Il-17a inhibitors

Abstract

The invention provides certain tetrahydropyran-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 INHIBITORS BACKGROUND OF THE INVENTION

[0001] The invention provides certain tetrahydropyran-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 Th17 cells which may act as a homodimer or a heterodimer to signal through IL-17R. (Isono, F., et al., Inhibiting RORgt / Th17 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 biologics dramatically improve skin and joint symptoms in patients with moderate-to-severe psoriasis and psoriatic arthritis.

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

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

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

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

[0011] The present invention provides a compound of formula I, wherein R1 is or a pharmaceutically acceptable salt thereof. The present invention provides a compound of formula I or II, wherein R1 is a pharmaceutically acceptable salt thereof. The present invention provides a compound of formula I or II, wherein R1 isor a pharmaceutically acceptable salt thereof.

[0014] The present invention provides a compound of formula I or II, wherein R1 is, or a pharmaceutically 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 whereinpharmaceutically acceptable salt thereof.

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

[0018] The present invention provides a compound according to any of the above embodiments wherein R3 is, or a pharmaceutically acceptable salt thereof.

[0019] The present invention provides a compound according to any of the above embodiments whereinpharmaceutically acceptable salt thereof.

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

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

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

[0023] Further, the present invention provides a compound selected from the group consisting of:1-methyl-N-((1S)-((1r,4S)-4-methylcyclohexyl)(2-((3-oxomorpholin-2-yl)methyl)-3-(tetrahydro- 2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1H-pyrazole-5-carboxamide (isomer 1); 1-methyl-N-((1S)-((1r,4S)-4-methylcyclohexyl)(2-((3-oxomorpholin-2-yl)methyl)-3-(tetrahydro- 2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1H-pyrazole-5-carboxamide (isomer 2); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-pyrazole-5- carboxamide (isomer 1); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-pyrazole-5- carboxamide (isomer 2); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-pyrazole-5- carboxamide (isomer 3); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-pyrazole-5- carboxamide (isomer 4); N-((1S)-(4,4-difluorocyclohexyl)(2-((6-methyl-3-oxomorpholin-2-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-pyrazole-5-carboxamide (isomer 1); N-((1S)-(4,4-difluorocyclohexyl)(2-((6-methyl-3-oxomorpholin-2-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-pyrazole-5-carboxamide (isomer 2); N-((1S)-(4,4-difluorocyclohexyl)(2-((6-methyl-3-oxomorpholin-2-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-pyrazole-5-carboxamide (isomer 3); N-((1S)-(4,4-difluorocyclohexyl)(2-((6-methyl-3-oxomorpholin-2-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-pyrazole-5-carboxamide (isomer 4);1-methyl-N-((1S)-(2-((6-methyl-3-oxomorpholin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H-pyrazole-5- carboxamide (isomer 1); 1-methyl-N-((1S)-(2-((6-methyl-3-oxomorpholin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H-pyrazole-5- carboxamide (isomer 2); 1-methyl-N-((1S)-(2-((6-methyl-3-oxomorpholin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H-pyrazole-5- carboxamide (isomer 3); 1-methyl-N-((1S)-(2-((6-methyl-3-oxomorpholin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H-pyrazole-5- carboxamide (isomer 4); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-methyl-1H-pyrazole-5- carboxamide (isomer 1); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-methyl-1H-pyrazole-5- carboxamide (isomer 2); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-methyl-1H-pyrazole-5- carboxamide (isomer 3); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-methyl-1H-pyrazole-5- carboxamide (isomer 4); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-4-methyl-1,2,5-oxadiazole- 3-carboxamide (isomer 1); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-4-methyl-1,2,5-oxadiazole- 3-carboxamide (isomer 2);N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-4-methyl-1,2,5-oxadiazole- 3-carboxamide (isomer 3); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-4-methyl-1,2,5-oxadiazole- 3-carboxamide (isomer 4); N-((1S)-((S)-3,3-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-pyrazole-5- carboxamide (isomer 1); N-((1S)-((S)-3,3-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-pyrazole-5- carboxamide (isomer 2); N-((1S)-((S)-3,3-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-pyrazole-5- carboxamide (isomer 3); N-((1S)-((S)-3,3-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-pyrazole-5- carboxamide (isomer 4); 1-ethyl-N-((1S)-((1r,4S)-4-methylcyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1H-pyrazole- 5-carboxamide (isomer 1); 1-ethyl-N-((1S)-((1r,4S)-4-methylcyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1H-pyrazole- 5-carboxamide (isomer 2); 1-ethyl-N-((1S)-((1r,4S)-4-methylcyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1H-pyrazole- 5-carboxamide (isomer 3); 1-ethyl-N-((1S)-((1r,4S)-4-methylcyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1H-pyrazole- 5-carboxamide (isomer 4);N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-1,2,4-triazole-5- carboxamide (isomer 1); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-1,2,4-triazole-5- carboxamide (isomer 2); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-1,2,4-triazole-5- carboxamide (isomer 3); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-1,2,4-triazole-5- carboxamide (isomer 4); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl-1H-1,2,4- triazole-5-carboxamide (isomer 1); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl-1H-1,2,4- triazole-5-carboxamide (isomer 2); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl-1H-1,2,4- triazole-5-carboxamide (isomer 3); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl-1H-1,2,4- triazole-5-carboxamide (isomer 