Il-17a inhibitors

Abstract

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

Description

IL-17A INHIBITORSBACKGROUND OF THE INVENTION

[0001] The invention provides certain difluorotetrahydropyran-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 rapid recovery of the ability to respond to an infection. In addition, anti-drug antibodies against anti-IL-17A antibodies may arise in some patients and may reduce the efficacy of antibodies directed to IL-17A over time. This inactivation pathway would not be operative for small molecule IL- 17A inhibitors. For some patients with psoriasis, orally administered small molecule inhibitors of interleukin (IL)-17A may represent a convenient alternative to IL-17A-targeting monoclonal antibodies.

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

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

[0007] In certain aspects, the present disclosure provides a compound of Formula (I):wherein:or a pharmaceutically acceptable salt thereof.

[0008] Further, the present invention provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0009] The following particular embodiments are compounds and / or salts of formula I.

[0010] The present invention provides a compound of formula I, wherein R1is, or a pharmaceutically acceptable salt thereof.

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

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

[0013] The present invention provides a compound according to any of the above embodiments whereinpharmaceutically acceptable salt thereof.

[0014] The present invention provides a compound according to any of the above embodiments whereinpharmaceutically acceptable salt thereof.

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

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

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

[0018] Further, the present invention provides a compound selected from the group consisting of:N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-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-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-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);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-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-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-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-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-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-(2- fluoroethyl)-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-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-(2- fluoroethyl)-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-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- fluorocyclopropane-1 -carboxamide (isomer 1);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-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- fluorocyclopropane-1 -carboxamide (isomer 2);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((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 (isomer 1);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((2-oxopiperidin-3-yl)methyl)imidazo[l,2- b][ 1,2, 4]triazin-6-yl)((lS,3R)-3-methylcy cl ohexyl)methyl)-l -methyl- lH-pyrazole-5- carboxamide (isomer 2);N-((lS)-cyclohexyl(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-(((3R,5S)-5-methyl-2- oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -methyl- lH-pyrazole-5- carboxamide (isomer 1);N-((lS)-cyclohexyl(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-(((3R,5S)-5-methyl-2- oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -methyl- lH-pyrazole-5- carboxamide (isomer 2);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3-methylcyclohexyl)methyl)-4-ethyl-l,2,5- oxadiazole-3 -carboxamide (isomer 1);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3-methylcyclohexyl)methyl)-4-ethyl-l,2,5- oxadiazole-3 -carboxamide (isomer 2);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-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- fluorocyclopropane-1 -carboxamide (isomer 1);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-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- fluorocyclopropane-1 -carboxamide (isomer 2);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-(((3R,5R)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3-methylcyclohexyl)methyl)-l-(2- fluoroethyl)-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-(((3R,5R)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3-methylcyclohexyl)methyl)-l-(2- fluoroethyl)-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((3-oxo-2-azabicyclo[3.1.1]heptan-4- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3-methylcyclohexyl)methyl)-l-ethyl-lH- pyrazole-5-carboxamide (isomer 1);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((3-oxo-2-azabicyclo[3.1.1]heptan-4- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3-methylcyclohexyl)methyl)-l-ethyl-lH- pyrazole-5-carboxamide (isomer 2);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((3-oxo-2-azabicyclo[3.1.1]heptan-4- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3-methylcyclohexyl)methyl)-l-methyl-lH- pyrazole-5-carboxamide (isomer 1);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((3-oxo-2-azabicyclo[3.1.1]heptan-4- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3-methylcyclohexyl)methyl)-l-methyl-lH- pyrazole-5-carboxamide (isomer 2);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-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- pyrazole-5-carboxamide (isomer 1);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-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- pyrazole-5-carboxamide (isomer 2);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((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 (isomer 1);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((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 (isomer 2);N-((lR)-l-(3-(4,4-difluorotetrahydro-2H-pyran-3-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)- l-ethyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lR)-l-(3-(4,4-difluorotetrahydro-2H-pyran-3-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)- l-ethyl-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-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- l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-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- l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-l-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-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 - methyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-l-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-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 - methyl- lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-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 (isomer 1);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-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 (isomer 2);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-(((3R,5S)-5- methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-4-ethyl-l,2,5- oxadiazole-3 -carboxamide (isomer 1);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-(((3R,5S)-5- methyl-2-oxopiperi din-3 -yl)methyl)imidazo[l,2-b] [1,2, 4]triazin-6-yl)methyl)-4-ethyl- 1,2,5- oxadiazole-3 -carboxamide (isomer 2);N-((lS)-((R)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-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- pyrazole-5-carboxamide (isomer 1);N-((lS)-((R)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-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- pyrazole-5-carboxamide (isomer 2);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((2-oxopiperidin-3-yl)methyl)imidazo[l,2- b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l-methyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((2-oxopiperidin-3-yl)methyl)imidazo[l,2- b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l-methyl-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((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 (isomer 1);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((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 (isomer 2);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-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- pyrazole-5-carboxamide (isomer 1);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-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- pyrazole-5-carboxamide (isomer 2);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-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-ethyl-lH- l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-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-ethyl-lH- l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-(((3R,5S)-5- methyl-2-oxopiperi din-3 -yl)methyl)imidazo[l,2-b] [1,2, 4]triazin-6-yl)methyl)-4-methyl- 1,2,5- oxadiazole-3 -carboxamide (isomer 1); andN-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-(((3R,5S)-5- methyl-2-oxopiperi din-3 -yl)methyl)imidazo[l, 2-b][ 1,2, 4]triazin-6-yl)methyl)-4-methyl- 1,2,5- oxadiazole-3 -carboxamide (isomer 2); or a pharmaceutically acceptable salt thereof.

[0019] 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.

[0020] 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

[0021] Compounds of the present invention are potent inhibitors of IL-17A, 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.

[0022] Further, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0023] In another embodiment, the present invention provides a pharmaceutical composition comprising the compound of formula I, 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 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 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 a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers, or diluents.

[0024] 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, 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 a pharmaceutically acceptable salt thereof.

[0025] In one embodiment, the present invention provides a compound of formula I, 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 a pharmaceutically acceptable salt thereof, for use in treating spondyloarthritis. In another particular embodiment the invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, foruse 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.

[0026] In yet another embodiment, the present invention provides the use of a compound of formula I, 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 a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of spondyloarthritis.

[0027] The compounds or salts of the present invention are usually administered in the form of pharmaceutical compositions comprising the compound of formula I, 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).

[0028] Compositions of compounds of formula I, 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.

[0029] 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 allprocesses 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, 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, 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.

[0030] "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.

[0031] 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.

[0032] Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. The stereochemistry of pure enantiomers can be specified at each chiral carbon by either R or S.Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.

[0033] 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

[0034] 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; “aq” refers to aqueous; “BOC2O” refers to di- / c / 7-butyl dicarbonate; “CDF’ refers to carbonyldiimidazole; “DCC” refers to 7V,7V-dicyclohexylcarbodiimide; “DCE” refers to dichloroethane; “DCM” refers to dichloromethane; “DDQ” refers to 2,3-dichloro-5,6-dicyano- 1,4-benzoquinone; “DIPEA” refers to diisopropyl ethylamine; “DMAP” refers to 4- dimethylaminopyridine; “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 tohour(s); “KO / Bu” refers to potassium tert-butoxide; “LAH” refers to lithium aluminium hydride; “LED” refers to light-emitting diode; “LiHMDS” refers to lithium bis(trimethylsilyl)amide;“MeOH” refers to methanol; “min” refers to minutes; “Pd(dppf)C12” refers to [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II); “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; “TEA” refers to triethylamine; “TFA” refers to trifluoroacetic acid; “THF” refers to tetrahydrofuran; “TMEDA” refers to A,A,A'A'-tetramethylethylenediamine; “TMSC1” refers to trimethyl silyl chloride;“TMSCN” refers to trimethyl silyl cyanide; “TMSI” refers to iodotrimethyl silane; “T4P” refers to 2,4,6-tributyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide; “4DPAIPN” refers to 2,4, 5,6- tetrakis(diphenylamino)isophthalonitrile.

