Il-17a inhibitors

Abstract

The invention provides certain imidazotriazine compounds of formula I 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 INHIBITORS BACKGROUND 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 the body, thus enabling more rapidrecovery 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):or 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 following particular embodiments are compounds and / or salts of formula I orII.

[0011] The present invention provides a compound according to any of the above embodiments wherein R2 isor a pharmaceutically acceptable salt thereof.

[0012] The present invention provides a compound according to any of the above embodiments wherein R2 isor a pharmaceutically acceptable salt thereof.

[0013] The present invention provides a compound according to any of the above embodiments wherein R2 is or a pharmaceutically acceptable salt thereof.

[0014]

[0015] The present invention provides a compound according to any of the above embodiments wherein R2 isor a pharmaceutically acceptable salt thereof.

[0016] The present invention provides a compound according to any of the above embodiments wherein R2 is, or a pharmaceutically acceptable salt thereof.

[0017] The present invention provides a compound according to any of the above embodiments wherein R2 isor a pharmaceutically acceptable salt thereof.

[0018] The present invention provides a compound according to any of the above embodiments wherein R2 is, or a pharmaceutically acceptable salt thereof.

[0019] The present invention provides a compound according to any of the above embodiments wherein R3 is or a pharmaceutically acceptable salt thereof.

[0020] The present invention provides a compound according to any of the above embodiments wherein R3 isor a pharmaceutically acceptable salt thereof.

[0021] The present invention provides a compound according to any of the above embodiments wherein R3 is , or a pharmaceutically acceptable salt thereof.

[0022]

[0023] The present invention provides a compound according to any of the above embodiments wherein R3 is , or a pharmaceutically acceptable salt thereof.

[0024] The present invention provides a compound according to any of the above embodiments wherein R3 is, or a pharmaceutically acceptable salt thereof.

[0025] The present invention provides a compound according to any of the above embodiments wherein R3 is, or a pharmaceutically acceptable salt thereof.

[0026] The present invention provides a compound according to any of the above embodiments wherein R3 is or a pharmaceutically acceptable salt thereof.

[0027] The present invention provides a compound according to any of the above embodiments wherein R3 isor a pharmaceutically acceptable salt thereof.

[0028] The present invention provides a compound according to any of the above embodiments wherein R4 is or a pharmaceutically acceptable salt thereof.

[0029] The present invention provides a compound according to any of the above embodiments wherein R4 isor a pharmaceutically acceptable salt thereof.

[0030] The present invention provides a compound according to any of the above embodiments wherein R4 is, or a pharmaceutically acceptable salt thereof.

[0031] The present invention provides a compound according to any of the above embodiments wherein R4 is, or a pharmaceutically acceptable salt thereof.

[0032] The present invention provides a compound according to any of the above embodiments wherein R4 is or a pharmaceutically 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 wherein R4 is, or a pharmaceutically 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 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 isor 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 wherein R4 is , or a pharmaceutically acceptable salt thereof.

[0046] The present invention provides a compound according to any of the above embodiments wherein R4 is, or a pharmaceutically 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] Further, the present invention provides a compound selected from the group consisting of:N-((S)-(3-(l-(2-amino-2-oxoethyl)piperidin-4-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;N-((S)-(3-((R)-4,4-difluoro-l-methylpiperidin-3-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 (Isomer 1);N-((S)-(3-((R)-4,4-difluoro-l-methylpiperidin-3-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 (Isomer 2);N-((S)-(3-((R)-4,4-difluoro-l-methylpiperidin-3-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-l,4-dihydroimidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l- (2-fluoroethyl)-lH-pyrazole-5-carboxamide (Isomer 1);N-((S)-(3-((R)-4,4-difluoro-l-methylpiperidin-3-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-l,4-dihydroimidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l- (2 -fluoroethyl)- lH-pyrazole-5-carboxamide (Isomer 2); l-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((S)-tetrahydrofuran-3- yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-lH-pyrazole-5- carboxamide (Isomer 1); l-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)-tetrahydrofuran-3- yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-lH-pyrazole-5- carboxamide (Isomer 2); l-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((3-methyloxetan-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-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)-tetrahydro-2H- pyran-3-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-lH-pyrazole- 5-carboxamide (Isomer 1);1-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)-tetrahydro-2H- pyran-3-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-lH-pyrazole- 5-carboxamide (Isomer 2);2-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)-tetrahydro-2H-pyran- 3 -yl)- 1 ,4-dihydroimidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)((l r,4S)-4-methylcyclohexyl)methyl)-4,5- dihydro-112,214-pyrazole-3-carboxamide (Isomer 1);2-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)-tetrahydro-2H-pyran- 3 -yl)- 1 ,4-dihydroimidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)((l r,4S)-4-methylcyclohexyl)methyl)-4,5- dihydro-112,214-pyrazole-3-carboxamide (Isomer 2);l-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(oxetan-3-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-(oxetan-3- ylmethyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-lH-pyrazole-5- carboxamide;N-((S)-(3-(l,l-dioxidotetrahydro-2H-thiopyran-4-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)-2-ethyl-4H- 214-pyrazole-3 -carboxamide;N-((S)-(3-((S)-l,l-dioxidotetrahydrothiophen-3-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 -ethyl- 1H- pyrazole-5-carboxamide (Isomer 1);N-((S)-(3-((S)-l,l-dioxidotetrahydrothiophen-3-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 -ethyl- 1H- pyrazole-5-carboxamide (Isomer 2);1 -ethyl -N-(( 1 S)-(3 -(1 -methyl- 1 -oxidophosphinan-4-yl)-2-(((3R, 5 S)-5-methyl-2-oxopiperi din-3 - yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-lH-pyrazole-5- carboxamide (Isomer 1);1 -ethyl-N-(( 1 S)-(3 -(1 -methyl- 1 -oxidophosphinan-4-yl)-2-(((3R, 5 S)-5-methyl-2-oxopiperi din-3 - yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-lH-pyrazole-5- carboxamide (Isomer 2);N-((S)-(3-((S)-2,2-dimethyl-l,l-dioxidotetrahydro-2H-thiopyran-4-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-ethyl-lH-pyrazole-5-carboxamide (Isomer 1);N-((S)-(3-((S)-2,2-dimethyl-l,l-dioxidotetrahydro-2H-thiopyran-4-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-ethyl-lH-pyrazole-5-carboxamide (Isomer 2);N-((S)-(3-(l,l-dioxidotetrahydro-2H-thiopyran-4-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- 113, 212, 5-oxadiazole-3 -carboxamide;N-((S)-(3-((R)-2,2-dimethyl-l,l-dioxidotetrahydro-2H-thiopyran-4-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 (Isomer 1);N-((S)-(3-((R)-2,2-dimethyl-l,l-dioxidotetrahydro-2H-thiopyran-4-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 (Isomer 2);N-((S)-(3-(l,l-dioxidotetrahydro-2H-thiopyran-4-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)-4-ethyl- 1,2,5- oxadiazole-3 -carboxamide;N-((S)-(3-((S)-2,2-dimethyl-l,l-dioxidotetrahydro-2H-thiopyran-4-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-ethyl-l,2,5-oxadiazole-3-carboxamide (Isomer 1);N-((S)-(3-((S)-2,2-dimethyl-l,l-dioxidotetrahydro-2H-thiopyran-4-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-ethyl-l,2,5-oxadiazole-3-carboxamide (Isomer 2);4-cyclopropyl-N-((lS)-(3-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)octahydroimidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-2,5-dihydro-l,2,5-oxadiazole-3-carboxamide;1-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(oxetan-3- ylmethyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)((l r,4S)-4-methylcyclohexyl)methyl)- 1H- 1 ,2,4- tri azol e- 5 -carb oxami de;N-((S)-((S)-3,3-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((S)- tetrahydrofuran-3 -yl)- 1 ,4-dihydroimidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -methyl- 1H- pyrazole-5-carboxamide (Isomer 1);N-((S)-((S)-3,3-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((S)- tetrahydrofuran-3 -yl)- 1 ,4-dihydroimidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -methyl- 1H- pyrazole-5-carboxamide (Isomer 2);2-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)-tetrahydrofuran-3- yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3-methylcyclohexyl)methyl)-4H-214-pyrazole-3- carboxamide (Isomer 1);2-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)-tetrahydrofuran-3- yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3-methylcyclohexyl)methyl)-4H-214-pyrazole-3- carboxamide (Isomer 2);N-((S)-(3-isopropyl-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;4-cyclopropyl-N-((S)-(3-(l,l-dioxidotetrahydro-2H-thiopyran-4-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; l-methyl-N-((S)-l-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)-tetrahydrofuran-3- yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-3 -( 1 -(trifluoromethyl)cyclopropyl)propyl)- lH-pyrazole-5- carboxamide (Isomer 1);1-methyl-N-((S)-l-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)-tetrahydrofuran-3- yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-3 -( 1 -(trifluoromethyl)cyclopropyl)propyl)- lH-pyrazole-5- carboxamide (Isomer 2);4-cyclopropyl-N-((R)-l-((R)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)- tetrahydrofuran-3 -yl)-3 ,4-dihydroimidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-2-(( 1,1,1 -trifluoro-2- methylpropan-2-yl)oxy)ethyl)-l,2,5-oxadiazole-3-carboxamide (Isomer 1);4-cyclopropyl-N-((R)-l-((R)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)- tetrahydrofuran-3 -yl)-3 ,4-dihydroimidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-2-(( 1,1,1 -trifluoro-2- methylpropan-2-yl)oxy)ethyl)-l,2,5-oxadiazole-3-carboxamide (Isomer 2);4-cyclopropyl-N-((R)-l-(3-(l,l-dioxidotetrahydro-2H-thiopyran-4-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;N-((R)-l-(3-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-2-((l , 1 , 1 -trifluoro-2-methylpropan-2-yl)oxy)ethyl)- 4-ethyl-l,2,5-oxadiazole-3-carboxamide;N-((lS)-(3-(l-(cyanoimino)-l-oxidohexahydro-116-thiopyran-4-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-ethyl-lH-pyrazole-5-carboxamide (Isomer 2);N-((lS)-(3-(l-(cyanoimino)-l-oxidohexahydro-116-thiopyran-4-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-ethyl-lH-pyrazole-5-carboxamide (Isomer 2);4-cyclopropyl-N-((lS)-(4,4-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3-(tetrahydrofuran-3-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l,2,5-oxadiazole-3- carboxamide (Isomer 1);4-cyclopropyl-N-((lS)-(4,4-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3-(tetrahydrofuran-3-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l,2,5-oxadiazole-3- carboxamide (Isomer 2);4-cyclopropyl-N-((S)-(4,4-difluorocyclohexyl)(3-(l,l-dioxidotetrahydro-2H-thiopyran-4-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;4-ethyl-N-((lR)-l-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydrofuran-3- yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-2-((l , 1 , 1 -trifluoro-2-methylpropan-2-yl)oxy)ethyl)- 1,2,5- oxadiazole-3 -carboxamide (Isomer 1);4-ethyl-N-((lR)-l-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydrofuran-3- yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-2-((l , 1 , 1 -trifluoro-2-methylpropan-2-yl)oxy)ethyl)- 1,2,5- oxadiazole-3 -carboxamide (Isomer 2);N-((S)-(3-((2R,6R)-2,6-dimethylmorpholino)-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-((2S,6S)-2,6-dimethylmorpholino)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)- l,4-dihydroimidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l-methyl-lH- pyrazole-5-carboxamide;N-((S)-(3-((2R,6S)-2,6-dimethylmorpholino)-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;N-((lS)-(3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-l,4-dihydroimidazo[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)-(3-((lR,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-l,4-dihydroimidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l- methyl - 1 H-py razol e- 5 -carb oxami de;1-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)-2- methylmorpholino)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-lH- pyrazole-5-carboxamide;N-((S)-(3-((2R,6R)-2,6-dimethylmorpholino)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[l, 2-b][l, 2, 4]triazin-6-yl)((lr,4S)-4-methylcy cl ohexyl)methyl)-l -isopropyl- lH-l,2,4-triazole-5-carboxamide;N-((S)-(3-((2R,6R)-2,6-dimethylmorpholino)-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- fluoroethyl)-lH-pyrazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-((2S,6S)-2,6-dimethylmorpholino)-2-(((3R,5S)-5-methyl-2- oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -ethyl- 1H- 1 ,2,4-triazole-5- carboxamide;N-((S)-((S)-3 ,3 -difluorocy clohexyl)(3 -((2R, 6R)-2, 6-dimethylmorpholino)-2-(((3R, 5 S)-5 -methyl -2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,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-((2R,6R)-2,6-dimethylmorpholino)-2-(((3R,5S)-5-methyl- 2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -isopropyl- 1H- 1 ,2,4- tri azol e- 5 -carb oxami de;N-((S)-((S)-3,3-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- morpholinoimidazof 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -isopropyl- 1H- 1 ,2,4-triazole-5- carboxamide;N-((S)-(3-((2R,6R)-2,6-dimethylmorpholino)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-1.4-dihydroimidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)(( 1 S,3R)-3 -methylcy cl ohexyl)m ethyl)- 1 -methyl- lH-pyrazole-5-carboxamide;N-((S)-(3-((2R,6R)-2,6-dimethylmorpholino)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-1.4-dihydroimidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3-methylcyclohexyl)methyl)-l-isopropyl- 3H-114,2,4-triazole-5-carboxamide;N-((lS)-l-(3-((2R,6R)-2,6-dimethylmorpholino)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3,4,4a,5-tetrahydroimidazo[l,2-b][l,2,4]triazin-6-yl)-3-(l- (trifluoromethyl)cyclopropyl)propyl)-l-methyl-lH-pyrazole-5-carboxamide;N-((S)-l-(3-((2R,6S)-2,6-dimethylmorpholino)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-3 -(1 -(trifluoromethyl)cyclopropyl)propyl)- 1 -ethyl - lH-pyrazole-5-carboxamide; l-ethyl-N-((S)-l-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4-oxa-7- azaspiro[2.5]octan-7-yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-3 -( 1 - (trifluoromethyl)cyclopropyl)propyl)-lH-pyrazole-5-carboxamide;N-((S)-l-(3-((2R,6R)-2,6-dimethylmorpholino)-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-(2- fluoroethyl)- 1 H-py razol e- 5 -carb oxami de; l-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((S)-2- methylmorpholino)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-lH- pyrazole-5-carboxamide;N-((lS)-(3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)(cy clohexyl)methyl)- 1 -methyl- lH-pyrazole-5- carboxamide;N-((S)-(3-((lR,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)(cy clohexyl)methyl)- 1 -methyl- lH-pyrazole-5- carboxamide;N-((S)-cyclohexyl(3-((2R,6R)-2,6-dimethylmorpholino)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -methyl- lH-pyrazole-5-carboxamide;N-((S)-cyclohexyl(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)-2- methylmorpholino)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -methyl- lH-pyrazole-5- carboxamide;N-((S)-cyclohexyl(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((S)-2- methylmorpholino)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -methyl- lH-pyrazole-5- carboxamide;N-((lS)-(3-(l-(cyanoimino)hexahydro-114-thiopyran-4-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-ethyl-lH- pyrazole-5-carboxamide;4-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)-tetrahydrofuran-3- yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l,2,5-oxadiazole-3- carboxamide (Isomer 1);4-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)-tetrahydrofuran-3- 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-((S)-(4,4-difluorocyclohexyl)(3-isopropyl-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -ethyl- lH-pyrazole-5 -carboxamide (Isomer1);N-((S)-(4,4-difluorocyclohexyl)(3-isopropyl-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl-lH-pyrazole-5-carboxamide (Isomer2);N-((S)-(3-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)(cyclohexyl)methyl)- 1 -methyl- lH-pyrazole-5- carboxamide;N-((S)-(3-((lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin- 3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)(( 1 r,4S)-4-methylcyclohexyl)methyl)- 1 -methyl- lH-pyrazole-5-carboxamide;N-((S)-(3-((lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin- 3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)(cyclohexyl)methyl)- 1 -methyl- lH-pyrazole-5- carboxamide;N-((lS)-(3-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(((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;1 -ethyl -N-((S)-(3 -(1 -imino- 1 -oxidohexahydro- 116-thiopyran-4-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 (Isomer 1);1 -ethyl -N-((S)-(3 -(1 -imino- 1 -oxidohexahydro- 116-thiopyran-4-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 (Isomer 2);N-((S)-((S)-3 ,3 -difluorocy clohexyl)(3 -((2R, 6R)-2, 6-dimethylmorpholino)-2-(((3R, 5 S)-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; andN-((S)-(3-((2R,6R)-2,6-dimethylmorpholino)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[l,2-b] [1,2, 4]triazin-6-yl)((S)-8-fluoro- 1,2,3, 4-tetrahy dronaphthalen-2- yl)m ethyl)- 1 -methyl- lH-pyrazole-5-carboxamide; or a pharmaceutically acceptable salt thereof.

[0051] 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.

[0052] 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

[0053] 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.

[0054] Further, the present invention provides a compound of formula I or II, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0055] 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 for treating 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.

[0056] 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 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.

[0057] 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 apharmaceutically 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.

[0058] 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.

[0059] 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).

[0060] 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.

[0061] 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.

[0062] "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.

[0063] 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.

[0064] 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” arestereoisomers 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 chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.

[0065] 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.EXAMPLES AND PREPARATIONS

[0066] 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-tert-butyl dicarbonate; “CbzOSu” refers to N-(benzyloxycarbonyloxy)succinimide; “CDI” refers to carbonyldiimidazole; “Cu(OAc)2” refers to diacetoxycopper; “DBN” refers to l,5-diazabicyclo(4.3.0)non-5-ene; “DCC” refers to N,N'-dicyclohexylcarbodiimide; “DCE”refers to dichloroethane; “DCM” refers to dichloromethane; “DDQ” refers to 2,3-dichloro-5,6- di cyano- 1,4-benzoquinone; “DIBAL-H” refers to diisobutylaluminium hydride; “DIPEA” refers to diisopropylethylamine; “DMA” refers to N,N-dimethylacetamide; “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); “HATU” refers to hexafluorophosphate azabenzotri azole tetramethyl uranium; “IBD” refers to (diacetoxyiodo)benzene; “iPrOH” refers to isopropanol; “KOtBu” refers to potassium tert-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 minute(s); “MsOH” refers to methanesulfonic acid; “NaBH3CN” refers to sodium cyanoborohydride; “NaOAc” refers to sodium acetate; “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;“RT” refers to room temperature; “sat” refers to saturated; “tBuOH” refers to tert-butanol; “TBAP” refers to tetrabutylammonium perchlorate; “TEA” refers to triethylamine; “TFA” refers to trifluoroacetic acid; “THF” refers to tetrahydrofuran; “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; “TMSOTf ’ refers to trimethyl silyl trifluoromethanesulfonate; “T4P” refers to 2,4,6-tributyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6- trioxide.