4); N-((1S)-((S)-3,3-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl-1H-1,2,4- triazole-5-carboxamide (isomer 1); N-((1S)-((S)-3,3-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl-1H-1,2,4- triazole-5-carboxamide (isomer 2);N-((1S)-((S)-3,3-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl-1H-1,2,4- triazole-5-carboxamide (isomer 3); N-((1S)-((S)-3,3-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl-1H-1,2,4- triazole-5-carboxamide (isomer 4); 1-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H-pyrazole-5- carboxamide; 1-(2-fluoroethyl)-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H-pyrazole- 5-carboxamide; 1-(2-fluoroethyl)-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1R,3S)-3-methylcyclohexyl)methyl)-1H-pyrazole- 5-carboxamide; 1-ethyl-N-((S)-1-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)-3-(1-(trifluoromethyl)cyclopropyl)propyl)-1H-pyrazole-5- carboxamide; N-((S)-cyclohexyl(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)-1,4-dihydroimidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-4-ethyl-1,2,5-oxadiazole-3- carboxamide; N-((S)-cyclohexyl(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-methyl-1H-pyrazole-5-carboxamide; N-((S)-cycloheptyl(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H-pyran- 4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-1,2,4-triazole-5-carboxamide; N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)-1,4-dihydroimidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl- 1H-1,2,4-triazole-5-carboxamide;N-((S)-((R)-3,3-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-1,2,4-triazole-5- carboxamide; N-((1S)-((S)-3,3-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)octahydroimidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-4,5- dihydro-1H-1,2,4-triazole-5-carboxamide; 1-isopropyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H-pyran- 4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H-1,2,4-triazole-5- carboxamide; 2-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-2,5-dihydro-1H-1,2,4- triazole-3-carboxamide; N-((R)-((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl- 1H-1,2,4-triazole-5-carboxamide; N-((S)-((1R,4s,7S)-bicyclo[5.1.0]octan-4-yl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)- 3-(tetrahydro-2H-pyran-4-yl)-1,5-dihydroimidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl- 1H-1,2,4-triazole-5-carboxamide (Isomer 1); N-((S)-((1R,4s,7S)-bicyclo[5.1.0]octan-4-yl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)- 3-(tetrahydro-2H-pyran-4-yl)-1,5-dihydroimidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl- 1H-1,2,4-triazole-5-carboxamide (Isomer 2); N-((S)-cyclohexyl(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)-1,5-dihydroimidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl-1H-1,2,4-triazole-5- carboxamide; N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-3-(4-methylpiperazin- 1-yl)benzamide; 1-ethyl-4-fluoro-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H-pyrazole- 5-carboxamide;4-fluoro-1-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H-pyrazole- 5-carboxamide; 4-cyclopropyl-N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1,2,5- oxadiazole-3-carboxamide; N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-4-ethyl-1,2,5-oxadiazole-3- carboxamide; N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-4-ethyl-1l3,2l2,5- oxadiazole-3-carboxamide (Isomer 1); N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-4-ethyl-1l3,2l2,5- oxadiazole-3-carboxamide (Isomer 2); N-((S)-((R)-3,3-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-pyrazole-5- carboxamide; N-((S)-((S)-3,3-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-2-ethyl-4H-2l4-pyrazole-3- carboxamide; 4-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1,2,5-oxadiazole-3- carboxamide; 4-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1,2,5-oxadiazole-3- carboxamide; 1-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H-pyrazole-5- carboxamide;N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H-pyrazole-5- carboxamide; 1-(2-fluoroethyl)-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1S,3R)-3-methylcyclohexyl)methyl)-1H-pyrazole- 5-carboxamide; 2-ethyl-N-((S)-5,5,5-trifluoro-4,4-dimethyl-1-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)pentyl)-1l2,2l4- pyrazole-3-carboxamide; 1-methyl-N-((S)-5,5,5-trifluoro-4,4-dimethyl-1-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)pentyl)-1H-pyrazole-5- carboxamide; 1-methyl-N-((S)-1-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H-pyran- 4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)-3-(1-(trifluoromethyl)cyclopropyl)propyl)-1H-pyrazole-5- carboxamide; 4-cyclopropyl-N-((1R)-1-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroimidazo[1,2-b][1,2,4]triazin-6-yl)-2-((1,1,1-trifluoro-2-methylpropan-2- yl)oxy)ethyl)-1,2,5-oxadiazole-3-carboxamide; 4-ethyl-N-((R)-1-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)ethyl)-1,2,5- oxadiazole-3-carboxamide; 1-ethyl-N-((R)-1-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)-1,5-dihydroimidazo[1,2-b][1,2,4]triazin-6-yl)-2-((1,1,1-trifluoro-2-methylpropan-2- yl)oxy)ethyl)-1H-pyrazole-5-carboxamide; 1-methyl-N-((1R,2S)-1-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)-2-((1,1,1-trifluoro-2-methylpropan-2- yl)oxy)propyl)-1H-pyrazole-5-carboxamide (Isomer 1); 1-methyl-N-((1S,2R)-2-methyl-1-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)-3-(1- (trifluoromethyl)cyclopropyl)propyl)-1H-pyrazole-5-carboxamide (Isomer 1);1-methyl-N-((1S,2R)-2-methyl-1-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)-3-(1- (trifluoromethyl)cyclopropyl)propyl)-1H-pyrazole-5-carboxamide (Isomer 2); 1-ethyl-N-((1S,2R)-2-methyl-1-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)-1,5-dihydroimidazo[1,2-b][1,2,4]triazin-6-yl)-3-(1- (trifluoromethyl)cyclopropyl)-propyl)-1H-pyrazole-5-carboxamide (Isomer 1); 1-ethyl-N-((1S,2R)-2-methyl-1-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)-1,5-dihydroimidazo[1,2-b][1,2,4]triazin-6-yl)-3-(1- (trifluoromethyl)cyclopropyl)-propyl)-1H-pyrazole-5-carboxamide (Isomer 2); 1-ethyl-N-((R)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((R)-tetrahydro-2H-pyran-2-yl)methyl)-1H-pyrazole-5- carboxamide (Isomer 2); and N-((S)-cyclohexyl(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-2-ethyl-3H-2l4-pyrazole-3-carboxamide; or a pharmaceutically acceptable salt thereof.

