-(4-methylpiperazin- l-yl)-2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperi din-3-yl)methyl)imidazo[l,2-b][l, 2, 4]tri azin-6- yl)methyl)carbamate (80.0 mg, 121 pmol) in AcOH (0.2 mL) was added concentrated HC1 (aq.37.0%, 2 mL). The reaction mixture was stirred at 60 °C for 1 h. The reaction mixture was cooled to RT. The pH was adjusted to 8-9 with sat. aq. NaHCCh solution and extracted with EtOAc. The combined organic layers were dried over anhydrous ISfeSCU, filtered, andconcentrated under reduced pressure to afford the title product (45.0 mg, 86.1 pmol, 71%) as a yellow solid. ES / MS (m / z): 523 (M+H).[000241] The compounds in the following table were prepared essentially as described in Preparation 300 using the appropriate protected amine.Preparation 306 (3R,5R)-3-((6-((S)-l-amino-5,5,5-trifluoro-4,4-dimethylpentyl)-3-(4-methyl-4,7- diazaspiro[2.5]octan-7-yl)imidazo[l,2-b][l,2,4]triazin-2-yl)methyl)-5-methylpiperidin-2-one[000242] To a solution of benzyl ((S)-5,5,5-trifluoro-4,4-dimethyl-l-(2-(((3R,5R)-5-methyl- 2-oxopiperidin-3-yl)methyl)-3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)imidazo[l,2- b][l,2,4]triazin-6-yl)pentyl)carbamate (130 mg, 193 pmol) in MeOH (2 mL) was added Pd / C (60.0 mg, 10 % purity) and NH4COOH (73.3 mg, 1.16 mmol). The mixture was stirred at 20 °C for 2 h under N2 atmosphere. The reaction mixture was filtered with EtOAc and the filter was concentrated under reduced pressure to afford the title product (90.0 mg, 167 mol, 87%) as a yellow solid. ES / MS (m / z): 537 (M+H).Preparation 307 tert-butyl 4-(2-chloroacetyl)-3-(hydroxymethyl)piperazine-l-carboxylate[000243] To a mixture of tert-butyl 3 -(hydroxymethyl)piperazine-l -carboxylate (110 g, 508 mmol, 1.0 eq) and TEA (77.2 g, 762 mmol, 106 mL, 1.5 eq) in THF (1.10 L) was added dropwise 2-chloroacetyl chloride (63.1 g, 559 mmol, 44.5 mL, 1.1 eq) at 0 °C, then the reaction mixture was stirred at 25 °C for 2 h under N2 atmosphere. The crude product was purified by column to give tert-butyl 4-(2-chloroacetyl)-3-(hydroxymethyl)piperazine-l-carboxylate (99.1 g, 333 mmol, 65.5% yield, 98.5% purity) was obtained as a white solid. ES / MS (m / z): 237 (M-55)Preparation 308 tert-butyl 4-oxohexahydropyrazino[2,l-c][l,4]oxazine-8(lH)-carboxylate[000244] To a solution of tert-butyl 4-(2-chloroacetyl)-3-(hydroxymethyl)piperazine-l- carboxylate (49.5 g, 166 mmol, 1.0 eq) in THF (2.00 L) was added KO / Bu (37.3 g, 333 mmol, 2.0 eq) at 0 °C. The mixture was stirred at 0 °C for 2 h to give a crude tert-butyl 4-oxo-6,7,9,9a- tetrahydro-lH-pyrazino[2,l-c][l,4]oxazine-8-carboxylate (64.1 g, 234 mmol, 70.2% yield, 93.6% purity) was obtained as a yellow solid.JH NMR (400 MHz, CDCh) 3 4.58 - 4.55 (m, 1H), 4.21 - 3.99 (m, 5H), 3.56 - 3.51 (m, 2H), 2.71 - 2.64 (m, 3H), 1.47 (s, 9H), ES / MS (m / z): 201 (M-55).Preparation 309 tert-butyl 4-oxo-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)hexahydropyrazino[2,l- c][l,4]oxazine-8(lH)-carboxylate[000245] To a solution of tert-butyl 4-oxo-6,7,9,9a-tetrahydro-lH-pyrazino[2,l- c][l,4]oxazine-8-carboxylate (7.00 g, 25.5 mmol, 1 eq) in THF (75.0 mL) was added zinc(II) diethylcarbamodithioate (2.0 M, 14.0 mL, 1.1 eq) at -70 °C under N2. Then the mixture was stirred at -70 °C for 30 min. Then 2-(2-bromoethoxy)tetrahydropyran (6.25 g, 29.8 mmol, 4.5 mL, 1.2 eq) was added in one portion to the mixture at -70 °C under N2. Then the mixture was stirred at 0 °C for 2.0 h to give crude tert-butyl 4-oxo-3-(2-tetrahydropyran-2-yloxyethyl)- 6,7,9,9a-tetrahydro-lH-pyrazino[2,l-c][l,4]oxazine-8-carboxylate (20.0 g, 31.2 mmol, 61.0% yield, 60.0% purity) was obtained as yellow oil. ES / MS (m / z): 301 (M-THP).Preparation 310 tert-butyl 3-(2-hydroxyethyl)-4-oxohexahydropyrazino[2,l-c][l,4]oxazine-8(lH)-carboxylate[000246] To a solution of tert-butyl 4-oxo-3-(2-tetrahydropyran-2-yloxyethyl)-6,7,9,9a- tetrahydro-lH-pyrazino[2,l-c][l,4]oxazine-8-carboxylate (20.0 g, 31.2 mmol, 1.0 eq) in MeOH (200 mL) was added (7,7-dimethyl-2-oxo-norboman-l-yl)methanesulfonic acid (1.45 g, 6.24 mmol, 0.2 eq) at 25 °C under N2. Then the resulting mixture was stirred at 25 °C for 3 h. The residue was purified by reversed-phase Prep-HPLC separation (Column: 330 g Flash Column Welch Ultimate XB_C18 20-40pm; 120 A, Solvent for sample dissolution, about 1.00 grams of sample dissolved in 50.0 ml of MeOH, Flow rate: 100 mL / min; Mobile phase: ACN: H2O, Gradient B%: 10-100% 60 min;% min, Instrument: AS-204PII). The fractions were concentrated and the residual aqueous mixture was lyophilized to give tert-butyl 3-(2-hydroxyethyl)-4-oxo- 6,7,9,9a-tetrahydro-lH-pyrazino[2,l-c][l,4]oxazine-8-carboxylate (7.30 g, 24.3 mmol, 77.8% yield, 100% purity) was obtained as red oil. 'H NMR (400 MHz, CDCI3) <54.56 - 4.53 (m, 1H), 4.18 - 3.82 (m, 6H), 3.75 - 3.49 (m, 3H), 2.84 - 2.66 (m, 4H), 2.25 - 2.06 (m, 1H), 1.90 - 1.76 (m, 1H), 1.48 (s, 9H). ES / MS (m / z): 301 (M+H).Preparation 311 tert-butyl 4-oxo-3-(2-(tosyloxy)ethyl)hexahydropyrazino[2,l-c][l,4]oxazine-8(lH)-carboxylate[000247] To a solution of tert-butyl 3-(2-hydroxyethyl)-4-oxo-6,7,9,9a-tetrahydro-lH- pyrazino[2,l-c][l,4]oxazine-8-carboxylate (7.30 g, 24.3 mmol, 1 eq) in DCM (73.0 mL) was added TEA (5.41 g, 53.4 mmol, 7.4 mL, 2.2 eq), DMAP (593 mg, 4.86 mmol, 0.2 eq) and Ts-Cl (5.56 g, 29.1 mmol, 1.2 eq) at 0 °C under N2. Then the resulting mixture was stirred at 25 °C for 2 h to give tert-butyl 4-oxo-3-[2-(p-tolylsulfonyloxy)ethyl]-6,7,9,9a-tetrahydro-lH-pyrazino[2,l- c][l,4]oxazine-8-carboxylate (9.00 g, 9.42 mmol, 38.7% yield, 47.6% purity) was obtained as yellow oil. ES / MS (m / z): 399 (M-55).Preparation 312 tert-butyl 4'-oxotetrahydro-4'H-spiro[cyclopropane-l,3'-pyrazino[2,l-c][l,4]oxazine]-8'(l'H)- carb oxy late[000248] To a solution of tert-butyl 4-oxo-3-[2-(p-tolylsulfonyloxy)ethyl]-6,7,9,9a- tetrahydro-lH-pyrazino[2,l-c][l,4]oxazine-8-carboxylate (9.00 g, 9.42 mmol, 1.0 eq) in THF (270 mL) was added KHMDS (1.0 M, 28.2 mL, 3.0 eq) at 0 °C under N2. Then the mixture was stirred at 0 °C for 1 h then the mixture was stirred at 25 °C for 11 h. The residue was purified by Prep-HPLC (column: Phenomenex luna C 18 (250 * 70 mm, 10 um); mobile phase: [H2O (0.225% FA)-ACN]; gradient: 10%-50% B over 28.0 min). The fractions were concentrated and the residual aqueous mixture was lyophilized to give tert-butyl 4-oxospiro[6,7,9,9a-tetrahydro- lH-pyrazino[2,l-c][l,4]oxazine-3,l'-cyclopropane]-8-carboxylate (1.50 g, 5.15 mmol, 54.6% yield, 97.0% purity) was obtained as brown solid. 'H NMR (400 MHz, CDCI3) <5 4.59 - 4.56 (m, 1H), 4.07 - 4.02 (m, 3H), 3.67 - 3.63 (m, 2H), 2.85 - 2.80 (m, 1H), 2.75 - 2.69 (m, 2H), 1.49 (s, 9H), 1.41 - 1.29 (m, 2H), 1.02 - 0.96 (m, 2H). ES / MS (m / z): 227 (M-55).Preparation 313 tert-butyl tetrahydro-4'H-spiro[cyclopropane- 1 ,3 '-pyrazino[2, 1 -c] [ 1 ,4]oxazine]-8'(l'H)- carb oxy late[000249] To a solution of tert-butyl 4-oxospiro[6,7,9,9a-tetrahydro-lH-pyrazino[2,l- c][l,4]oxazine-3,l'-cyclopropane]-8-carboxylate (0.770 g, 2.65 mmol, 1.0 eq) in THF (16.0 mL) was added BHs’THF (1.0 M, 13.2 mL, 5.0 eq) at 0 °C under N2. The mixture was stirred at 75 °C for 4 h. Afford tert-butyl spiro[l,4,6,7,9,9a-hexahydropyrazino[2,l-c][l,4]oxazine-3,l'- cyclopropane]-8-carboxylate (1.50 g, 5.07 mmol, 95.8% yield, 90.7% purity) was obtained as yellow oil. 'H NMR / 4.10 - 3.97 (m, 2H), 3.67 - 3.64 (m, 1H), 3.42 - 3.37 (m, 1H), 3.05 (s, 1H), 2.85 - 2.81 (m, 1H), 2.70 - 2.65 (m, 1H), 2.55 (s, 1H), 2.24 - 2.13 (m, 3H), 1.45 (s, 9H), 0.96 - 0.81 (m, 2H), 0.63 - 0.62 (m, 1H), 0.54 - 0.48 (m, 1H).Preparation 314 hexahydro-4'H-spiro[cyclopropane- 1 ,3 '-pyrazino[2, 1 -c] [ 1 ,4]oxazine][000250] The solution of tert-butyl spiro[ 1,4, 6,7,9, 9a-hexahy dropyrazino[2,l - c][l,4]oxazine-3,l'-cyclopropane]-8-carboxylate (750 mg, 2.53 mmol, 1.0 eq) in THF (8.0 mL) was added to flow reactor 1 {FLR1, PF A, Coils reactor, 3.175(1 / 8”) mm, 10 mL,4.00 mL / min,15 min, 260 °C}. Take a sample for analysis after 15 min. To give title compound (0.940 g, 5.03 mmol, 99.1% yield, 90% purity) was obtained as yellow oil. 