[0067] 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.

[0068] 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 with trimethyl borate, in the presence of an appropriate base, such as DIPEA, in a suitablesolvent, such as 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 the 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 l,3-dioxoisoindolin-2-yl acetate in presence a suitable radical initiator, such as 4DPAIPN, in an appropriate solvent, such as DMSO. The reaction is stirred at RT, under N2 atmosphere, under LED (395-456 nm) irradiation, for 16 h.

[0069] Optionally, a protected amine is present on group R3 of intermediate (v) 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 NaBEECN, in a suitable solvent, such as MeOH. Alternatively, the deprotected amine is reacted with an appropriate alkyl chloride, in presence of a suitable base, such as DIPEA, in an appropriate solvent such as ACN, at 80 °C for 1 h.

[0070] Optionally, a thiopyran is present on group R3 of intermediate (v) and is reacted with cyanamide in presence of an appropriate hypervalent iodine reagent, such as IBD, in a suitable solvent, such as ACN, at 0 °C for 1 h, to generate a cyanoimimothiopyran.

[0071] Optionally, a thiopyran is present on group R3 of intermediate (v) and is reacted with ammonium carbamate in presence of an appropriate hypervalent iodine reagent, such as IBD, in a suitable solvent, such as MeOH, at 25 °C for 1 h, to generate an iminooxidothiopyran. The resulting intermediate is reacted Cu-catalyzed alkylation conditions and include reacting the iminooxidothiopyran with methylboronic acid, in presence of an appropriate Cu catalyst, such as CU(OAC)2 and a suitable base, such as pyridine, in an appropriate solvent, such as dioxane, at 100 °C for 2 h.

[0072] The skilled artisan will appreciate that the sequence of the steps described in Scheme 1 may be changed depending on the availability of starting materials.

[0073] Scheme 2 depicts the preparation of compounds of the present invention beginning with a suitable imidazotriazine (v). The resulting intermediate (vi) is reacted with a suitable amine in presence of Ag(pyr2)MnO4 in an appropriate solvent, such as THF, at 0-5°C for 15 min.

[0074] Scheme 3 depicts the preparation of the triazine intermediate (i) beginning with a suitable triazine amine (vi). The triazine amine (vi) 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 (vii) under conditions well known to the skilled artisan, intermediate (viii) 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 (ix) and protected lactam (x) 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 (xi) under acidic conditions well known to the skilled person, the ester (xii) 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 (xiii) with NaCl in a suitable solvent, such as DMF, at 100 °C for 12 h.

[0075] Scheme 4 depicts an alternative preparation of the triazine intermediate (i) beginning with a suitable piperidone (xiv). The piperidone (xiv) is reacted in the presence of TMSC1, TMEDA and 12 in an appropriate solvent, such as toluene, at 0 °C for 2 h. The resulting intermediate (xv) 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 (xvi) and the aldehyde (xvii) are reacted under Wittig-Homer conditions and include a suitable base, such as KOtBu, in an appropriate solvent, such as THF. The olefin intermediate (xviii) 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 (xix) into the intermediate (xx), 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 1 2-(3-methyloxetan-3-yl)acetic acid

[0076] To a solution of ethyl 2-(oxetan-3-ylidene)acetate (5.00 g, 35.1 mmol) and iodocopper (669 mg, 3.52 mmol) in THF (40 mL) was added to a solution of chloro(trimethyl)silane (7.64 g, 70.3 mmol, 8.93 mL) in THF (120 mL) under N2. The mixture was stirred for 15 min and cooled to 0 °C, and bromo(methyl)magnesium (3 M, 46.9 mL) was added dropwise under N2. The reaction mixture was heated to 25 °C for 1 h, then diluted with H2O and extracted with EtOAc. The combined organic layers were washed with sat. NaCl (aq), dried over ISfeSCU, filtered, and concentrated under reduced pressure to afford the title compound (4.10 g, 74%) as yellow oil. *H NMR (400 MHz, CDCI3) 8 4.58 - 4.57 (m, 2H), 4.41 - 4.40 (m, 2H), 4.16 - 4.11 (m, 2H), 2.66 (s, 2H), 1.40 (s, 3H), 1.25 - 1.24 (m, 3H).Preparation 2 2-(3-methyloxetan-3-yl)acetic acid

[0077] To a solution of ethyl 2-(3-methyloxetan-3-yl)acetate (500 mg, 3.16 mmol) in MeOH (5 mL) was added a solution of sodium hydroxide (189 mg, 4.74 mmol) in water (1 mL) at 0 °C and the mixture was stirred at 0 °C for 2 h. The reaction mixture was then adjusted to pH = 5 with a 1.0 M aq. HC1 at 0 °C and the resulting solution was concentrated under reduced pressure to afford the title compound (250 mg, 61% yield) as yellow oil.1H NMR (400 MHz, CDCI3) 6 4.60 - 4.59 (m, 2H), 4.44 - 4.29 (m, 2H), 2.72 (s, 2H), 1.43 (s, 3H).Preparation 3Methyl 3 -((3 -m ethoxy-3 -oxopropyl)thio)-3 -methylbutanoate

[0078] Pyridine (13.1 g, 166 mmol, 13.4 mL) was added dropwise to a solution of methyl 3-methylbut-2-enoate (23.7 g, 208 mmol, 25.4 mL) and benzyl(trimethyl)ammonium hydroxide (1.74 g, 10.4 mmol, 1.89 mL) in MeOH (85 mL) at 0 °C followed by the dropwise addition of methyl 3-mercaptopropanoate (25.0 g, 208 mmol, 22.5 mL) at 0 °C. The reaction mixture was heated to 60 °C and stirred for 24 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc. The combined organic layers were washed with sat. NaCl (aq), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, PEZEtOAc) to afford the title compound (30.0 g, 62%) as a white solid. *H NMR (400 MHz, CDCI3) 8 3.66 - 3.59 (m, 6H), 2.79 - 2.72 (m, 2H), 2.54 - 2.48 (m, 4H), 1.37 (s, 6H).Preparation 4Methyl 6,6-dimethyl-4-oxotetrahydro-2H-thiopyran-3-carboxylate and methyl 2,2-dimethyl-4- oxotetrahydro-2H-thiopyran-3-carboxylate

[0079] To a solution of methyl 3 -((3 -m ethoxy-3 -oxopropyl)thio)-3 -methylbutanoate (30.0 g, 128 mmol) in THF (6 mL) was added LDA (2 M, 192 mL) at -70°C under N2. The mixture was stirred at -70 °C for 3 h and was then quenched by addition of sat. NH4CI (aq) at 0 °C. The mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with sat. NaCl (aq), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a 1 : 1 mixture of the title compound isomers (25 g, 96%) as a white solid.1H NMR (400 MHz, CDCI3) 6 3.79 (d, J = 3.8 Hz, 3H), 3.72 - 3.66 (m, 2H), 3.43 - 3.40 (m, 1H), 3.11 - 3.02 (m, 1H), 2.72 - 2.64 (m, 1H), 1.39 - 1.35 (m, 6H).Preparation 52,2-dimethyltetrahydro-4H-thiopyran-4-one

[0080] A solution of a mixture of methyl 6,6-dimethyl-4-oxotetrahydro-2H-thiopyran-3- carboxylate and methyl 2,2-dimethyl-4-oxotetrahydro-2H-thiopyran-3-carboxylate (25 g, 124 mmol) in 1 M HC1 (aq) (6 M, 250 mL) was stirred at 100 °C for 12 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc. The combined organic layers were washed with sat. NaCl (aq), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, PE / EtOAc) to afford the title compound (5.60 g, 63% yield) as a white solid. 'H NMR (400 MHz, CDCI3) 5 3.04 - 2.95 (m, 2H), 2.65 - 2.58 (m, 2H), 2.55 (s, 2H), 1.36 (s, 6H).Preparation 62, 2-dimethyltetrahydro-2H-thiopyran-4-carbonitrile

[0081] To a solution of 2,2-dimethyltetrahydro-4H-thiopyran-4-one (5.60 g, 38.8 mmol) and l-(isocyanomethylsulfonyl)-4-methyl-benzene (8.34 g, 42.7 mmol) in 1,2-dimethoxy ethane (50 mL) at 0 °C was added potassium 2-methylpropan-2-olate (8.71 g, 77.6 mmol). The mixture was stirred at 25 °C for 12 h, diluted with H2O, and extracted with EtOAc. The combined organic layers were washed with sat. NaCl (aq), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc) to afford the title compound (3.60 g, 60% yield) as a yellow oil. 'H NMR (400 MHz, CDCI3) 8 2.83 - 2.72 (m, 2H), 2.66 - 2.56 (m, 1H), 2.35 - 2.27 (m, 1H), 2.08 - 1.80 (m, 3H), 1.35 (d, J = 6.6 Hz, 6H).Preparation 72, 2-dimethyltetrahydro-2H-thiopyran-4-carboxylic acid

[0082] To a solution of 2, 2-dimethyltetrahydro-2H-thiopyran-4-carbonitrile (3.60 g, 23.1 mmol) in EtOH (6 mL) and H2O (30 mL) was added NaOH (aq) (2 M, 34.7 mL). The mixturewas stirred at 80°C for 5 h. The reaction mixture was diluted with H2O and 1 M HC1 (aq) was added to adjusted pH to 2. The mixture was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound (3.90 g, 96%) as a white solid. *H NMR (400 MHz, DMSO-d6) 5 = 12.2 (s, 1H), 2.84 - 2.71 (m, 1H), 2.48 - 2.44 (m, 1H), 2.18 - 2.08 (m, 1H), 1.94 - 1.83 (m, 1H), 1.59 - 1.34 (m, 2H), 1.31 (s, 3H), 1.20 (s, 3H).Preparation 82, 2-dimethyltetrahydro-2H-thiopyran-4-carboxylic acid 1, 1 -dioxide

[0083] To a solution of 2,2-dimethyltetrahydro-2H-thiopyran-4-carboxylic acid (3.70 g, 21.2 mmol) in tetrahydrofuran (40 mL), H2O (13 mL) was added Oxone (39.1 g, 63.7 mmol) at 0 °C and the mixture was stirred at 0 °C for 1 h. The reaction mixture was filtered, and the filter cake washed with DCM. The filtrate was diluted with H2O and extracted with DCM. The combined organic layers were washed with sat. Na2S20s (aq), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (2.40 g, 55%) as a white solid. 'H NMR (400 MHz, DMSO-d6) 5 12.3 (s, 1H), 3.43 - 3.41 (m, 1H), 3.03 - 2.91 (m, 1H), 2.82 - 2.71 (m, 1H), 2.21 - 2.12 (m, 1H), 2.06 - 1.80 (m, 3H), 1.39 (s, 3H), 1.20 (s, 3H).Preparation 91 -ethyl -4-fluoro- 1 H-py razol e- 5 -carb oxy li c aci d

[0084] l-ethyl-lH-pyrazole-5-carboxylic acid (0.500 g, 3.57 mmol) and 1- (chloromethyl)-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane di tetrafluorob orate (2.53 g, 7.14 mmol) were taken up into a microwave tube in ACN (8 mL) and AcOH (3 mL). The sealed tube was heated at 110 °C for 6 h under microwave. The mixture was concentrated to remove solvent. The residue was purified by Prep-HPLC (column: Phenomenex luna C18 150^40 mmx l5 um; mobile phase: [water (FA) - ACN]; gradient: 18% - 48% B over 15 min) to afford the title compound (100 mg, 18%) as off-white solid. ES / MS (m / z): 159 (M+H).Preparation 104-fluoro- 1 -methyl- lH-pyrazole-5-carboxylic acid

[0085] Beginning with 1 -methyl- lH-pyrazole-5-carboxylic acid (0.500 g, 3.96 mmol), the title compound was prepared (0.10 g, 18%) as a white solid. ES / MS (m / z): 145 (M+H).Preparation 11Ethyl 4-methyl-2,3-dioxopentanoate

[0086] To a solution of ethyl 4-methyl-3-oxo-pentanoate (100 g, 632 mmol, 101 mL) in dioxane (1000 mL) was added SeO2 (105 g, 948 mmol, 103 mL) in portions and the resulting mixture was stirred at 90 °C for 12 h under N2. The mixture was filtered and concentrated to remove solvent to afford the title compound (100 g, 92% yield) was obtained as red oil.

[0087] The compound in the following table was prepared essentially as described in Preparation 11, beginning with the appropriate P-ketoester.Preparation 13Ethyl 3-amino-5-isopropyl-l,2,4-triazine-6-carboxylate

[0088] To a solution of ethyl 4-methyl-2,3-dioxo-pentanoate (100 g, 580 mmol), 2- aminoguanidine hydrochloride (64.2 g, 580 mmol) in EtOH (500 mL) and H2O (500 mL) was added NaHCCE (97.5 g, 1.16 mol) and the mixture was stirred at 90 °C for 1 h. The mixture was concentrated to remove EtOH, then extracted with DCM, washed with sat. NaCl (aq), dried over Na2SO4, filtered, and concentrated to remove solvent. The residue was purified by column (SiO2, PEZEtOAc) to afford the title compound (20.0 g, 16%) as a yellow solid. ES / MS (m / z): 211 (M+H).

[0089] The compound in the following table was prepared essentially as described in Preparation 13, beginning with the appropriate a, P-diketoester.Preparation 15Ethyl 3-((tert-butoxycarbonyl)amino)-5-isopropyl-l,2,4-triazine-6-carboxylate

[0090] To a solution of ethyl 3-amino-5-isopropyl-l,2,4-triazine-6-carboxylate (20.0 g, 95.1 mmol) in THF (200 mL) was added LiHMDS (1 M, 142 mL) at -78 °C under N2 and the mixture was stirred at -78 °C for 0.5 h at which time Boc2O (31.1 g, 142 mmol, 32.7 mL) was added and the resulting mixture was stirred at -78 °C for 0.5 h. The reaction mixture was quenched with sat. NH4CI (aq) and H2O, extracted with EtOAc, and the combined organic layer was washed with sat. NaCl (aq), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column (SiCh, PEZEtOAc) to afford the title compound (22.5 g, 76%) as a yellow solid. ES / MS (m / z): 255 (M-55).

[0091] The compound in the following table was prepared essentially as described in Preparation 15, beginning with the appropriate amine.Preparation 17 3-((tert-butoxycarbonyl)amino)-5-isopropyl-l,2,4-triazine-6-carboxylic acid

[0092] To a solution of ethyl 3-(tert-butoxycarbonylamino)-5-isopropyl-l,2,4-triazine-6- carboxylate (22.5 g, 72.5 mmol) in THF (200 mL) was added a solution of LiOH H2O (4.56 g, 108 mmol) in H2O (40 mL) at 0 °C and the mixture was stirred at 25 °C for 1 h at which time IM HC1 (aq) was added to adjust the pH = 3. The mixture was then extracted with DCM and the combined organic layers washed with sat. NaCl (aq), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (20.0 g, 98%) as a yellow solid. ES / MS (m / z): 227 (M-55).

[0093] The compound in the following table was prepared essentially as described in Preparation 17, beginning with the appropriate ester.Preparation 19 tert-butyl (6-(hydroxymethyl)-5-isopropyl-l,2,4-triazin-3-yl)carbamate

[0094] To a solution of 3-(tert-butoxycarbonylamino)-5-isopropyl-l,2,4-triazine-6- carboxylic acid (20.0 g, 70.8 mmol) in THF (200 mL) was added 4-methylmorpholine (7.17 g, 70.8 mmol, 7.79 mL), isobutyl chloroformate (9.68 g, 70.8 mmol, 9.27 mL) at 0 °C. After stirring for 0.5 h the reaction mixture was filtered and to the filtrate was added a solution of NaBPL (1.34 g, 35.4 mmol) in H2O (20 mL) at 0 °C under N2 and this mixture was stirred at 0 °C for 0.5 h. The reaction mixture was quenched by sat. NH4CI (aq), extracted with DCM, and the combined organic layer was washed with sat. NaCl (aq), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column (SiCL, DCM / MeOH) to afford the title compound (4 g, 21%) as a yellow oil. ES / MS (m / z): 213 (M-55).