[0024] Further, the present invention provides a compound selected from the group consisting of: 1-methyl-N-((1S)-((1r,4S)-4-methylcyclohexyl)(2-((3-oxomorpholin-2-yl)methyl)-3-(tetrahydro- 2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1H-pyrazole-5-carboxamide (isomer 1); 1-methyl-N-((1S)-((1r,4S)-4-methylcyclohexyl)(2-((3-oxomorpholin-2-yl)methyl)-3-(tetrahydro- 2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1H-pyrazole-5-carboxamide (isomer 2); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-pyrazole-5- carboxamide (isomer 1); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-pyrazole-5- carboxamide (isomer 2);N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-pyrazole-5- carboxamide (isomer 3); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-pyrazole-5- carboxamide (isomer 4); N-((1S)-(4,4-difluorocyclohexyl)(2-((6-methyl-3-oxomorpholin-2-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-pyrazole-5-carboxamide (isomer 1); N-((1S)-(4,4-difluorocyclohexyl)(2-((6-methyl-3-oxomorpholin-2-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-pyrazole-5-carboxamide (isomer 2); N-((1S)-(4,4-difluorocyclohexyl)(2-((6-methyl-3-oxomorpholin-2-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-pyrazole-5-carboxamide (isomer 3); N-((1S)-(4,4-difluorocyclohexyl)(2-((6-methyl-3-oxomorpholin-2-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-pyrazole-5-carboxamide (isomer 4); 1-methyl-N-((1S)-(2-((6-methyl-3-oxomorpholin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H-pyrazole-5- carboxamide (isomer 1); 1-methyl-N-((1S)-(2-((6-methyl-3-oxomorpholin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H-pyrazole-5- carboxamide (isomer 2); 1-methyl-N-((1S)-(2-((6-methyl-3-oxomorpholin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H-pyrazole-5- carboxamide (isomer 3); 1-methyl-N-((1S)-(2-((6-methyl-3-oxomorpholin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H-pyrazole-5- carboxamide (isomer 4);N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-methyl-1H-pyrazole-5- carboxamide (isomer 1); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-methyl-1H-pyrazole-5- carboxamide (isomer 2); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-methyl-1H-pyrazole-5- carboxamide (isomer 3); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-methyl-1H-pyrazole-5- carboxamide (isomer 4); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-4-methyl-1,2,5-oxadiazole- 3-carboxamide (isomer 1); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-4-methyl-1,2,5-oxadiazole- 3-carboxamide (isomer 2); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-4-methyl-1,2,5-oxadiazole- 3-carboxamide (isomer 3); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-4-methyl-1,2,5-oxadiazole- 3-carboxamide (isomer 4); N-((1S)-((S)-3,3-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-pyrazole-5- carboxamide (isomer 1); N-((1S)-((S)-3,3-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-pyrazole-5- carboxamide (isomer 2);N-((1S)-((S)-3,3-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-pyrazole-5- carboxamide (isomer 3); N-((1S)-((S)-3,3-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-pyrazole-5- carboxamide (isomer 4); 1-ethyl-N-((1S)-((1r,4S)-4-methylcyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1H-pyrazole- 5-carboxamide (isomer 1); 1-ethyl-N-((1S)-((1r,4S)-4-methylcyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1H-pyrazole- 5-carboxamide (isomer 2); 1-ethyl-N-((1S)-((1r,4S)-4-methylcyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1H-pyrazole- 5-carboxamide (isomer 3); 1-ethyl-N-((1S)-((1r,4S)-4-methylcyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1H-pyrazole- 5-carboxamide (isomer 4); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-1,2,4-triazole-5- carboxamide (isomer 1); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-1,2,4-triazole-5- carboxamide (isomer 2); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-1,2,4-triazole-5- carboxamide (isomer 3); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-1,2,4-triazole-5- carboxamide (isomer 4);N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl-1H-1,2,4- triazole-5-carboxamide (isomer 1); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl-1H-1,2,4- triazole-5-carboxamide (isomer 2); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl-1H-1,2,4- triazole-5-carboxamide (isomer 3); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl-1H-1,2,4- triazole-5-carboxamide (isomer 4); N-((1S)-((S)-3,3-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl-1H-1,2,4- triazole-5-carboxamide (isomer 1); N-((1S)-((S)-3,3-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl-1H-1,2,4- triazole-5-carboxamide (isomer 2); N-((1S)-((S)-3,3-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl-1H-1,2,4- triazole-5-carboxamide (isomer 3); N-((1S)-((S)-3,3-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl-1H-1,2,4- triazole-5-carboxamide (isomer 4); 1-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H-pyrazole-5- carboxamide; 1-(2-fluoroethyl)-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H-pyrazole- 5-carboxamide;or a pharmaceutically acceptable salt thereof.

[0025] 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.

[0026] 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

[0027] 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.

[0028] Further, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0029] 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 anotherembodiment 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.

[0030] Further, the present invention provides a method of treating a disease or disorder selected from the group consisting of psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, palmoplantar psoriasis, rheumatoid arthritis, multiple sclerosis, systemic sclerosis, psoriatic arthritis, spondyloarthritis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma, non-infectious uveitis, and / or COPD, comprising administering to a patient in need thereof an effective amount of a compound of formula I and / or II, or a pharmaceutically acceptable salt thereof. Further, the present invention provides a method of treating psoriasis, comprising administering to a patient in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. Further, the present invention provides a method of treating spondyloarthritis, comprising administering to a patient in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0031] 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, for use in treating a disease or disorder selected from the group consisting of psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, palmoplantar psoriasis, rheumatoid arthritis, multiple sclerosis, psoriatic arthritis, spondyloarthritis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma, non- infectious uveitis, and / or COPD.

[0032] 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.

[0033] 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).

[0034] 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.

[0035] As used herein, the term “patient” refers to a mammal, preferably a human. As used herein, the terms “treatment”, “treating”, or “mitigating” are intended to refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of an existing disorder and / or a reduction in symptoms thereof, but does not necessarily indicate a total elimination of all symptoms. As used herein, the term “effective amount” of a compound of formula I, 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.

[0036] "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.

[0037] 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.

[0038] “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. The stereochemistry of pure enantiomers can be specified at each chiral carbon by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiralchromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.

[0039] 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

[0040] 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-tert-butyl decarbonate; “CDI” refers to carbonyldiimidazole; “DCM” refers to dichloromethane; “DIPEA” refers to diisopropylethylamine; “DMAP” refers to 4-dimethylaminopyridine; “DMSO” refers to dimethyl sulfoxide; “EDCI” refers to 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; “EtOAc” refers to ethyl acetate; “EtOH” refers to ethanol; “ES / MS” refers to electron spray - mass spectrometry; “FA” refers to formic acid; “h” refers to hour(s); “KOtBu” refers to potassium tert-butoxide; “LiHMDS” refers to lithium bis(trimethylsilyl)amide; “MeOH” refers to methanol; “min” refers to minute(s); “PE” refers to petroleum ether; “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; “TMSI” refers to iodotrimethylsilane; “T4P” refers to 2,4,6-tributyl-1,3,5,2,4,6- trioxatriphosphinane 2,4,6-trioxide.