'H NMR (400 MHz, CDCI3) 6 3.61 - 3.57 (m, 1H), 3.43 - 3.38 (m, 1H), 3.05 - 2.95 (m, 2H), 2.87 - 2.85 (m, 2H), 2.75 - 2.65 (m, 1H), 2.50 - 2.47 (m, 1H), 2.26 - 2.23 (m, 2H), 2.12 - 2.09 (m, 1H), 1.85 (s, 1H), 0.82 - 0.78 (m, 2H), 0.64 - 0.62 (m, 1H), 0.54 - 0.52 (m, 1H).Preparation 315See TABLE FOR PREPARATION 300Preparation 316 methyl 2-(((benzyloxy)carbonyl)amino)-2-(4-(trifluoromethyl)cyclohexylidene)acetate[000251] DBU (5.96 g, 39.1 mmol, 5.90 mL, 1.3 eq) was added to a mixture of 4- (trifluoromethyl)cyclohexanone (5 g, 30.0 mmol, 1 eq) and methyl 2-(benzyloxycarbonylamino)- 2-dimethoxyphosphoryl -acetate (9.97 g, 30.0 mmol, 1 eq) in EtOAc (100 mL). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated to give a residue (10 g crude, light yellow oil), which was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® Silica Flash Column, Eluent of 0~ 40% EtOAc: PE gradient @ 70 mL / min) to afford title compound (7.8 g, 17.58 mmol, 58.42% yield, 83.7% purity) as white solid. 'H NMR (400 MHz, CDC13) d 7.41 - 7.33 (m, 5H), 6.08 (s, 1H), 5.15 (s, 2H), 3.83 - 3.70 (m, 3H), 3.60 (d, J= 14.4 Hz, 2H), 2.28 - 2.24 (m, 1H), 2.13 - 1.95 (m, 4H), 1.60 - 1.43 (m, 2H). ES / MS (m / z): 635 (M+H). ES / MS (m / z): 328 (M-43).Preparation 317 methyl 2-amino-2-(4-(trifluoromethyl)cyclohexyl)acetate[000252] Pd / C (900 mg, 10% purity) was added to a bottle and a solution of methyl 2- (((benzyloxy)carbonyl)amino)-2-(4-(trifluoromethyl)cyclohexylidene)acetate (6.00g, 13.5 mmol, 1 eq) in MeOH (100 mL) was added, the reaction mixture was evacuated and backfilled three times with hydrogen, then mixture was stirred under H2 (50 psi) at 25 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated to afford title compound (3.20 g, 12.5 mmol, 92.1% yield, 93.1% purity) as light yellow oil. ’H NMR (400 MHz, CDCI3) d 3.74 (s, 3H), 2.22 - 1.85 (m, 3H), 1.84 - 1.63 (m, 4H), 1.60 (s, 2H), 1.56 - 1.45 (m, 1H), 1.42 - 1.07 (m, 3H). ES / MS (m / z): 240 (M+H).Preparation 318 2-(((benzyloxy)carbonyl)amino)-2-(4-(trifluoromethyl)cyclohexyl)acetic acid[000253] To a solution of methyl 2-amino-2-(4-(trifluoromethyl)cyclohexyl)acetate (3.20 g, 12.5 mmol, 1 eq) in H2O (15 mL) and THF (15 mL) was added NaOH (996 mg, 24.9 mmol, 2 eq) at 0 °C, then the mixture was stirred at 25 °C for 2 h. Benzyl (2,5-dioxopyrrolidin-l-yl) carbonate (4.66 g, 18.7 mmol, 1.5 eq) was added and the mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with H2O (50 mL), and adjusted with IM HC1 to pH = 2, extracted with EtOAc (50 mL x 3), the combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep- HPLC (column: Phenomenex luna C18 (250 x 70mm, 10 um);mobile phase: [H2O (0.225% FA) - ACN]; gradient:35% - 65% B over 21.0 min) to afford title compound (4.6 g, 9.64 mmol, 77.41% yield, 75.3% purity) as a yellow oil. ES / MS (m / z): 360 (M+H).Preparation 319 benzyl (3-(dimethyl(oxo)-16-sulfaneylidene)-2-oxo-l-(4-(trifluoromethyl)cyclohexyl)propyl)carbamate[000254] The preparation of mixture A: trimethyl sulfoxonium iodide (2.84 g, 12.9 mmol, 1.5 eq) in THF (45 mL) was added to a solution of KO / Bu (1 M, 12.9 mL, 1.5 eq) at 0 °C and the resulting mixture was stirred at 25 °C for 1.5 h to obtain the mixture A. The preparation of mixture B: To a solution of 2-(((benzyloxy)carbonyl)amino)-2-(4- (trifluoromethyl)cyclohexyl)acetic acid (4.10 g, 8.59 mmol, 1 eq) in THF (45 mL) was added di(lH-imidazol-l-yl)methanone (1.95 g, 12.0 mmol, 1.4 eq) at 0 °C. The resulting mixture was stirred at 25 °C for 1.5 h to obtain the mixture B. The mixture B was added to the mixture A at 0 °C. The resulting mixture was stirred at 25 °C for 1 h. The residue was purified by column to afford title compound (4.6 g, 8.46 mmol, 78.25% yield, 79.7% purity) as a white solid. ES / MS (m / z): 434 (M+H).Preparation 320 benzyl (3-bromo-2-oxo-l-(4-(trifluoromethyl)cyclohexyl)propyl)carbamate[000255] To a solution of benzyl (3-(dimethyl(oxo)-16-sulfaneylidene)-2-oxo-l-(4- (trifluoromethyl)cyclohexyl)propyl)carbamate (3.70 g, 6.80 mmol, 1 eq) in THF (40 mL)was added HBr (3.00 g, 12.25 mmol, 2.01 mL, 33% purity, 1.8 eq). The reaction mixture was stirred at 55 °C for 3 h. The residue was purified by column to afford title compound (2.05 g, 4.70 mmol, 69.07% yield) as a yellow solid. ES / MS (m / z): 392 (M+H).Preparation 321See TABLE FOR PREPARATION 137Preparation 322See TABLE FOR PREPARATION 300Preparation 323See TABLE FOR PREPARATION 181Preparation 324 benzyl 4-(l-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3-(hydroxymethyl)piperazine-l- carb oxy late[000256] To a solution of benzyl 3 -(hydroxymethyl)piperazine-l -carboxylate (15.0 g, 56.3 mmol, 1.00 eq) and l-[tert-butyl(dimethyl)silyl]oxypropan-2-one (53.0 g, 281 mmol, 5.00 eq) in MeOH (150 mL) was added NaBH3CN (7.08 g, 112 mmol, 2.00 eq) and NaOAc (6.93 g, 84.5 mmol, 1.5. eq) at 0 °C. The mixture was stirred at 75 °C for 20 h. The residue was purified by reversed phase HPLC (mobile phase: ACN- FEO (0.1%FA); B%:0% - 22%, gradient @100 mL / min) to afford title compound (14.0 g, 24.2 mmol, 43.1% yield, 73.3% purity) as a white solid. ES / MS (m / z): 423 (M+H).Preparation 325 benzyl 3-(hydroxymethyl)-4-(l-hydroxypropan-2-yl)piperazine-l-carboxylate[000257] To a solution of benzyl 4-(l-((tert-butyldimethylsilyl)oxy)propan-2-yl)-3- (hydroxymethyl)piperazine-l -carboxylate (14.0 g, 24.2 mmol, 1.00 eq) in DCM (140 mL) was added HCl / dioxane (2 M, 20 mL, 1.65 eq). The mixture was stirred at 25 °C for 1 h. The residue was purified by Prep-HPLC (column: Phenomenex lunacl8 250 mm x 100 mm x 10 urn; mobile phase: [H2O (0.225% FA) - ACN]; gradient: 2% - 22% B over 20.0 min) to afford title compound (7.2 g, 23.3 mmol, 96.1% yield, 100% purity) as yellow oil. 'H NMR (400 MHz, CDC13) d 7.35 (s, 5H), 5.22 - 5.08 (m, 2H), 4.25 - 3.54 (m, 9H), 3.45 - 2.59 (m, 3H), 1.40 - 1.08 (m, 3H). ES / MS (m / z): 309 (M+H).Preparation 326 benzyl 4-methylhexahydropyrazino[2,l-c][l,4]oxazine-8(lH)-carboxylate[000258] To a solution of benzyl 3-(hydroxymethyl)-4-(l-hydroxypropan-2-yl)piperazine- 1 -carboxylate (7.20 g, 23.3 mmol, 1.00 eq) in DMF (100 mL) was added chloromethylene(dimethyl)ammonium chloride (4.48 g, 35.0 mmol, 1.50 eq) at 0 °C and then heated to 170 °C for 3 h. The residue was purified by Prep-HPLC (column: Phenomenex lunac 18 250 mm x 100 mm x 10 um; mobile phase: [H2O (0.225% FA) - ACN]; gradient: 5% - 25% B over 25.0 min). The residue was purified by Prep-HPLC (column: LUJA Sep Silica 250 x 50 mm x 5 um; mobile phase: [Hexane - EtOH]; gradient: 1% - 10% B over 15.0 min) to afford title compound (1.20 g, 4.13 mmol, 17.7% yield, 100% purity) as yellow oil. *HNMR (400 MHz, CDCh) d 1A1 - 7.29 (m, 5H), 5.23 - 5.05 (m, 2H), 4.16 - 3.51 (m, 4H), 3.35 - 2.96 (m, 2H), 2.91- 1.95 (m, 6H), 1.41 - 1.09 (m, 3H). ES / MS (m / z): 291 (M+H).Preparation 3274-methyloctahydropyrazino[2, 1 -c] [ 1 ,4]oxazine[000259] A solution of Pd / C (0.200 g, 187 pmol, 10% purity, 4.55e-2 eq) in THF (12.0 mL) was degassed with argon, and benzyl 4-methylhexahydropyrazino[2,l-c][l,4]oxazine-8(lH)- carboxylate (1.20 g, 4.13 mmol, 1.00 eq) was added. The reaction mixture was evacuated and backfilled three times with EE. The mixture was stirred at 25 °C for 2 h under an atmosphere of EE (15 psi). To afford title compound (630 mg, 4.03 mmol, 97.5% yield) as yellow oil. 