[0095] The compound in the following table was prepared essentially as described in Preparation 19, beginning with the appropriate carboxylic acid.Preparation 21 benzyl ((S)-(3-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(hydroxymethyl)imidazo[l,2- b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)carbamate

[0096] To a solution of Isobutyl 6-((S)-(((benzyloxy)carbonyl)amino)((lr,4S)-4-methyl- cyclohexyl)methyl)-3-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)imidazo[l,2-b][l,2,4]tria- zine-2-carboxylate (900 mg, 1.45 mmol) in THF (10 mL) was added NaBEL (109 mg, 2.90 mmol) in H2O (0.5 mL) at 0 °C. The reaction mixture was stirred at 15 °C for 1 h. The reaction mixture was quenched by the addition of a sat. NH4Cl(aq) at 0 °C, and then diluted with H2O and extracted with EtOAc. The combined organic layers were dried over ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (condition: column: Phenomenex luna C18 150^40 mmx l5 um; mobile phase: [water (FA) - ACN]; gradient: 32% - 62% B over 10 min) to afford the title compound (470 mg, 64%) as a yellow solid. ES / MS (m / z): 507 (M+H).Preparation 22 tert-butyl (6-(chloromethyl)-5-isopropyl-l,2,4-triazin-3-yl)carbamate

[0097] To a solution of tert-butyl (6-(hydroxymethyl)-5-isopropyl-l,2,4-triazin-3- yl)carbamate (900 mg, 3.35 mmol) in DCM (10 mL) was added SOC12 (798 mg, 6.71 mmol, 487 pL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h and was then concentrated under reduced pressure to afford the title compound (950 mg, 99%) as a brown solid. ES / MS (m / z): 231 (M-55)

[0098] The compound in the following table was prepared essentially as described in Preparation 22, beginning with the appropriate alcohol.Preparation 25 l-(tert-butyl) 3-methyl (5S)-3-((3-((terZ-butoxycarbonyl)amino)-5-isopropyl-l,2,4-triazin-6- yl)methyl)-5-methyl-2-oxopiperidine-l,3-dicarboxylate