[0035] In the schemes below, all substituents unless otherwise indicated, are as previously defined. The reagents and starting materials are either commercially available or may be prepared by methods well known to one of ordinary skill in the art, some of which are presented in the preparations below. Without limiting the scope of the invention, the following schemes, preparations, and examples are provided to further illustrate the invention.Scheme 1

[0036] 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 4,4-difluorotetrahydro-2H- pyran-3-carboxylate 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.Scheme 2

[0037] Scheme 2 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 the presence of an appropriate Pd catalyst, such as Pd(dppf)C12, and a suitable base, such as K3PO4, in an appropriate solvent mixture, 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) is hydrolyzed in the presence of a suitable base, such as LiOH, in an appropriate mixture ofsolvents, 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.Scheme 3

[0038] Scheme 3 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 I2 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, NHi.MeOH and Pd / AhCh, in a suitable mixture of solvents, such as DCM and MeOH. Following the rearomatization of the triazine (xix) into theintermediate (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 (l-(trifluoromethyl)cy cl opropyl)m ethanol

[0039] To the flow reactor 1 was added a solution of 1- (trifluoromethyl)cyclopropanecarboxylic acid (500 g, 3.24 mol) in THF (1000 mL) and BH3 THF complex (IM, 6.49 L). The temperature of flow reactor 1 was set at 80 °C. The flow rate of pump 1 was adjusted to 15 mL / min for solution 1. The mixture was collected with a bottle containing aq. NH4CI solution. The reaction mixture was collected after running for 180 min. The reaction mixture was diluted with H2O and extracted with EtOAc, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (250 g, 1.78 mol, 55%) as a yellow oil. 'HNMR (400 MHz, CDCI3) d 3.72 (s, 2H), 1.10 - 0.95 (m, 2H), 0.83 - 0.70 (m, 2 H).Preparation 2 l-(trifluoromethyl)cyclopropane-l-carbaldehyde

[0040] To a solution of methyl sulfinylmethane (87.0 g, 1.11 mol, 87 mL) in DCM (900 mL) was added oxalyl dichloride (70.6 g, 556 mmol, 48.7 mL). The mixture was stirred at -70 °C for 0.5 h. Then l-(trifluoromethyl)cyclopropyl)methanol (60.0 g, 428 mmol) in DCM (100 mL) was added and the mixture was stirred at -70 °C for 0.5 h. To the mixture was then added TEA (212 g, 2.10 mol, 292 mL). The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was diluted with H2O and washed with sat. aq. NaCl solution, the combined organic layers were dried over anhydrous Na2SO4 to afford the title product (59.0 g, crude) as a yellow oil.1H NMR (400 MHz, CDCI3) d 9.68 (s, 1H), 1.28 - 1.15 (m, 2H), 0.83 - 0.80 (m, 2H).Preparation 3 ethyl 3-(l-(trifluoromethyl)cyclopropyl)acrylate

[0041] A mixture of l-(trifluoromethyl)cyclopropane-l-carbaldehyde (59.0 g, 427 mmol), ethyl 2-(dimethoxyphosphoryl)acetate (92.1 g, 469 mmol), DBN (58.3 g, 469 mmol, 56.2 mL) and LiCl (19.9 g, 469 mmol, 9.63 mL) in DCM (600 mL) was stirred at 20 °C for 4 h. The reaction mixture was diluted with H2O and extracted with EtOAc, dried over anhydrous ISfeSCU, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCh, PE / EtOAc) to afford the title product (43.0 g, 206 mmol, 48%) as a yellow oil.XH NMR (400 MHz, CDCI3) d 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)Preparation 4 ethyl 3-(l-(trifluoromethyl)cyclopropyl)propanoate

[0042] To a solution of Pd / C (5.11 g, 4.80 mmol, 10.0 % purity) in THF (200 mL) was added ethyl 3-(l-(trifluoromethyl)cyclopropyl)acrylate (20.0 g, 96.0 mmol). The mixture was stirred at 20 °C under H2 atmosphere for 3 h. The reaction mixture was filtered and the cake was washed with MeOH. The filtrate was concentrated under reduced pressure to afford the title product (12.0 g, 57.0 mmol, 59%) as a white oil. 'HNMR (400 MHz, CDCI3) d 4.14 (q, J= 7.2 Hz, 2 H), 2.49 (t, J= 7.6 Hz, 2H), 1.90 (t, J= 8.0 Hz, 2H), 1.27 (t, J= 7.2 Hz, 3H), 1.00 - 0.96 (m, 2H), 0.65 - 0.62 (m, 2H).Preparation 53 -( 1 -(trifluoromethyl)cy clopropyl)propan- 1 -ol

[0043] Ethyl 3-(l-(trifluoromethyl)cyclopropyl)propanoate (20.0 g) was dissolved in THF (240 mL) (solution 1). LAH (2.50 M, 7.22 g) (solution 2). The solution 1 was pumped by pump 1 {SI, Pl, 22.5 mL / min} to flow reactor 1 {FLR1, PF A, Coils reactor, 3.175 (1 / 8”) mm, 60 mL, 25 °C}. The solution 2 was pumped by pump 2 {S2, P2, 7.492 mL / min} to flow reactor 1 {FLR1, PF A, Coils reactor, 3.175 (1 / 8”) mm, 60 mL, 25 °C}. The residence time of flow reactor 1 was 2 min. The mixture was collected with a bottle contained Na2SO4 . 10 H2O . The Pump 2 was started, after 2 min Pump 1 was started, the reaction time was 30 min. The reaction mixture was filtered and the cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to afford the title product (15.0 g, 89.2 mmol, 94%) as a white oil. 'H NMR (400 MHz, CDCI3) d 3.65 (t, J= 6.0 Hz, 2H), 1.75 - 1.63 (m, 4H), 0.98 - 0.92 (m, 2H), 0.65 - 0.58 (m, 2H).Preparation 63-(l-(trifluoromethyl)cyclopropyl)propanal

[0044] To a solution of methyl sulfinylmethane (19.3 g, 247 mmol, 19.3 mL) in DCM (160 mL) was added oxalyl dichloride (15.7 g, 123 mmol, 10.8 mL) at -70 °C and the mixture was stirred at -70 °C for 0.5 h. Then a solution of 3-(l-(trifluoromethyl)cyclopropyl)propan-l-ol (16.0 g, 95.1 mmol) in DCM (40 mL) was added at -70 °C and the mixture was stirred for 0.5 h. Finally TEA was added (47.1 g, 466 mmol, 64.8 mL) at -70 °C and the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was diluted with H2O. The organic layers were washed with H2O, dried over anhydrous Na2SO4 to afford the title product (15.8 g, 95.1 mmol, 100%) as a yellow oil. 'H NMR (400 MHz, CDCI3) d 9.80 (s, 1H), 2.68 (t, J= 7.6 Hz, 2H), 1.92 - 1.88 (m, 2H), 1.00 - 0.97 (m, 2H), 0.63 - 0.52 (m, 2H).Preparation 7 (S,E)-2-methyl-N-(3-(l-(trifluoromethyl)cyclopropyl)propylidene)propane-2-sulfinamide

[0045] To a solution of 3-(l-(trifluoromethyl)cyclopropyl)propanal (15.0 g, 90.2 mmol) in DCE (150 mL) and DCM (150 mL) were added CuSCh (43.2 g, 270 mmol, 41.5 mL) and (S)- 2-methylpropane-2-sulfinamide (21.8 g, 180 mmol). The mixture was stirred at 60 °C for 8 h. The reaction mixture was filtered and washed with EtOAc. The filtrate was diluted with H2O and extracted with EtOAc, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PEZEtOAc) to afford the title product (13.0 g, 48.2 mmol, 53%) as a yellow oil.JH NMR (400 MHz, CDCI3) d 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 8(S)-N-((S)- 1 -cyano-3 -( 1 -(trifluoromethyl)cyclopropyl)propyl)-2-methylpropane-2-sulfmamide

[0046] A mixture of (S,E)-2-methyl-N-(3-(l- (trifluoromethyl)cyclopropyl)propylidene)propane-2-sulfmamide (13.0 g, 48.2 mmol), TMSCN (19.1 g, 193 mmol, 24.1 mL, 4.01 eq), H2O (1.74 g, 96.5 mmol, 1.74 mL, 2.00 eq) and CsF (1.47 g, 9.65 mmol) in DCM (130 mL) was degassed and purged with N2 for 3 times at 0 °C, and then the mixture was stirred at 25 °C under N2 atmosphere for 12 h. The reaction mixture was diluted with H2O and extracted with EtOAc, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PEZEtOAc) to afford the title product (10.0 g, 31.1 mmol, 65%) as a yellow oil.1H NMR (400 MHz, CDCI3) d 4.22 - 4.21 (m, 1H), 4.18 (d, J= 7.2 Hz, 1H), 2.14 - 2.06 (m, 2H), 1.83 - 1.70 (m, 2H), 1.26 - 1.25 (m, 9H), 1.03 (s, 2H), 0.67 - 0.60 (m, 2H).Preparation 9 (S)-2-amino-4-(l-(trifluoromethyl)cyclopropyl)butanoic acid