[0041] In the schemes below, all substituents unless otherwise indicated, are as previously defined. The reagents and starting materials are either commercially available or maybe 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

[0042] 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 presence of an appropriate base, such as DIPEA, and in a suitable solvent, 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. HCl and AcOH, at 60 °C for at least 30 min. Alternatively, intermediate (iii) is reacted with TMSI in a suitable solvent, such as DCM, at 20 °C for 2 h. Alternatively, the deprotection of intermediate (iii) is accomplished in presence of Pd / C and ammonium formate 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.Scheme 2

[0043] Scheme 2 depicts the preparation of the triazine intermediate (xii) beginning with a suitable acid (v). The acid (v) is reacted with potassium 3-ethoxy-3-oxopropanoate in presence of CDI, MgCl2 and an appropriate base, such as TEA, in a suitable solvent, such as ACN. The reaction mixture is stirred and refluxed at 80 °C. The resulting intermediate (vi) is converted into (vii) in presence of SeO2, in an appropriate solvent, such as dioxane, at 90 °C for 18 h. The triazine intermediate (viii) is generated by reacting the diketone (vii) with carbonohydrazonic diamide hydrochloride, in presence of a suitable base, such as NaHCO3, in an appropriate mixture of solvent, such as EtOH and H2O, at 90 °C for 1 h. Following the protection of the amine on intermediate (viii) under conditions well known to the skilled artisan, the ester (ix) is hydrolyzed in presence of a suitable base, such as LiOH, in an appropriate mixture of solvent, such as THF and H2O. The carboxylic acid (x) is reduced under conditions well known to the skilled person and include reacting (x) with isobutyl carbonochloridate, in presence of a suitablebase, such as 4-methylmorpholine, followed by the addition of an appropriate reducing agent, such as NaBH4, in a suitable solvent, such as THF. The resulting alcohol (xi) is converted into the triazine intermediate (xii) in presence of SOCl2, in an appropriate solvent, such as DCM, at 0 °C for 1 h. Scheme 3

[0044] Scheme 3 depicts the triazine intermediate (i) beginning with a suitable amine (xiii). The amine (xiii) is reacted with chloroacetyl chloride in presence of an appropriate base, such as K2CO3, in a suitable solvent, such as THF, at 0 °C for 1 h. The resulting intermediate (xiv) is cyclized in presence of an appropriate base, such as KOtBu, at 0 °C for 1 h. Following the protection of the amide (xv) under conditions well known to the skilled artisan, intermediate (xvi) is reacted with methyl carbonochloridate in presence of a suitable base, such as LiHMDS,in an appropriate solvent, such as THF, at -70 °C for 1 h. The morpholinone (xvii) and triazine intermediate (xii) are reacted under standard nucleophilic substitution conditions and include a suitable base, such as Cs2CO3, in an appropriate solvent, such as THF or DMF. Following the deprotection of the amines of intermediate (xviii) under acidic conditions well known to the skilled person, the ester (xix) is hydrolyzed under conditions previously described. The triazine intermediate (i) is generated under decarboxylation conditions and include reacting (xx) with NaCl in a suitable solvent, such as DMSO. PREPARATIONS Preparation 1 2-Chloro-N-(3,3,3-trifluoro-2-hydroxypropyl)acetamide

[0045] To a solution of 3-amino-1,1,1-trifluoropropan-2-ol (25.0 g, 193 mmol) in THF (250 mL) was added a solution of K2CO3(80.3 g, 581 mmol) in H2O (100 mL), then 2- chloroacetyl chloride (24.0 g, 213 mmol, 16.9 mL) was added at 0 °C and the resulting mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with H2O (300 mL), extracted with EtOAc (100 mL × 3). The combined organic layers were washed with sat. aq. NaCl solution (400 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title product (38.0 g, 184 mmol) as yellow oil. ES / MS (m / z): 206 (M+H). Preparation 2 6-(Trifluoromethyl)morpholin-3-one

[0046] To a solution of 2-chloro-N-(3,3,3-trifluoro-2-hydroxypropyl)acetamide (38.0 g, 184 mmol) in THF (500 mL) was added KOtBu (82.9 g, 739 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. The residue was diluted with H2O (900 mL) at 0 °C and extracted with EtOAc (200 mL × 3). 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 (20.0 g, crude) as yellow oil. ES / MS (m / z): 170 (M+H).Preparation 3 tert-Butyl 3-oxomorpholine-4-carboxylate

[0047] To a solution of morpholin-3-one (10.0 g, 98.9 mmol) and DMAP (3.63 g, 29.6 mmol) in DCM (100 mL) was added dropwise Boc2O (25.9 g, 118 mmol, 27.2 mL) at 0 °C, then the reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc) to give the title product (17.0 g, 84.4 mmol, 85%) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 6.18 (s, 2H), 5.92 - 5.81 (m, 2H), 5.75 - 5.65 (m, 2H), 3.55 (s, 9H).

[0048] The compounds in the following table were prepared essentially as described in Preparation 3 using the appropriate morpholinone.Preparation 6 4-(tert-Butyl) 2-methyl 3-oxomorpholine-2,4-dicarboxylate

[0049] To a solution of tert-butyl 3-oxomorpholine-4-carboxylate (5.00 g, 24.8 mmol) in THF (50.0 mL) was added dropwise LiHMDS (1M, 37.2 mL) at -70 °C under N2atmosphere. After addition, the mixture was stirred at -70 °C for 1 h, and then methyl carbonochloridate (4.70 g, 49.7 mmol, 3.84 mL) was added dropwise at -70 °C. The resulting mixture was stirred at -70 °C for 4 h. The reaction mixture was quenched by addition of sat. aq. NH4Cl (20.0 mL) at 0 °C, and then diluted with H2O (50.0 mL) and extracted with EtOAc (50.0 mL × 3). The combined organic layers were washed with sat. aq. NaCl solution (50.0 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc) to afford the title product (2.50 g, 9.64 mmol, 39%) as a white solid.1H NMR (400 MHz, CDCl3) δ 3.91 - 3.87 (m, 5H), 3.86 - 3.82 (m, 2H), 3.69 - 3.67 (m, 1H), 1.55 (s, 9H).