'H NMR (400 MHz, CDCh) 3 4.04 - 3.58 (m, 2H), 3.57 - 3.29 (m, 1H), 3.02 - 1.95 (m, 9H), 1.39 - 1.11 (m, 3H).Preparation 328See TABLE FOR PREPARATION 181Preparation 329(3S,9aS)-3-(methoxymethyl)octahydropyrazino[2,l-c][l,4]oxazine[000260] To a solution of benzyl (3S,9aS)-3-(methoxymethyl)-3,4,6,7,9,9a-hexahydro-lH- pyrazino[2,l-c][l,4]oxazine-8-carboxylate (3 g, 9.36 mmol, 1 eq) in THF (30 mL) was added Pd / C (0.5 g, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 3 times. The mixture was stirred under H2 (15 psi.) at 25°C for 12 h. Title compound (1.7 g, 9.13 mmol, 97.48% yield) was obtained as a colorless oil. ’H NMR (400 MHz, CDCI3) 3 3.90 - 3.79 (m, 1H), 3.75 - 3.72 (m, 1H), 3.47 - 3.26 (m, 6H), 3.02 - 2.88 (m, 2H), 2.83 - 2.64 (m, 3H), 2.42 (t, J = 11.1 Hz, 1H), 2.28 - 2.10 (m, 3H), 1.72 (s, 1H).Preparation 330 benzyl 3-(methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazine-8(lH)-carboxylate-4,4-d2[000261] A solution of benzyl 3-(methoxymethyl)-4-oxo-6,7,9,9a-tetrahydro-lH- pyrazino[2,l-c][l,4]oxazine-8-carboxylate (2.50 g, 7.32 mmol, 1.00 eq) in THF (25.0 mL) was degassed and purged with N2 3 times, and the solution was cooled to 0 °C. Then trideuterioborane (1.00 M, 14.6 mL, 2.00 eq) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 24 h. The residue was purified by Prep-HPLC (column: Welch Ultimate XB-SiOH 250 x 70 mm x 10 urn; mobile phase: [Heptane - EtOH (0.1% NH3H2O)]; gradient: 1% - 5% B over 15.0 min) to afford title compound (1.70 g, 5.06 mmol, 69.0% yield, 95.9% purity) as yellow oil. 'HNMR (400 MHz, CDCI3) d 7.45 - 7.29 (m, 5H), 5.13 (s, 2H), 4.21 - 3.74 (m, 4H), 3.63 - 3.23 (m, 6H), 3.14 - 2.95 (m, 1H), 2.76 - 2.40 (m, 2H), 2.36 - 2.08 (m, 2H). ES / MS (m / z): 323 (M+H).Preparation 3313-(methoxymethyl)octahydropyrazino[2,l-c][l,4]oxazine-4,4-d2[000262] A solution of Pd / C (287 mg, 270 pmol, 10% purity, 1.14e-l eq) in THF (10.0 mL) was degassed with argon, and benzyl 3-(methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazine- 8(lH)-carboxylate-4,4-d2 (800 mg, 2.38 mmol, 1.00 eq) was added. The reaction mixture wasevacuated and backfilled three times with hydrogen. The mixture was stirred at 25 °C for 12 h under an atmosphere of H2 (15 psi). The filtrate was concentrated under reduced pressure to afford title compound (420 mg, 2.23 mmol, 93.75% yield) as yellow oil. 'H NMR (400 MHz, CDCI3) 3 4.04 - 3.58 (m, 2H), 3.57 - 3.29 (m, 1H), 3.02 - 1.95 (m, 9H), 1.39 - 1.11 (m, 3H).EXAMPLESExample 1N-((S)-(4,4-difluorocyclohexyl)(3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)-2-(((3R,5R)-2-oxo- 5-(trifluoromethyl)piperidin-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -ethyl- 1H- pyrazole-5-carboxamide[000263] To a solution of N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-2-oxo-5- (trifluoromethyl)piperidin-3-yl)methyl)-3-(4,7-diazaspiro[2.5]octan-7-yl)imidazo[l,2- b][l,2,4]triazin-6-yl)methyl)-l-ethyl-lH-pyrazole-5-carboxamide (60.0 mg, 88.4 pmol) in MeOH (I mL) were added NaBHjCN (11.1 mg, 177 pmol) and formaldehyde (143 mg, 1.77 mmol, 132 pL, 37% purity). The mixture was stirred at 25 °C for 1 h. The reaction mixture was partitioned between H2O (20 mL) and EtOAc (20 mL x 3). The organic phase was separated, the combined organic layers were dried over anhydrous ISfeSCU, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (DCM: MeOH= 10: 1) to afford the title product (35.4 mg, 50.8 pmol, 57%, 96.8% purity) as a yellow solid. ES / MS (m / z): 693 (M+H).[000264] The compounds in the following table were prepared essentially as described in Example 1 using the appropriate amine.a: Isomer 1 was isolated as the first eluting, single stereoisomer by Prep-SFC (column: DAICEL CHIRALCEL OD (250 mm><30 mm, 10 um); mobile phase: [CO2 - iPrOH]; B%:35%, isocratic elution mode); (22.16 mg, 31.0 pmol, 29%, 99.0% purity) and was obtained as a yellow solid. b: Isomer 2 was isolated as the second eluting, single stereoisomer by Prep-SFC (column: DAICEL CHIRALCEL OD (250 mmx30 mm, 10 um); mobile phase: [CO2 - iPrOH]; B%:35%, isocratic elution mode) (20.8 mg, 29.0 pmol, 27%, 98.6% purity) and was obtained as a yellow solid.Example 25 l-ethyl-N-((S)-5,5,5-trifluoro-4,4-dimethyl-l-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3-(4-methylpiperazin-l-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)pentyl)-lH-pyrazole-5- carboxamide[000265] To a solution of l-ethyl-N-((S)-5,5,5-trifhioro-4,4-dimethyl-l-(2-(((3R,5S)-5- methyl-2-oxopiperi din-3 -yl)methyl)-3 -(piperazin- 1 -yl)imidazo[ 1 ,2-b ] [ 1 ,2,4]triazin-6-yl)pentyl)- lH-pyrazole-5-carboxamide (44.0 mg, 67.1 pmol, HC1) and formaldehyde (10.0 mg, 335 pmol, 9.25 pL) in MeOH (2 mL) were added NaOAc (22.0 mg, 268 pmol) and NaBHsCN (8.44 mg, 134 pmol) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. The residue was diluted with H2O (1 mL) and extracted with EtOAc, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (FA condition, column: Phenomenex luna C18 150^25 mmx lO um; mobile phase: [H2O (FA) - ACN]; gradient: 16% - 46% B over 10 min) to afford the title product (10.2 mg, 15.7 pmol, 23%, 97.5% purity) as a yellow solid. ES / MS (m / z): 633 (M+H).Example 26 N-((lS)-(4,4-difluorocyclohexyl)(3-(octahydro-2H-pyrido[l,2-a]pyrazin-2-yl)-2-(((3R,5R)-2- oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl- lH-pyrazole-5-carboxamide (isomer 1)Example 27 N-((lS)-(4,4-difluorocyclohexyl)(3-(octahydro-2H-pyrido[l,2-a]pyrazin-2-yl)-2-(((3R,5R)-2- oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl- lH-pyrazole-5-carboxamide (isomer 2)[000266] To a solution of N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-2-oxo-5- (trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl-lH- pyrazole-5-carboxamide (100 mg, 175 pmol), octahydro-2H-pyrido[l,2-a]pyrazine (246 mg, 1.76 mmol) in THF (1.50 mL) were added AgNCL (74.7 mg, 439 pmol) and TBAP (879 pmol) sequentially. The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was filtered with EtOAc (30 mL) and the filtrate was concentrated under reduced pressure to give a residue, which was purified by Prep-TLC (SiO2, EtOAc: MeOH = 10: 1) to afford a mixture of stereoisomers(80.0 mg, 105 pmol, 60%) as yellow solid. ES / MS (m / z): 707 m / z (M+H). Single stereoisomer was isolated by Prep-SFC (column: DAICEL CHIRALCEL OD (250 mm><30 mm, 10 um); mobile phase: [CCh+PrOH (0.1%NH3H2O)]; B%:40%, isocratic elution mode). The first eluting isomer (26.1 mg, 36.8 pmol, 35%) was obtained as a yellow solid. ES / MS (m / z): 707 (M+H).The second eluting isomer (26.1 mg, 36.8 pmol, 35%) as a yellow solid. ES / MS (m / z): 707 (M+H).[000267] The compounds in the following table were prepared essentially as described in Example 26 using the appropriate amine and imidazotriazine.Example 38N-((lS)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)-3-(4-(tetrahydrofuran-3-yl)piperazin-l-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl-lH- pyrazole-5-carboxamide[000268] A solution of (3R,5R)-3-((6-((S)-amino(4,4-difluorocyclohexyl)methyl)-3-(4- (tetrahydrofuran-3-yl)piperazin-l-yl)imidazo[l,2-b][l,2,4]triazin-2-yl)methyl)-5- (trifluoromethyl)piperidin-2-one (30.0 mg, 49.9 pmol), 1 -ethyl- lH-pyrazole-5-carboxylic acid (10.5 mg, 74.9 pmol) and EDCI (19.1 mg, 99.9 pmol) in pyridine (0.5 mL) was stirred at RT for 1 h. The reaction mixture was then diluted with H2O and extracted with EtOAc. The combined organic layers were washed with H2O then sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, and the residue was purified by Prep-HPLC (FA condition; column: Phenomenex luna C18 150^25 mmx lO um; mobile phase: [H2O (FA) - ACN]; gradient: 15% - 45% B over 9 min) to afford the title product (13.56 mg, 17.2 pmol, 35%, 92.0% purity) as a yellow solid. ES / MS (m / z): 723 (M+H).[000269] The compounds in the following table were prepared essentially as described in Example 38 using the appropriate amine imidazotriazine and carboxylic acid.