[0047] A solution of (S)-N-((S)-l-cyano-3-(l-(trifluoromethyl)cyclopropyl)propyl)-2- methylpropane-2-sulfmamide (10.0 g, 31.1 mmol) in HC1 (100 mL) and AcOH (10 mL) was stirred at 80 °C for 3.5 h. The reaction mixture was concentrated under reduced pressure to afford the title product (7.00 g, crude, HC1) as a yellow oil. ES / MS (m / z): 212 (M+H).Preparation 10(S)-2-(((benzyloxy)carbonyl)amino)-4-(l-(trifluoromethyl)cyclopropyl)butanoic acid

[0048] A mixture of (S)-2-amino-4-(l-(trifluoromethyl)cyclopropyl)butanoic acid (6.40 g, 30.3 mmol), benzyl (2,5-dioxopyrrolidin-l-yl) carbonate (11.3 g, 45.4 mmol), K2CO3 (12.5 g, 90.9 mmol) and H2O (20 mL) in THF (100 mL) was stirred at 20 °C under N2 atmosphere for 1 h. The reaction mixture was quenched by IM aq. HC1 (50 mL) at 0 °C, and then diluted with H2O and extracted with EtOAc. The combined organic layer was dried over anhydrous ISfeSCU, filtered and concentrated under reduced pressure to give a residue, which was purified by prep- HPLC (column: Phenomenex luna C18 (250^70 mm, 10 um); mobile phase: [H2O (FA) - ACN]; gradient: 34% - 64% B over 20 min) to afford the title product (8.00 g, 22.5 mmol, 78% yield) as a yellow solid. ES / MS (m / z): 346 (M+H).Preparation 11 benzyl (S)-(l-(dimethyl(oxo)-16-sulfaneylidene)-2-oxo-5-(l-(trifluoromethyl)cyclopropyl)pentan-3-yl)carbamate

[0049] Trimethylsulfoxoniumiodide (2.78 g, 12.6 mmol) in THF (30 mL) was added to a solution of KO / Bu (IM, 12.6 mL) and the resulting mixture was stirred at 25 °C for 1 h to obtain a first mixture. To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-4-(l- (trifluoromethyl)cyclopropyl)butanoic acid (3.00 g, 8.44 mmol) in THF (30 mL) was added CDI (1.78 g, 10.9 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for 1 h. The suspension was then filtered and the filtrate was cooled to 25 °C to obtain a second mixture. The second mixture was added to the first at 25 °C. The resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCh, PEZEtOAc) and then was purified by prep-HPLC (column: Phenomenex luna C 18 (250^70 mm, 10 um); mobile phase: [H2O (FA) - ACN]; gradient: 40% - 70% B over 30 min). Then residue was purified by prep-SFC (column: DAICEL CHIRALPAK AD (250 mmx30 mm, 10 um); mobile phase: [CO2- EtOH (0.1% NH3H2O)]; B%:45%, isocratic elution mode) to afford the title product (2.80 g, 6.43 mmol, 61%) as a yellow solid. ES / MS (m / z): 420 (M+H).Preparation 12 benzyl (S)-(l-bromo-2-oxo-5-(l-(trifluoromethyl)cyclopropyl)pentan-3-yl)carbamate

[0050] To a solution of benzyl (S)-(l-(dimethyl(oxo)-16-sulfaneylidene)-2-oxo-5-(l- (trifluoromethyl)cyclopropyl)pentan-3-yl)carbamate (1.80 g, 4.13 mmol) in THF (20 mL) was added HBr (1.01 g, 4.13 mmol, 680 pL, 33.0% purity). The mixture was stirred at 55 °C for 2 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PEZEtOAc) to afford the title product as a yellow solid (1.74 g, 4.12 mmol, 97% yield). ESZMS (m / z): 422 (M+H).Preparation 132-((l , 1 , 1 -trifluoro-2-methylpropan-2-yl)oxy)acetic acid

[0051] To a solution of l,l,l-trifluoro-2-methylpropan-2-ol (38.4 g, 299 mmol, 32.8 mL) in THF (600 mL) was added NaH (23.9 g, 599 mmol, 60.0% purity) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. A solution of 2-bromoacetic acid (50.0 g, 359 mmol, 25.8 mL) was added. The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was quenched by addition NH4CI at 0 °C, and then diluted with H2O and extracted with EtOAc. The combined organic layers were dried over by anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCL, PEZEtOAc) to afford the title product (34.0 g, 182 mmol, 61% yield) as a yellow oil.JH NMR (400 MHz, CDCI3) 8 10.4 (s, 1H), 4.23 (s, 2H), 1.41 (s, 6H).Preparation 14N-methoxy-N-methyl-2-((l , 1 , 1 -trifluoro-2-methylpropan-2-yl)oxy)acetamide

[0052] To a solution of 2-((l,l,l-trifluoro-2-methylpropan-2-yl)oxy)acetic acid (32.0 g, 171 mmol), HATU (130 g, 343 mmol) and DIPEA (88.8 g, 687 mmol, 119 mL) in DCM (600 mL) was added N,O-dimethylhydroxylamine (20.1 g, 206 mmol, HC1 salt) at RT. The reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over by anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PEZEtOAc) to afford the title product (27.0 g, 117 mmol, 69%) as a colorless oil. ESZMS (m / z): 230 (M+H).Preparation 152-((l , 1 , 1 -trifluoro-2-methylpropan-2-yl)oxy)acetaldehyde

[0053] 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 (IM, 236 mL) at - 75 °C. The reaction mixture was stirred at -75 °C for 2 h. The reaction mixture was quenched by addition of FLO at 0 °C, and then diluted with H2O and extracted with EtOAc. The combined organic layers were dried over by anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title product (22.0 g, crude) as a yellow oil.JH NMR (400 MHz, CDCI3) 8 9.67 (s, 1H), 4.10 (s, 2H), 1.36 (s, 6H).Preparation 16 (S,E)-2-methyl-N-(2-((l,l,l-trifluoro-2-methylpropan-2-yl)oxy)ethylidene)propane-2- sulfinamide

[0054] To a solution of 2-((l,l,l-trifluoro-2-methylpropan-2-yl)oxy)acetaldehyde (22.0 g, 129 mmol) and (S)-2-methylpropane-2-sulfinamide (18.8 g, 155 mmol) in DCM (300 mL) was added CuSCU (41.2 g, 258 mmol, 39.6 mL) at RT. The reaction mixture was stirred at RT for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCh, PE / EtOAc) to afford the title product (6.00 g, 18.6 mmol, 14%) as a colorless oil. ES / MS (m / z): 274 (M+H).Preparation 17(R)-N-((S)- 1 -cyano-2-((l , 1 , 1 -trifluoro-2-methylpropan-2-yl)oxy)ethyl)-2-methylpropane-2- sulfinamide

[0055] To a solution of (S,E)-2-methyl-N-(2-((l,l,l-trifluoro-2-methylpropan-2- yl)oxy)ethylidene)propane-2-sulfinamide (5.00 g, 18.2 mmol) in DCM (50.0 mL) were added CsF (555 mg, 3.66 mmol, 135 pL), H2O (659 mg, 36.5 mmol, 659 pL) and TMSCN (3.63 g, 36.5 mmol, 4.58 mL). The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with H2O and extracted with PE. The combined organic layers were dried over by anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PEZEtOAc) to afford the title product (3.00 g, 9.77 mmol, 53%) as a yellow oil. ES / MS (m / z): 301 (M+H).Preparation 18O-( 1,1,1 -trifluoro-2-methylpropan-2-yl)-L-serine

[0056] To a solution of (R)-N-((S)-l-cyano-2-((l,l,l-trifluoro-2-methylpropan-2- yl)oxy)ethyl)-2-methylpropane-2-sulfinamide (3.00 g, 9.99 mmol) in AcOH (15.7 g, 262 mmol, 15.0 mL) was added HC1 (12 M, 15.0 mL). The reaction mixture was stirred at 110 °C for 12 h. The reaction mixture was concentrated under reduced pressure to afford the title product (2.50 g, 9.94 mmol, 99%, HC1 salt) as a brown solid. ES / MS (m / z): 216 (M+H).Preparation 19N-((benzyloxy)carbonyl)-O-(l,l,l-trifluoro-2-methylpropan-2-yl)-L-serine

[0057] To a solution of O-(l,l,l-trifluoro-2-methylpropan-2-yl)-L-serine (2.50 g, 9.94 mmol, HC1 salt), CbzOSu (2.48 g, 9.94 mmol) and K2CO3 (4.12 g, 29.8 mmol) in THF (15.0 mL) was added H2O (15.0 mL). The reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCL, PEZEtOAc) to afford the title product (2.50 g, 7.16 mmol, 72%) as a yellow oil. ES / MS (m / z): 350 (M+H).Preparation 20 benzyl (S)-(4-(dimethyl(oxo)-16-sulfaneylidene)-3 -oxo- 1 -((1 , 1 , 1 -trifluoro-2-methylpropan-2- yl)oxy)butan-2-yl)carbamate