[0099] To a solution of tert-butyl (6-(chloromethyl)-5-isopropyl-l,2,4-triazin-3- yl)carbamate (880 mg, 3.07 mmol) and 1 -(tert-butyl) 3-methyl (5S)-5-methyl-2-oxopiperidine- 1,3 -di carb oxy late (874 mg, 3.22 mmol) in THF (10 mL) was added CS2CO3 (2.00 g, 6.14 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h and was then diluted with H2O and extracted with EtOAc. The combined organic layers were washed with sat. NaCl (aq), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCh, PEZEtOAc) to afford the title compound (700 mg 44%) as a yellow oil. ES / MS (m / z): 522 (M+H).[000100] The compound in the following table was prepared essentially as described in Preparation 25, beginning with the appropriate haloalkyl.Preparation 28 l-(tert-butyl) 3-methyl (5S)-3-((3-((terZ-butoxycarbonyl)amino)-5-isopropyl-l,2,4-triazin-6- yl)methyl)-5-methyl-2-oxopiperidine-l,3-dicarboxylate trifluoroacetate[000101] To a solution of 1 -(tert-butyl) 3-methyl (5S)-3-((3-((tert-butoxycarbonyl)amino)- 5-isopropyl-l,2,4-triazin-6-yl)methyl)-5-methyl-2-oxopiperidine-l,3-dicarboxylate (700 mg, 1.34 mmol) in DCM (8 mL) was added TFA (459 mg, 4.03 mmol, 299 pL) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to afford the title compound (580 mg, 99%) as a yellow oil. ES / MS (m / z): 322 (M+H).[000102] The compound in the following table was prepared essentially as described in Preparation #, beginning with the appropriately protected amine.Preparation 30Methyl (5S)-3-((6-((S)-(((benzyloxy)carbonyl)amino)((lr,4S)-4-methylcyclohexyl)methyl)-3- ((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)imidazo[l,2-b][l,2,4]triazin-2-yl)methyl)-5- methyl-2-oxopiperidine-3-carboxylate hydrochloride[000103] To a solution of 1 -(tert-butyl) 3-methyl (5S)-3-((6-((S)- (((benzyloxy)carbonyl)amino)((lr,4S)-4-methylcyclohexyl)methyl)-3-((lR,4R)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)imidazo[l,2-b][l,2,4]triazin-2-yl)methyl)-5-methyl-2- oxopiperidine-l,3-dicarboxylate (250 mg, 329 pmol) in DCM (3 mL) was added a solution of HCl / dioxane (2 M, 822 pL) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h and was then concentrated under reduced pressure to afford the title compound (200 mg 87%) as a yellow solid. ES / MS (m / z): 660 (M+H).Preparation 31(5S)-3-((3-amino-5-isopropyl-l,2,4-triazin-6-yl)methyl)-5-methyl-2-oxopiperidine-3-carboxylic acid[000104] To a solution of methyl (5S)-3-((3-amino-5-isopropyl-l,2,4-triazin-6-yl)methyl)- 5-methyl-2-oxopiperidine-3-carboxylate trifluoroacetate (580 mg, 1.33 mmol) in THF (7 mL) was added LiOH H2O (167 mg, 4.00 mmol) and H2O (1.40 mL) at 0 °C. The mixture was stirred at 25 °C for 8 h and then IM HC1 (aq) was added to adjust pH = 4. The reaction mixture was concentrated under reduced pressure to afford the title compound (400 mg, 98%) as a yellow oil. ES / MS (m / z): 308 (M+H).[000105] The compound in the following table was prepared essentially as described in Preparation 31, beginning with the appropriate ester.Preparation 34(5S)-3-((3-amino-5-isopropyl-l,2,4-triazin-6-yl)methyl)-5-methylpiperidin-2-one[000106] To a solution of (5S)-3-((3-amino-5-isopropyl-l,2,4-triazin-6-yl)methyl)-5- methyl-2-oxopiperidine-3-carboxylic acid (400 mg, 1.30 mmol) in DMSO (3 mL) was added NaCl (228 mg, 3.90 mmol). The mixture was stirred at 100 °C for 1 h and was then purified directly by prep-HPLC (column: Waters Xbridge C18 150x50 mmx lO um; mobile phase: [water (NH4HCO3) - ACN]; gradient: 9% - 39% B over 10 min) to afford the title compound (200 mg, 58%) as a white solid. ES / MS (m / z): 264 (M+H).[000107] The compound in the following table was prepared essentially as described in Preparation 34, beginning with the appropriate a-ketoacid.Preparation 37(3R,5S)-3-((3-amino-5-(tetrahydro-2H-pyran-4-yl)-l,2,4-triazin-6-yl)methyl)-5-methylpiperidin-2-one[000108] (5S)-3-((3-amino-5-(tetrahydro-2H-pyran-4-yl)-l,2,4-triazin-6-yl)methyl)-5- methylpiperidin-2-one was subjected to Prep-SFC chromatography (column: DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 um); mobile phase: [CO2 - i-PrOH (0.1% NH3H2O)]; B%:40%, isocratic elution mode) to provide the title compound (140 mg, 33.3% yield) as a white solid. ES / MS (m / z): 306.4 (M+H).Preparation 38 tert-butyl (S)-4-(((benzyloxy)carbonyl)amino)-4-(4,4-difluorocyclohexyl)-3-oxobutanoate[000109] 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 to 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. NH4CI (aq), extracted with EtOAc, washed with sat. NaCl (aq), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCh, PE / EtOAc) to afford the title compound (30.0 g, 77% yield) as a yellow oil. ES / MS (m / z): 448 (M+Na).Preparation 29 tert-Butyl (4S)-4-(((benzyloxy)carbonyl)amino)-2-bromo-4-(4,4-difluorocyclohexyl)-3- oxobutanoate[000110] To a solution of tert-butyl (S)-4-(((benzyloxy)carbonyl)amino)-4-(4,4- difluorocyclohexyl)-3-oxobutanoate (30.0 g, 70.5 mmol) in MeOH (300 mL) was added N- bromosuccinimide (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 a sat. NaHCCL (aq), extracted with EtOAc, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (20.0 g, 56%) as a yellow solid.Preparation 40 benzyl (5)-(3-bromo-l-(4,4-difluorocyclohexyl)-2-oxopropyl)carbamate[000111] 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. NaHCCL (aq) and extracted with EtOAc. The combined organic phases were dried over 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 mm); mobile phase: [water (NH4HCO3)-ACN]; B%: 45%-70%) to afford the title compound 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, 67%) as a white solid. ES / MS (m / z): 404 (M+H).Preparation 411 -(tert-butyl) 4-( 1 ,3 -dioxoisoindolin-2-yl) piperidine- 1 ,4-dicarboxylate[000112] To a solution of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1.00 g, 4.36 mmol) and 2-hydroxyisoindoline-l,3-dione (853 mg, 5.23 mmol) in DCM (10 mL) was added diisopropylcarbodiimide (660 mg, 5.23 mmol, 810 pL) and DMAP (53.2 mg, 436 pmol). The mixture was stirred at 25 °C for 5 h and was then diluted with H2O and extracted with DCM.The combined organic layers were washed with sat. NaCl (aq) and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, PE: EA) to afford the title compound (1.20 g, 73.4%) as a white solid. 'H NMR (400 MHz, CDCI3) 5 7.91 - 7.78 (m, 2H), 7.83 - 7.78 (m, 2H), 4.10 - 3.95 (m, 2H), 3.07 - 2.87 (m, 3H), 2.11 - 2.03 (m, 2H), 1.91 - 1.80 (m, 2H), 1.47 (s, 9H).[000113] The compounds in the following table were prepared essentially as described in Preparation 41 beginning with the appropriate carboxylic acid.Preparation 50 l,3-dioxoisoindolin-2-yl 2-(3-methyloxetan-3-yl)acetate[000114] To a solution of 2-(3-methyloxetan-3-yl)acetic acid (250 mg, 1.92 mmol) and 2- hydroxyisoindoline-l,3-dione (344 mg, 2.11 mmol) in THF (5 mL) was added DMAP (23.4 mg, 192 pmol) and DCC (792 mg, 3.84 mmol). The mixture is stirred at 25 °C for 2 h. The reaction mixture was then adjusted to pH = 5 with a 1.0 M HC1 (aq) at 0 °C and the resulting solution concentrated under reduced pressure to afford the title compound (100 mg, 19%) as a white solid.JH NMR (400 MHz, CDCI3) 6 7.90 - 7.88 (m, 2H), 7.81 - 7.79 (m, 2H), 4.66 - 4.65 (m, 2H), 4.49- 4.48 (m, 2H), 3.04 (s, 2H), 1.54 (s, 3H).[000115] The compounds in the following table were prepared essentially as described in Preparation 50 beginning with the appropriate carboxylic acid.Preparation 57 6-vinyl- 1 , 2, 4-tri azin-3 -amine[000116] 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 cyclopentyl(diphenyl)phosphane dichloropalladium iron (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. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiCL, PE / EtOAc) to afford the title compound (139 g) as a white solid. *H NMR (400 MHz, CDCI3) δ 8.34 (s, 1H), 6.99 - 6.77 (m, 1H), 6.08 (d, J = 16.0 Hz, 1H), 5.71 - 5.41 (m, 3H).Preparation 58 tert-butyl (6-vinyl- 1, 2, 4-triazin-3-yl)carbamate[000117] To a solution of 6-vinyl- 1, 2, 4-triazin-3 -amine (100 g, 818 mmol) in THF (300 mL) was added LiHMDS (1.00 M, 1.15 L, 1.15 mol) at -65 °C for 1 h. A solution of BOC2O (232 g, 1.06 mol, 244 mL) in THF (200 mL) was added at -650for 1 h. The resulting mixture was stirred at -65 °C for 1 h under N2. The reaction mixture was diluted with sat. aq. NH4CI and extracted with EtOAc. The combined organic layers were filtered then concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, PE / EtOAc) to afford the title compound (100 g) as a white solid. ES / MS (m / z): 123 (M-99).Preparation 59 tert-butyl (6-formyl-l,2,4-triazin-3-yl)carbamate[000118] 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 OsCh (3.50 g, 13.7 mmol, 714 pL) at 0 °C. The resulting mixture was stirred for 10 min, NaICU (240 g, 1.12 mol, 62.3 mL) was added at 0 °C in four portions, and the reaction mixture was stirred at 0 °C for another 4 h under N2. The reaction mixture was filtered, and the filtrate 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, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography ( Si O2, PEZEtOAc) to afford the title compound (80.0 g, 75.3%) as a yellow oil. ES / MS (m / z): 223 (M-H).Preparation 60(5S)-3-iodo-5-methylpiperidin-2-one[000119] Chloro(trimethyl)silane (201 g, 1.86 mol, 235 mL) was added dropwise to a solution of (S)-5-methylpiperidin-2-one (105 g, 927 mmol) and N,N,N',N' -tetramethylethane- 1,2- diamine (323 g, 2.78 mol, 420 mL) in toluene (1000 mL) cooled to 0 °C under N2. The mixture was stirred at 0 °C for 0.5 hr, then I2 (282 g, 1.11 mol, 224 mL) was added in three portions and the resulting mixture stirred at 0 °C for 2 h. The reaction mixture was poured into 20% Na2SOs solution at 0 °C, diluted with H2O and extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl, filtered, and concentrated under reduced pressure to give a residue which was triturated with PEZEtOAc at 25 °C for 30 min. This mixture was filtered and the filtrate was purified by column chromatography (SiO2, PEZEtOAc) to afford the title compound (150 g) as a white solid. ES / MS (m / z): 240 (M+H).Preparation 61 diethyl ((5S)-5-methyl-2-oxopiperidin-3-yl)phosphonate[000120] A solution of (5S)-3-iodo-5-methylpiperidin-2-one (150 g, 627 mmol) and triethyl phosphite (521 g, 3.14 mol, 537 mL) in toluene (750 mL) was stirred at 100 °C for 12 h under N2. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, PEZEtOAc) to afford the title compound (150 g) as a white solid. ES / MS (m / z): 250 (M+H).Preparation 62 tert-butyl (S,E)-(6-((5-methyl-2-oxopiperidin-3-ylidene)methyl)-l,2,4-triazin-3-yl)carbamate[000121] To a solution of diethyl ((5S)-5-methyl-2-oxopiperidin-3-yl)phosphonate (75.8 g, 304 mmol) in THF (400 mL) was added potassium 2-methylpropan-2-olate (1.00 M, 318 mL) at 0 °C for 1 h and then tert-butyl (6-formyl-l,2,4-triazin-3-yl)carbamate (65.0 g, 289 mmol) in THF (400 mL) was added. The mixture was stirred at 25°C for 1 h and was then diluted with H2O and extracted with EtOAc. The combined organic layers were filtered and concentrated under reduced pressure to give a residue. The residue was triturated with PE and EtOAc at 25 °C for 20 min and then purified by column chromatography (SiO2, PEZEtOAc) to afford the title compound (75.0 g) as a white solid. ES / MS (m / z): 264 (M-55).Preparation 63 tert-butyl (6-(((5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-l,6-dihydro-l,2,4-triazin-3- yl)carbamate[000122] A solution of tert-butyl (6-(((5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-l,6- dihydro-l,2,4-triazin-3-yl)carbamate (75.0 g, 234 mmol) in DCM (500 mL) and MeOH (2000 mL) was stirred at 20 °C until becoming a clear solution. A fixed bed Pd / AhCh (100 g, 234 mmol) was heated to 25 °C and the solution was pumped into the reactor at a flow rate of 7 mL / min. After the reaction was finished, the tubing was washed with MeOH (200 mL) and the wash solution combined with the reaction mixture. The resulting solution was concentrated under reduced pressure to give a residue which was triturated with DCM at 25 °C for 10 min to provide the title compound (70.0 g) as a white solid. ES / MS (m / z): 324 (M+H).Preparation 64 tert-butyl (6-(((5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-l,2,4-triazin-3-yl)carbamate[000123] To a solution of tert-butyl (6-(((5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-l,6- dihydro-l,2,4-triazin-3-yl)carbamate (55.0 g, 170 mmol) in THF (550 mL) was added 4,5- dichloro-3,6-dioxo-cyclohexa-l,4-diene-l,2-dicarbonitrile (30.8 g, 136 mmol) at 0 °C and the mixture stirred at 25 °C for 0.5 h. The reaction mixture was quenched with sat. aq. NaHCCL at 0 °C, diluted with H2O and extracted with DCM: MeOH (10: 1). The combined organic layers were filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with PE: EtOAc (1 : 1) at 25 °C for 20 min to afford the title compound (40.0 g, 73.1%) as a white solid. ES / MS (m / z): 322 (M+H).Preparation 65(3R,5S)-3-((3-amino-l,2,4-triazin-6-yl)methyl)-5-methylpiperidin-2-one[000124] To a solution of tert-butyl (6-(((5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-l,2,4- triazin-3-yl)carbamate (40.0 g, 124 mmol) in DCM (600 mL) was added TFA (283 g, 2.49 mol, 184 mL) at 0 °C and the mixture stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by PREP-HPLC (0.1% NH3»H2O condition) and prep-HPLC (column: Kromasil Eternity XT 250^80 mmx lO um; mobile phase: [water (NH3H2O)-ACN]; gradient: 1%- 17% B over 20 min) and 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 compound (2.50 g, 8.87%) as a white solid. 'H NMR (400 MHz, CDC13) 8 8.18 (m, 1H), 6.10 (s, 1H), 5.46 - 5.34 (m, 2H), 3.40 - 3.19 (m, 2H), 3.13 - 2.84 (m, 3H), 2.14 - 2.03 (m, 1H), 1.91 - 1.80 (m, 1H), 1.71 - 1.56 (m, 1H), 1.03 (d, J = 8.0 Hz, 3H).Preparation 663 , 3 ,3 -trifluoro-2,2-dimethylpropan- 1 -ol[000125] Solution 1 : 3,3,3-trifhioro-2,2-dimethylpropanoic acid (280 g, 1.79 mol) in 2.8 L THF. Solution 2: LAH in THF (2.5 M, 1.43 L). Each solution was pumped independently into 3 90 mL flow reactors at 25 °C under an N2 atmosphere with a residence time of 3 min. The mixture was quenched sequentially with H2O (137 mL), 15% NaOH (aq) (137 mL), and H2O (411 mL) at 0 °C. Then 800 g ISfeSCU was added and the mixture was stirred at 25 °C for 15 min. The mixture was filtered and the filtrate concentrated under reduced pressure to afford the title compound (170 g, 67%) as colorless oil. 'H NMR (400 MHz, CDCI3) 6 3.60 (s, 2H), 1.73 (s, 1H), 1.14 (s, 6H).[000126] The compounds in the following table were prepared essentially as described in Preparation 66 beginning with an appropriate carboxylic acid or ester.Preparation 70( 1 -(trifluoromethyl)cyclopropyl)methanol[000127] To a flow reactor was added a solution of 1- (trifluoromethyl)cyclopropanecarboxylic acid (500 g, 3.24 mol) in THF (1 L) and borane tetrahydrofuran complex (1.00 M, 6.49 L). The temperature of the flow reactor was set at 80 °C and the flow rate was adjusted to 15 mL / min. The mixture was collected in a bottle containing NH4CI (aq) after 3 h. The reaction mixture was diluted with H2O and extracted with EtOAc.The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (250 g, 55%) as a yellow oil.Preparation 71Ethyl 5,5,5-trifluoro-4,4-dimethylpent-2-enoate[000128] To a solution of 3,3,3-trifluoro-2,2-dimethylpropanal (270 g, 1.92 mol) in DCM (2.5 L) was added LiCl (89.8 g, 2.12 mol), 2,3,4,6,7,8-hexahydropyrrolo[l,2-a]pyrimidine (262 g, 2.12 mol) and ethyl 2-(dimethoxyphosphoryl)acetate (414 g, 2.12 mol). The reaction mixture was stirred at 25 °C for 10 h. The reaction mixture was diluted with water and extracted withDCM, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was purified by column chromatography (SiC2, PE / EtOAc) to afford the title compound (200 g, 49%) as a yellow oil. 'HNMR (400 MHz, CDCI3) δ 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 72 ethyl 5,5,5-trifluoro-4,4-dimethylpentanoate[000129] To a solution of PtCh (24.6 g, 108 mmol) in THF (1.8 L) 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 compound (170 g, 89%) as yellow oil. 'H 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 735,5,5-trifluoro-4,4-dimethylpentan-l-ol[000130] To a solution of ethyl 5,5,5-trifluoro-4,4-dimethylpentanoate (130 g, 612 mmol) in THF (1.2 L) was added LAH (2.5 M in THF, 294 mL) at 0 °C and the mixture was stirred at 0°C under N2 for 1 h. The reaction was quenched by the sequential addition of H2O, 15% NaOH (aq), and H2O at 0 °C. Then 250 g Na2SO4 was added and the mixture was stirred at 25 °C for 15 min. The mixture was filtered and the filtrate concentrated under reduced pressure to afford the title compound (101 g, 97%) as yellow oil. 'HNMR (400 MHz, CDCI3) δ 3.70 - 3.59 (m, 2H), 1.65 - 1.51 (m, 4H), 1.41 (s, 1H), 1.11 (s, 6H).[000131] The compounds in the following table were prepared essentially as described in Preparation 73 beginning with an appropriate alcohol.Preparation 74 5,5,5-trifluoro-4,4-dimethylpentanal[000132] To a solution of oxalyl chloride (29.0 g, 229 mmol, 20 mL) in DCM (300 mL) was added a solution of DMSO (35.8 g, 458 mmol, 35.8 mL) in DCM (300 mL) at -78 °C. After stirring at -78 °C for 0.5 h, a solution of 5,5,5-trifluoro-4,4-dimethylpentan-l-ol (30.0 g, 176 mmol) in DCM (300 mL) was added and the mixture was stirred at -78 °C for 0.5 h.Triethylamine (87.4 g, 863 mmol, 120 mL) was added and the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was diluted with H2O and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (30.0 g) as a yellow oil.1H NMR (400 MHz, CDCI3) 8 9.76 (s, 1H), 2.52 - 2.48 (m, 2H), 1.81 - 1.77 (m, 2H), 1.07 (s, 6H).[000133] The compounds in the following table were prepared essentially as described in Preparation 74 beginning with an appropriate alcohol.Preparation 80Ethyl 3-(l-(trifluoromethyl)cyclopropyl)acrylate[000134] A mixture of l-(trifluoromethyl)cyclopropanecarbaldehyde (59.0 g, 427 mmol), ethyl 2-(dimethoxyphosphoryl)acetate (92.1 g, 469 mmol), DBN (58.3 g, 469 mmol, 56.2 mL), and LiCl (19.9 g, 469 mmol) in DCM (600 mL) was stirred at 20 °C for 4 h. The reaction mixture was diluted with water and extracted with EtOAc, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCL, PE / EtOAc) to afford the title compound (43.0 g, 48%) as a yellow oil.1H NMR (400 MHz, CDC13) δ 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).[000135] The compounds in the following table were prepared essentially as described in Preparation 80 beginning with an appropriate aldehyde.Preparation 82 Ethyl 3-(l-(trifluoromethyl)cyclopropyl)propanoate[000136] To a solution of Pd / C (5.11 g, 4.80 mmol) in THF (200 mL) was added ethyl 3-(l- (trifluoro-methyl)cyclopropyl)acrylate (20.0 g, 96.0 mmol) and the mixture was stirred at 20 °C under H2 atmosphere for 3 h. The reaction mixture was filtered, and the filter cake washed with MeOH. The filtrate was concentrated under reduced pressure to afford the title compound (12.0 g, 59%) as a white oil.1H NMR (400 MHz, CDCh) 84.14 (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 83Ethyl 2-methyl-3-(l-(trifluoromethyl)cyclopropyl)propanoate[000137] To a mixture of PtO2 (102 mg, 450 μmol) in THF (20 mL) was added ethyl 2- methyl-3-(l-(trifluoromethyl)cyclopropyl)acrylate (1.00 g, 4.50 mmol) and the reaction mixture was stirred at 25 °C under H2 (15.0 psi) for 10 h. The mixture was filtered and the filtrate concentrated under reduced pressure to afford the title compound (800 mg, 79%) as a yellow oil. 'H NMR (400 MHz, CDCh) δ 4.18 - 4.10 (m, 2H), 2.81 - 2.68 (m, 1H), 2.02 - 1.91 (m, 1H), 1.74- 1.64 (m, 1H), 1.27 (t, J = 7.2 Hz, 3H), 1.19 (d, J = 6.8 Hz, 3H), 1.01 - 0.88 (m, 2H), 0.71 - 0.54 (m, 2H).Preparation 84 ethyl 3,3-difluorocyclohexane-l-carboxylate[000138] To a solution of N,N-diethylamino-S,S-difluorosulfmium tetrafluoroborate (5.05 kg, 22.0 mol) and TEA 3 HF (2.13 kg, 13.2 mol, 2.15 L) in DCE (25 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 a sat. NaHCCE (aq) (15 L) at 20 °C and the organic phase was separated. The aqueous phase was extracted with DCM, the combined organic phases were washed with a 10% aqueous solution of citric acid and sat. NaCl (aq). Upon concentration under reduced pressure to give a residue, a distillation under vacuum (80 °C, -0.095 Mpa) was performed to afford the title compound (1.26 kg, 74%) as a yellow oil. 