[0050] The compounds in the following table were prepared essentially as described in Preparation 6 using the appropriate protected morpholinone.Preparation 9 Ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate

[0051] CDI (80.9 g, 499 mmol) was added to a solution of tetrahydro-2H-pyran-4- carboxylic acid (50.0 g, 384 mmol) in ACN (800 mL), the solution was stirred for 2 h at 20 °C. TEA (116 g, 1.15 mol, 160 mL) was added into a mixture of potassium 3-ethoxy-3- oxopropanoate (71.9 g, 422 mmol) and MgCl2(91.4 g, 960 mmol, 39.4 mL) in ACN (1.20 mL). The mixture was stirred for 2 h at 20 °C. Then the first solution was added to the second solution mixture and the resulting mixture was heated to reflux at 80 °C and stirred for 4 h. The reaction mixture was quenched by addition of 1M HCl, then extracted with EtOAc , dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc) to afford the title product (50.0 g, 249 mmol, 65%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 4.14 - 4.09 (m, 2H), 3.94 - 3.91 (m, 2H), 3.42 (s, 2H), 3.37 - 3.34 (m, 2H), 2.64 - 2.60 (m, 1H), 1.71 - 1.64 (m, 4H), 1.22 - 1.17 (m, 3H). Preparation 10 Ethyl 2,3-dioxo-3-(tetrahydro-2H-pyran-4-yl)propanoate

[0052] To a solution of ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl) propanoate (100 g, 499 mmol) in dioxane (1.00 L) was added SeO2(83.1 g, 749 mmol, 81.4 mL). The mixture was stirred at 90 °C for 18 h. The reaction mixture was filtered with EtOAc and the filtrate wasconcentrated under reduced pressure to give a residue to afford the title product (100 g, crude) as a brown solid. Preparation 11 Ethyl 3-amino-5-(tetrahydro-2H-pyran-4-yl)-1,2,4-triazine-6-carboxylate

[0053] To a solution of ethyl 2,3-dioxo-3-(tetrahydro-2H-pyran-4-yl) propanoate (100 g, 466 mmol) and carbonohydrazonic diamide HCl (34.5 g, 466 mmol) in EtOH (2.00 L) and H2O (2.00 L) was added NaHCO3(78.4 g, 933 mmol, 36.3 mL) at 0 °C. The mixture was stirred at 90 °C for 1 h. The reaction mixture was filtered with EtOAc and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc) to afford the title product (40.0 g, 158 mmol, 34%) as a yellow solid. ES / MS (m / z): 253 (M+H). Preparation 12 Ethyl 3-((tert-butoxycarbonyl)amino)-5-(tetrahydro-2H-pyran-4-yl)-1,2,4-triazine-6-carboxylate

[0054] To a solution of ethyl 3-amino-5-(tetrahydro-2H-pyran-4-yl)-1,2,4-triazine-6- carboxylate (40.0 g, 158 mmol) in THF (800 mL) was added LiHMDS (1M, 198 mL) at -70 °C. After addition, the mixture was stirred at -70 °C for 0.5 h, and then Boc2O (43.2 g, 198 mmol, 45.5 mL) was added dropwise at -70 °C. The resulting mixture was stirred at -70 °C for 2 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc) to afford the title product (30.0 g, 85.1 mmol, 54%) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 4.54 - 4.47 (m, 2H), 4.15 - 4.07 (m, 2H), 3.73 - 3.63 (m, 1H), 3.58 - 3.52 (m, 2H), 2.10 - 2.05 (m, 2H), 1.80 - 1.73 (m, 2H), 1.57 (s, 9H), 1.48 - 1.44 (m, 3H).Preparation 13 3-((tert-Butoxycarbonyl)amino)-5-(tetrahydro-2H-pyran-4-yl)-1,2,4-triazine-6-carboxylic acid

[0055] To a solution of ethyl 3-((tert-butoxycarbonyl)amino)-5-(tetrahydro-2H-pyran-4- yl)-1,2,4-triazine-6-carboxylate (80.0 g, 227 mmol) in THF (800 mL) was added a solution of LiOH·H2O (19.0 g, 454 mmol) in H2O (160 mL) at 0 °C, the mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by addition of 1M aq. HCl then extracted with DCM, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title product (66.0 g, 203 mmol, 90%) as a yellow oil. ES / MS (m / z): 269 (M-55). Preparation 14 tert-Butyl (6-(hydroxymethyl)-5-(tetrahydro-2H-pyran-4-yl)-1,2,4-triazin-3-yl)carbamate

[0056] To a solution of 3-((tert-butoxycarbonyl)amino)-5-(tetrahydro-2H-pyran-4-yl)- 1,2,4-triazine-6-carboxylic acid (50.0 g, 154 mmol) in THF (500 mL) were added 4- methylmorpholine (15.6 g, 154 mmol, 16.8 mL), isobutyl carbonochloridate (21.1 g, 154 mmol, 20.1 mL) at 0 °C, the mixture was stirred at 20 °C for 0.5 h. Then the mixture was filtered, and to the filtrate was added NaBH4(2.92 g, 77.1 mmol) in H2O (20.0 mL) at 0 °C, and the resulting mixture was stirred at 0 °C for 0.5 h. The mixture was quenched by sat. aq. NH4Cl and concentrated to remove THF. The residue was diluted with H2O and extracted with DCM, the combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and concentrated to remove solvent. The residue was purified by column chromatography (SiO2, DCM / MeOH) to afford the title product (23.9 g, 77.0 mmol, 28%) as a light yellow solid. ES / MS (m / z): 255 (M-55).Preparation 15 tert-Butyl (6-(chloromethyl)-5-(tetrahydro-2H-pyran-4-yl)-1,2,4-triazin-3-yl)carbamate