[0058] To trimethyl sulfoxonium iodide (4.44 g, 20.1 mmol) was added to a solution of KO / Bu (2.26 g, 20.1 mmol) in THF (30.0 mL) and the reaction mixture was stirred at 65 °C for 2 h under N2 atmosphere. After that time, the solution was cooled to 0 °C to obtain the first mixture. To a solution of N-((benzyloxy)carbonyl)-O-(l,l,l-trifluoro-2-methylpropan-2-yl)-L- serine (2.35 g, 6.73 mmol) in THF (30.0 mL) was added TEA (1.36 g, 13.4 mmol, 1.87 mL) and HATU (5.12 g, 13.4 mmol) at RT. The reaction mixture was stirred at RT for 2 h. The suspension was then filtered, and the filtrate was cooled to 0 °C to obtain the second mixture. The second mixture was added to the first mixture at 0 °C. The resulting mixture was stirred at RT for 1 h. The reaction mixture was quenched by the addition of H2O at RT, and extracted withEtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by prep-TLC (SiCL, DCM / MeOH) to afford the title product (850 mg, 1.85 mmol, 27%) as a white solid. ES / MS (m / z): 424 (M+H).Preparation 21 benzyl (S)-(4-bromo-3 -oxo- 1 -((1 , 1 , 1 -trifluoro-2-methylpropan-2-yl)oxy)butan-2-yl)carbamate

[0059] To a solution benzyl (S)-(4-(dimethyl(oxo)-16-sulfaneylidene)-3-oxo-l-((l,l,l- trifluoro-2-methylpropan-2-yl)oxy)butan-2-yl)carbamate (600 mg, 1.42 mmol) in THF (5.00 mL) were added LiBr (246 mg, 2.83 mmol, 71.1 pL) and MsOH (408 mg, 4.25 mmol, 303 pL) at 0 °C. The reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title product (600 mg, crude) as a black oil. ES / MS (m / z): 426 (M+H).Preparation 22 tert-butyl (S)-2-((diphenylmethylene)amino)-2-((S)-3-oxocyclohexyl)acetate

[0060] To a solution of tert-butyl 2-((diphenylmethylene)amino)acetate (250 g, 846 mmol) in DCM (17.0 L) was added 4-[(R)-allyloxy-[(2S,4S,5R)-l-(9-anthrylmethyl)-5-vinyl- quinuclidin-l-ium-2-yl]methyl]quinoline; bromide (51.2 g, 84.6 mmol), followed by CSOH.H2O (1.42 kg, 8.46 mol) under N2 atmosphere. The mixture was cooled to -70 °C. A solution of cyclohex-2-en-l-one (244 g, 2.54 mol, 246 mL) in DCM (450 mL) was added dropwise over 30 min at -70 °C under N2 atmosphere. The mixture was stirred at -70 °C under N2 atmosphere for 6h. 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 product (352 g, 53%) as a white solid. ES / MS (m / z): 392 (M+H).Preparation 23 tert-butyl (S)-2-((diphenylmethylene)amino)-2-((S)-3-methylenecyclohexyl)acetate

[0061] To a solution of methyltriphenylphosphonium iodide (186 g, 459 mmol) in THF (1000 mL) was added KO / Bu (IM, 460 mL) at -30 °C and stirred for 0.5 h. Then a solution of tert-butyl (S)-2-((diphenylmethylene)amino)-2-((S)-3-oxocyclohexyl)acetate (100 g, 255 mmol) in THF (2000 mL) was dropwise added at 0 °C, the reaction mixture was stirred at 0 °C for 2 h. The mixture was diluted with H2O and extracted with EtOAc, the combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCL, PE / EtOAc) to afford the title product (160 g, 323 mmol, 29%) as a yellow oil. ES / MS (m / z): 390 (M+H).Preparation 24 tert-butyl (S)-2-amino-2-((S)-3-methylenecyclohexyl)acetate

[0062] To a solution of tert-butyl (S)-2-((diphenylmethylene)amino)-2-((S)-3- methylenecyclohexyl)acetate (100 g, 257 mmol) in THF (1000 mL) was added citric acid (0.5 M, 2.57 L). The mixture was diluted with H2O and extracted with EtOAc, the combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue to afford the title product (50.0 g, 215 mmol, 84%) as a white solid. ES / MS (m / z): 226 (M+H).Preparation 25 tert-butyl (S)-2-amino-2-((l S,3R)-3-methylcyclohexyl)acetate

[0063] tert-butyl (S)-2-amino-2-((S)-3-methylenecyclohexyl)acetate (50.0 g, 222 mmol) was dissolved in MeOH (1000 mL). The fixed bed (50 mL) was completely packed with granular catalyst Pd / C (5%). The H2 back pressure regulator was adjusted to 1 MPa, and the flow rate of H2 was 95 mL / min. Then the reaction mixture was pumped by Pump 1 (SI, Pl, 3.003 mL / min) to the fixed bed {FLR1, SS, Fixed bed, 12.70 (1 / 2”) mm, 10 mL, 50 °C}. The reaction mixture was flowing through the fixed bed to leave the reactor zone, then the reaction mixture was collected from the reactor output. The mixture was filtered and concentrated under reduced pressure to give a residue to afford the title product (50.0 g, 210 mmol, 95%) as white solid. ES / MS (m / z): 228 (M+H).Preparation 26 tert-butyl (S)-2-(((benzyloxy)carbonyl)amino)-2-((lS,3R)-3-methylcyclohexyl)acetate

[0064] To a solution of tert-butyl (S)-2-amino-2-((lS,3R)-3-methylcyclohexyl)acetate (50.0 g, 220 mmol) in THF (500 mL) and H2O (250 mL) were added NaHCO3(27.7 g, 330 mmol, 12.8 mL) and benzyl (2,5-dioxopyrrolidin-l-yl) carbonate (82.2 g, 330 mmol) at 0 °C, the reaction mixture was stirred at 25 °C for 12 h. The mixture was diluted with H2O and extracted with EtOAc, the combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCL, PEZEtOAc) to afford the title product (72.0 g, 199 mmol, 91%) as a yellow solid. ES / MS (m / z): 384 (M+Na).Preparation 27(S)-2-(((benzyloxy)carbonyl)amino)-2-((lS,3R)-3-methylcyclohexyl)acetic acid

[0065] To a solution of Zc / V-butyl (S)-2-(((benzyloxy)carbonyl)amino)-2-((lS,3R)-3- methylcyclohexyl)acetate (72.0 g, 199 mmol) in DCM (720 mL) was added TFA dropwise (332 g, 2.91 mol, 216 mL) at 0 °C. The mixture was stirred at 20 °C for 12 h. The mixture was diluted with H2O and extracted with EtOAc, the combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue to afford the title product (60.0 g, 179 mmol, 90%) as a white solid. ES / MS (m / z): 328 (M+Na).Preparation 28 benzyl ((S)-3-(dimethyl(oxo)-16-sulfaneylidene)-l-((lS,3R)-3-methylcyclohexyl)-2- oxopropyl)carbamate

[0066] To a solution of trimethyl sulfoxonium iodide (29.7 g, 135 mmol) in THF (275 mL) was added to a solution of KO / Bu (IM, 144 mL, 1) at 0 °C and the resulting mixture was stirred at 20 °C for 3 h to obtain a first mixture. To a flask with (S)-2- (((benzyloxy)carbonyl)amino)-2-((lS,3R)-3-methylcyclohexyl)acetic acid (27.5 g, 90.1 mmol) in THF (275 mL) was added CDI (18.9 g, 117 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 3 h. The suspension was then filtered and the filtrate was cooled to 0 °C to obtain a second mixture. The mixture was diluted with H2O and extracted with EtOAc, the combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, which was purified by columnchromatography (SiCh, DCM / MeOH) to afford the title product (13.0 g, 35.2 mmol, 39%) as a white solid. ES / MS (m / z): 380 (M+H).Preparation 29 benzyl ((S)-3-bromo-l-((lS,3R)-3-methylcyclohexyl)-2-oxopropyl)carbamate