'H NMR (400 MHz, CDC13) 54.15 (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 853,3-difluorocyclohexane-l-carboxylic acid[000139] To a solution of ethyl 3, 3 -difluorocy cl ohexane-1 -carboxylate (1.26 kg, 6.56 mol) in EtOH (7.56 L) and H2O (5.04 L) was added portionwise LiOH H2O (330 g, 7.88 mol) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h and was then concentrated under reduced pressure. The resulting residue was diluted with a 3M HC1 (aq) to adjust pH = 3 and then extracted with DCM. The combined organic phases were dried Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was stirred in PE at room temperature for 5 h to afford the title compound (655 g) as a white solid.1H NMR (400 MHz, CDCI3) δ 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 86 (3,3-difluorocyclohexyl)methanol[000140] To a solution of 3,3-difluorocyclohexane-l-carboxylic acid (50.0 g, 305 mmol) in THF (600 mL) was added portionwise NaBH4 (12.7 g, 335 mmol) at 0 °C followed by a dropwise addition of BF3 Et2O (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. NH4CI (aq) and then extracted with EtOAc. The organic phases are combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (45.0 g, 98% yield) as a yellow oil. 'H NMR (400 MHz, DMSO-d6) δ 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 873,3-difluorocyclohexane-l-carbaldehyde[000141] To a solution of (3,3-difluorocyclohexyl)methanol (40.0 g, 266 mmol) in DCM (1.00 L) was added Dess-Martin periodinane (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 compound (39.0 g, 99% yield) as a yellow oil.1H NMR (400 MHz, CDCI3) 6 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 88(S)-N-((3,3-difluorocyclohexyl)methylene)-2-methylpropane-2-sulfinamide[000142] To a solution of 3,3-difluorocyclohexane-l-carbaldehyde (39.0 g, 263 mmol) and (S)-2-methylpropane-2-sulfinamide (38.2 g, 316 mmol) in DCM (600 mL) was added CuSCh (42.0 g, 263 mmol). The reaction mixture was stirred at room temperature for 10 h. The reaction mixture was diluted with H2O and extracted with DCM. The combined organic layers were washed with sat. NaCl (aq), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (49.0 g, 74%) as a yellow oil.JH NMR (400 MHz, CDCI3) 5 8.00- 8.02 (m, 1H), 2.75-2.82 (m, 1H), 2.30-2.36 (m, 1H), 2.11-2.13 (m, 1H), 1.87-1.93 (m, 1H), 1.53- 1.84 (m, 5H), 1.18 (s, 9H).[000143] The compounds in the following table were prepared essentially as described in Preparation 88 beginning with an appropriate aldehyde.Preparation 90(S,Z)-2-methyl-N-(5,5,5-trifluoro-4,4-dimethylpentylidene)propane-2-sulfmamide[000144] To a solution of 5,5,5-trifluoro-4,4-dimethylpentanal (30.0 g, 178 mmol) in THF (300 mL) was 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 MgSO4 was added and the mixture was stirred at 25 °C for 0.5 h. The mixture was filtered and the filtrate concentrated under reduced pressure to give a residue that was purified by column chromatography (SiCL, PE / EtOAc) to afford the title compound (32.0 g, 66%) as a yellow solid.1H NMR (400 MHz, CDCI3) 5 8.10 (t, J = 4.4 Hz, 1H), 2.66 - 2.52 (m, 2H), 1.89 - 1.75 (m, 2H), 1.20 (s, 9H), 1.15 (s, 6H). ES / MS (m / z): 272 (M+H).[000145] The compounds in the following table were prepared essentially as described in Preparation 90 beginning with an appropriate aldehyde.Preparation 92(S,E)-2-methyl-N-(3-(l-(trifluoromethyl)cyclopropyl)propylidene)propane-2-sulfinamide[000146] To a solution of 3-(l-(trifluoromethyl)cyclopropyl)propanal (15.0 g, 90.2 mmol) in 1,2-di chloroethane (150 mL) and DCM (150 mL) was added CuSCL (43.2 g, 270 mmol, 41.5 mL) and (S)-2-methylpropane-2-sulfinamide (21.8 g, 180 mmol) and the mixture was stirred at60 °C for 8 h. The reaction mixture was filtered and washed with EtOAc. The filtrate was diluted with H2O and extracted with EtOAc. The combined organic phases are dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PEZEtOAc) to afford the title compound (13.0 g, 48.2 mmol, 53%) as a yellow oil.1H NMR (400 MHz, CDCI3) δ 8.08 (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 93(S)-N-(cyano(3,3-difluorocyclohexyl)methyl)-2-methylpropane-2-sulfmamide[000147] To a solution of (S)-N-((3,3-difluorocyclohexyl)methylene)-2-methylpropane-2- sulfinamide (49.0 g, 195 mmol) in DCM (600 mL) was successively added H2O (7.00 g, 389 mmol, 7 mL), CsF (5.92 g, 39.0 mmol, 1.44 mL) and TMSCN (39.0 g, 390 mmol, 49 mL). The reaction mixture was stirred at 20 °C for 5 h. The reaction mixture was quenched by the addition of H2O at 0 °C and then extracted with DCM. The combined organic layers were washed with sat. NaCl (aq), dried over Na2SO4 , filtered, and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiCL, PEZEtOAc) to afford the title compound (49.0 g, 90%) as a yellow oil. 'HNMR (400 MHz, CDCI3) 64.11-4.16 (m, 1H), 2.27 - 2.30 (m, 1H), 2.11-2.20 (m, 2H), 1.89-2.02 (m, 2H), 1.38-1.75 (m, 4H), 1.26 (s, 9H).[000148] The compounds in the following table were prepared essentially as described in Preparation 93 beginning with an appropriate sulfmamide.Preparation 100(2S)-2-amino-2-(3,3-difluorocyclohexyl)acetic acid[000149] To a solution of (S)-N-(cyano(3,3-difluorocyclohexyl)methyl)-2-methylpropane- 2-sulfinamide (49.0 g, 176 mmol) in AcOH (250 mL) was added 250 mL 12 M HC1 and the reaction mixture was stirred at 110 °C for 12 h. The reaction mixture was concentrated under reduced pressure to afford the title compound (31.0 g, 91%) as a brown solid. ES / MS (m / z): 194 (M+H).[000150] The compounds in the following table were prepared essentially as described in Preparation 100 beginning with an appropriate sulfmamide.Preparation 107 (5)-2-amino-2-((lA,45)-4-methylcyclohexyl)acetic acid hydrochloride[000151] To a solution of (S)-2-((tert-butoxycarbonyl)amino)-2-((lR,4S)-4- methylcyclohexyl)acetic acid (250 g, 921 mmol) in EtOAc (500 mL) was added a solution of HC1 in EtOAc (4 M, 2.5 L). The reaction mixture was stirred with the temperature maintained between 0 and 10 °C for 2 h. The reaction mixture was then concentrated under reduced pressure to afford the title compound (200 g) as a white solid.Preparation 108 nona-l,8-dien-5-ol[000152] To a solution of ethyl formate (120.0 g, 202 mmol, 16.3 mL) in THF (200 mL) was added dropwise but-3-en-l-ylmagnesium bromide (1.00 M, 486 mL) at 0 °C, then the mixture was stirred at 25 °C for 12 h. The mixture was poured into a slurry of ice and NH4CI (aq) and was then extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated to give a residue which was purified by column chromatography (SiCL, PEZEtOAc) to provide the title compound (130 g, 57%) as a yellow oil.JH NMR (400 MHz, CDCI3) δ 5.89 - 5.82 (m, 2H), 5.06 (dd, JI = 17.2 Hz, J2 = 1.6 Hz, 2H), 4.99 (d, J = 10.0 Hz, 2H), 3.70 - 3.64 (m, 1H), 2.23 - 2.14 (m, 4H), 1.60 - 1.53 (m, 4H).Preparation 109 cyclohept-4-en-l-ol[000153] To a solution of nona-l,8-dien-5-ol (60.0 g, 428 mmol) in DCM (1.5 L) was added Grubbs catalyst (4.41 g, 5.35 mmol) and the mixture was stirred at 45 °C for 5 h. The mixture was concentrated to give a residue that was purified by column chromatography (SiCh, PEZEtOAc) to afford the title compound cyclohept-4-en-l-ol (30.0 g, 62%) as a yellow oil. 'H NMR (400 MHz, CDCI3) 6 5.83 - 5.79 (m, 2H), 3.89 - 3.86 (m, 1H), 2.25 - 2.23 (m, 2H), 1.99 - 1.94 (m, 4H), 1.48 - 1.45 (m, 2H).Preparation 110 tertbutyl(cyclohept-4-en- 1 -yloxy)diphenylsilane[000154] To a solution of cyclohept-4-en-l-ol (45.0 g, 401 mmol) in DCM (500 mL) was added imidazole (54.6 g, 802 mmol) and tert-butyl-chloro-diphenyl-silane (116 g, 421 mmol, 108 mL) at 0 °C, then the mixture was stirred at 25 °C for 2 h. The mixture was diluted with H2Oand extracted with DCM. The combined organic phase was washed with sat. NaCl (aq), dried over Na2SO4, and concentrated to give a residue that was purified by column chromatography (SiO2, PEZEtOAc) to afford the title compound (130 g, 92%) as a light yellow oil.1H NMR (400 MHz, CDC13) δ 7.70 - 7.68 (m, 4H), 7.43 - 7.36 (m, 6H), 5.79 - 5.72 (m, 2H), 4.00 - 3.95 (m, 1H), 2.36 - 2.33 (m, 2H), 1.82 - 1.78 (m, 2H), 1.69 - 1.66 (m, 2H), 1.63 - 1.60 (m, 2H), 1.08 (s, 9H).Preparation 111(bicyclo[5.1 ,0]octan-4-yloxy)(tert-butyl)diphenylsilane[000155] To a solution of tert-butyl(cyclohept-4-en-l-yloxy)diphenylsilane (40.0 g x 2, 114 mmol) in DCM (400 mL) was added dropwise diiodomethane (122 g, 456 mmol, 36.8 mL) and diethylzinc (1.00 M, 456 mL) at 0 °C. The mixture was stirred at 25 °C for 12 h. The mixture was poured into a slurry of ice and sat. NH4CI (aq) then filtered, and the filter cake was washed with DCM. The combined filtrate was extracted with DCM. The combined organic phases were dried over Na2SO4, and concentrated to give a residue that was purified by column chromatography (SiO2, PEZEtOAc) to afford the title compound (75.0 g, 90%) as a yellow oil. 5 7.68 - 7.64 (m, 4H), 7.42 - 7.35 (m, 6H), 4.15 - 3.47 (m, 1H), 1.90 - 1.85 (m, 3H),1.77 - 1.71 (m, 1H), 1.61 - 1.58 (m, 1H), 1.45 - 1.42 (m, 1H), 1.05 (s, 9H), 0.91 - 0.87 (m, 1H), 0.77 - 0.54 (m, 4H), 0.15 -0.20 (m, 1H).Preparation 112 bicyclo[5.1 ,0]octan-4-ol[000156] To a solution of (bicyclo[5.1.0]octan-4-yloxy)(tert-butyl)diphenylsilane (45.0 g, 123 mmol) in THF (300 mL) was added TBAF (1.00 M, 370 mL) and the mixture was stirred at 50 °C for 8 h. The mixture was diluted with H2O (1 L) and extracted with EtOAc, the combined organic phase was washed with sat. NaCl (aq), dried over Na2SO4, and concentrated to give a residue that was purified by column chromatography (SiO2, PEZEtOAc) to afford the titlecompound (29.0 g) as a yellow oil. 1H NMR (400 MHz, CDC13) 64.16 - 3.46 (m, 1H), 2.10 - 2.05 (m, 1H), 2.02 - 1.96 (m, 1H), 1.84 - 1.67 (m, 3H), 1.49 - 1.42 (m, 1H), 1.39 - 1.27 (m, 1H), 0.82 - 0.64 (m, 4H), 0.13 -0.09 (m, 1H).Preparation 113 bicyclo[5.1.0]octan-4-one[000157] To a solution of bicyclo[5.1.0]octan-4-one (15.0 g, 119 mmol) in DCM (150 mL) was added (l,l-diacetoxy-3-oxo-l,2-benziodoxol-l-yl) acetate (60.5 g, 143 mmol, 44.2 mL) at 0 °C, then the mixture was stirred at 25 °C for 2 h. The mixture was diluted with sat. Na2SO4 (aq) at 0 °C and extracted with DCM. The combined organic phase was washed with sat. NaCl (aq), dried over Na2SO4, and concentrated to give a residue that was purified by column chromatography (SiO2, PE / EtOAc) to afford the title compound (12.0 g, 81%) as a yellow oil. 'HNMR (400 MHz, CDCI3) δ 2.53 - 2.50 (m, 4H), 2.27 - 2.22 (m, 2H),1.10 - 1.04 (m, 4H), 0.77 - 0.75 (m, 1H), 0.08 - 0.05 (m, 1H).Preparation 1144-(methoxymethylene)bicyclo[5.1.0]octane[000158] To a solution of (methoxymethylene)triphenylphosphine hydrochloride (33.1 g, 96.6 mmol) in THF (100 mL) was added dropwise potassium 2-methylpropan-2-olate (1.00 M, 96.6 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h, then bicyclo[5.1.0]octan-4-one (10.0 g, 80.5 mmol) in THF (20 mL) was added and the mixture was stirred at 25 °C for 3 h. The mixture was diluted with H2O and extracted with EtOAc. The combined organic phase was washed with sat. NaCl (aq), dried over Na2SO4, and concentrated to give a residue that was purified by column chromatography (SiCL, PE / EtOAc) to afford the title compound (8.50 g,69%) as a yellow oil. *H NMR (400 MHz, CDC13) 6 5.72 (s, 1H), 3.52 (s, 3H), 2.82 (dd, JI = 13.6 Hz, J2 = 6.8 Hz, 1H), 2.25 - 2.20 (m, 2H), 2.09 - 1.99 (m, 2H), 1.75 - 1.72 (m, 1H), 0.91 - 0.83 (m, 4H), 0.69 - 0.67 (m, 1H), 0.04 - 0.01 (m, 1H).Preparation 115 bicyclo[5.1 ,0]octane-4-carbaldehyde[000159] To a solution of 4-(methoxymethylene)bicyclo[5.1.0]octane (4.50 g, 29.6 mmol) in THF (40 mL) was added HC1 (4.00 M, 11.1 mL) at 0 °C, then the mixture was stirred at 25 °C for 0.5 h. A solution of sat. NaHCCL (aq) was added to adjust pH to about 8, then the mixture was extracted with EtOAc. The combined organic phase was washed with sat. NaCl (aq), dried over Na2SO4, and concentrated to afford the title compound (4.00 g) as a yellow oil.1H NMR (400 MHz, CDCI3) δ 9.65 - 9.62 (m, 1H), 2.47 - 2.29 (s, 2H), 2.10 - 2.05 (m, 3H), 1.79 - 1.62 (m, 1H), 1.43 - 1.40 (m, 1H), 1.15 - 1.05 (m, 1H), 0.94 - 0.83 (m, 3H), 0.75 - 0.59 (m, 1H), 0.08 - 0.06 (m, 1H).Preparation 116 5-(bicyclo[5.1.0]octan-4-yl)imidazolidine-2, 4-dione[000160] To a solution of bicyclo[5.1.0]octane-4-carbaldehyde (4.00 g, 28.9 mmol) in EtOH (30 mL) and H2O (30 mL) was added ammonium carbonate (11.4 g, 145 mmol, 11.9 mL) and trimethyl silyl cyanide (3.59 g, 36.2 mmol, 4.53 mL), then the mixture was stirred at 90 °C for 12 h. H2O (100 mL) was added to the mixture, then filtered, and the filter cake was washed with H2O (50 mL) and DCM (50 mL) and the filtrate was concentrated to afford the title compound (2.50 g) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 5 10.56 (s, 1H), 7.90 - 7.86 (m, 1H), 3.92 (d, J = 2.4 Hz, 1H), 2.11 - 2.07 (m, 1H), 1.66 - 1.63 (m, 3H), 1.40 - 1.31 (m, 4H), 0.90 - 0.76 (m, 3H), 0.61 - 0.28 (m, 1H), 0.22 - -0.01 (m, 1H).Preparation 1172-amino-2-(bicyclo[5.1 ,0]octan-4-yl)acetic acid[000161] A solution of 5-(bicyclo[5.1.0]octan-4-yl)imidazolidine-2, 4-dione (2.50 g, 12.0 mmol) in NaOH (aq) (2.00 M, 25 mL) was stirred at 120 °C for 12 h. 1 M HC1 (aq) was added to adjust pH to about 9, the mixture was used to next step directly. 2-amino-2-(bicyclo[5.1.0]octan- 4-yl)acetic acid (2.20 g, crude) as yellow liquid was used to next step directly. ES / MS (m / z): 184 (M+H).Preparation 118 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. The mixture was cooled to -70 °C then 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. The mixture was stirred at -70 °C under N2 for 6 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PE / EtOAc) to afford the title compound (352 g, 53.2%) as a white solid. ES / MS (m / z): 392 (M+H).Preparation 119 tert-butyl (S)-2-((diphenylmethylene)amino)-2-((S)-3-methylenecyclohexyl)acetate[000163] To a solution of methyltriphenylphosphonium iodide (186 g, 459 mmol) in THF (1 L) was added t-BuOK (1 M, 460 mL) at -30 °C and the mixture was 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 (2 L) was added dropwise at 0 °C and the reaction mixture was stirred at 0 °C for 2. The mixture was diluted with water and extracted with EtOAc, the combined organic layers were washed with sat. NaCl(aq), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PEZEtOAc) to afford the title compound (160 g, 29%) as a yellow oil. ES / MS (m / z): 390 (M+H).Preparation 120 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 (1 L) was added citric acid (0.500 M, 2.57 L). The mixture was diluted with water and extracted with EtOAc, the combined organic layers were washed with sat. NaCl(aq), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (50.0 g, 84%) as a white solid. ES / MS (m / z): 226 (M+H).Preparation 121 tert-butyl (S)-2-amino-2-((l S,3R)-3-methylcyclohexyl)acetate[000165] A solution of tert-butyl (S)-2-amino-2-((S)-3-methylenecyclohexyl)acetate (50.0 g, 222 mmol) in MeOH (1 L) was prepared and a fixed bed (50 mL) was packed with granular catalyst 5% Pd / C. The hydrogen back pressure regulator was adjusted to 1 MPa, and the flowrate of H2 was 95 mL / min. Then the MeOH solution was pumped through the fixed bed (3 mL / min). The reaction mixture was collected from the reactor output, filtered, and concentrated under reduced pressure to afford title compound (50.0 g, 95%) as a white solid. ES / MS (m / z): 228 (M+H).Preparation 122 2-((l , 1 , 1 -trifluoro-2-methylpropan-2-yl)oxy)acetic acid[000166] 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) at 0 °C and the reaction mixture stirred at 0 °C for 1 h. A solution of 2-bromoacetic acid (50.0 g, 359 mmol, 25.8 mL) was added and the reaction mixture stirred at 70 °C for 16 h. The reaction mixture was quenched by the addition of NH4CI at 0 °C, and then diluted with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PEZEtOAc) to afford the title compound (34.0 g, 61% yield) as a yellow oil. 'H NMR (400 MHz, CDCI3) 8 10.4 (s, 1H), 4.23 (s, 2H), 1.41 (s, 6H).Preparation 123 2-((l , 1 , 1 -trifluoro-2-methylpropan-2-yl)oxy)propanoic acid[000167] To a solution of 2-((l,l,l-trifluoro-2-methylpropan-2-yl)oxy)acetic acid (20.0 g, 107 mmol) in THF (320 mL) was added LDA (2 M in THF, 161 mL) at -70°C. After stirring for 1 h, a solution of methyl iodide (22.8 g, 161 mmol, 10 mL) in THF (80 mL) was added dropwise. The mixture was warmed to 20 °C and stirred for 12 h. The reaction mixture was quenched by the addition of IN HC1 at 0 °C, and extracted with EtOAc. The combined organic layers were washed with sat. NaCl (aq), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was purified by column chromatography (SiCh, PE: EtOAc) to afford thetitle compound (8.00 g, 37%) as a colorless oil. 'HNMR (400 MHz, CDC13) 8 12.6 (s, 1H), 4.32 - 4.27 (m, 1H), 1.41 - 1.31 (m, 6H), 1.26 (d, J = 6.8 Hz, 3H).Preparation 124N-methoxy-N-methyl-2-((l , 1 , 1 -trifluoro-2-methylpropan-2-yl)oxy)acetamide[000168] 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 hydrochloride (20.1 g, 206 mmol) at RT and 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 Na2SC>4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCL, PEZEtOAc) to afford the title compound (27.0 g, 68.5%) as a colorless oil. ES / MS (m / z): 230 (M+H).[000169] The compounds in the following table were prepared essentially as described in Preparation 124 beginning with an appropriate carboxylic acid.Preparation 126 2-((l , 1 , 1 -trifluoro-2-methylpropan-2-yl)oxy)acetaldehyde[000170] 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 and the reaction mixture stirred at -75 °C for 2 h. The reaction mixture was quenched byaddition of H2O at 0 °C, and then diluted with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (22.0 g) as a yellow oil.[000171] The compound in the following table was prepared essentially as described in Preparation 126.Preparation 128 (S)-2-methyl-N-(2-((l,l,l-trifluoro-2-methylpropan-2-yl)oxy)ethylidene)propane-2-sulfmamide[000172] 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 CuSO4 (41.2 g, 258 mmol, 39.6 mL) at RT and the reaction mixture 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 ( Si O2, PE / EtOAc) to afford the title compound (6.00 g, 14%) as a colorless oil. *H NMR (400 MHz, CDCI3) δ 7.97 (s, 1H), 4.37 (s, 2H), 1.33 (s, 6H), 1.12 (s, 9H). ES / MS (m / z): 274 (M+H).[000173] The compound in the following table was prepared essentially as described in Preparation 128 beginning with an appropriate aldehyde.Preparation 130 (S)-2-(((benzyloxy)carbonyl)amino)-2-((lR,4S)-4-methylcyclohexyl)acetic acid[000174] To a solution of (S)-2-amino-2-((lR,4S)-4-methylcyclohexyl)acetic acid (193 g, 934 mmol) in THF (800 mL) and H2O (800 mL) was added K2CO3 (387 g, 2.80 mol) followed by CbzOSu (233 g, 934 mmol). The reaction mixture was stirred at a temperature maintained between 10 and 20 °C for 12 h. The reaction mixture was extracted twice with EtOAc. The combined organic layers were washed with sat. NaCl (aq), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was triturated with isopropanol at 25 °C for 30 min to afford the title compound (200 g, 67.8%) as a white solid. ES / MS (m / z): 328 (M+Na).[000175] The compounds in the following table were prepared essentially as described in Preparation 130 beginning with an appropriate amine.Preparation 139(S)-2-(((benzyloxy)carbonyl)amino)-2-((lS,3R)-3-methylcyclohexyl)acetic acid[000176] 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 water and extracted with EtOAc, the combined organic layers were washed with sat. NaCl (aq), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (60.0 g, 90.1%) as a white solid. ES / MS (m / z):261 (M-44).Preparation 1402-(((benzyloxy)carbonyl)amino)-2-(bicyclo[5.1 ,0]octan-4-yl)acetic acid[000177] To a solution of 2-amino-2-(bicyclo[5.1.0]octan-4-yl)acetic acid (2.20 g, 12.0 mmol) in THF (25 mL) and H2O (25 mL) was added NaHCCL (2.02 g, 24.0 mmol) and benzyl (2,5-dioxopyrrolidin-l-yl) carbonate (3.59 g, 14.4 mmol) and the mixture was stirred at 25 °C for1 h. 1.00 M HC1 (aq) was added to adjust the pH to about 5, then the mixture was extracted with EtOAc. The combined organic phase was dried over Na2SO4 and concentrated to give a residue which was purified by Prep-HPLC (column: PHenomenex luna Cl 8 250 x 80 mm x 10 urn; mobile phase: [water (FA) - ACN]; gradient: 40% - 70% B over 20 min) to afford 2- (((benzyloxy)carbonyl)amino)-2-(bicyclo[5.1.0]octan-4-yl)acetic acid (2.50 g, 7.88 mmol, 65.6% yield) was obtained as white solid. ES / MS (m / z): 318 (M+H).