[0057] To a solution of tert-butyl (6-(hydroxymethyl)-5-(tetrahydro-2H-pyran-4-yl)- 1,2,4-triazin-3-yl)carbamate (1.00 g, 3.22 mmol) in DCM (10.0 mL) was added SOCl2(766 mg, 6.44 mmol, 468 μL) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, PE / EtOAc) to afford the title product (0.800 g, 2.43 mmol, 76%) as a white solid. ES / MS (m / z): 273 (M-55). Preparation 16 4-(tert-Butyl) 2-methyl 2-((3-((tert-butoxycarbonyl)amino)-5-(tetrahydro-2H-pyran-4-yl)-1,2,4- triazin-6-yl)methyl)-3-oxomorpholine-2,4-dicarboxylate

[0058] To a solution of 4-(tert-butyl) 2-methyl 3-oxomorpholine-2,4-dicarboxylate (756 mg, 2.92 mmol) in THF (10.0 mL) was added Cs2CO3 (2.38 g, 7.30 mmol). The mixture was stirred at 25 °C for 0.5 h. Then tert-butyl (6-(chloromethyl)-5-(tetrahydro-2H-pyran-4-yl)-1,2,4- triazin-3-yl)carbamate (0.800 g, 2.43 mmol) was added into the mixture and then was stirred at 25 °C for 2 h. The reaction mixture was diluted with H2O (30.0 mL) and extracted with EtOAc (90 mL). The combined organic layers were washed with sat. aq. NaCl solution (60 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a residue, the residue was purified by column chromatography (SiO2, PE / EtOAc), and then purified by prep-HPLC (H2O (FA)-ACN) to afford the title product (230 mg, 416 μmol, 17%) as a white solid. ES / MS (m / z): 552 (M+H).

[0059] The compounds in the following table were prepared essentially as described in Preparation 16 using the appropriate protected morpholinone and triazine.Preparation 19 Methyl 2-((3-amino-5-(tetrahydro-2H-pyran-4-yl)-1,2,4-triazin-6-yl)methyl)-3-oxomorpholine-2- carboxylate; TFA

[0060] To a solution of 4-(tert-butyl) 2-methyl 2-((3-((tert-butoxycarbonyl)amino)-5- (tetrahydro-2H-pyran-4-yl)-1,2,4-triazin-6-yl)methyl)-3-oxomorpholine-2,4-dicarboxylate (230mg, 416 μmol) in DCM (2.00 mL) was added TFA (713 mg, 6.25 mmol, 464 μL) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford the title product (190 mg, 408 μmol, 98%, TFA salt) as a white solid. ES / MS (m / z): 352 (M+H).

[0061] The compounds in the following table were prepared essentially as described in Preparation 19.Preparation 22 2-((3-Amino-5-(tetrahydro-2H-pyran-4-yl)-1,2,4-triazin-6-yl)methyl)-3-oxomorpholine-2- carboxylic acid

[0062] To a solution of methyl 2-((3-amino-5-(tetrahydro-2H-pyran-4-yl)-1,2,4-triazin-6- yl)methyl)-3-oxomorpholine-2-carboxylate (190 mg, 408 μmol, TFA salt) in THF (2.00 mL) was added a solution of LiOH·H2O (34.2 mg, 816 μmol) in H2O (0.200 mL) at 0 °C. The mixture was stirred at 25 °C for 2 h. To the reaction mixture was added 1M aq. HCl to adjust pH to 2. Themixture was concentrated under reduced pressure to afford the title product (130 mg, 385 μmol, 94%) as a white solid. ES / MS (m / z): 338 (M+H).

[0063] The compounds in the following table were prepared essentially as described in Preparation 22.Preparation 25 2-((3-Amino-5-(tetrahydro-2H-pyran-4-yl)-1,2,4-triazin-6-yl)methyl)morpholin-3-one

[0064] To a solution of 2-((3-amino-5-(tetrahydro-2H-pyran-4-yl)-1,2,4-triazin-6- yl)methyl)-3-oxomorpholine-2-carboxylic acid (130 mg, 385 μmol) in DMSO (1.00 mL) was added NaCl (112 mg, 1.93 mmol). The mixture was stirred at 80 °C for 0.5 h. The residue was purified by prep-HPLC (H2O (FA)-ACN) to afford the title product (66.0 mg, 225 μmol, 58%) as a white solid. ES / MS (m / z): 294 (M+H).

[0065] The compounds in the following table were prepared essentially as described in Preparation 25 using the appropriate carboxylic acid.Preparation 28 Benzyl ((1S)-((1r,4S)-4-methylcyclohexyl)(2-((3-oxomorpholin-2-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)carbamate

[0066] To a solution of 2-((3-amino-5-(tetrahydro-2H-pyran-4-yl)-1,2,4-triazin-6- yl)methyl)morpholin-3-one (66.0 mg, 225 μmol), benzyl ((S)-3-bromo-1-((1r,4S)-4- methylcyclohexyl)-2-oxopropyl)carbamate (129 mg, 337 μmol) in THF (2.00 mL) were added trimethyl borate (116 mg, 1.13 mmol, 127 μL) and DIPEA (145 mg, 1.13 mmol, 195 μL). The mixture was stirred at 70 °C for 8 h. The reaction mixture was diluted with H2O (60 mL) and extracted with EtOAc (90 mL). The combined organic layers were washed with sat. aq. NaCl solution (60 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by Prep-TLC (SiO2, EtOAc / MeOH = 10:1) to afford the title product (100 mg, 173 μmol, 77%) as a white solid. ES / MS (m / z): 577 (M+H).