-no-Example 49N-((S)-(4,4-difluorocyclohexyl)(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2- (((3R, 5R)-2-oxo-5-(trifluoromethyl)piperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)m ethyl)- 1 -isopropyl- 1H- 1 ,2,4-triazole-5-carboxamide[000270] To a solution of (3R,5R)-3-((6-((S)-amino(4,4-difluorocyclohexyl)methyl)-3-((S)- hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)imidazo[l,2-b][l,2,4]triazin-2-yl)methyl)-5- (trifluoromethyl)piperidin-2-one (50.0 mg, 85.2 pmol) and lithium l-isopropyl-lH-l,2,4-triazole- 5-carboxylate (16.5 mg, 102 pmol) in DCM (1 mL) were added DIPEA (55.0 mg, 426 pmol, 74.2 pL) and T4P (122 mg, 170 pmol, 50% purity) were stirred at RT for 1 h. The reaction mixture was then diluted with H2O and extracted with EtOAc. The combined organic layers were washed with H2O then sat. aq, NaCl solution, dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to give a residue, and the residue was purified by Prep-TLC (SiC>2, DCM: MeOH = 10: 1), then by Prep-HPLC (column: Phenomenex luna C18 150^25 mmx lO um; mobile phase: [H2O (FA) - ACN]; gradient: 28% - 48% B over 10 min) to afford the title product (36.22 mg, 49.5 pmol, 58%, 98.9% purity) as a yellow solid. ES / MS (m / z): 724 (M+H).[000271] The compounds in the following table were prepared essentially as described in Example 49 using the appropriate amine imidazotriazine and carboxylic acid.Example 62N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4- methylpiperazin-l-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl-lH-pyrazole-5- carboxamide[000272] To a solution ofN-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl-lH-pyrazole-5- carboxamide (40.0 mg, 77.7 pmol) and 1 -methylpiperazine (155 mg, 1.55 mmol, 172 pL) in THF (1 mL) at 0-5 °C was added Py^AgMnCh (150 mg, 388 pmol) in small portions over the course of 15 min. The reaction mixture was then diluted with DCM and filtered through packed MgSCU atop diatomaceous earth with DCMZEtOAc washes. The residue was purified by Prep-HPLC (FA condition; column: Phenomenex luna C18 150^25 mmx lO um; mobile phase: [H2O (FA) - ACN]; gradient: 13% - 43% B over 10 min) to afford the title product (16.74 mg, 27.1 pmol, 35%, 99.3% purity) as yellow solid. ES / MS (m / z): 613 (M+H).[000273] The compounds in the following table were prepared essentially as described in Example 62 using the appropriate amine.a: Isomer 1 was isolated as the first eluting, single stereoisomer by Prep-SFC (column: DAICEL CHIRALCEL OX (250 mmx30 mm, 10 urn); mobile phase: [CO2 - EtOH (0.1% NH3H2O)]; B%: 35%, isocratic elution mode) and Prep-HPLC (column: Phenomenex luna C18 150^25 mmx lO um; mobile phase: [H2O (FA) - ACN]; gradient: 21% - 41% B over 8 min) and was obtained (11.56 mg, 15.98 mol, 39%, 99.8% purity) as a yellow solid. b: Isomer 2 was isolated as the second eluting, single stereoisomer by Prep-SFC (column: DAICEL CHIRALCEL OX (250 mmx30 mm, 10 um); mobile phase: [CO2 - EtOH (0.1% NH3H2O)]; B%: 35%, isocratic elution mode) and Prep-HPLC (column: Phenomenex luna C18 150x25 mmx lO um; mobile phase: [H2O (FA) - ACN]; gradient: 21% - 41% B over 8 min) and was obtained (15.54 mg, 20.82 mol, 50%, 96.7% purity) as yellow solid.Example 1014-(6-((S)-(l-ethyl-lH-pyrazole-5-carboxamido)((lr,4S)-4-methylcyclohexyl)methyl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-3-yl)-N- methylpiperazine- 1 -carboxamide[000274] To a solution of l-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3 -(piperazin- 1 -yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)(( 1 r,4S)-4- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide (50.0 mg, 81.5 pmol, HC1) and methylcarbamic chloride (15.3 mg, 163 pmol) in ACN (1 mL) was added DIPEA (31.6 mg, 244 pmol, 42.6 pL). The mixture was stirred at 80 °C for 1 h. The residue was purified by Prep- HPLC (neutral condition; column: Waters Xbridge 150x25 mmx5 um; mobile phase: [H2O (NH4HCO3) - ACN]; gradient: 28% - 58% B over 10 min) to afford the title product (30.43 mg, 47.7 pmol, 59%, 99.4% purity) as a yellow solid. ES / MS (m / z): 634 (M+H).Example 102 l-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4-sulfamoylpiperazin-l- yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-lH-pyrazole-5- carboxamide[000275] To a solution of l-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3 -(piperazin- 1 -yl)imidazo[ 1 ,2-b ] [ 1 ,2,4]triazin-6-yl)(( 1 r,4S)-4- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide (50.0 mg, 86.7 pmol) and tert-butyl N- chlorosulfonylcarbamate (37.39 mg, 173.39 pmol) in DCM (1 mL) was added TEA (26.3 mg, 260 pmol, 36.2 pL). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was diluted with H2O and extracted with DCM, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure and was purified by Prep-TLC (SiCh, DCM: MeOH= 10: 1) to afford the title product (30.0 mg, 39.6 pmol, 46%) as yellow solid. ES / MS (m / z): 656 (M+H).Example 103N-((S)-(3-(4-(2-amino-2-oxoethyl)piperazin-l-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l-methyl-lH- pyrazole-5-carboxamide[000276] To a solution of l-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3 -(piperazin- 1 -yl)imidazo[ 1 ,2-b ] [ 1 ,2,4]triazin-6-yl)(( 1 r,4S)-4- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide hydrochloride (80.0 mg, 133 mol, HC1) in ACN (2 mL) were added DIPEA (86.2 mg, 667 pmol, 116 pL) and 2-chloroacetamide (18.7 mg, 200 pmol), the mixture was stirred at 80 °C for 3 h. The residue was purified by Prep-HPLC (column: Phenomenex luna C18 150x25 mmxlOum; mobile phase: [H2O (FA) - ACN]; gradient: 13% - 43% B over 10 min) to afford the title product (34.51 mg, 55.2 pmol, 41%, 99.2% purity) as a yellow solid. ES / MS (m / z): 620 (M+H).[000277] The compounds in the following table were prepared essentially as described in Example 103 using the appropriate amine and alkyl halide.Example 1084-methyl-N-((lS)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-4'H- spirofcyclopropane- 1 ,3 '-pyrazino[2, 1 -c] [ 1 ,4]oxazin]-8'(l'H)-yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)((lr,4S)-4-methylcyclohexyl)methyl)-l,2,5-oxadiazole-3-carboxamide (isomer 1) 34519, EW54389-468 Example 1094-methyl-N-((lS)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-4'H- spirofcyclopropane- 1 ,3 '-pyrazino[2, 1 -c] [ 1 ,4]oxazin]-8'(l'H)-yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)((lr,4S)-4-methylcyclohexyl)methyl)-l,2,5-oxadiazole-3-carboxamide (isomer 2) 34520, EW54389-468[000278] To a solution of 4-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[l, 2-b] [1,2, 4]triazin-6-yl)((lr,4S)-4-methylcy cl ohexyl)methyl)- 1,2,5- oxadiazole-3 -carboxamide (100 mg, 206 pmol, 1.0 eq) and hexahydro-4'H-spiro[cyclopropane- l,3'-pyrazino[2,l-c][l,4]oxazine] (309 mg, 1.65 mmol, 8.0 eq) at 0-5 °C was added bis(pyridine)silver(I) permanganate (1.50 eq) in small portions over the course of 15 min. Additional bis(pyridine)silver(I) permanganate was added at 5 °C until the reaction was complete. The reaction mixture was then diluted with DCM and filtered through packed MgSCU atop diatomaceous earth with DCM / EtOAc washes. Purification by Prep-TLC (SiCh, DCM / MeOH) to afford 4-methyl-N-((lS)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-4'H-spiro[cyclopropane- 1 ,3 '-pyrazino[2, 1 -c] [ 1 ,4]oxazin] -8'( 1 'H)-yl)imidazo[ 1 ,2- b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l,2,5-oxadiazole-3-carboxamide (60.0 mg, 87.9 pmol, 42.5% yield, 94.8% purity).[000279] Isomer 1 (34519) was isolated as the first eluting, single stereoisomer by Prep- SFC (column: DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 um); mobile phase: [CCh-IPA (0.1% NH3H2O)]; B%:45%, isocratic elution mode); (27.7 mg, 41.8 pmol, 47.5% yield, 97.4% purity) and was obtained as a yellow solid.JH NMR (400 MHz, CDCI3) <5 7.69 - 7.66 (m, 1H), 7.52 (s, 1H), 5.79 (s, 1H), 5.09 - 5.05 (m, 1H), 3.96 - 3.90 (m, 1H), 3.76 - 3.65 (m, 2H), 3.48 - 3.39 (m, 3H), 3.30 - 3.19 (m, 2H), 3.03 - 2.87 (m, 5H), 2.60 (s, 3H), 2.55 - 2.45 (m, 2H), 2.25 - 2.12 (m, 2H), 2.00 - 1.94 (m, 2H), 1.80 - 1.71 (m, 2H), 1.63 - 1.59 (m, 2H), 1.25 - 1.10 (m, 3H), 1.07 (d, J= 6.8 Hz, 3H), 0.99 - 0.75 (m, 8H), 0.70 - 0.55 (m, 2H). ES / MS (m / z): 647 (M+H). [000280] Isomer 2 (34520) was isolated as the second eluting, single stereoisomer by Prep- SFC (column: DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 um); mobile phase: [CO2-IPA (0.1% NH3H2O)]; B%:45%, isocratic elution mode); (23.0 mg, 35.3 pmol, 40.1% yield, 99.0% purity) and was obtained as a yellow solid.1H NMR (400 MHz, CDCI3) S 7.67 - 7.65 (m, 1H), 7.52 (s, 1H), 5.79 (s, 1H), 5.09 - 5.05 (m, 1H), 3.86 - 3.84 (m, 1H), 3.77 - 3.68 (m, 2H), 3.47 -3.35 (m, 3H), 3.24 - 3.21 (m, 2H), 3.03 - 2.89 (m, 4H), 2.60 (s, 3H), 2.55 - 2.45 (m, 2H), 2.25 - 2.10 (m, 2H), 2.05 - 1.95 (m, 3H), 1.68 - 1.66 (m, 2H), 1.63 - 1.61 (m, 2H), 1.26 - 1.10 (m, 3H). ES / MS (m / z): 647 (M+H).