[000178] The compound in the following table was prepared essentially as described in Preparation 140.Preparation 142 benzyl ((5)-3-(dimethyl(oxo)-l6-sulfaneylidene)-l-((lA,45)-4-methylcyclohexyl)-2- oxopropyl)carbamate[000179] To a solution of trimethyl sulfoxonium iodide (648 g, 2.95 mol) in THF (1.5 L) was added KOtBu (330 g, 2.95 mol) and the mixture was stirred at 80 °C for 2 h (Reaction 1). In a separate flask, to a solution of (S)-2-(((benzyloxy)carbonyl)amino)-2-((lR,4S)-4- methylcyclohexyl)acetic acid (300 g, 982 mmol) in THF (1.5 L) was added N,N- diisopropylethylamine (165 g, 1.28 mol, 222 mL) followed by HATU (448 g, 1.18 mol). The reaction mixture was stirred at 25 °C for 2 h then Reaction 1 was slowly added at 25 °C and the resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by the addition of water and then diluted with EtOAc. An extraction was performed twice with EtOAc. The combined organic layers were washed with sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by columnchromatography (SiO2, PE / EtOAc) to afford the title compound (400 g) as an off-white solid. ES / MS (m / z): 380(M+H).[000180] The compound in the following table was prepared essentially as described in Preparation 142 beginning with an appropriate carboxylic acid.a: Isolated by chiral SFC purification (column: Daicel Chiralpak IF (250 mm x 30 mm, 10 pm); mobile phase: [CO2- 0.1% NH3«H2O in EtOH]; B%: 35%).Preparation 149 benzyl ((3S)-l-(dimethyl(oxo)-16-sulfaneylidene)-4-methyl-2-oxo-5-(l- (trifluoromethyl)cyclopropyl)pentan-3-yl)carbamate[000181] To a solution of trimethyl sulfoxonium iodide (395 mg, 1.79 mmol) in THF (6 mL) was added a solution of KOtBu (1 M in THF, 1.79 mL) and the resulting mixture was stirred at 25 °C for 1 h. A second solution of (2S)-2-(((benzyloxy)carbonyl)amino)-3-methyl-4-(l- (trifluoromethyl)-cyclopropyl)butanoic acid (430 mg, 1.20 mmol) in THF (6 mL) and CDI (252 mg, 1.56 mmol) was prepared at 0 °C and then was stirred at 25 °C for 1 h. The two solutionswere cooled to 0 °C, combined, and stirred at 25°C for 1 h. The reaction mixture was diluted with sat. NH4CI (aq) and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO2, DCM / MeOH) to afford the title compound (260 mg, 50%) as a yellow oil. ES / MS (m / z): 434 (M+H).[000182] The compound in the following table was prepared essentially as described in Preparation 149 beginning with an appropriate carboxylic acid.Preparation 154benzyl ((5)-3-bromo-l-((lA,45)-4-methylcyclohexyl)-2-oxopropyl)carbamate[000183] 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 (1.5 L) was added LiBr (34.3 g, 395 mmol) followed by methanesulfonic acid (38.0 g, 395 mmol, 28.1 mL). The reaction mixture was stirred at 45 °C for 12 h and then quenched by the addition of H2O and extracted twice with EtOAc. The combined organic layers were washed with sat. NaCl (aq), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Phenomenex luna C18 250 * 100 mm * 10 mm; mobile phase: [water (FA) - ACN]; B%: 60%-80%) to afford the title compound (18.2 g, 12.1%) as a white solid. ES / MS (m / z): 382 (M+H).[000184] The compound in the following table was prepared essentially as described in Preparation 154 beginning with appropriate sulfanylidene.Preparation 158 benzyl ((S)-3-bromo-l-((lS,3R)-3-methylcyclohexyl)-2-oxopropyl)carbamate[000185] 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) at 0 °C under N2. 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* 100 mm* 10 um; mobile phase: [water (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: [CO2 - i - PrOH (0.1%NH3H2O)]; B%: 15%, isocratic elution mode) to afford the title compound (13.0 g, 52.0%) as an off-white solid. ES / MS (m / z): 382 (M+H).[000186] The compound in the following table was prepared essentially as described in Preparation 158 beginning with appropriate sulfaneylidene.Preparation 162(S)-benzyl (l-bromo-2-oxo-5-(l-(trifluoromethyl)cyclopropyl)pentan-3-yl)carbamate[000187] To a solution of benzyl N-[(lS)-3-[dimethyl(oxo)-sulfanylidene]-2-oxo-l-[2-[l- (trifluoromethyl)cyclopropyl]ethyl]propyl]carbamate (1.80 g, 4.13 mmol) in THF (20 mL) was added HBr (4.13 mmol, 680 pL) and the mixture was stirred at 55 °C for 2 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, whichwas purified by column chromatography (SiO2, PE / EtOAc) to afford the title compound as a yellow solid.[000188] The compound in the following table was prepared essentially as described in Preparation 162 beginning with appropriate sulfaneylidene.Preparation 166 tert-butyl (S)-4-(((benzyloxy)carbonyl)amino)-4-cycloheptyl-3-oxobutanoate[000189] 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 (2 M, 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 wasquenched by the addition of a sat. NH4CI (aq) and was extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiCL, PE / EtOAc) to afford the title compound (36.0 g, 49%) as a white solid. ES / MS (m / z): 426 (M+Na).Preparation 167 tert-butyl (4S)-4-(((benzyloxy)carbonyl)amino)-2-bromo-4-cycloheptyl-3-oxobutanoate[000190] 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 N-bromosuccinimide (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 and was then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with sat. NaHCO3 (aq), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (40.0 g, 93% yield) as a yellow oil. ES / MS (m / z): 426 (M-55).Preparation 168 benzyl (,S')-(3 -bromo- 1-cy cl oheptyl-2-oxopropyl)carbamate[000191] 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 and was then diluted with H2O and sat. NaHCCh was added to adjust the pH = 9. The resulting mixture was extracted with DCM and the combined organic layers were dried over 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 pm); mobile phase: [water (NH4OH)-acetonitrile]; B%: 55%-85%, 20 min) to afford benzyl (S)-(3 -bromo- 1-cy cl oheptyl-2- oxopropyl)carbamate. The title compound was isolated as the first eluting, single stereoisomer by chiral SFC purification (column: Daicel Chiralcel OJ (250 mm x 30 mm, 10 pm); mobile phase:[0.1% NH3H2O in IP A]; B%: 20%-20%, 3 min); (11.3 g, 36%) as a white solid. ES / MS (m / z): 384 (M+H).Preparation 169 tert-butyl (S)-5-methyl-2-oxopiperidine-l-carboxylate[000192] To a solution of (5S)-5-methylpiperidin-2-one (19.0 g, 167.91 mmol) in DCM (190 mL) was added DMAP (2.05 g, 16.79 mmol) and di-tert-butyl dicarbonate (54.97 g, 251.86 mmol, 57.86 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue that was purified by column chromatography (Si Ch, PE / EtOAc) to afford the title compound (35 g) as a white solid.JH NMR (400 MHz, CDC13) 5 3.81 - 3.77 (m, 1H), 3.14 - 3.08 (m, 1H), 2.56 - 2.46 (m, 2H), 2.09 - 1.76 (m, 2H), 1.52 (s, 9H), 1.48 - 1.47 (m, 1H), 1.35 (d, J = 6.8, 3H).Preparation 170 1 -(tert-butyl) 3-methyl (5S)-5-methyl-2-oxopiperidine-l,3-dicarboxylate[000193] To a solution of tert-butyl (5S)-5-methyl-2-oxo-piperidine-l-carboxylate (20.0 g, 93.78 mmol) in THF (200 mL) was added dropwise LiHMDS (1 M, 140.66 mL) at -70 °C under N2. After addtion, the mixture was stirred at -70 °C for 1 hr, and methyl chloroformate (13.89 g, 146.99 mmol, 11.36 mL) was added dropwise at -70 °C under N2. the mixture was stirred at -70 °C for Ih. The reaction mixture was quenched by NH4CI at 0°C, and then diluted with H2O, and extracted with EtOAc. The combined organic layers were washed with sat. NaCl (aq) and concentrated under reduced pressure to give a residue which was purified by column (SiCh, PE / EtOAc)to afford the title compound (20.0 g, 77%) as a yellow oil.1H NMR (400 MHz, CDCI3) d 3.91 - 3.80 (m, IH), 3.77 (s, 3H), 3.59 - 3.51 (m, IH), 3.23 - 3.10 (m, IH), 2.35 - 2.00 (m, 2H), 1.89 - 1.65 (m, IH), 1.59 - 1.53 (m, 9H), 1.08 - 1.05 (m, 3H).Preparation 171 ethyl 5-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-3-(methylthio)-l,2,4-triazine-6- carb oxy late[000194] To a solution of ethyl 5-chloro-3-(methylthio)-l,2,4-triazine-6-carboxylate (3.00 g, 12.8 mmol) in DMF (15 mL) was added TEA (2.60 g, 25.7 mmol, 3.57 mL) followed by (lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (1.91 g, 14.1 mmol). The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over ISfeSCU, filtered, and concentrated under reduced pressure to afford the title compound (3.45 g, 91% yield) as a yellow solid. ES / MS (m / z): 297 (M+H).[000195] The compound in the following table was prepared essentially as described in Preparation 171.Preparation 173Ethyl 5-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-3-(methylsulfinyl)-l,2,4-triazine-6- carb oxy late[000196] To a solution of ethyl 5-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-3- (methylthio)-l,2,4-triazine-6-carboxylate (3.45 g, 11.6 mmol) in DCM (30 mL) was added 3- chloroperbenzoic acid (3.55 g, 17.4 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was concentrated under reduced pressure to afford the title compound (3.60 g) as a yellow oil. ES / MS (m / z): 313 (M+H).[000197] The compound in the following table was prepared essentially as described in Preparation 173.Preparation 175Ethyl 3-amino-5-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-l,2,4-triazine-6-carboxylate[000198] A solution of ethyl 5-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-3- (methylsulfinyl)-l,2,4-triazine-6-carboxylate (3.60 g, 11.5 mmol) was addedammonia in isopropanol (3.5 M, 13.2 mL) and stirred at 20 °C for 3 h. The reaction mixture was purified by prep-HPLC (column: Phenomenex luna C18 (250^70 mm, 10 um) to afford the title compound (1.20 g, 39%) as a yellow solid. ES / MS (m / z): 266 (M+H).[000199] The compound in the following table was prepared essentially as described in Preparation 175.Preparation 177Benzyl ((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)carbamate[000200] To a solution of (3R,5S)-3-((3-amino-l,2,4-triazin-6-yl)methyl)-5- methylpiperidin-2-one (2.10 g, 9.49 mmol) and benzyl ((S)-3-bromo-l-((lr,4S)-4- methylcyclohexyl)-2-oxopropyl)carbamate (5.08 g, 13.2 mmol) in THF (20 mL) was added DIPEA (6.13 g, 47.5 mmol, 8.27 mL) and trimethyl borate (2.96 g, 28.5 mmol, 3.22 mL) and the reaction mixture stirred at 70 °C for 5 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO2, DCM / MeOH) to afford the title compound (4.50 g, 94%) as yellow solid. ES / MS (m / z)'. 505 (M+H).[000201] The compounds in the following table were prepared essentially as described in Preparation 177 beginning with the appropriate reagents.Preparation 191 (3R,5S)-3-((6-((S)-amino((lr,4S)-4-methylcyclohexyl)methyl)imidazo[l,2-b][l,2,4]triazin-2- yl)methyl)-5-methylpiperidin-2-one[000202] A solution of benzyl ((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)carbamate (4.40 g, 8.72 mmol) in AcOH (4.62 g, 76.86 mmol, 4.40 mL) was treated with concentrated aqueous HC1 (37%) (12 M, 44.00 mL) and the resulting mixture was stirred at 50 °C fori h. The reaction was then cooled to RT, the pH adjusted to 8-9 with sat. NaHCCL (aq), and the mixture extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentratedunder reduced pressure to provide the title compound (2.20 g, 68.1%) as yellow solid. ES / MS (m / z): 371 (M+H).[000203] The compounds in the following table were prepared essentially as described in Preparation 191 beginning with the appropriately protected amines.-OSPreparation 207 (5S)-3-((6-((S)-amino(4,4-difluorocyclohexyl)methyl)-3-isopropylimidazo[l,2-b][l, 2, 4]tri azin-2- yl)methyl)-5-methylpiperidin-2-one[000204] To a solution of benzyl ((lS)-(4,4-difluorocyclohexyl)(3-isopropyl-2-(((5S)-5- methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)carbamate (130 mg, 228 pmol) in DCM (2 mL) was added iodo(trimethyl)silane (137 mg, 685 pmol, 93.3 pL) at 0 °C and the resulting mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with 1.0 M HC1 (aq) and washed with EtOAc. The pH of the aqueous phase was adjusted to 8 - 9 withsat. NaHCCh (aq) and extracted with EtOAc. These combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound (70.0 mg, 70%) as a yellow solid. ES / MS (m / z): 435 (M+H).Preparation 2081 -methyl -N-((S)-(2-(((3R, 5 S)-5-methyl-2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin- 6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide[000205] A solution of (3R,5S)-3-((6-((S)-amino((lr,4S)-4- methylcyclohexyl)methyl)imidazo[l,2-b][l,2,4]triazin-2-yl)methyl)-5-methylpiperidin-2-one (400 mg, 1.08 mmol), 1 -methyl- lH-pyrazole-5-carboxylic acid (204 mg, 1.62 mmol), and EDCI (413.94 mg, 2.16 mmol) in pyridine (4 mL) at RT for 2 h. The reaction mixture was then diluted with H2O and extracted with EtOAc. The combined organic layers were washed with sat. NaCl (aq), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by prep-TLC (SiO2, Plate 1, EtOAc: MeOH) to afford the title compound (235 mg, 45.4%) as a yellow solid. ES / MS (m / z): 479 (M+H).[000206] The compounds in the following table were prepared essentially as described in Preparation 208 beginning with the appropriate amine and and an appropriate carboxylic acid.Preparation 226 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-l,2,4-triazole-5-carboxamide[000207] To a solution of (3R,5S)-3-((6-((S)-amino((lr,4S)-4- methylcyclohexyl)methyl)imidazo[l,2-b][l,2,4]triazin-2-yl)methyl)-5-methylpiperidin-2-one (100 mg, 270 pmol) and lithium l-ethyl-lH-l,2,4-triazole-5-carboxylate (119 mg, 810 pmol) in DCM (2 mL) were added T4P (583 mg, 810 pmol, 50% EtOAc solution) and N-ethyl-N- isopropyl-propan-2-amine (140 mg, 1.08 mmol, 188 pL). The reaction mixture was stirred at RT fori h. The reaction mixture was then diluted with H2O and extracted with EtOAc. The combined organic layers were washed with H2O then sat. NaCl (aq), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC (SiO2, DCM / MeOH) to afford the title compound (90.0 mg, 68%) as yellow solid. ES / MS (m / z): 494 (M+H).[000208] The compounds in the following table were prepared essentially as described in Preparation 226 beginning with an appropriate amine and carboxylic acid salt.Preparation 232 tert-butyl 4-(6-((S)-(l-methyl-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]tri azin-3 -yl)piperi dine- 1 -carboxylate[000209] A solution of l-methyl-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 (150 mg, 313 pmol) and 1 -(tert-butyl) 4-(l,3-dioxoisoindolin-2-yl) piperidine- 1,4- dicarboxylate (352 mg, 940 pmol) and 4DPAIPN (12.49 mg, 15.67 pmol) TFA (71.5 mg, 627 pmol, 46.56 pL) in DMSO (2 mL). The reaction mixture was degassed, purged with N2, and irradiated with LED (395-456 nm) for 16 h at RT. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases are washed with water, washed with sat. NaCl (aq), dried over Na2SO4, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by prep-TLC (SiO2, Ethyl acetate / Methanol), then prep-HPLC (FA condition; column: Phenomenex luna C18 150x25 mmx 10 um; mobile phase: [water (FA)- ACN]; gradient: 60%-90% B over 10 min) to afford the title compound (130 mg, 62.6%) as yellow solid. ES / MS (m / z): 662 (M+H).[000210] The compounds in the following table were prepared essentially as described in Preparation 232 beginning with the appropriate reagents.Preparation 237 l-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(piperidin-4- yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-lH-pyrazole-5- carboxamide[000211] To a solution of tert-butyl 4-(6-((S)-(l-methyl-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)piperidine-l-carboxylate (130 mg, 196 pmol) in DCM (1 mL) was added HCl / dioxane (2 M, 982 pL). The mixture was stirred at 25 °C for 5 h. The reaction mixture was concentrated under reduced pressure to afford the title compound (110 mg, 93.6%) as a white solid. ES / MS (m / z): 562 (M+H).[000212] The compounds in the following table were prepared essentially as described in Preparation 237 beginning with the appropriate BOC-protected amine.-I l l-Preparation 2406-((S)-(((benzyloxy)carbonyl)amino)((lr,4S)-4-methylcyclohexyl)methyl)-3-((lR,4R)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)imidazo[l,2-b][l,2,4]triazine-2-carboxylic acid[000213] To a solution of ethyl 6-((S)-(((benzyloxy)carbonyl)amino)((lr,4S)-4- methylcyclohexyl)methyl)-3-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)imidazo[l,2- b][l,2,4]triazine-2-carboxylate (1.00 g, 1.73 mmol) in THF (10 mL) and H2O (3 mL) was added LiOH H2O (217 mg, 5.19 mmol) at 0 °C. The reaction mixture was stirred at 15 °C for 1 h. Thereaction mixture was then adjusted to pH = 5 with a 1.0 M HC1 (aq) at 0 °C. The resulting solution was concentrated under reduced pressure to afford the title compound (800 mg, 89%) as a yellow solid. ES / MS (m / z): 521 (M+H).[000214] The compounds in the following table were prepared essentially as described in Preparation 240 beginning with an appropriate ester.Preparation 2446-((S)-(((benzyloxy)carbonyl)amino)((lr,4S)-4-methylcyclohexyl)methyl)-3-((lR,4R)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)imidazo[l,2-b][l,2,4]triazine-2-carboxylic (isobutyl carbonic) anhydride[000215] To a solution of 6-((S)-(((benzyloxy)carbonyl)amino)((lr,4S)-4- methylcyclohexyl)methyl)-3-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)imidazo[l,2- b][l,2,4]triazine-2-carboxylic acid (800 mg, 1.54 mmol) in THF (14 mL) was added isobutyl chloroformate (839 mg, 6.15 mmol, 804 pL) and N,N-diethylethanamine (466 mg, 4.61 mmol, 641 pL) at 0 °C for 0.5 h under N2. The reaction mixture was stirred at 15 °C for 1 h. The mixture was filtered and concentrated under reduced pressure to afford the title compound (900 mg) as a yellow solid.Preparation 245 benzyl ((S)-(3-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(hydroxymethyl)imidazo[l,2- b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)carbamate[000216] To a solution of 6-((S)-(((benzyloxy)carbonyl)amino)((lr,4S)-4- methylcyclohexyl)methyl)-3-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)imidazo[l,2- b][l,2,4]triazine-2-carboxylic (isobutyl carbonic) anhydride (900 mg, 1.45 mmol) in THF (10 mL) was added NaBH4 (109 mg, 2.90 mmol) in water (0.5 mL) at 0 °C. The reaction mixture was stirred at 15 °C for 1 h. The reaction mixture was quenched by the addition of a sat. NH4CI (aq) 0 °C, and then diluted with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (condition: column: Phenomenex luna C18 150^40 mmx l5um; mobile phase: [water (FA) - ACN]; gradient: 32% - 62% B over 10 min) to afford the title compound (470 mg, 64% yield) as a yellow solid. ES / MS (m / z): 507 (M+H).Preparation 246 benzyl ((S)-(3-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(hydroxymethyl)imidazo[l,2- b][l,2,4]triazin-6-yl)(cyclohexyl)methyl)carbamate[000217] To a solution of 6-((S)-(((benzyloxy)carbonyl)amino)(cyclohexyl)methyl)-3- ((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)imidazo[l,2-b][l,2,4]triazine-2-carboxylic acid (0.550 g, 1.09 mmol) in THF (10 mL) was added isobutyl chloroformate (593 mg, 4.34 mmol, 568 pL) and N,N-diethyl ethanamine (329 mg, 3.26 mmol, 453 pL) at 0 °C for 0.5 h under N2. Then NaBH4 (102 mg, 2.71 mmol) in H2O (0.7 mL) was added at 0 °C under N2. The reaction mixture was quenched by the addition of sat. NH4CI (aq) at 0 °C, and then diluted with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCh, DCM / MeOH) to afford the title compound (0.400 g, 72%) as a yellow solid. ES / MS (m / z): 493 (M+H).[000218] The compounds in the following table were prepared essentially as described in Preparation 246.Preparation 249 benzyl ((S)-(3-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(chloromethyl)imidazo[l,2- b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)carbamate[000219] To a solution of benzyl ((S)-(3-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2- (hydroxymethyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)- carbamate (470 mg, 927 pmol) in DCM (5 mL) was added thionyl chloride (331 mg, 2.78 mmol, 202 pL). The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford the title compound (450 mg, 92%) as a yellow solid. ES / MS (m / z): 525 (M+H)[000220] The compounds in the following table were prepared essentially as described in Preparation 249 beginning with an appropriate ester.Preparation 2531 -(tert-butyl) 3 -methyl (5 S)-3 -((6-((S)-(((b enzyloxy)carbonyl)amino)(( 1 r,4 S)-4- methylcyclohexyl)methyl)-3-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)imidazo[l,2- b] [ 1 ,2,4]triazin-2-yl)methyl)-5-methyl-2-oxopiperidine- 1 ,3 -dicarboxylate[000221] To a solution of benzyl ((S)-(3-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2- (chloromethyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)carbamate (200 mg, 380 pmol) and 1 -(tert-butyl) 3-methyl (5S)-5-methyl-2-oxopiperidine-l,3- dicarboxylate (124 mg, 457 pmol) in DMF (4 mL) was added CS2CO3 (372 mg, 1.14 mmol). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography ( Si O2, PE / EtOAc) to afford the title compound (250 mg) as a yellow solid. ES / MS (m / z): 760(M+H).[000222] The compounds in the following table were prepared essentially as described in Preparation 253 beginning with an appropriate ester.Preparation 257Methyl (5S)-3-((6-((S)-(((benzyloxy)carbonyl)amino)((lr,4S)-4-methylcyclohexyl)methyl)-3- ((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)imidazo[l,2-b][l,2,4]triazin-2-yl)methyl)-5- methyl-2-oxopiperidine-3-carboxylate hydrochloride[000223] To a solution of l-(tert-butyl) 3-methyl (5S)-3-((6-((S)-(((benzyloxy)carbonyl)amino)((lr,4S)-4-methylcyclohexyl)methyl)-3-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)imidazo[l,2-b][l,2,4]triazin-2-yl)methyl)-5-methyl-2- oxopiperidine-l,3-dicarboxylate (250 mg, 329 pmol) in DCM (3 mL) was added a solution of HCl / dioxane (2 M, 822 pL) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford the title compound (200 mg, 87%) as a yellow solid. ES / MS (m / z): 660(M+H).[000224] The compounds in the following table were prepared essentially as described in Preparation 257.Preparation 261(5S)-3-((6-((S)-(((benzyloxy)carbonyl)amino)((lr,4S)-4-methylcyclohexyl)methyl)-3-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)imidazo[l,2-b][l,2,4]triazin-2-yl)methyl)-5-methyl-2- oxopiperidine-3 -carboxylic acid[000225] To a solution of methyl (5S)-3-((6-((S)-(((benzyloxy)carbonyl)amino)((lr,4S)-4- methylcyclohexyl)methyl)-3-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)imidazo[l,2- b][l,2,4]triazin-2-yl)methyl)-5-methyl-2-oxopiperidine-3-carboxylate (200 mg, 303 pmol) in THF (5 mL) was added LiOH H2O (38.2 mg, 909 pmol) and H2O (1 mL). The reaction mixture was then adjusted to pH = 5 with a 1.0 M HC1 (aq) at 0 °C. The resulting solution was concentrated under reduced pressure to afford the title compound (180 mg, 92%) as a yellow solid. ES / MS (m / z): 646 (M+H).[000226] The compounds in the following table were prepared essentially as described in Preparation 261.Preparation 265Benzyl ((lS)-(3-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(((5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)carbamate[000227] To a solution of (5S)-3-((6-((S)-(((benzyloxy)carbonyl)amino)((lr,4S)-4- methylcyclohexyl)-methyl)-3-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)imidazo[l,2- b][l,2,4]triazin-2-yl)methyl)-5-methyl-2-oxopiperidine-3-carboxylic acid (180 mg, 278 pmol) in DMF (2 mL) was added NaCl (81.4 mg, 1.39 mmol). The reaction mixture was stirred at 80 °C for 1 h then cooled to RT. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (160 mg, 95% yield) as a yellow solid. ES / MS (m / z): 602(M+H).[000228] The compounds in the following table were prepared essentially as described in Preparation 265.Preparation 275 methyl (E)-2-fluoro-6-(4-methoxy-4-oxobut- 1 -en- 1 -yl)benzoate[000229] A mixture of methyl 2-bromo-6-fluoro-benzoate (30.0 g, 128 mmol, 1.00 eq), methyl but-3-enoate (25.7 g, 257 mmol, 27.4 mL, 2.00 eq), DIPEA (33.2 g, 257 mmol, 44.8 mL, 2.00 eq), Pd(OAc)2 (5.78 g, 25.7 mmol, 0.200 eq) and tris-o-tolylphosphane (7.84 g, 25.7 mmol, 0.200 eq) in DMF (300 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 120 °C for 3 h under N2 atmosphere. The residue was purified by column chromatography (SiO2, PE: EtOAc = 3: 1, Rf = 0.6) to afford title compound (25.0 g, 99.1 mmol, 76.9% yield) as yellow oil. 'H NMR (400 MHz, CDCI3) δ 7.39 - 7.31 (m, 2H), 7.04 - 6.92 (m, 1H), 6.70 - 6.51 (m, 1H), 6.40 - 6.25 (m, 1H), 3.97 - 3.92 (m, 3H), 3.74 - 3.71 (m, 3H), 3.35 - 3.22 (m, 2H)Preparation 276 methyl 2-fluoro-6-(4-methoxy-4-oxobutyl)benzoate[000230] A solution of Pd / C (5.00 g, 4.70 mmol, 10% purity, 4.39e-2 eq) in THF (300 mL) was degassed with Argon, and methyl 2-fluoro-6-[(E)-4-methoxy-4-oxo-but-l-enyl]benzoate(27.0 g, 107 mmol, 1.00 eq) was added. The reaction mixture was evacuated and backfilled three times with hydrogen. The mixture was stirred at 25 °C for 12 h under an atmosphere of H2 (50 psi). Afford title compound (26.0 g, 102 mmol, 95.5% yield) as yellow oil. *HNMR (400 MHz, CDCI3) δ 7.39 - 7.26 (m, 1H), 7.12 - 6.91 (m, 2H), 3.99 - 3.90 (m, 3H), 3.74 - 3.66 (m, 3H), 2.78 - 2.68 (m, 2H), 2.40 - 2.28 (m, 2H), 1.84 - 0.97 (m, 2H).Preparation 277 methyl 8-fluoro-l-oxo-l,2,3,4-tetrahydronaphthalene-2-carboxylate[000231] A solution of methyl 2-fluoro-6-(4-methoxy-4-oxobutyl)benzoate (26.0 g, 1.00 eq, 102 mmol) in THF (750 mL) was degassed and refilled with N2 for 3 times and the solution was cooled to -78 °C. Then LiHMDS (37.6 g, 225 mL, 1 molar, 2.20 eq, 225 mmol) was added dropwise at -78 °C over 0.5 h. The reaction mixture was stirred at -78 °C for 1.5 h. The reaction mixture was stirred at 25 °C for 12 h. The residue was purified by reversed phase HPLC to afford title compound (8.50 g, 38.3 mmol, 37.4 %) as yellow oil. 'H NMR (400 MHz, CDCI3) δ 12.7 (s, 0.5H), 7.51 - 7.27 (m, 1H), 7.11 - 6.92 (m, 2H), 3.91 - 3.76 (m, 3H), 3.72 - 3.54 (m, 0.5H), 3.16 - 2.93 (m, 1H), 2.85 - 2.74 (m, 1H), 2.58 - 2.29 (m, 2H).Preparation 278 methyl 8-fluoro-l,2,3,4-tetrahydronaphthalene-2-carboxylate[000232] To a mixture of methyl 8-fluoro-l-oxo-l,2,3,4-tetrahydronaphthalene-2- carboxylate (8.30 g, 1 eq, 37.4 mmol) in DCM (80.0 mL) was added TFA (118 g, 80.0 mL, 27.8 eq, 1.04 mol), triethylsilane (8.74 g, 12.0 mL, 2.01 eq, 75.1 mmol) at 25 °C, the reaction mixture was stirred at 25 °C for 12 h. The residue was purified by flash silica gel chromatography (PE: EtOAc = 3: 1, 254 nm) to afford title compound (7.20 g, 34.6 mmol, 92.6 %) as colorless oil. 'H NMR 9 7.24 - 7.04 (m, 1H), 7.00 - 6.80 (m, 2H), 3.89 - 3.72 (m, 3H), 3.17 - 3.06 (m, 1H), 2.96 - 2.61 (m, 5H), 2.28 - 2.15 (m, 1H), 1.93 - 1.78 (m, 1H).Preparation 279See TABLE FOR PREPARATION 73 Preparation 280 8-fluoro-l,2,3,4-tetrahydronaphthalene-2-carbaldehyde[000233] To a mixture of (8-fluoro- 1,2, 3, 4-tetrahydronaphthalen-2-yl)m ethanol (6.15 g,LOO eq, 34.1 mmol), DMSO (27.0 g, 24.5 mL, 10.1 eq, 345 mmol) in DCM (70.0 mL) was added DIPEA (22.3 g, 30.0 mL, 5.05 eq, 172 mmol), sulfur trioxide pyridine (11.0 g, 2.03 eq, 69.1 mmol) at 0 °C, the reaction mixture was stirred at 0 °C for 1 h. Afford title compound (6.00 g, 33.7 mmol, 98.7 %) as yellow oil. 'HNMR (400 MHz, CDC13) δ 9.80 (s, 1H), 7.15 - 7.02 (m, 1H), 6.91 - 6.80 (m, 2H), 3.24 - 3.14 (m, 4H), 2.89 - 2.85 (m, 1H), 2.26 - 2.15 (m, 1H), 1.87 - 1.71 (m, 1H).Preparation 281See TABLE FOR PREPARATION 90Preparation 282See TABLE FOR PREPARATION 93Preparation 283See TABLE FOR PREPARATION 100Preparation 284See TABLE FOR PREPARATION 130Preparation 285See TABLE FOR PREPARATION 149Preparation 286See TABLE FOR PREPARATION 158 Preparation 287See TABLE FOR PREPARATION 177 Preparation 288See TABLE FOR PREPARATION 191Preparation 289See TABLE FOR PREPARATION 208EXAMPLESExample 1[000234] N-((S)-(3-(l-(2-amino-2-oxoethyl)piperidin-4-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[000235] To a solution of l-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3-(piperidin-4-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide (55.0 mg, 91.9 μmol), 2-bromoacetamide (12.9 mg, 137 pmol) in ACN (1 mL) was added N-ethyl-N-isopropylpropan-2-amine (59.4 mg, 459 pmol, 80.0 pL). The mixture was stirred at 80 °C for 1 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, 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 150x25 mmx lO um; mobile phase: [water (FA)-ACN]; gradient: 16%-46% B over 10 min) to afford the title compound (36.25 mg, 58.4 pmol, 63.5% yield, 99.7% purity) as a white solid. ES / MS (m / z): 619 (M+H).Example 2[000236] N-((S)-(3-((R)-4,4-difluoro-l-methylpiperidin-3-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 (Isomer 1)Example 3[000237] N-((S)-(3-((R)-4,4-difluoro-l-methylpiperidin-3-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 (Isomer 2)[000238] To a solution of N-((lS)-(3-(4,4-difluoropiperidin-3-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)meth- yl)-l-methyl-lH-pyrazole-5-carboxamide hydrochloride (80.0 mg, 133 pmol) in MeOH (1 mL) was added sodium cyanoborohydride (16.8 mg, 267 pmol) and formaldehyde (32.6 mg, 401 pmol, 29.9 pL). The mixture was stirred at 20 °C for 0.5 h and was purified by prep-HPLC (column: Phenomenex luna C18 150^25 mmx lO um; mobile phase: [water (FA) - ACN]; gradient: 18% - 48% B over 10 min) to afford N-((lS)-(3-(4,4-difluoro-l-methylpiperidin-3-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 as a yellow solid.Isomer 1 was isolated as the first eluting, single stereoisomer by prep-HPLC (FA condition; column: Phenomenex luna C18 150x25 mmx lO um; mobile phase: [water (FA) - ACN]; gradient: 18% - 48% B over 10 min) and was obtained as a white solid. ES / MS (m / z): 612(M+H). Isomer 2 was isolated as the second eluting, single stereoisomer by prep-HPLC (FA condition; column: Phenomenex luna C18 150x25 mmx lO um; mobile phase: [water (FA) - ACN]; gradient: 18% - 48% B over 10 min); (8.00 mg, 18.0%) and was obtained as a white solid. ES / MS (m / z): 612(M+H).[000239] The compounds in the following table were prepared essentially as described in Example 3 using the corresponding appropriate reagents, bases and solvents with the reaction time adjusted to reach completion.Example 6[000240] 1 -methyl -N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((S)- tetrahydrofuran-3-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-lH- pyrazole-5-carboxamide (Isomer 1)Example 7[000241] 1 -methyl -N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)- tetrahydrofuran-3-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-lH- pyrazole-5-carboxamide (Isomer 2)[000242] A solution of l-methyl-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 (87.3 mg, 334 pmol), l,3-dioxoisoindolin-2-yl tetrahydrofuran-3 -carboxylate (80.0 mg, 167 pmol), 4DPAIPN (6.66 mg, 8,36 pmol), and TFA (28.59 mg, 250.74 pmol, 18.63 pL) in DMSO (2 mL). The reaction mixture was degassed, purged with N2, and irradiated with LED (395-456 nm) for 16 h at RT. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases are washed with water, washed with sat. NaCl (aq), dried over Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by prep-TLC (SiO2, EtOAc / MeOH) to afford the title compound (70.0 mg, 76.3%) as white solid.[000243] Isomer 1 was isolated as the first eluting, single stereoisomer by prep- SFC(column: DAICEL CHIRALPAK AD (250 mm><30 mm, 10 um); mobile phase: [CCL-EtOH (O.1%NH3H2O]; B%: 35%, isocratic elution mode (25.6 mg, 36%) and was obtained as a white solid. ES / MS (m / z): 549 (M+H).[000244] Isomer 2 was isolated as the second eluting, single stereoisomer by prep- SFC(column: DAICEL CHIRALPAK AD (250 mm><30 mm, 10 um); mobile phase: [CCL-EtOH (0.1%NH3H2O)]; B%: 35%, isocratic elution mode) and prep-SFC (column: DAICEL CHIRALCEL OD (250 mmx30 mm, 10 um); mobile phase: [CO2-i-PrOH (0.1%NH3H2O)]; B%: 40%, isocratic elution mode); (25.1 mg, 35%) and was obtained as a white solid. ES / MS (m / z): 549 (M+H).[000245] The compounds in the following table were prepared essentially as described in Example 7 using the corresponding appropriate reagents, bases and solvents with the reaction time adjusted to reach completion.-ISO-Example 49[000246] N-((S)-(3-((2R,6R)-2,6-dimethylmorpholino)-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[000247] To a solution of l-methyl-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 (50.0 mg, 104 pmol) and (2R,6R)-2,6-dimethylmorpholine (180 mg, 1.57 mmol) in THF (1 mL) at 0-5 °C was added bis(pyridine)silver(I) permanganate (40.43 mg, 104.47 pmol) 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 dichloromethane and filtered through packed MgSO4 atop diatomaceous earth with DCM / EtOAc washes. The filtrate was concentrated under reduced pressure and the residue purified by prep- HPLC (FA condition; column: Phenomenex luna C18 150^25 mmx lO um; mobile phase: [water (FA)-ACN]; gradient: 25% - 55% B over 10 min) and SFC separation column: DAICEL CHIRALPAK AS-H (250 mmx30 mm, 5 um); mobile phase: [CO2-EtOH (0.1%NH3H2O)]; B%: 35%, isocratic elution mode, Rt = 1.324, 1.699 min) to afford the title compound (9.92 mg, 32%) as yellow solid. ES / MS (m / z): 592 (M+H)[000248] The compounds in the following table were prepared essentially as described in Example 49 using the corresponding appropriate reagents, bases and solvents with the reaction time adjusted to reach completion.b: Isolated by Prep-SFC (column: ChiralPak IH, 250 x 30 mm, lOum; mobile phase: [A: CO2; B: EtOH (0.1% NH3H2O)]; B%: 50.00% - 50.00%, 7.00 min; flow rate: 150.00 ml / min, peak 1, peak 2).[000249] The compounds in the following table were prepared essentially as described in Example 49 using the corresponding appropriate reagents, bases and solvents with the reaction time adjusted to reach completion.Example 73[000250] N-((lS)-(3-(l-(cyanoimino)hexahydro-114-thiopyran-4-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-ethyl-lH-pyrazole-5-carboxamidel-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H-thiopyran-4-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-lH-pyrazole-5- carb oxami de[000251] Beginning with 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 and l,3-dioxoisoindolin-2-yl tetrahydro-2H-thiopyran-4-carboxylate, the intermediate thiopyran was prepared essentially as described in Preparation 237.[000252] To a solution of the intermediate thiopyran (40.0 mg, 67.4 pmol) in ACN (1 mL) was added cyanamide (2.84 mg, 67.4 pmol, 2.84 pL) and IBD (26.1 mg, 80.9 pmol). The mixture was stirred at 0 °C for 1 h and then diluted with H2O and extracted with EtOAc. The combined organic layer was dried over ISfeSCU, filtered, and concentrated under reduced pressure to give a residue which was purified by prep-TLC (SiCL, DCM / MeOH) and was further purified by prep- SFC (column: DAICEL CHIRALPAK IK (250 mm><30 mm, 10 um); mobile phase: [CO2 - ACN / EtOH (0.1% NH3H2O)]; B%: 65%, isocratic elution mode) to afford the title compound (16.01 mg, 63%) as yellow solid. ES / MS (m / z): 593(M+H).Example 74[000253] 4-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)- tetrahydrofuran-3-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)- l,2,5-oxadiazole-3-carboxamide (Isomer 1)Example 75[000254] 4-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)- tetrahydrofuran-3-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)- l,2,5-oxadiazole-3-carboxamide (Isomer 2)[000255] To a solution of (3R,5S)-3-((6-((S)-amino((lr,4S)-4-methylcyclohexyl)methyl)-3- (tetrahydrofuran-3-yl)imidazo[l,2-b][l,2,4]triazin-2-yl)methyl)-5-methylpiperidin-2-one (80.0 mg, 179 pmol) and 4-ethyl-l,2,5-oxadiazole-3-carboxylic acid (50.9 mg, 358 pmol) in DCM (2 mL) was added DIPEA (92.74 mg, 717.60 pmol, 124.99 pL) and T4P (258.52 mg, 358.80 pmol,50% purity in EtOAc) and the reaction mixture was stirred at RT fori h. The reaction mixture was then diluted with H2O and extracted with EtOAc. The combined organic layers were washed with H2O then sat. NaCl (aq), dried over Na2SO4, filtered, and concentrated under reduced pressure to provide a residue that was purified by prep-HPLC (column: Phenomenex luna C18 150x25 mmx lOum; mobile phase: [water (FA) - ACN]; gradient: 54% - 74% B over 10 min) to afford a stereoisomeric mixture of the title compound (50.0 mg, 49%) as a white solid.[000256] Isomer 1 was isolated as the first eluting, single stereoisomer by prep-SFC (column: DAICEL CHIRALPAK AS (250mmx30mm, lOum); mobile phase: [CO2 - MeOH (0.1%NH3H2O)]; B%: 35%, isocratic elution mode); (20.1 mg, 38%) as a light yellow solid. ES / MS (m / z): 565 (M+H)[000257] Isomer 2 was isolated as the second eluting, single stereoisomer by prep-SFC (column: DAICEL CHIRALPAK AS (250mmx30mm, lOum); mobile phase: [CO2 - MeOH (0.1%NH3H2O)]; B%: 35%, isocratic elution mode); (16.7 mg, 32%) as a yellow solid. ES / MS (m / z): 565 (M+H).Preparation 268N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-3-(4-methylpiperazin- l-yl)benzamide[000258] A solution of (3R,5S)-3-((6-((S)-amino((lr,4S)-4-methylcyclohexyl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[l,2-b][l,2,4]triazin-2-yl)methyl)-5-methylpiperidin-2-one (45.0 mg, 98.9 pmol), 3-(4-methylpiperazin-l-yl)benzoic acid (43.6 mg, 197 pmol), and EDCI (56.93 mg, 296.96 pmol) in pyridine (2 mL) was stirred at RT for 2 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic phases were washed with H2O then sat. NaCl (aq), dried over Na2SO4, filtered, and concentrated under reduced pressure to provide a residue that was purified by prep-HPLC (column: Phenomenex luna C18 150x25mmx 10 um; mobile phase: [water (FA) - ACN]; gradient: 23%-53% B over 10 min) to afford the title compound (30.1 mg, 46%) as white solid. ES / MS (m / z): 657 (M+H).The compounds in the following table were prepared essentially as described in Preparation 268 using the corresponding appropriate amines and carboxylic acids.Example 82[000259] 1 -ethyl -N-((S)-(3 -(1 -imino- 1 -oxidohexahydro- 116-thiopyran-4-yl)-2-(((3R,5 S)-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 (Isomer 1)Example 83[000260] 1 -ethyl -N-((S)-(3 -(1 -imino- 1 -oxidohexahydro- 116-thiopyran-4-yl)-2-(((3R,5 S)-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 (Isomer 2)[000261] To a solution of l-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl) methyl)-3-(tetrahydro-2H-thiopyran-4-yl) imidazo [1,2-b] [1,2,4] triazin-6-yl) ((lr,4S)-4- methylcyclohexyl) methyl)- lH-pyrazole-5-carboxamide (70.0 mg, 118 pmol) in MeOH (4 mL) was added ammonium carbamate (46.0 mg, 590 pmol) and IBD (190 mg, 590 pmol). 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. NaCl(aq), filtered, and concentrated under reduced pressure to give a residue which was purified by prep-TLC (SiCh, DCM / MeOH) to afford the intermediate l-ethyl-N-((S)-(3-(l-imino-l-oxidohexahydro-116- thiopyran-4-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl) methyl) imidazof 1,2-b] [1,2,4] triazin-6-yl) ((lr,4S)-4-methylcyclohexyl) methyl)-lH-pyrazole-5-carboxamide (50.0 mg) as a white solid. ES / MS (m / z): 624 (M+H).[000262] To a solution of the intermediate l-ethyl-N-((S)-(3-(l-imino-l-oxidohexahydro- 116-thiopyran-4-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 (40.0 mg, 64.1 pmol) and methylboronic acid (7.68 mg, 128 pmol) in dioxane (3 mL) was added cupric acetate (17.4 mg, 96.1 pmol) and pyridine (12.1 mg, 153 pmol, 12.4 pL) and the mixture was stirred at 100 °C for 2 h. The reaction mixture was then filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, DCM / MeOH) to provide a isomeric mixture of the title compounds (40.0 mg) as a white solid. ES / MS (m / z):638(M+H). This isomeric mixture was subjected to prep-SFC (column: DAICEL CHIRALPAK IK (250 mmx30 mm, 10 um); mobile phase: [CO2-ACN / MeOH (0.1% NH3H2O)]; B%: 65%, isocratic elution mode) and prep-HPLC (column: Phenomenex luna C18 150x25 mmx lO um; mobile phase: [water (FA)-ACN]; gradient: 24%-54% B over 10 min) to provide Isomer 1 as the first eluting isomer (11.4 mg, 38%) (ES / MS (m / z): 638 (M+H)) and Isomer 2 as the second eluting isomer (14.9 mg, 47%) (ES / MS (m / z): 638 (M+H)).IL-17 A / A HEK-Blue Cell Assay[000263] 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 to expressed IL-17RA, IL-17RC, and the Actl adapter molecule, the combination of which, when stimulated by IL-17A / A or IL-17A / F activates a NFαB 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 A630.[000264] 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). IL-17A / A (Genscript #Z03228) or IL-17A / 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 IL-17A / 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[000265] The data provided for selected examples in Table A demonstrate inhibition of ILIYA / A and / or IL-17 A / F mediated signaling in the HEK-Blue Cell Assay.[000266] 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