[0067] 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) were added HBr in AcOH (29.6 g, 120 mmol, 19.8 mL, 33% purity) at 0 °C under N2 atmosphere. The mixture was stirred at 45 °C for 3 h under N2 atmosphere. The mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Phenomenex luna cl8 250 mm x 100 mm x 10 um; mobile phase: [H2O (FA) - ACN]; gradient: 65% - 85% B over 20 min) and prep-SFC (column: DAICEL CHIRALCEL OJ (250 mm x 50 mm, 10 um); mobile phase: [CCh / zPrOH (0.1%NH3H2O)]; B%: 15%, isocratic elution mode) to afford the title product (13.0 g, 34.0 mmol, 52%) as off-white solid. ES / MS (m / z): 382 (M+H).Preparation 30 l,3-dioxoisoindolin-2-yl 4, 4-difluorotetrahydro-2H-pyran-3 -carboxylate

[0068] To a solution of 4,4-difluorotetrahydro-2H-pyran-3-carboxylic acid (1.00 g, 6.02 mmol) in THF (10.0 mL) were added DMAP (110 mg, 902 pmol) and DCC (1.37 g, 6.62 mmol, 1.34 mL) and 2-hydroxyisoindoline-l, 3-dione (1.96 g, 12.04 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered with THF (10.0 mL) and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, PEZEtOAc) to afford the title product (1.00 g, 3.21 mmol, 53%) as a yellow solid. 'HNMR (400 MHz, CDCI3) 8 7.96 - 7.86 (m, 2H), 7.86 - 7.77 (m, 2H), 4.23 - 4.08 (m, 2H), 3.98 - 3.81 (m, 2H), 3.51 - 3.31 (m, 1H), 2.52 - 2.36 (m, 1H), 2.20 - 2.06 (m, 1H)Preparation 31 6-vinyl- 1 , 2, 4-tri azin-3 -amine

[0069] 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) were added Pd(dppf)C12 (41.8 g, 57.1 mmol) and K3PO4 (509 g, 2.40 mol). The mixture was stirred at 80 °C for 3 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCh, PE / EtOAc) to afford the title product (139 g, crude) as a white solid.JH NMR (400 MHz, CDCI3) 8 8.34 (s, 1H), 6.99 - 6.77 (m, 1H), 6.08 (d, J = 16.0 Hz, 1H), 5.71 - 5.41 (m, 3H)

[0070] The compound in the following table was prepared essentially as described in Preparation 31 using the appropriate triazine amine.Preparation 33 tert-butyl (terZ-butoxycarbonyl)(6-methyl-l,2,4-triazin-3-yl)carbamate

[0071] To a solution of 6-methyl-l,2,4-triazin-3-amine (60.0 g, 544 mmol) in DCM (400 mL) were added BOC2O (297 g, 1.36 mol, 312 mL) and DMAP (53.2 g, 435 mmol). The mixture was stirred at 25 °C for 12 h. The mixture was concentrated to afford the title product (40.0 g, 128 mmol, 24%) as a yellow solid. ES / MS (m / z): 311 (M+H).Preparation 34 tert-butyl (6-vinyl-l,2,4-triazin-3-yl)carbamate

[0072] To a solution of 6-vinyl-l,2,4-triazin-3-amine (100 g, 818 mmol) in THF (300 mL) was added LiHMDS (1.00 M, 1.15 L) at -65 °C for 1 h. Then Boc2O (232 g, 1.06 mol, 244 mL) in THF (200 mL) was added at -65 °C for 1 h. The mixture was stirred at -65 °C for 1 h under N2atmosphere. The reaction mixture was diluted with sat. aq. NH4CI and extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PEZEtOAc) to afford the title product (100 g, crude) as a white solid. ES / MS (m / z): 123 (M-99).Preparation 35 tert-butyl (6-formyl-l,2,4-triazin-3-yl)carbamate

[0073] To a solution of tert-butyl (6-vinyl-l,2,4-triazin-3-yl)carbamate (100 g, 449 mmol) in THF (1750 mL) and H2O (1150 mL) was added OsCL (3.50 g, 13.7 mmol, 714 pL) at 0 °C and the mixture was stirred for 10 min. Then NaKL was added (240 g, 1.12 mol, 62.3 mL) at 0 °C in four portions, the reaction mixture was stirred at 0 °C for another 4 h under N2atmosphere. The reaction mixture was filtered, and then filtrate was quenched by FeCl2solution, then stirred for another 0.5 h. The mixture was extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PEZEtOAc) to afford the title product (80.0 g, 338 mmol, 75%) as a yellow oil. ES / MS (m / z): 223 (M-H).Preparation 36 tert-butyl (tert-butoxycarbonyl)(6-(chloromethyl)-l,2,4-triazin-3-yl)carbamate

[0074] To a solution of tert-butyl A-tert-butoxycarbonyl-N-(6-methyl-l,2,4-triazin-3- yl)carbamate (40.0 g, 128 mmol) in DCE (400 mL) was added l,3,5-trichloro-l,3,5-triazinane- 2, 4, 6-trione (20.9 g, 90.2 mmol). The mixture was stirred at 70 °C for 12 h. The mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiCh, PE / EtOAc) to afford the title product (16.0 g, 46.4 mmol, 36%) as yellow oil. ES / MS (m / z): 245 (M-99)Preparation 372-(tert-butyl) 4-methyl 4-((3-(bis(terZ-butoxycarbonyl)amino)-l,2,4-triazin-6-yl)methyl)-3-oxo-2-azabicyclo[3.1.1 ]heptane-2,4-dicarboxylate

[0075] To a solution of 2-(tert-butyl) 4-methyl 3-oxo-2-azabicyclo[3.1.1]heptane-2,4- dicarboxylate (10.3 g, 38.2 mmol) in THF (150 mL) was added CS2CO3 (22.6 g, 69.6 mmol) at 0 °C under N2 atmosphere. The mixture was stirred at 0°C for 1 h, then was added tert-butyl (tert- butoxycarbonyl)(6-(chloromethyl)-l,2,4-triazin-3-yl)carbamate (12.0 g, 34.8 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was partitioned between H2O and EtOAc. The organic phase was separated, washed with sat. aq. NaCl solution, dried over anhydrous ISfeSCU, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, PE / EtOAc) to afford the title product (18.0 g, 31.1 mmol, 90%) as yellow oil. ES / MS (m / z): 578 (M+H)Preparation 38methyl 4-((3-amino-l,2,4-triazin-6-yl)methyl)-3-oxo-2-azabicyclo[3.1.1]heptane-4-carboxylate;TFA

[0076] To a solution of 2-( / c / 7-butyl) 4-methyl 4-((3-(bis(tert-butoxycarbonyl)amino)- l,2,4-triazin-6-yl)methyl)-3-oxo-2-azabicyclo[3.1.1]heptane-2,4-dicarboxylate (18.0 g, 31.1 mmol) in DCM (180 mL) was added TFA (35.5 g, 311 mmol, 23.1 mL). The mixture was stirred at 25 °C for 12 h. The residue was concentrated to afford the title product (12.0 g, 30.6 mmol, 98%, TFA) as yellow oil. ES / MS (m / z): 278 (M+H)Preparation 394-((3-amino-l,2,4-triazin-6-yl)methyl)-3-oxo-2-azabicyclo[3.1.1]heptane-4-carboxylic acid

[0077] To a solution of methyl 4-((3-amino-l,2,4-triazin-6-yl)methyl)-3-oxo-2- azabicyclo[3.1.1]heptane-4-carboxylate; TFA (12.0 g, 30.6 mmol) in THF (120 mL) and FEO (20.0 mL) was added LiOH.FEO (3.86 g, 92.0 mmol). The mixture was stirred at 25 °C for 12 h. The residue was adjusted with IM aq. HC1 to pH = 6, the mixture was concentrated to the title product (8.00 g, 30.3 mmol, 99%) as yellow oil. ES / MS (m / z): 264 (M+H)Preparation 404-((3-amino-l,2,4-triazin-6-yl)methyl)-2-azabicyclo[3.1.1]heptan-3-one

[0078] To a solution of 4-((3-amino-l,2,4-triazin-6-yl)methyl)-3-oxo-2- azabicyclo[3.1.1]heptane-4-carboxylic acid (4.00 g, 10.6 mmol) in DMF (50.0 mL) was added NaCl (1.24 g, 21.2 mmol). The mixture was stirred at 100 °C for 12 h. The mixture was filteredand concentrated to give a residue. The residue was purified by reversed-phase HPLC (column: Welch Ultimate XB > C18 20 - 40pm; 120 A; mobile phase: [H2O (NH4HCO3) - ACN]; B%: 30 - 50% 45min; % min) to afford the title product (1.20 g, 5.47 mmol, 52%) as a yellow solid.ES / MS (m / z): 220 (M+H).Preparation 414-((3 -amino- 1 ,2,4-triazin-6-yl)methyl)-2-azabicyclo[3.1.1 ]heptan-3 -one (isomer 1 ) Preparation 424-((3 -amino- 1 ,2,4-triazin-6-yl)methyl)-2-azabicyclo[3.1.1 ]heptan-3 -one (isomer 2)