[000281] The compounds in the following table were prepared essentially as described in Example 109 using the appropriate amine and imidazotriazine.a: Isolated by Prep-SFC (column: DAICEL CHIRALPAK IF (250 mm x 30 mm, 10 um); mobile phase: [CCL-EtOH: ACN = 4: 1 (0.1% NH3 H2O)]; B%:70%, isocratic elution mode). b: Isolated by Prep-SFC (column: REGIS (s, s) WHELK-01 (250 mm x 30 mm, 10 um); mobile phase: [CO2-IPA: ACN = 4: 1 (0.1% NH3 H2O)]; B%:50%, isocratic elution mode). c: Isolated by Prep-SFC (column: DAICEL CHIRALPAK IM (250 mm x 30 mm, 10 um); mobile phase: [Heptane-EtOH (0.1% NH3H2O)]; B%: 25%, isocratic elution mode, P1+ P2, P3+P4; column: DAICEL CHIRALCEL OD (250 mm x 30 mm, 10 um); mobile phase: [CO2 - IPA: ACN = 4: 1 (0.1% NH3H2O)]; B%: 30%, isocratic elution mode, Pl, P2).d: Isolated by Prep-HPLC (column: Phenomenex Luna Cl 8 150 x 25 mm x 10 um; mobile phase: [H2O (0.225% FA)-ACN]; gradient: 28%-48% B over 10.0 min). e: Isolated by Prep-SFC (column: DAICEL CHIRALPAK IK (250 mm x 25 mm, 10 um); mobile phase: [CO2 - MeOH (0.1% NH3H2O)]; B%: 55%, isocratic elution mode, Peak 1, Peak 2 + Peak 3, Peak 4; column: DAICEL CHIRALCEL OD (250 mm x 30 mm, 10 um); mobile phase: [CO2 - IPA (0.1% NH3H2O)]; B%: 32%, isocratic elution mode, Peak 2, Peak 3). f: Isolated by Prep-SFC (column: REGIS (s,s) WHELK-01 (250mm x 30 mm, 10 um); mobile phase: [CO2 - EtOH (0.1% NH3H2O)]; B%: 55%, isocratic elution mode, peak 1+peak 2, peak 3, peak 4; column: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 um); mobile phase: [CO2 - IPA: ACN = 4: 1 (0.2% NH3H2O)]; B%:60%, isocratic elution mode, peak 1, peak 2). g: Isolated by Prep-SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 um); mobile phase: [A: CO2; B: IPA (0.1% NH3H2O)]; B%: 30.00% - 30.00%, 14.00 min; flow rate: 65.00 mL / min), peak 1 + peak 2 (overlap), peak 3 + peak 4+ peak 5 (overlap) and peak 6+peak 7 (overlap); column: REGIS (s,s) WHELK-01 (250 mm x 30 mm, 10 um); mobile phase: [A: CO2; B: IPA: ACN = 4: 1 (0.2% NH3H2O)]; B%: 45.00% - 45.00%, 5.00 min; flow rate: 120.00mL / min), peak 3 and peak 4 + peak 5 (overlap). SFC (DICE-C03214-017-3A C19); column: DAICEL CHIRALPAK IM (250 mm x 30 mm, 10 um); mobile phase: [A: CO2; B: EtOH (0.1% NH3H2O)]; B%: 42.00% - 42.00%, 3.50 min; flow rate: 150.00mL / min), peak 6 + peak 7. SFC (DICE-C03214- 017-4A C9); column: DAICEL CHIRALPAK IE (250 mm x 30 mm, 10 um); mobile phase: [A: CO2; B: EtOH: ACN = 4: 1 (0.1% NH3H2O)]; B%: 60.00% - 60.00%, 3.90 min; flow rate: 120.00mL / min), peak 1 + peak 2. SFC (DICE-C03214-017-2A_E1101); column: DAICEL CHIRALPAK IK (250 mm x 25 mm, 10 um); mobile phase: [A: CO2; B: IPA: ACN = 4: 1 (0.2% NH3H2O)]; B%: 35.00% - 35.00%, 3.90 min; flow rate: 150.00 mL / min), peak 4+ peak 5 (overlap). SFC (DICE-C03214-017-3C C2302); column: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 um); mobile phase: [A: CO2; B: IPA (0.1% NH3H2O)]; B%: 60.00% - 60.00%, 9.00 min; flow rate: 120.00 mL / min), peak 4 + peak 5. SFC (DICE-C03214-017-3D_C1803). h: Isolated by Prep-HPLC (column: Phenomenex Luna C18 150 x 25 mm x 10 um; mobile phase: [A: H2O (0.225% FA); B: ACN]; B%: 22.00% - 52.00%, 10.00 min; flow rate: 25.00mL / min).IL-17 A / A HEK-Blue Cell Assay[000282] The HEK-Blue IL-17A reporter cell line (Fisher #NC1408637) is used for cellbased IL-17A / A inhibition assays. Cells are grown and prepared for assays according to the manufacturer’s instructions. This cell line consists of HEK 293 cells that are designed toexpressed IL-17RA, IL-17RC, and the Actl adapter molecule, the combination of which, when stimulated by IL-17A / A or IL17A / F activates a NFaB promoter and drives expression of the recombinant Secreted Alkaline Phosphatase (SEAP) gene. Media from the cells is then added to a development reagent (Quanti-Blue Substrate, Fisher #NC9711613), and read at Aeso.[000283] Compounds are dispensed in DMSO to an empty clear 384-well tissue culture plate in a titration ranging from 10 pM to 27 pM, with DMSO added to every well to a final concentration of 0.1%. Cells are then added to the plate (45 pL / well at a concentration of 280,000 cells / mL). IL17A / A (Genscript #Z03228) or IL17A / F (R&D Systems) is added to the plate to a final concentration of 5 ng / mL and a final well volume of 50 pL. The cells, compound, and IL- 17A / A or IL17A / F are then incubated for 20 hours before media is removed for SEAP analysis. The resulting inhibition curve is then analyzed using Dotmatics’ integrated 4-parameter fit screening protocol to generate IC50 values. Table A includes IC50 values for IL-17A / A and IL- 17A / F inhibition of selected compounds.Table A: IL-17 A / A and IL-17 A / F Inhibition Data for Selected Compounds[000284] The data provided for selected examples in Table A demonstrate inhibition of IL-17A / A and / or IL-17 A / F mediated signaling in the HEK-Blue Cell Assay.Kinetic Solubility in 50 mM Phosphate Buffer (pH 7.4)[000285] 50 mM Phosphate Buffer at pH 7.4 preparation: 3.549 g of Na2HPO4 was dissolved in 500 mL of water with a measured pH of approximately 9.4. Then 50 mM NaH2PO4 was prepared by dissolving 3.000 g of NaH2PO4 in 500 mL of water with a measured pH of approximately 4.5. Lastly, made the 50 mM Phosphate Buffer pH 7.4 solution by adding 15 mL of the Na2HPO4 solution (pH 9.4) to a 50 mL tube and adjusting the pH to 7.4 ± 0.05 using the NaH2PC>4 (pH 4.5) solution.[000286] Assay procedure: Each well of a 96-well plate received 10 pL of 10 mM DMSO stock solution for both test and control (amiodarone, carbamezapine, chloramphenicol) compounds. Next, 490 pL of medium (50 mM Phosphate Buffer at pH 7.4) was pipetted into each corresponding well for a target concentration of 200 pM. The wells were then vortexed for no less than 2 minutes to ensure sample solubility. The plate was subsequently placed on a shaker and agitated at room temperature at 800 rpm for a period of 24 hours. Following this, it was centrifuged at a temperature of 25°C for 10 minutes at 4000 rpm. The resulting supernatant was carefully transferred to a PTFE Filter Media with polyolefin copolymer plate (Millipore Merck MultiScreen® Solvinert). Filtration was performed by centrifuging for a minimum of 5 minutes, collecting the filtrates into a fresh 96-well plate. These final filtrate concentrations were measured using an LC-UV system. Mobile Phase A consisted of 0.1% TFA and 5 mM NH4OAC in water / ACN (v:v, 95:5); Mobile Phase B consisted of 0.1% TFA and 5 mM NH4OAC in water / ACN (v:v, 5:95).[000287] Table B shows the kinetic solubility in 50 mM Phosphate Buffer at pH 7.4 of selected compounds.Table B. Kinetic Solubility in 50 mM Phosphate Buffer (pH 7.4)[000288] Compounds of the present invention provide novel inhibitors of IL-17A mediated signaling and demonstrate an advantageous combination of pharmacological properties such as potent inhibition of IL-17A binding to and signaling through the IL- 17 receptor and oral bioavailability. As such, compounds of the present invention, in particular the compounds of Formula I, and the examples provided herein, are believed to be useful in the treatment of psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, palmoplantar psoriasis, rheumatoid arthritis, multiple sclerosis, systemic sclerosis, psoriatic arthritis, spondyloarthritis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma, non-infectious uveitis, and COPD.