[0067] The compounds in the following table were prepared essentially as described in Preparation 28 using the appropriate alkyl halide and triazine.Preparation 34 2-((6-((S)-Amino((1r,4S)-4-methylcyclohexyl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2- b][1,2,4]triazin-2-yl)methyl)morpholin-3-one

[0068] A solution of benzyl ((1S)-((1r,4S)-4-methylcyclohexyl)(2-((3-oxomorpholin-2- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)carbamate (100 mg, 173 μmol) in concentrated HCl (12M, 1.00 mL) and AcOH (104 mg, 1.75 mmol, 100 μL) was stirred at 55 °C for 1 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL × 2). To the aq. phase was added sat. aq. NaHCO3to adjust pH to 9. The mixture was extracted with DCM (20 mL × 2). The combined organic layers were dried overNa2SO4, filtered and concentrated under reduced pressure to afford the title product (70.0 mg, 158 μmol, 91%) as a white solid. ES / MS (m / z): 443 (M+H).

[0069] The compounds in the following table were prepared essentially as described in Preparation 34 using the appropriate protected amine.Preparation 372-((6-((S)-Amino((S)-3,3-difluorocyclohexyl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2- b][1,2,4]triazin-2-yl)methyl)-6-(trifluoromethyl)morpholin-3-one

[0070] To a solution of benzyl ((1S)-((S)-3,3-difluorocyclohexyl)(2-((3-oxo-6- (trifluoromethyl)morpholin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2- b][1,2,4]triazin-6-yl)methyl)carbamate (650 mg, 975 μmol) in DCM (10 mL) was added TMSI (585 mg, 2.93 mmol, 398 μL) at 0 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with 1M aq. HCl and washed with EtOAc. The aq. phase was adjusted to pH = 8-9 with a sat. aq. solution of NaHCO3and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title product (440 mg, 826 μmol) as a yellow solid. ES / MS (m / z): 533 (M+H).

[0071] The compound in the following table was prepared essentially as described in Preparation 37 by using the appropriate protected amine.Preparation 392-((6-((S)-Amino((1r,4S)-4-methylcyclohexyl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2- b][1,2,4]triazin-2-yl)methyl)-6-(trifluoromethyl)morpholin-3-one

[0072] To a solution of Pd / C (64.3 mg, 60.4 μmol, 10.0 % purity) in MeOH (2.00 mL) was added benzyl ((1S)-((1r,4S)-4-methylcyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)carbamate (0.39 g, 604 μmol) in MeOH (2.00 mL) and ammonia; FA (381 mg, 6.05 mmol). The mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue. Then the residue was quenched by sat. Na2CO3solution (10.0 mL) and extracted with solvent (DCM:MeOH), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title product (300 mg, 587 μmol, 97%) as a yellow solid. ES / MS (m / z): 511 (M+H). EXAMPLES Example 1 1-Methyl-N-((1S)-((1r,4S)-4-methylcyclohexyl)(2-((3-oxomorpholin-2-yl)methyl)-3-(tetrahydro- 2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1H-pyrazole-5-carboxamide (isomer 1) Example 2 1-Methyl-N-((1S)-((1r,4S)-4-methylcyclohexyl)(2-((3-oxomorpholin-2-yl)methyl)-3-(tetrahydro- 2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1H-pyrazole-5-carboxamide (isomer 2)

[0073] To a solution of 2-((6-((S)-amino((1r,4S)-4-methylcyclohexyl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-2-yl)methyl)morpholin-3-one (70.0 mg, 158 μmol), 1-methyl-1H-pyrazole-5-carboxylic acid (29.9 mg, 237 μmol) in pyridine (2.00 mL) was added EDCI (90.9 mg, 474 μmol). The mixture was stirred at 25 °C for 3 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with sat. aq. NaCl solution (30 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep- TLC (SiO2, DCM / MeOH) to afford a mixture of stereoisomers (65.0 mg, 118 μmol, 75%) as a white solid. ES / MS (m / z): 551 (M+H). Single stereoisomers were isolated by Prep-SFC column: DAICEL CHIRALPAK AD (250 mm×30 mm, 10 um); mobile phase: [CO2-MeOH (0.1% NH3H2O)]; B%: 45%, isocratic elution mode). The first eluting isomer (26.4 mg, 47.9 μmol, 44%, 99.9% purity) was obtained as a white solid. ES / MS (m / z): 551 (M+H). The second eluting isomer (28.44 mg, 50.3 μmol, 46%, 97.4% purity) was obtained as a white solid. ES / MS (m / z): 551 (M+H).

[0074] The compounds in the following table were prepared essentially as described in Example 1 using the corresponding appropriate reagents, bases and solvents with the reaction time adjusted to reach completion.Example 31

[0075] N-((1S)-(4,4-Difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H- 1,2,4-triazole-5-carboxamide (isomer 1)Example 32

[0076] N-((1S)-(4,4-Difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H- 1,2,4-triazole-5-carboxamide (isomer 2) Example 33

[0077] N-((1S)-(4,4-Difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H- 1,2,4-triazole-5-carboxamide (isomer 3) Example 34

[0078] N-((1S)-(4,4-Difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H- 1,2,4-triazole-5-carboxamide (isomer 4)

[0079] A solution of 2-((6-((S)-amino(4,4-difluorocyclohexyl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-2-yl)methyl)-6-(trifluoromethyl)morpholin-3-one (190 mg, 356 μmol), lithium 1-ethyl-1H-1,2,4-triazole-5-carboxylate (157 mg, 1.07 mmol) in DCM (3 mL) was added DIPEA (231 mg, 1.78 mmol, 311 μL) and T4P (50% EtOAc solution, 514 mg, 714 μmol) were stirred at RT for1 hr. The reaction mixture was then diluted with H2O and extracted with EtOAc. The combined organic layers were washed with H2O then sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, and the residue was purified by Prep-TLC (SiO2, EtOAc / MeOH) to afford the title product (140 mg, 213 μmol, 60%) as off-white solid. ES / MS (m / z): 656 (M+H). Single stereoisomers were isolated by Prep-SFC (column: DAICEL CHIRALCEL OD (250 mm×30 mm, 10 um); mobile phase: [CO2- EtOH (0.1% NH3H2O)]; B%: 45%, isocratic elution mode). The first eluting stereoisomer (28.68 mg, 43.4 μmol, 20%, 99.2% purity) was obtained as an off-white solid. ES / MS (m / z): 656 (M+H). The second eluting stereoisomer (18.42 mg, 27.7 μmol, 13%, 98.9% purity) was obtained as an off-white solid. ES / MS (m / z): 656 (M+H). The third eluting stereoisomer (18.19 mg, 27.2 μmol, 13%, 98.2% purity) was obtained as an off-white solid. ES / MS (m / z): 656 (M+H). The fourth eluting stereoisomer (28.64 mg, 43.5 μmol, 20%, 99.7% purity) was obtained as an off-white solid. ES / MS (m / z): 656 (M+H).