[0079] The mixture of stereoisomers of 4-((3-amino-l,2,4-triazin-6-yl)methyl)-2- azabicyclo[3.1.1]heptan-3-one was purified by prep-SFC (column: DAICEL CHIRALPAK IG (250 mm * 30 mm, 10 urn); mobile phase: [CO2- ACN / EtOH (0.1% NH3H2O)]; B%: 70%, isocratic elution mode). The first eluting isomer (1.20 g, 5.47 mmol, 55%) was obtained as yellow solid. ES / MS (m / z): 220 (M+H). The second eluting isomer (1.30 g, 5.93 mmol, 59%) was obtained as yellow solid. ES / MS (m / z): 220 (M+H).Preparation 433 -iodopiperidin-2-one

[0080] TMSC1 (219 g, 2.02 mol, 256 mL) was added dropwise to a solution cooled to 0 °C of piperidin-2-one (100 g, 1.01 mol) and TMEDA (351 g, 3.03 mol, 456 mL) in toluene (1000 mL) under N2 atmosphere, the mixture was stirred at 0 °C for 0.5 h, then molecular iodine (307 g, 1.21 mol, 243 mL) was introduced in three portions. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched by addition sat. aq. NaHCCL at 0 °C. The reaction mixture was diluted with H2O and extracted with DCM. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCL, PEZEtOAc) to afford the title product (177 g, crude) as a white solid. H NMR (400 MHz,CDCI3) 8 7.32 (s, 1H), 4.76 (t, J = 4.0 Hz, 1H), 3.30 - 3.20 (m, 2H), 2.17 - 1.99 (m, 2H), 1.94 - 1.80 (m, 1H), 1.75 - 1.73 (s, 1H).

[0081] The compounds in the following table were prepared essentially as described in Preparation 43 using the appropriate piperidone.Preparation 46 diethyl (2-oxopiperi din-3 -yl)phosphonate

[0082] A solution of 3-iodopiperidin-2-one (177 g, 786 mmol) and triethyl phosphite (653 g, 3.93 mol, 674 mL) in toluene (600 mL) was stirred at 100 °C for 12 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography ( Si O2, PEZEtOAc then DCM / MeOH) to afford the title product (150 g, crude) as a white solid. 'H NMR (400 MHz, CDCI3) 5 6.47 (s, 1H), 4.34 - 4.00 (m, 4H), 3.44 - 3.26 (m, 2H), 3.11 - 2.88 (m, 1H), 2.30 - 1.96 (m, 3H), 1.88 - 1.66 (m, 1H), 1.41 - 1.28 (m, 6H).

[0083] The compounds in the following table were prepared essentially as described in Preparation 46 using the appropriate iodopiperidone.Preparation 49 tert-butyl (E)-(6-((2-oxopiperi din-3 -ylidene)m ethyl)- 1, 2, 4-triazin-3-yl)carbamate

[0084] To a solution of diethyl (2-oxopiperidin-3-yl)phosphonate (55.9 g, 237 mmol) in THF (500 mL) was added KO / Bu (IM, 246 mL) at 0 °C for 1 h. tert-Butyl (6-formyl- 1,2,4- triazin-3-yl)carbamate (41.0 g, 182 mmol) in THF (250 mL) was added. The mixture was stirred at 25°C for 1 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCL, DCM / MeOH) to afford the title product (45.0 g, 147 mmol, 81%) as a white solid. ES / MS (m / z): 250 (M-55).

[0085] The compounds in the following table were prepared essentially as described in Preparation 49 using the appropriate piperidone phosphonate.Preparation 52 tert-butyl (6-((2-oxopiperi din-3 -yl)m ethyl)- 1,6-dihydro-l, 2, 4-triazin-3-yl)carbamate

[0086] A mixture of tert-butyl (E)-(6-((2-oxopiperi din-3 -ylidene)m ethyl)- 1,2, 4-triazin-3- yl)carbamate (45.0 g, 147 mmol) and NHLMeOH (7M, 63.1 mL) in MeOH (2000 mL) was stirred at 20 °C until becoming a clear solution. The H2 back pressure regulator was adjusted to 0 MPa, the flow rate of H2 to 95 mL / min, the fixed bed of Pd / AhCh (30.0 g, 147 mmol, 5% purity) was heated to 20 °C. Then the solution was pumped into the reactor at a flow rate of 3 mL / min, for 25 h in total. After the reaction was finished, the tubing was washed with MeOH (400 mL), all the reaction solution was collected for analysis. The reaction mixture was concentrated under reduced pressure to give a residue, which was triturated with DCM at 25 °C for 10 min to afford the title product (40.0 g, crude) as a white solid. ES / MS (m / z): 310 (M+H)

[0087] The compound in the following table was prepared essentially as described in Preparation 52 using the appropriate piperidone triazine.Preparation 55 tert-butyl (6-((2-oxopiperidin-3-yl)methyl)-l,2,4-triazin-3-yl)carbamate

[0088] To a solution of tert-butyl (6-((2-oxopiperi din-3 -yl)m ethyl)- 1,6-dihydro- 1,2,4- triazin-3-yl)carbamate (49.0 g, 158 mmol) in THF (500 mL) was added DDQ (35.9 g, 158 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by addition sat. aq. NaHCCh at 0 °C, and then extracted with DCM / MeOH (10: 1). The combined organic layers were washed with aq. NaHCCh, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, which was triturated with PEZEtOAc (1 : 1) at 25 °C for 20 min to afford the title product (40.0 g, crude) as a white solid. ES / MS (m / z): 308 (M+H).

[0089] The compounds in the following table were prepared essentially as described in Preparation 55 using the appropriate piperidone triazine.Preparation 58 3-((3-amino-l,2,4-triazin-6-yl)methyl)piperidin-2-one (isomer 2)

[0090] To a solution of tert-butyl (6-((2-oxopiperi din-3 -yl)m ethyl)- 1, 2, 4-triazin-3- yl)carbamate (40.0 g, 130 mmol) in DCM (300 mL) was added TFA (230 g, 2.02 mol, 150 mL) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue, then the residue was adjusted to pH = 8 by addition of NHs / MeOH (7M) and concentrated under reduced pressure to give a residue. The title compound was isolated as the second eluting, single stereoisomer by chiral SFC purification (column: DAICEL CHIRALPAK AY (250 mm * 50 mm, 10 urn); mobile phase: [CCh-ACNZ / PrOH (0.1% NH3H2O)]; B%:50%, isocratic elution mode) and reversed-phase HPLC (column: Welch Ultimate XB-NH2 250 * 50 * 10 um; mobile phase: [Hexane-EtOH 0.1% NH3.H2O ]; gradient: 25%-65% B over 15 min. The title product (8.00 g, 34.7 mmol, 27%, 89.9% purity) was obtained as a white solid. ES / MS (m / z): 208 (M+H).

[0091] The compounds in the following table were prepared essentially as described in Preparation 58 using the appropriate piperidone triazine.Preparation 61 benzyl ((lS)-((S)-3,3-difluorocyclohexyl)(2-((2-oxopiperidin-3-yl)methyl)imidazo[l,2- b] [ 1 ,2,4]triazin-6-yl)methyl)carbamate

[0092] To a solution of (R)-3-((3-amino-l,2,4-triazin-6-yl)methyl)piperidin-2-one (450 mg, 2.17 mmol), benzyl ((S)-3-bromo-l-((S)-3,3-difluorocyclohexyl)-2-oxopropyl)carbamate (1.14 g, 2.82 mmol) in THF (5 mL) were added trimethyl borate (1.13 g, 10.8 mmol, 1.23 mL) and DIPEA (1.40 g, 10.8 mmol, 1.89 mL). The mixture was stirred at 75 °C for 4 h. The residue was diluted with H2O and extracted with EtOAc, the combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, which was purified by column (SiCh, EtOAc / MeOH) to afford the title product (778 mg, 1.52 mmol, 70%) as a yellow solid. ES / MS (m / z): 513 (M+H).