Claims

1. CLAIMSWhat is claimed is:

1. A compound of the formula:orandor a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 wherein R1isacceptable salt thereof.3 The compound according to claim 1 wherein R1ispharmaceutically acceptable salt thereof.

4. The compound according to claim 1 wherein R1is, or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 wherein R1is, or a pharmaceutically acceptable salt thereof.6 The compound according to any of claims 2 to 5 whereinpharmaceutically acceptable salt thereof.7 The compound according to any of claims 2 to 5 wherein R2ispharmaceutically acceptable salt thereof.8 The compound according to any of claims 2 to 5 whereinpharmaceutically acceptable salt thereof.9 The compound according to any of claims 2 to 5 wherein R2ispharmaceutically acceptable salt thereof.

10. The compound according to any of claims 2 to 5 whereinpharmaceutically acceptable salt thereof.11 The compound according to any of claims 2 to 5 whereinpharmaceutically acceptable salt thereof.

12. The compound according to any of claims 2 to 5 whereinpharmaceutically acceptable salt thereof.

13. The compound according to any of claims 2 to 5 whereinpharmaceutically acceptable salt thereof.

14. The compound according to any of claims 2 to 5 whereinpharmaceutically acceptable salt thereof.15 The compound according to any of claims 2 to 5 whereinpharmaceutically acceptable salt thereof.

16. The compound according to any of claims 2 to 5 whereinpharmaceutically acceptable salt thereof.

17. The compound according to any of claims 2 to 5 whereinpharmaceutically acceptable salt thereof.

18. The compound according to any of claims 2 to 5 wherein R4is, or a pharmaceutically acceptable salt thereof.

19. The compound according to any of claims 2 to 5 wherein R4isor a pharmaceutically acceptable salt thereof.

20. The compound according to any of claims 2 to 5 wherein R4is, or a pharmaceutically acceptable salt thereof.

21. The compound according to any of claims 2 to 5 whereinpharmaceutically acceptable salt thereof.

22. The compound according to any of claims 2 to 5 whereinpharmaceutically acceptable salt thereof.

23. The compound according to any of claims 2 to 5 wherein R4is, or a pharmaceutically acceptable salt thereof.

24. The compound according to any of claims 2 to 5 whereinpharmaceutically acceptable salt thereof.

25. The compound according to any of claims 2 to 5 wherein R4isor a pharmaceutically acceptable salt thereof. o26. The compound according to any of claims 2 to 5 wherein R4isor a pharmaceutically acceptable salt thereof.