CLAIMSWhat is claimed is:

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

2. The compound according to claim 1 wherein R2isor a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 wherein R2is or a pharmaceuticallyacceptable salt thereof.

4. The compound according to claim 1 wherein R2is or a pharmaceuticallyacceptable salt thereof.

5. The compound according to claim 1 wherein R2isor a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 wherein R2is or a pharmaceuticallyacceptable salt thereof.

7. The compound according to claim 1 wherein R2is, or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 wherein R2is, or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 wherein R2 is or a pharmaceuticallyacceptable salt thereof.

10. The compound according to any one of claims 2 to 9 wherein R3is, or a pharmaceutically acceptable salt thereof.

11. The compound according to any one of claims 2 to 9 wherein R3is , or apharmaceutically acceptable salt thereof.

12. The compound according to any one of claims 2 to 9 wherein R3is or apharmaceutically acceptable salt thereof.

13. The compound according to any one of claims 2 to 9 wherein R3is or apharmaceutically acceptable salt thereof.

14. The compound according to any one of claims 2 to 9 wherein R3is or apharmaceutically acceptable salt thereof.

15. The compound according to any one of claims 2 to 9 wherein R3is or apharmaceutically acceptable salt thereof.

16. The compound according to any one of claims 2 to 9 wherein R3is or apharmaceutically acceptable salt thereof.

17. The compound according to any one of claims 2 to 9 wherein R isor a pharmaceutically acceptable salt thereof.

18. The compound of claim 1 selected from the group consisting of:N-((S)-(3-(l-(2-amino-2-oxoethyl)piperidin-4-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;N-((S)-(3-((R)-4,4-difluoro-l-methylpiperidin-3-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 (Isomer 1);N-((S)-(3-((R)-4,4-difluoro-l-methylpiperidin-3-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 (Isomer 2);N-((S)-(3-((R)-4,4-difluoro-l-methylpiperidin-3-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)-l,4-dihydroimidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-l-(2-fluoroethyl)-lH-pyrazole-5-carboxamide (Isomer 1);N-((S)-(3-((R)-4,4-difluoro-l-methylpiperidin-3-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)-l,4-dihydroimidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-l-(2-fluoroethyl)-lH-pyrazole-5-carboxamide (Isomer 2);l-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((S)- tetrahydrofuran-3-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide (Isomer 1); l-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)- tetrahydrofuran-3-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide (Isomer 2); l-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((3-methyloxetan- 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-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)-tetrahydro- 2H-pyran-3-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)- lH-pyrazole-5-carboxamide (Isomer 1);1-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)-tetrahydro- 2H-pyran-3-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)- lH-pyrazole-5-carboxamide (Isomer 2);2-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)-tetrahydro-2H- pyran-3 -yl)- 1 ,4-dihydroimidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)((l r,4S)-4- methylcyclohexyl)methyl)-4,5-dihydro-112,214-pyrazole-3-carboxamide (Isomer 1);2-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)-tetrahydro-2H- pyran-3 -yl)- 1 ,4-dihydroimidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)((l r,4S)-4- methylcyclohexyl)methyl)-4,5-dihydro-112,214-pyrazole-3-carboxamide (Isomer 2); l-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(oxetan-3- 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-(oxetan-3- ylmethyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-lH- pyrazole-5-carboxamide;N-((S)-(3-(l,l-dioxidotetrahydro-2H-thiopyran-4-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)-2-ethyl-4H-214-pyrazole-3-carboxamide;N-((S)-(3-((S)-l,l-dioxidotetrahydrothiophen-3-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- ethyl-lH-pyrazole-5-carboxamide (Isomer 1);N-((S)-(3-((S)-l,l-dioxidotetrahydrothiophen-3-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- ethyl-lH-pyrazole-5-carboxamide (Isomer 2); l-ethyl-N-((lS)-(3-(l-methyl-l-oxidophosphinan-4-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 (Isomer 1); l-ethyl-N-((lS)-(3-(l-methyl-l-oxidophosphinan-4-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 (Isomer 2);N-((S)-(3-((S)-2,2-dimethyl-l,l-dioxidotetrahydro-2H-thiopyran-4-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-ethyl-lH-pyrazole-5-carboxamide (Isomer 1);N-((S)-(3-((S)-2,2-dimethyl-l,l-dioxidotetrahydro-2H-thiopyran-4-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-ethyl-lH-pyrazole-5-carboxamide (Isomer 2);N-((S)-(3-(l,l-dioxidotetrahydro-2H-thiopyran-4-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-113,212,5-oxadiazole-3-carboxamide;N-((S)-(3-((R)-2,2-dimethyl-l,l-dioxidotetrahydro-2H-thiopyran-4-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 (Isomer 1);N-((S)-(3-((R)-2,2-dimethyl-l,l-dioxidotetrahydro-2H-thiopyran-4-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 (Isomer 2);N-((S)-(3-(l,l-dioxidotetrahydro-2H-thiopyran-4-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-ethyl-l,2,5-oxadiazole-3-carboxamide;N-((S)-(3-((S)-2,2-dimethyl-l,l-dioxidotetrahydro-2H-thiopyran-4-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-ethyl-l,2,5-oxadiazole-3-carboxamide (Isomer 1);N-((S)-(3-((S)-2,2-dimethyl-l,l-dioxidotetrahydro-2H-thiopyran-4-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-ethyl-l,2,5-oxadiazole-3-carboxamide (Isomer 2);4-cyclopropyl-N-((lS)-(3-(l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-2-(((3R,5S)-5- methyl-2-oxopiperidin-3-yl)methyl)octahydroimidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)- 4-methylcy cl ohexyl)methyl)-2,5-dihydro-l, 2, 5-oxadiazole-3 -carboxamide;1-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(oxetan-3- ylmethyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-lH- l,2,4-triazole-5-carboxamide;N-((S)-((S)-3,3-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- ((S)-tetrahydrofuran-3 -yl)- 1 ,4-dihydroimidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 - methyl-lH-pyrazole-5-carboxamide (Isomer 1);N-((S)-((S)-3,3-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- ((S)-tetrahydrofuran-3 -yl)- 1 ,4-dihydroimidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 - methyl- lH-pyrazole-5-carboxamide (Isomer 2);2-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)- tetrahydrofuran-3-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcy cl ohexyl)methyl)-4H-214-pyrazole-3 -carboxamide (Isomer 1);2-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)- tetrahydrofuran-3-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcy cl ohexyl)methyl)-4H-214-pyrazole-3 -carboxamide (Isomer 2);N-((S)-(3-isopropyl-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;4-cyclopropyl-N-((S)-(3-(l,l-dioxidotetrahydro-2H-thiopyran-4-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;l-methyl-N-((S)-l-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)- tetrahy drofuran-3 -yl)imidazo[ 1 ,2-b ] [ 1 , 2 , 4 ] tri azin-6-yl)-3 -( 1 - (trifluoromethyl)cyclopropyl)propyl)-lH-pyrazole-5-carboxamide (Isomer 1);1-methyl-N-((S)-l-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)- tetrahy drofuran-3 -yl)imidazo[ 1 ,2-b ] [ 1 , 2 , 4 ] tri azin-6-yl)-3 -( 1 - (trifluoromethyl)cyclopropyl)propyl)-lH-pyrazole-5-carboxamide (Isomer 2);4-cyclopropyl-N-((R)-l-((R)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)- tetrahy drofuran-3 -yl)-3 ,4-dihydroimidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-2-(( 1,1,1 -trifluoro-2- methylpropan-2-yl)oxy)ethyl)-l,2,5-oxadiazole-3-carboxamide (Isomer 1);4-cyclopropyl-N-((R)-l-((R)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)- tetrahy drofuran-3 -yl)-3 ,4-dihydroimidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-2-(( 1,1,1 -trifluoro-2- methylpropan-2-yl)oxy)ethyl)-l,2,5-oxadiazole-3-carboxamide (Isomer 2);4-cyclopropyl-N-((R)- 1 -(3 -(1 , 1 -dioxidotetrahydro-2H-thiopyran-4-yl)-2-(((3R,5 S)-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;N-((R)-l-(3-(l,l-dioxidotetrahydro-2H-thiopyran-4-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)-4-ethyl- 1 ,2, 5-oxadiazole-3 -carboxamide;N-((lS)-(3-(l-(cyanoimino)-l-oxidohexahydro-116-thiopyran-4-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-ethyl-lH-pyrazole-5-carboxamide (Isomer 2);N-((lS)-(3-(l-(cyanoimino)-l-oxidohexahydro-116-thiopyran-4-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-ethyl-lH-pyrazole-5-carboxamide (Isomer 2);4-cyclopropyl-N-((lS)-(4,4-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3-(tetrahydrofuran-3-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l,2,5- oxadiazole-3 -carboxamide (Isomer 1);4-cyclopropyl-N-((lS)-(4,4-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3-(tetrahydrofuran-3-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l,2,5- oxadiazole-3 -carboxamide (Isomer 2);4-cyclopropyl-N-((S)-(4,4-difluorocyclohexyl)(3-(l,l-dioxidotetrahydro-2H-thiopyran-4- yl)-2-(((3 R, 5 S)-5-m ethyl -2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)methyl)-l,2,5-oxadiazole-3-carboxamide;4-ethyl-N-((lR)-l-(2-(((3R, 5 S)-5-methyl -2-oxopiperi din-3 -yl)methyl)-3- (tetrahydrofuran-3 -yl)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 (Isomer 1);4-ethyl-N-((lR)-l-(2-(((3R, 5 S)-5-methyl -2-oxopiperi din-3 -yl)methyl)-3- (tetrahydrofuran-3 -yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-2-(( 1,1,1 -trifluoro-2- methylpropan-2-yl)oxy)ethyl)-l,2,5-oxadiazole-3-carboxamide (Isomer 2);N-((S)-(3-((2R,6R)-2,6-dimethylmorpholino)-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;N-((S)-(3-((2S,6S)-2,6-dimethylmorpholino)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)m ethyl)- 1 ,4-dihydroimidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)(( 1 r,4S)-4- methylcyclohexyl)methyl)-l-methyl-lH-pyrazole-5-carboxamide;N-((S)-(3-((2R,6S)-2,6-dimethylmorpholino)-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;N-((lS)-(3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin- 3-yl)methyl)-l,4-dihydroimidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-l-methyl-lH-pyrazole-5-carboxamide;N-((S)-(3-((lR,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)-l,4-dihydroimidazo[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-((R)-2- methylmorpholino)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide;N-((S)-(3-((2R,6R)-2,6-dimethylmorpholino)-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)-(3-((2R,6R)-2,6-dimethylmorpholino)-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- fluoroethyl)-lH-pyrazole-5-carboxamide;N-((S)-(4,4-difluorocyclohexyl)(3-((2S,6S)-2,6-dimethylmorpholino)-2-(((3R,5S)-5- methyl-2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -ethyl- 1H- l,2,4-triazole-5-carboxamide;N-((S)-((S)-3,3-difluorocyclohexyl)(3-((2R,6R)-2,6-dimethylmorpholino)-2-(((3R,5S)-5- methyl-2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -ethyl- 1H- l,2,4-triazole-5-carboxamide;N-((S)-((S)-3,3-difluorocyclohexyl)(3-((2R,6R)-2,6-dimethylmorpholino)-2-(((3R,5S)-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)-((S)-3,3-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- morpholinoimidazof 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -isopropyl- 1H- 1 ,2,4-triazole-5 - carboxamide;N-((S)-(3-((2R,6R)-2,6-dimethylmorpholino)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)m ethyl)- 1 ,4-dihydroimidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)(( 1 S,3R)-3 - methylcyclohexyl)methyl)-l-methyl-lH-pyrazole-5-carboxamide;N-((S)-(3-((2R,6R)-2,6-dimethylmorpholino)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)m ethyl)- 1 ,4-dihydroimidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)(( 1 S,3R)-3 - methylcy cl ohexyl)methyl)-l -isopropyl -3H- 114, 2, 4-triazole-5-carboxamide;N-((lS)-l-(3-((2R,6R)-2,6-dimethylmorpholino)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3, 4,4a, 5-tetrahydroimidazo[l,2-b] [1,2, 4]tri azin-6-yl)-3-(l - (trifluoromethyl)cyclopropyl)propyl)-l-methyl-lH-pyrazole-5-carboxamide;N-((S)-l-(3-((2R,6S)-2,6-dimethylmorpholino)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-3 -(1 -(trifluoromethyl)cyclopropyl)propyl)- 1 - ethyl - 1 H-py razol e- 5 -carb oxami de; l-ethyl-N-((S)-l-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(4-oxa-7- azaspiro[2.5]octan-7-yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-3 -( 1 - (trifluoromethyl)cyclopropyl)propyl)-lH-pyrazole-5-carboxamide;N-((S)-l-(3-((2R,6R)-2,6-dimethylmorpholino)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-3 -(1 -(trifluoromethyl)cyclopropyl)propyl)- 1 - (2-fluoroethyl)-lH-pyrazole-5-carboxamide; l-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((S)-2- methylmorpholino)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-lH-pyrazole-5-carboxamide;N-((lS)-(3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin- 3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)(cyclohexyl)methyl)- 1 -methyl- 1H- pyrazole-5-carboxamide;N-((S)-(3-((lR,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-(((3R,5S)-5-methyl-2- oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)(cyclohexyl)methyl)- 1 - methyl - 1 H-py razol e- 5 -carb oxami de;N-((S)-cyclohexyl(3-((2R,6R)-2,6-dimethylmorpholino)-2-(((3R,5S)-5-methyl-2- oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -methyl- 1H- py razol e- 5 -carb oxami de;N-((S)-cyclohexyl(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)-2- methylmorpholino)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -methyl- lH-pyrazole-5- carboxamide;N-((S)-cyclohexyl(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((S)-2- methylmorpholino)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -methyl- lH-pyrazole-5- carboxamide;N-((lS)-(3-(l-(cyanoimino)hexahydro-114-thiopyran-4-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcy cl ohexyl)m ethyl)- 1 -ethyl- lH-pyrazole-5 -carboxamide;4-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)- tetrahydrofuran-3-yl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-l,2,5-oxadiazole-3-carboxamide (Isomer 1);4-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)- tetrahydrofuran-3-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-((S)-(4,4-difluorocyclohexyl)(3-isopropyl-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -ethyl- lH-pyrazole-5 -carboxamide (Isomer 1);N-((S)-(4,4-difluorocyclohexyl)(3-isopropyl-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -ethyl- lH-pyrazole-5 -carboxamide (Isomer 2);N-((S)-(3-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(((3R,5S)-5-methyl-2- oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)(cyclohexyl)methyl)- 1 - methyl - 1 H-py razol e- 5 -carb oxami de;N-((S)-(3-((lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-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-((lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(((3R,5S)-5-methyl-2- oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)(cyclohexyl)methyl)- 1 - methyl - 1 H-py razol e- 5 -carb oxami de;N-((lS)-(3-((lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(((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;1 -ethyl -N-((S)-(3 -(1 -imino- 1 -oxidohexahydro- 116-thiopyran-4-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 (Isomer 1);1 -ethyl-N-((S)-(3 -( 1 -imino- 1 -oxidohexahydro- 116-thiopyran-4-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 (Isomer 2);N-((S)-((S)-3,3-difluorocyclohexyl)(3-((2R,6R)-2,6-dimethylmorpholino)-2-(((3R,5S)-5- methyl-2-oxopiperi din-3 -yl)methyl)imidazo[l,2-b][ 1,2, 4]tri azin-6-yl)methyl)-4-m ethyl- l,2,5-oxadiazole-3-carboxamide; andN-((S)-(3-((2R,6R)-2,6-dimethylmorpholino)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[l,2-b] [1,2, 4]triazin-6-yl)((S)-8-fluoro- 1,2,3, 4-tetrahy dronaphthalen-2- yl)m ethyl)- 1 -methyl- lH-pyrazole-5-carboxamide;or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

20. 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 18, or a pharmaceutically acceptable salt thereof.

21. A method of treating psoriasis according to claim 20 comprising administering to a patient in need thereof an effective amount of a compound according to claim 18, or a pharmaceutically acceptable salt thereof.

22. A compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use in therapy.

23. A compound according to any one of claims 1 to 18, 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.

24. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use in the treatment of psoriasis.

25. Use of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating psoriasis.

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