[0093] The compounds in the following table were prepared essentially as described in Preparation 61 using the appropriate triazine and bromoketone.Preparation 71 benzyl ((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)carbamate

[0094] To a solution of benzyl ((lS)-((lr,4S)-4-methylcyclohexyl)(2-((2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)carbamate (700 mg, 1.43 mmol), and 1,3- dioxoisoindolin-2-yl 4,4-difluorotetrahydro-2H-pyran-3-carboxylate (888 mg, 2.85 mmol) in DMSO (2 mL) were added 4DPAIPN (56.8 mg, 71.3 pmol) and TFA (488 mg, 4.28 mmol, 317 pL). The reaction mixture was pumped by Pump 1 {SI, Pl, 10.045 mL / min} to flow reactor 1 {FLR1, FEP, Coils reactor, 3.175 (1 / 8”) mm, 40.179 mL, 50 °C}, and the reaction was irradiated with a 394 nm or 420 nm or 455nm LED. The residence time of flow reactor 1 was 4 min. The mixture was collected with a bottle. The Pump 1 was started. Total reaction time: 12 h. The mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, and the residue was purified prep-HPLC (FA condition; column: Phenomenex luna C18 150 * 25 mm * 10 um; mobile phase: [H2O (FA) - ACN]; gradient: 55% - 85% B over 10 min) to afford the title product (200 mg, 327 pmol, 23%) as yellow solid. ES / MS (m / z): 611 (M+H).

[0095] The compounds in the following table were prepared essentially as described in Preparation 71 using the appropriate triazine.Preparation 743-((6-((S)-amino((S)-3,3-difluorocyclohexyl)methyl)imidazo[l,2-b][l,2,4]triazin-2- yl)methyl)piperidin-2-one

[0096] A solution of benzyl ((1 S)-((S)-3, 3 -difluorocycloh exyl)(2-((2-oxopiperi din-3 - yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)carbamate (700 mg, 1.37 mmol) in HC1 (6.3 mL) and AcOH (0.7 mL) was stirred at 50 °C for 1 h. The residue was diluted with H2O and extracted with EtOAc, then the aq phase was adjusted to pH = 8 with a sat. aq. NaHCO3 solution and extracted with DCM, the combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title product (373 mg, 985 pmol, 72%) as a yellow solid. ES / MS (m / z): 379 (M+H)

[0097] The compounds in the following table were prepared essentially as described in Preparation 74 using the appropriate protected amine.Preparation 85N-((lS)-((S)-3,3-difluorocyclohexyl)(2-((2-oxopiperidin-3-yl)methyl)imidazo[l,2- b][l,2,4]triazin-6-yl)methyl)-l-ethyl-lH-l,2,4-triazole-5-carboxamide

[0098] To a solution of 3-((6-((S)-amino((S)-3,3-difluorocyclohexyl)methyl)imidazo[l,2- b][l,2,4]triazin-2-yl)methyl)piperidin-2-one (350 mg, 924 pmol), lithium l-ethyl-lH-1,2,4- triazole-5-carboxylate (408 mg, 2.77 mmol) in DCM (4 mL) was added T4P (2.00 g, 2.77 mmol, 50% solution in EtOAc). The mixture was stirred at 20 °C for 4 h. The residue was diluted with H2O and extracted with DCM, the combined organic layers were washed with sat. aq. NaCl solution dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, DCM / MeOH) to afford the title product (352 mg, 701 pmol, 76%) as a yellow solid. ES / MS (m / z): 502 (M+H).

[0099] The compounds in the following table were prepared essentially as described in Preparation 85 using the appropriate amine and carboxylic acid.Preparation 90l-methyl-N-((lS)-((lS,3R)-3-methylcyclohexyl)(2-((2-oxopiperidin-3-yl)methyl)imidazo[l,2- b][l,2,4]triazin-6-yl)methyl)-lH-pyrazole-5-carboxamide[000100] To a solution of 3-((6-((S)-amino((l S,3R)-3- methylcyclohexyl)methyl)imidazo[l,2-b][l,2,4]triazin-2-yl)methyl)piperidin-2-one (0.69 g, 1.85 mmol), 1 -methyl- lH-pyrazole-5-carboxylic acid (349 mg, 2.77 mmol) in pyridine (2 mL) was added EDCI (1.06 g, 5.54 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was partitioned between H2O and EtOAc. The organic phase was separated, washed with sat. aq. NaCl solution, and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCh, DCM / MeOH) to afford the title product (0.60 g, 1.29 mmol, 70%) as yellow solid. ES / MS (m / z): 465 (M+H). [000101] The compounds in the following table were prepared essentially as described in Preparation 90 using the appropriate amine and carboxylic acid.EXAMPLES Example 1 N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)((l r,4S)-4-methylcyclohexyl)methyl)- 1 -ethyl- 1H- pyrazole-5-carboxamide (isomer 1) Example 2 N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)((l r,4S)-4-methylcyclohexyl)methyl)- 1 -ethyl- 1H- pyrazole-5-carboxamide (isomer 2)[000102] To a solution of 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 (100 mg, 203 mol), l,3-dioxoisoindolin-2-yl 4,4-difluorotetrahydro-2H-pyran-3- carboxylate (126 mg, 406 pmol) in DMSO (2 mL) were added 4DPAIPN (8.09 mg, 10.1 mol) and TFA (46.2 mg, 406 mol, 30.1 pL). The first solution was pumped by Pump 1 {SI, Pl, 10.045 mL / min} to flow reactor 1 {FLR1, FEP, Coils reactor, 3.175 (1 / 8”) mm, 40.179 mL, 50 °C}, and the reaction was irradiated with a 394 nm or 420 nm or 455 nm LED. The residence time of flow reactor 1 was 4 min. The mixture was collected with a bottle. The Pump 1 was started. Total reaction time: 12 h. The mixture was diluted with FEO and extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, and the residue was purified by prep-HPLC (column: Waters Xbridge 150 * 25 mm * 5 um; mobile phase: [H2O (NH4HCO3) - ACN]; gradient: 38% - 58% B over 10 min) to afford a mixture of stereoisomers. Single stereoisomers were isolated by prep-HPLC (column: Waters Xbridge 150 * 25 mm * 5 um; mobile phase: [H2O (NH4HCO3) - ACN]; gradient: 38% - 58% B over 10 min). The first eluting isomer (7.15 mg, 11.6 pmol, 6%) was obtained as a light yellow solid. ES / MS (m / z): 613 (M+H). The second eluting isomer (8.94 mg, 14.5 pmol, 7%) was obtained as a light yellow solid. ES / MS (m / z): 613 (M+H).[000103] The compounds in the following table were prepared essentially as described in Example 1 using the appropriate imidazotriazine.Example 39N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((2-oxopiperidin-3-yl)methyl)imidazo[l,2- b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l-methyl-lH-pyrazole-5-carboxamide (isomer 1)Example 40N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((2-oxopiperidin-3-yl)methyl)imidazo[l,2- b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l-methyl-lH-pyrazole-5-carboxamide (isomer 2)[000104] To a solution of (3R)-3-((6-((S)-amino((lr,4S)-4-methylcyclohexyl)methyl)-3- (4,4-difluorotetrahydro-2H-pyran-3-yl)imidazo[l,2-b][l,2,4]triazin-2-yl)methyl)piperidin-2-one (55.0 mg, 115 pmol), 1 -methyl- lH-pyrazole-5-carboxylic acid (29.1 mg, 230 pmol) in pyridine (2 mL) was added EDCI (66.3 mg, 346 pmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was partitioned between H2O and EtOAc. The organic phase was separated, washed with sat. aq. NaCl solution, dried over anhydrous ISfeSCU, filtered and concentrated under reduced pressure to give a residue, which was purified by prep-TLC (DCM / MeOH) to afford a mixture of stereoisomers. Single stereoisomers were isolated by prep-HPLC (FA condition; column: Phenomenex luna C18 150 * 25 mm * 10 um; mobile phase: [water (FA) - ACN]; gradient: 42% - 72% B over 10 min). The first eluting isomer (9.77 mg, 16.7 pmol, 20%, 100% purity) was obtained as a white solid. ES / MS (m / z): 585 (M+H). The second eluting isomer (10.27 mg, 17.2 pmol, 20%, 97.9% purity) was obtained as a white solid. ES / MS (m / z): 585 (M+H).[000105] The compounds in the following table were prepared essentially as described in Example 39 using the appropriate amine and carboxylic acid.Example 45 N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-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-ethyl-lH- 1 , 2, 4-triazole-5 -carboxamide (isomer 1)Example 46N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-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-ethyl-lH- 1 , 2, 4-triazole-5 -carboxamide (isomer 2)[000106] To a solution of (3R,5S)-3-((6-((S)-amino((lS,3R)-3-methylcyclohexyl)methyl)- 3-(4,4-difluorotetrahydro-2H-pyran-3-yl)imidazo[l,2-b][l,2,4]triazin-2-yl)methyl)-5- methylpiperidin-2-one (70.0 mg, 142 pmol), lithium l-ethyl-lH-l,2,4-triazole-5-carboxylate (62.9 mg, 428 pmol) in DCM (4 mL) were added T4P (50% purity, 308 mg, 428 pmol) and DIPEA (92.2 mg, 713 pmol, 124 pL). The mixture was stirred at 20 °C for 4 h. The residue was diluted with H2O and extracted with DCM, the combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCh, DCM / MeOH) to afford a mixture of stereoisomers. Single stereoisomers were isolated by prep-SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 urn); mobile phase: [CO2-EtOH (0.1%NH3H2O)]; B%:40%, isocratic elution mode). The first eluting isomer (20.97 mg, 99.4% purity) was obtained as a white solid. ES / MS (m / z): 614 (M+H). The second eluting isomer (23.97 mg, 98.0% purity) was obtained as a white solid. ES / MS (m / z): 614 (M+H).[000107] The compounds in the following table were prepared essentially as described in Example 45 using the appropriate amine and carboxylic acid.IL-17 A / A HEK-Blue Cell Assay[000108] 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 IL17A / F activates a NFaB promoter and drives expression of the recombinant Secreted Alkaline Phosphatase (SEAP) gene. Media from the cells is then added to a development reagent (Quanti-Blue Substrate, Fisher #NC9711613), and read at Aeso.[000109] Compounds are dispensed in DMSO to an empty clear 384-well tissue culture plate in a titration ranging from 10 pM to 27 pM, with DMSO added to every well to a final concentration of 0.1%. Cells are then added to the plate (45 pL / well at a concentration of 280,000 cells / mL). IL17A / A (Genscript #Z03228) or IL17A / F (R&D Systems) is added to the plate to a final concentration of 5 ng / mL and a final well volume of 50 pL. The cells, compound, and IL- 17A / A or IL17A / F are then incubated for 20 hours before media is removed for SEAP analysis. The resulting inhibition curve is then analyzed using Dotmatics’ integrated 4-parameter fit screening protocol to generate IC50 values. Table A includes IC50 values for IL-17A / A and IL- 17A / F inhibition of selected compounds.Table A: IL-17 A / A and IL-17 A / F Inhibition Data for Selected Compounds[000110] The data provided for selected examples in Table A demonstrate inhibition of IL- 17A / A and / or IL-17 A / F mediated signaling in the HEK-Blue Cell Assay.Rat Intravenous Half-life[000111] The test compound was administered as a solution (1 mg / mL) to fasted male Sprague Dawley rats intravenously (IV) at 1 mg / kg using a vehicle composed of 10% DMA (Dimethylacetamide), 50% Polyethylene Glycol 400, and 40% purified water. Three animals were dosed IV. Serial blood collections occurred at 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 h post IV bolus dose administration. Blood samples were collected into sample tubes containing K2EDTA anticoagulant. These samples were processed for plasma by centrifugation, then frozen and stored at -70 °C until analysis by LC-MS / MS. Test article concentration was determined in plasma and pharmacokinetics parameters were determined by non-compartmental analysis using Phoenix WinNonlin Version 8.3.5 and using individual plasma concentration time profiles. The following parameters were calculated:[000112] The terminal rate constant, kz(h-1) was determined by linear regression on a semilog concentration-time plot with a minimum of 3 data points.Half-life (ti / 2) was determined according to ti / 2 = 0.693 / kz[000113] Table B shows the rat intravenous half-life of selected compoundsTable B. Rat Intravenous Half-life (ti / 2) at 1 mg / kg of Selected Compounds[000114] The data provided in Table B illustrate that the selected compounds of the invention exhibit a range of pharmacologically advantageous pharmacokinetics properties as exemplified by their IV half-life.[000115] 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.The compound according to claim 1 wherein R1isor a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 wherein R1isor a pharmaceutically acceptable salt thereof.The compound according to claim 1 wherein R1isor a pharmaceutically acceptable salt thereof.