27. The compound according to any of claims 2 to 5 wherein R4isor a pharmaceutically acceptable salt thereof.

28. The compound according to any of claims 2 to 5 wherein R4is, or a pharmaceutically acceptable salt thereof.

29. The compound according to any of claims 2 to 5 wherein R4isor a pharmaceutically acceptable salt thereof.

30. The compound according to any of claims 2 to 5 wherein R is, or a pharmaceutically acceptable salt thereof.

31. The compound according to any of claims 2 to 5 wherein R4is, or a pharmaceutically acceptable salt thereof.

32. The compound according to any of claims 2 to 5 wherein R4is, or a pharmaceutically acceptable salt thereof.

33. The compound according to any of claims 2 to 5 wherein R4isor a pharmaceutically acceptable salt thereof.

34. The compound according to any of claims 2 to 5 wherein R4isor a pharmaceutically acceptable salt thereof.

35. The compound according to any of claims 2 to 5 whereinpharmaceutically acceptable salt thereof.

36. The compound according to any of claims 2 to 5 whereinpharmaceutically acceptable salt thereof.

37. The compound according to any of claims 2 to 5 wherein R4isor a pharmaceutically acceptable salt thereof.

38. The compound according to any of claims 2 to 5 wherein R4isor a pharmaceutically acceptable salt thereof.

39. The compound according to any of claims 2 to 5 wherein R4isor a pharmaceutically acceptable salt thereof.

40. The compound according to any of claims 2 to 5 wherein R4isor a pharmaceutically acceptable salt thereof.

41. The compound according to any of claims 2 to 5 whereinpharmaceutically acceptable salt thereof.

42. The compound according to any of claims 2 to 5 wherein R4isor a pharmaceutically acceptable salt thereof.

43. The compound according to any of claims 2 to 5 wherein R4isor a pharmaceutically acceptable salt thereof.

44. The compound according to any of claims 2 to 5 whereinpharmaceutically acceptable salt thereof.

45. The compound according to any of claims 2 to 5 wherein R4isor a pharmaceutically acceptable salt thereof.

46. The compound according to any of claims 2 to 5 wherein R4pharmaceutically acceptable salt thereof.

47. The compound according to any of claims 2 to 5 wherein R4a pharmaceutically acceptable salt thereof.

48. The compound according to any of claims 2 to 5 whereina pharmaceutically acceptable salt thereof.

49. The compound of claim 1 selected from the group consisting of:N-((S)-(4,4-difluorocyclohexyl)(3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)-2-(((3R,5R)- 2-oxo-5-(trifluoromethyl)piperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)m ethyl)- 1 -ethyl- lH-pyrazole-5-carboxamide;N-(( 1 S)-(3 -(3 -cyclopropyl -4-methylpiperazin- 1 -yl)-2-(((3R, 5R)-2-oxo-5 - (trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)(4,4- difluorocyclohexyl)methyl)-l-ethyl-lH-pyrazole-5-carboxamide (isomer 1);N-(( 1 S)-(3 -(3 -cyclopropyl -4-methylpiperazin- 1 -yl)-2-(((3R, 5R)-2-oxo-5 - (trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)(4,4- difluorocyclohexyl)methyl)-l-ethyl-lH-pyrazole-5-carboxamide (isomer 2);N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3- yl)methyl)-3-(3,3,4-trimethylpiperazin-l-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l- ethy 1 - 1 H-py razol e- 5 -carb oxami de; l-ethyl-N-((S)-5,5,5-trifhroro-4,4-dimethyl-l-(3-(4-methyl-4,7-diazaspiro[2.5]octan-7- yl)-2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2- b][l,2,4]triazin-6-yl)pentyl)-lH-pyrazole-5-carboxamide;N-((lS)-((S)-3,3-difhrorocyclohexyl)(3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)-2-((2- oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -isopropyl- 1H- 1, 2, 4-triazole-5 -carboxamide;N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3- yl)methyl)-3-((3S,5S)-3,4,5-trimethylpiperazin-l-yl)imidazo[l,2-b][l,2,4]triazin-6- yl)methyl)-l-ethyl-lH-pyrazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3- yl)methyl)-3-((3R,5S)-3,4,5-trimethylpiperazin-l-yl)imidazo[l,2-b][l,2,4]triazin-6- yl)m ethyl)- 1 -ethyl- lH-pyrazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3- yl)methyl)-3-((3R,5R)-3,4,5-trimethylpiperazin-l-yl)imidazo[l,2-b][l,2,4]triazin-6- yl)m ethyl)- 1 -ethyl- lH-pyrazole-5-carboxamide;1 -ethyl -N-((S)-5, 5, 5-trifluoro-4,4-dimethyl-l-(2-(((3R,5R)-5-methyl-2-oxopiperi din-3- yl)methyl)-3-(4-methylpiperazin-l-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)pentyl)-lH- pyrazole-5-carboxamide; l-ethyl-N-((lS)-5,5,5-trifluoro-4,4-dimethyl-l-(3-(4-methyl-4,7-diazaspiro[2.5]octan-7- yl)-2-((3-oxo-2-azabicyclo[3.1.1]heptan-4-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6- yl)pentyl)-lH-pyrazole-5-carboxamide; l-ethyl-4-fluoro-N-((S)-5,5,5-trifluoro-4,4-dimethyl-l-(2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)-3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)imidazo[l,2- b][l,2,4]triazin-6-yl)pentyl)-lH-pyrazole-5-carboxamide; l-ethyl-N-((S)-5,5,5-trifluoro-4,4-dimethyl-l-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3-(3,3,4-trimethylpiperazin-l-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)pentyl)-lH- py razol e- 5 -carb oxami de; l-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4-methyl-4,7- diazaspiro[2.5]octan-7-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide; l-ethyl-N-((S)-(3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)-2-(((3R,5R)-2-oxo-5- (trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide; l-methyl-N-((lS)-(3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)-2-((3-oxo-2- azabicyclo[3.1.1]heptan-4-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide; l-methyl-N-((lS)-(3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-lH- pyrazole-5-carboxamide;N-((lS)-(3-((R)-4,5-dimethyl-4,7-diazaspiro[2.5]octan-7-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l- methy 1 - 1 H-py razol e- 5 -carb oxami de;l-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4-methyl-4,7- diazaspiro[2.5]octan-7-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide;N-((S)-cyclohexyl(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4-methyl-4,7- diazaspiro[2.5]octan-7-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-methyl-lH- pyrazole-5-carboxamide; l-(2-fluoroethyl)-N-((S)-l-(2-(((3R,5R)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4- methyl-4,7-diazaspiro[2.5]octan-7-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)-3-(l- (trifluoromethyl)cyclopropyl)propyl)-lH-pyrazole-5-carboxamide;1 -methyl -N-((S)-l-(2-(((3R,5R)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4-methyl-4, 7- diazaspiro[2.5]octan-7-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)-3-(l- (trifluoromethyl)cyclopropyl)propyl)-lH-pyrazole-5-carboxamide; l-(2-fluoroethyl)-N-((S)-l-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4- methyl-4,7-diazaspiro[2.5]octan-7-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)-3-(l- (trifluoromethyl)cyclopropyl)propyl)-lH-pyrazole-5-carboxamide;4-cyclopropyl-N-((S)-l-(2-(((3R,5R)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4- methylpiperazin- 1 -yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-3 -(1 - (trifluoromethyl)cyclopropyl)propyl)- 1 ,2, 5-oxadiazole-3 -carboxamide; l-ethyl-N-((S)-5,5,5-trifluoro-4,4-dimethyl-l-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3 -(4-methylpiperazin- 1 -yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)pentyl)- 1H- pyrazole-5-carboxamide;N-((lS)-(4,4-difluorocyclohexyl)(3-(octahydro-2H-pyrido[l,2-a]pyrazin-2-yl)-2- (((3R,5R)-2-oxo-5-(trifluoromethyl)piperi din-3-yl)methyl)imidazo[l, 2-b][l, 2, 4]tri azin-6- yl)methyl)-l -ethyl- lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(4,4-difluorocyclohexyl)(3-(octahydro-2H-pyrido[l,2-a]pyrazin-2-yl)-2- (((3R,5R)-2-oxo-5-(trifluoromethyl)piperi din-3-yl)methyl)imidazo[l, 2-b][l, 2, 4]tri azin-6- yl)methyl)-l -ethyl- lH-pyrazole-5-carboxamide (isomer 2);N-((S)-(4,4-difluorocyclohexyl)(3-(4-(oxetan-3-yl)piperazin-l-yl)-2-(((3R,5R)-2-oxo-5- (trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl- lH-pyrazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3- yl)methyl)-3 -(4-(tetrahydro-2H-pyran-4-yl)piperazin- 1 -yl)imidazo[ 1 ,2-b ] [ 1 ,2,4]triazin-6- yl)m ethyl)- 1 -ethyl- lH-pyrazole-5-carboxamide;N-((lS)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3- yl)methyl)-3 -(tetrahydro- 1 'H-spiro[cyclopropane- 1 ,6'-pyrazino[2, 1 -c] [ 1 ,4]oxazin]- 8'(7'H)-yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -ethyl- lH-pyrazole-5-carboxamide;1-ethyl-N-((S)-5,5,5-trifluoro-l-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin- 6-yl)-4,4-dimethylpentyl)-lH-pyrazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-((S)-7,7-difluorohexahydropyrrolo[l,2-a]pyrazin- 2(lH)-yl)-2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2- b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -ethyl- lH-pyrazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-(4-methylpiperazin-l-yl)-2-(((3R,5R)-2-oxo-5- (trifluoromethyl)piperi din-3 -yl)methyl)imidazo[l,2-b][l, 2, 4]triazin-6-yl)m ethyl)- 1- isopropyl-lH-l,2,4-triazole-5-carboxamide; l-ethyl-N-((S)-((lr,4S)-4-methylcyclohexyl)(3-(4-methylpiperazin-l-yl)-2-(((3R,5R)-2- oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)- lH-pyrazole-5-carboxamide; l-isopropyl-N-((lS)-((lr,4S)-4-methylcyclohexyl)(3-(4-methylpiperazin-l-yl)-2-((2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-lH-l,2,4-triazole-5- carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-((R)-7,7-difluorohexahydropyrrolo[l,2-a]pyrazin- 2(lH)-yl)-2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2- b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -ethyl- lH-pyrazole-5-carboxamide; l-ethyl-N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5- methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide;N-((lS)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3- yl)methyl)-3-(4-(tetrahydrofuran-3-yl)piperazin-l -yl)imidazo[l,2-b][l, 2, 4]tri azin-6- yl)m ethyl)- 1 -ethyl- lH-pyrazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-(4-(2-methoxyethyl)-4,7-diazaspiro[2.5]octan-7-yl)-2- (((3R,5R)-2-oxo-5-(trifluoromethyl)piperi din-3-yl)methyl)imidazo[l, 2-b][l, 2, 4]tri azin-6- yl)methyl)-4-ethyl- 1 ,2, 5-oxadiazole-3 -carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-(4-(2-methoxyethyl)piperazin-l-yl)-2-(((3R,5R)-2- oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)- l-ethyl-lH-pyrazole-5-carboxamide; l-ethyl-N-((S)-5,5,5-trifluoro-4,4-dimethyl-l-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)imidazo[l,2-b][l,2,4]triazin-6- yl)pentyl)-lH-pyrazole-5-carboxamide; l-ethyl-N-((S)-5,5,5-trifluoro-4,4-dimethyl-l-(3-(4-methyl-4,7-diazaspiro[2.5]octan-7- yl)-2-((2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)pentyl)-lH- pyrazole-5-carboxamide;1 -ethyl -N-((S)-5, 5, 5-trifluoro-4,4-dimethyl-l-(2-(((3R,5R)-5-methyl-2-oxopiperi din-3- yl)methyl)-3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)imidazo[l,2-b][l,2,4]triazin-6- yl)pentyl)-lH-pyrazole-5-carboxamide; l-ethyl-N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5- methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide;N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide;4-ethyl-N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5- methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-l,2,5-oxadiazole-3-carboxamide;N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide;4-ethyl-N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5- methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-l,2,5-oxadiazole-3-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)- 2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin- 6-yl)methyl)-l-isopropyl-lH-l,2,4-triazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)- 2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin- 6-yl)methyl)-4-ethyl-l,2,5-oxadiazole-3-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)-2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)m ethyl)- 1 -isopropyl- 1H- 1 ,2,4-triazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-(4-(2-methoxyethyl)piperazin-l-yl)-2-(((3R,5R)-2- oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)- l-ethyl-lH-l,2,4-triazole-5-carboxamide;1 -isopropyl -N-((lS)-5, 5, 5-trifluoro-4,4-dimethyl-l-(3-(4-methyl-4, 7- diazaspiro[2.5]octan-7-yl)-2-((2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)pentyl)-lH-pyrazole-5-carboxamide; l-isopropyl-N-((S)-5,5,5-trifluoro-4,4-dimethyl-l-(2-(((3R,5R)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)imidazo[l,2-b][l, 2, 4]tri azin-6- yl)pentyl)-lH-l,2,4-triazole-5-carboxamide; l-isopropyl-N-((S)-5,5,5-trifluoro-4,4-dimethyl-l-(2-(((3R,5S)-5-methyl-2-oxopiperidin- 3-yl)methyl)-3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)imidazo[l,2-b][l, 2, 4]tri azin-6- yl)pentyl)-lH-l,2,4-triazole-5-carboxamide; l-ethyl-N-((S)-((lr,4S)-4-methylcyclohexyl)(3-(4-methylpiperazin-l-yl)-2-(((3R,5R)-2- oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)- lH-l,2,4-triazole-5-carboxamide;N-((lS)-cycloheptyl(3-(4-methylpiperazin-l-yl)-2-((3-oxo-2-azabicyclo[3.1.1]heptan-4- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -ethyl- 1H- 1 ,2,4-triazole-5- carboxamide; l-ethyl-N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5- methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-lH-l,2,4-triazole-5-carboxamide;N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-l-isopropyl-lH-l,2,4-triazole-5-carboxamide;1-ethyl-N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5- methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-lH-l,2,4-triazole-5-carboxamide;N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-l-isopropyl-lH-l,2,4-triazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5R)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4- methylpiperazin-l-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl-lH-pyrazole-5- carboxamide;N-((lS)-(4,4-difluorocyclohexyl)(3-(8-methyloctahydro-2H-pyrazino[l,2-a]pyrazin-2-yl)-2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin- 6-yl)methyl)-l-ethyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(4,4-difluorocyclohexyl)(3-(8-methyloctahydro-2H-pyrazino[l,2-a]pyrazin-2-yl)- 2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin- 6-yl)methyl)-l-ethyl-lH-pyrazole-5-carboxamide (isomer 2);N-((S)-((S)-3,3-difluorocyclohexyl)(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)- yl)-2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2- b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -ethyl- 1H- 1 ,2,4-triazole-5-carboxamide;N-((S)-((S)-3,3-difluorocyclohexyl)(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)- yl)-2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2- b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -isopropyl- 1H- 1 ,2,4-triazole-5 -carboxamide; l-ethyl-N-((R)-l-(3-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)-2-(((3R,5R)-2-oxo-5- (trifluoromethyl)piperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-2-((l , 1,1- trifluoro-2-methylpropan-2-yl)oxy)ethyl)-lH-pyrazole-5-carboxamide;N-((S)-(3-(2,2-difluoro-5-methyl-5,8-diazaspiro[3.5]nonan-8-yl)-2-(((3R,5R)-2-oxo-5- (trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)(4,4- difluorocyclohexyl)methyl)-l-ethyl-lH-pyrazole-5-carboxamide;1-ethyl-N-((lS)-5,5,5-trifluoro-l-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-((2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)-4,4-dimethylpentyl)- lH-l,2,4-triazole-5-carboxamide;N-((lS)-(4,4-difluorocyclohexyl)(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)- 2-((2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b ] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -isopropyl - lH-l,2,4-triazole-5-carboxamide;N-((S)-((S)-3,3-difluorocyclohexyl)(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)- yl)-2-(((3R,5R)-5-methyl-2-oxopiperi din-3-yl)methyl)imidazo[l, 2-b][l, 2, 4]tri azin-6- yl)methyl)- 1 -ethyl- 1H- 1 ,2,4-triazole-5-carboxamide;N-((S)-((S)-3,3-difluorocyclohexyl)(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)- yl)-2-((2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl-lH- l,2,4-triazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)- 2-(((3R,5R)-5-methyl-2-oxopiperi din-3-yl)methyl)imidazo[l, 2-b][l, 2, 4]tri azin-6- yl)methyl)- 1 -isopropyl- 1H- 1 ,2,4-triazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-((R)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)- 2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin- 6-yl)methyl)-l-isopropyl-lH-l,2,4-triazole-5-carboxamide; l-ethyl-N-((lS)-((lr,4S)-4-methylcyclohexyl)(3-(4-methylpiperazin-l-yl)-2-((2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-lH-l,2,4-triazole-5- carboxamide;1-ethyl-N-((lS)-5,5,5-trifluoro-l-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-((2-oxopiperi din-3 -yl)methyl)imidazo[l,2-b][ 1,2, 4]triazin-6-yl)-4,4-dimethylpentyl)- lH-pyrazole-5-carboxamide;N-((lS)-(4,4-difluorocyclohexyl)(3-(4,5-dimethyl-4,7-diazaspiro[2.5]octan-7-yl)-2- (((3R,5R)-2-oxo-5-(trifluoromethyl)piperi din-3-yl)methyl)imidazo[l, 2-b][l, 2, 4]tri azin-6- yl)m ethyl)- 1 -ethyl- lH-pyrazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)- 2-(((3R, 5 S)-5-methyl-2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)m ethyl)- 1 -isopropyl- 1H- 1 ,2,4-triazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-((R)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)- 2-(((3R,5R)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6- yl)methyl)-l -isopropyl- 1H-1, 2, 4-triazole-5-carboxamide (isomer 1);1-ethyl-N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5- methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide;N-((lS)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l- methy 1 - 1 H-py razol e- 5 -carb oxami de;N-((S)-(4,4-difluorocyclohexyl)(3-(4-isopropylpiperazin-l-yl)-2-(((3R,5R)-2-oxo-5- (trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl- lH-pyrazole-5-carboxamide;N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-l-methyl-lH-pyrazole-5-carboxamide;N-((S)- 1 -(3 -((S)-hexahydropyrazino[2, 1 -c] [ 1 ,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)-3-(l- (trifluoromethyl)cyclopropyl)propyl)-l-methyl-lH-pyrazole-5-carboxamide;N-((lS)-l-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-3 -(1 -(trifluoromethyl)cyclopropyl)propyl)- 1 - methyl - 1 H-py razol e- 5 -carb oxami de;N-((S)-(4,4-difluorocyclohexyl)(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R, 5 S)-5-methyl-2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)methyl)-4-ethyl- 1 ,2, 5-oxadiazole-3 -carboxamide;4-cyclopropyl-N-((S)-l-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2- (((3R,5R)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)-3-(l- (trifluoromethyl)cyclopropyl)propyl)-l,2,5-oxadiazole-3-carboxamide;4-cyclopropyl-N-((S)-(4,4-difluorocyclohexyl)(3-((S)-hexahydropyrazino[2,l- c][l,4]oxazin-8(lH)-yl)-2-(((3R,5R)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2- b][l,2,4]triazin-6-yl)methyl)-l,2,5-oxadiazole-3-carboxamide;4-cyclopropyl-N-((R)- 1 -(3 -((S)-hexahydropyrazino[2, 1 -c] [ 1 ,4]oxazin-8( lH)-yl)-2- (((3R,5R)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)-2- ((1,1,1 -trifluoro-2-methylpropan-2-yl)oxy)ethyl)- 1 ,2, 5-oxadiazole-3 -carboxamide;4-cyclopropyl-N-((R)- 1 -(3 -((S)-hexahydropyrazino[2, 1 -c] [ 1 ,4]oxazin-8(lH)-yl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)-2- ((1,1,1 -trifluoro-2-methylpropan-2-yl)oxy)ethyl)- 1 ,2, 5-oxadiazole-3 -carboxamide;4-ethyl-N-((R)-l-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5- methyl-2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-2-((l , 1 , 1 -trifluoro-2-methylpropan-2-yl)oxy)ethyl)-l,2,5-oxadiazole-3-carboxamide;4-cyclopropyl-N-((S)-(4,4-difluorocyclohexyl)(3-((S)-hexahydropyrazino[2,l- c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2- b][l,2,4]triazin-6-yl)methyl)-l,2,5-oxadiazole-3-carboxamide; l-ethyl-N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5R)-2- oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3-methylcyclohexyl)methyl)-lH-l,2,4-triazole-5-carboxamide; l-ethyl-N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-2- oxo-5-(trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)- 3-methylcyclohexyl)methyl)-lH-l,2,4-triazole-5-carboxamide;N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5R)-2-oxo-5- (trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-l-isopropyl-lH-l,2,4-triazole-5-carboxamide;N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-2-oxo-5- (trifluoromethyl)piperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-l-isopropyl-lH-l,2,4-triazole-5-carboxamide; l-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((S)-4- oxohexahydropyrazino[2, l-c][l,4]oxazin-8(lH)-yl)imidazo[l,2-b][l, 2, 4]tri azin-6- yl)((lr,4S)-4-methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide; l-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4- (methylsulfonyl)piperazin- 1 -yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)(( 1 r,4S)-4- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide;4-cyclopropyl-N-((S)-5,5,5-trifluoro-l-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin- 8(lH)-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin- 6-yl)-4,4-dimethylpentyl)-l,2,5-oxadiazole-3-carboxamide;4-cyclopropyl-N-((S)-(3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6- yl)((lr,4S)-4-methylcyclohexyl)methyl)-l,2,5-oxadiazole-3-carboxamide;4-(6-((S)-(l-ethyl-lH-pyrazole-5-carboxamido)((lr,4S)-4-methylcyclohexyl)methyl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-3-yl)-N- methylpiperazine- 1 -carboxamide; l-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4- sulfamoylpiperazin-l-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide;N-((S)-(3-(4-(2-amino-2-oxoethyl)piperazin-l-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l- methy 1 - 1 H-py razol e- 5 -carb oxami de; l-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4-(2-(methylamino)-2-oxoethyl)piperazin-l-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide;N-((S)-(3-(4-(2-(dimethylamino)-2-oxoethyl)piperazin-l-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-l-methyl-lH-pyrazole-5-carboxamide;N-((S)-(3-(4-(2-(3,3-difluoroazetidin-l-yl)-2-oxoethyl)piperazin-l-yl)-2-(((3R,5S)-5- methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-l-methyl-lH-pyrazole-5-carboxamide;N-((S)-(3-(4-(2-(dimethylamino)-2-oxoethyl)piperazin-l-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide;4-methyl-N-((lS)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-4'H- spirofcyclopropane- 1 ,3 '-pyrazino[2, 1 -c] [ 1 ,4]oxazin]-8'(l'H)-yl)imidazo[ 1 ,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l,2,5-oxadiazole-3- carboxamide (isomer 1);4-methyl-N-((lS)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-4'H- spiro[cyclopropane-l,3'-pyrazino[2,l-c][l,4]oxazin]-8'(l'H)-yl)imidazo[l,2- b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l,2,5-oxadiazole-3- carboxamide (isomer 2);N-((3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)(4- (trifluoromethyl)cyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer1);N-((3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)(4- (trifluoromethyl)cyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer2);N-((3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)(4- (trifluoromethyl)cyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer3);N-((3-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2- oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)(4- (trifluoromethyl)cyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer4);4-methyl-N-((lS)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4- methylhexahydropyrazino[2, 1 -c] [ 1 ,4]oxazin-8(lH)-yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)((lr,4S)-4-methylcyclohexyl)methyl)-l,2,5-oxadiazole-3-carboxamide (isomer 1);4-methyl-N-((lS)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4- methylhexahydropyrazino[2, 1 -c] [ 1 ,4]oxazin-8(lH)-yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)((lr,4S)-4-methylcyclohexyl)methyl)-l,2,5-oxadiazole-3-carboxamide (isomer 2);4-methyl-N-((lS)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4- methylhexahydropyrazino[2, 1 -c] [ 1 ,4]oxazin-8(lH)-yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)((lr,4S)-4-methylcyclohexyl)methyl)-l,2,5-oxadiazole-3-carboxamide (isomer 3);4-methyl-N-((lS)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4- methylhexahydropyrazino[2, 1 -c] [ 1 ,4]oxazin-8(lH)-yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)((lr,4S)-4-methylcyclohexyl)methyl)-l,2,5-oxadiazole-3-carboxamide (isomer 4);N-((S)-((S)-3 ,3 -difluorocyclohexyl)(3 -((3 S,9aS)-3 - (methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl- 2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)-4-ethyl- 1,2,5- oxadiazole-3 -carboxamide;N-((lS)-(3-(3-(methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl-4,4-d2)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6- yl)((lr,4S)-4-methylcyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer 1);N-((lS)-(3-(3-(methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl-4,4-d2)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6- yl)((lr,4S)-4-methylcyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer 2);N-((lS)-(3-(3-(methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl-4,4-d2)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6- yl)((lr,4S)-4-methylcyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer 3);N-((lS)-(3-(3-(methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl-4,4-d2)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6- yl)((lr,4S)-4-methylcyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer 4);N-((3-((3S,9aS)-3-(methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)(4- (trifluoromethyl)cyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer i);N-((3-((3S,9aS)-3-(methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)(4- (trifluoromethyl)cyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer2);N-((3-((3S,9aS)-3-(methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)(4- (trifluoromethyl)cyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer3);N-((3-((3S,9aS)-3-(methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)(4- (trifluoromethyl)cyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer4);N-((l,l-difluorospiro[2.5]octan-5-yl)(3-((3S,9aS)-3- (methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl- 2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)-4-methyl- 1,2,5- oxadiazole-3 -carboxamide (isomer 1);N-((l,l-difluorospiro[2.5]octan-5-yl)(3-((3S,9aS)-3- (methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl- 2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)-4-methyl- 1,2,5- oxadiazole-3 -carboxamide (isomer 2);N-((l,l-difluorospiro[2.5]octan-5-yl)(3-((3S,9aS)-3- (methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl- 2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)-4-methyl- 1,2,5- oxadiazole-3 -carboxamide (isomer 3);N-((l,l-difluorospiro[2.5]octan-5-yl)(3-((3S,9aS)-3- (methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl- 2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)-4-methyl- 1,2,5- oxadiazole-3 -carboxamide (isomer 4);N-((l,l-difluorospiro[2.5]octan-5-yl)(3-((3S,9aS)-3- (methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl-2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)-4-methyl- 1,2,5- oxadiazole-3 -carboxamide (isomer 5);N-((l,l-difluorospiro[2.5]octan-5-yl)(3-((3S,9aS)-3- (methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl- 2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)-4-methyl- 1,2,5- oxadiazole-3 -carboxamide (isomer 6);N-((l,l-difluorospiro[2.5]octan-5-yl)(3-((3S,9aS)-3- (methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-2-(((3R,5S)-5-methyl- 2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)-4-methyl- 1,2,5- oxadiazole-3 -carboxamide (isomer 7); andN-((S)-(3-((3S,9aS)-3-(methoxymethyl)hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)- 2-(((3R, 5 S)-5-methyl-2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)((lS,3R)-3-methylcyclohexyl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide; or a pharmaceutically acceptable salt thereof.

50. A pharmaceutical composition comprising a compound according to any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

51. A method of treating psoriasis comprising administering to a patient in need thereof an effective amount of a compound of any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof.

52. A method of treating psoriasis according to claim 51 comprising administering to a patient in need thereof an effective amount of a compound according to claim 43, or a pharmaceutically acceptable salt thereof.

53. A compound of any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, for use in therapy.

54. A compound according to any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder selected from the group consisting of psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, palmoplantar psoriasis, rheumatoid arthritis, multiple sclerosis, systemic sclerosis, psoriatic arthritis, axial spondyloarthritis, ankylosing spondylitis,hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma, non-infectious uveitis, and COPD.

55. A compound according to any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, for use in the treatment of psoriasis.

56. Use of a compound according to any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating psoriasis.

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