5. The compound according to any of claims 2 to 4 whereinpharmaceutically acceptable salt thereof.

6. The compound according to any of claims 2 to 4 whereinpharmaceutically acceptable salt thereof.

7. The compound according to any of claims 2 to 4 whereinpharmaceutically acceptable salt thereof.

8. The compound according to any of claims 2 to 4 wherein R2isor a pharmaceutically acceptable salt thereof.

9. The compound according to any of claims 2 to 4 whereinpharmaceutically acceptable salt thereof.

10. The compound of claim 1 selected from the group consisting of:N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-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-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-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);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-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-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-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-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-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-(2- fluoroethyl)-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-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-(2- fluoroethyl)-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-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- fluorocyclopropane-1 -carboxamide (isomer 1);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-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- fluorocyclopropane-1 -carboxamide (isomer 2);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)((l S,3R)-3 -methylcyclohexyl)methyl)- 1 - methyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)((l S,3R)-3 -methylcyclohexyl)methyl)- 1 - methyl-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-cyclohexyl(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-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- pyrazole-5-carboxamide (isomer 1);N-((lS)-cyclohexyl(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-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- pyrazole-5-carboxamide (isomer 2);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin- 3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3-methylcyclohexyl)methyl)-4- ethyl-l,2,5-oxadiazole-3-carboxamide (isomer 1);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin- 3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3-methylcyclohexyl)methyl)-4- ethyl-l,2,5-oxadiazole-3-carboxamide (isomer 2);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-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- fluorocyclopropane-1 -carboxamide (isomer 1);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-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- fluorocyclopropane-1 -carboxamide (isomer 2);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-(((3R,5R)-5-methyl-2-oxopiperidin- 3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3-methylcyclohexyl)methyl)-l-(2- fluoroethyl)-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-(((3R,5R)-5-methyl-2-oxopiperidin- 3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3-methylcyclohexyl)methyl)-l-(2- fluoroethyl)-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((3-oxo-2-azabicyclo[3.1.1]heptan-4- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)((l S,3R)-3 -methylcyclohexyl)methyl)- 1 -ethyl- lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((3-oxo-2-azabicyclo[3.1.1]heptan-4- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)((l S,3R)-3 -methylcyclohexyl)methyl)- 1 -ethyl- lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((3-oxo-2-azabicyclo[3.1.1]heptan-4- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)((l S,3R)-3 -methylcyclohexyl)methyl)- 1 - methyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((3-oxo-2-azabicyclo[3.1.1]heptan-4- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)((l S,3R)-3 -methylcyclohexyl)methyl)- 1 - methyl-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)- 1 -methyl- lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)- 1 -methyl- lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((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 (isomer 1);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((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 (isomer 2);N-((lR)-l-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-(((3R,5S)-5-methyl-2- oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-2-(( 1,1,1 -trifluoro-2- methylpropan-2-yl)oxy)ethyl)-l-ethyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lR)-l-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-(((3R,5S)-5-methyl-2- oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-2-(( 1,1,1 -trifluoro-2- methylpropan-2-yl)oxy)ethyl)-l-ethyl-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)- l-isopropyl-lH-l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)- l-isopropyl-lH-l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-l-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)-3-(l- (trifluoromethyl)cyclopropyl)propyl)-l -methyl- lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-l-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)-3-(l- (trifluoromethyl)cyclopropyl)propyl)-l -methyl- lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)- l-ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)- l-ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)- 4-ethyl-l,2,5-oxadiazole-3-carboxamide (isomer 1);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)- 4-ethyl-l,2,5-oxadiazole-3-carboxamide (isomer 2);N-((lS)-((R)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)- 1 -methyl- lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-((R)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)- 1 -methyl- lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)((l r,4S)-4-methylcyclohexyl)methyl)- 1 - methyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)((l r,4S)-4-methylcyclohexyl)methyl)- 1 - methyl-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)((l r,4S)-4-methylcyclohexyl)methyl)- 1 -(2- fluoroethyl)-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)((l r,4S)-4-methylcyclohexyl)methyl)- 1 -(2- fluoroethyl)-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)- 1 -ethyl- lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)- 1 -ethyl- lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-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- ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-(3-(4,4-difluorotetrahydro-2H-pyran-3-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- ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer 1); andN-((lS)-((S)-3,3-difluorocyclohexyl)(3-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)- 4-methyl-l,2,5-oxadiazole-3-carboxamide (isomer 2); or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

12. 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 10, or a pharmaceutically acceptable salt thereof.

13. A method of treating psoriasis according to claim 12 comprising administering to a patient in need thereof an effective amount of a compound according to claim 10, or a pharmaceutically acceptable salt thereof.

14. A compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in therapy.

15. A compound according to any one of claims 1 to 10, 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.

16. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in the treatment of psoriasis.

17. Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating psoriasis.

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