[0080] The compounds in the following table were prepared essentially as described in Example 31 using the corresponding appropriate reagents, bases and solvents with the reaction time adjusted to reach completion.Preparation 40

[0081] 1-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((S)- tetrahydrofuran-3-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H- pyrazole-5-carboxamide (Isomer 1) Preparation 41

[0082] 1-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-((R)- tetrahydrofuran-3-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H- pyrazole-5-carboxamide (Isomer 2)

[0083] A solution of 1-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H-pyrazole-5- carboxamide (87.3 mg, 334 μmol), 1,3-dioxoisoindolin-2-yl tetrahydrofuran-3-carboxylate (80.0 mg, 167 μmol), 4DPAIPN (0.02 eq), and TFA in DMSO. The reaction mixture was degassed, purged with N2, and irradiated with LED (395-456 nm) for 16 hr at RT. The reaction mixturewas diluted with water and extracted with EtOAc. The combined organic phases are washed with water, washed with sat. NaCl (aq), dried over Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by prep-TLC (SiO2, EtOAc / MeOH) to afford the title compound (70.0 mg, 76.3%) as white solid.

[0084] Isomer 1 was isolated as the first eluting, single stereoisomer by prep- SFC(column: DAICEL CHIRALPAK AD (250 mm×30 mm, 10 um); mobile phase: [CO2-EtOH (0.1%NH3H2O)]; B%: 35%, isocratic elution mode (25.6 mg, 36%) and was obtained as a white solid. ES / MS (m / z): 549 (M+H).

[0085] Isomer 2 was isolated as the second eluting, single stereoisomer by prep- SFC(column: DAICEL CHIRALPAK AD (250 mm×30 mm, 10 um); mobile phase: [CO2-EtOH (0.1%NH3H2O)]; B%: 35%, isocratic elution mode) and prep-SFC (column: DAICEL CHIRALCEL OD (250 mm×30 mm, 10 um); mobile phase: [CO2-i-PrOH (0.1%NH3H2O)]; B%: 40%, isocratic elution mode); (25.1 mg, 35%) and was obtained as a white solid. ES / MS (m / z): 549 (M+H).

[0086] The compounds in the following table were prepared essentially as described in Preparation 40 using the corresponding appropriate reagents, bases and solvents with the reaction time adjusted to reach completion.Preparation 42 N-((S)-(3-((2R,6R)-2,6-dimethylmorpholino)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1-methyl-1H- pyrazole-5-carboxamide

[0087] To a solution of 1-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H-pyrazole-5- carboxamide (50.0 mg, 104 μmol) and (2R,6R)-2,6-dimethylmorpholine (180 mg, 1.57 mmol) in THF at 0-5 °C was added bis(pyridine)silver(I) permanganate (1.50 eq) in small portions over the course of 15 min. Additional bis(pyridine)silver(I) permanganate was added at 5 °C until the reaction was complete. The reaction mixture was then diluted with dichloromethane and filtered through packed MgSO4atop diatomaceous earth with DCM / EtOAc washes. The filtrate was concentrated under reduced pressure and the residue purified by prep-HPLC (FA condition; column: Phenomenex luna C18150×25 mm×10 um; mobile phase: [water (FA)-ACN]; gradient: 25% - 55% B over 10 min) and SFC separation column: DAICEL CHIRALPAK AS-H (250 mm×30 mm, 5 um); mobile phase: [CO2-EtOH (0.1%NH3H2O)]; B%: 35%, isocratic elution mode, Rt = 1.324, 1.699 min) to afford the title compound (9.92 mg, 32%) as yellow solid. ES / MS (m / z): 592 (M+H).

[0088] The compounds in the following table were prepared essentially as described in Preparation 42 using the corresponding appropriate reagents, bases and solvents with the reaction time adjusted to reach completion.Example 50 N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)-1,4-dihydroimidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl- 1H-1,2,4-triazole-5-carboxamide

[0089] To a solution of (3R,5S)-3-((6-((S)-amino(4,4-difluorocyclohexyl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-2-yl)methyl)-5-methylpiperidin-2-one (35.0 mg, 73.4 μmol) with lithium 1-isopropyl-1H-1,2,4-triazole-5-carboxylate (22.8 mg, 141 μmol) were added T4P (106 mg, 147 μmol), N-ethyl-N-isopropyl-propan-2-amine (47.5 mg, 367 μmol, 64.0 μL) in DCM (1 mL). The reaction mixture was stirred at RT, and was then diluted with H2O and extracted with EtOAc. The combined organic layers were washed with H2O thensat. NaCl (aq), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Phenomenex luna C18150×25 mm×10 um; mobile phase: [water (FA) - ACN]; gradient: 44% - 64% B over 10 mins) to afford the title compound (26.7 mg, 58%) as a white solid. ES / MS (m / z): 614 (M+H).

[0090] The compounds in the following table were prepared essentially as described in Example 50 beginning with an appropriate amine and carboxylic acid salt.Example 59 N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-3-(4-methylpiperazin- 1-yl)benzamide

[0091] A solution of (3R,5S)-3-((6-((S)-amino((1r,4S)-4-methylcyclohexyl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-2-yl)methyl)-5-methylpiperidin-2-one (45.0 mg, 98.9 μmol), 3-(4-methylpiperazin-1-yl)benzoic acid (43.6 mg, 197 μmol), and EDCI in pyridine was stirred at RT. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic phases were washed with H2O then sat. NaCl (aq), dried over Na2SO4, filtered, and concentrated under reduced pressure to provide a residue that was purified by prep-HPLC (column: Phenomenex luna C18150×25 mm×10 um; mobile phase: [water (FA) - ACN]; gradient: 23%-53% B over 10 min) to afford the title compound (30.1 mg, 46%) as white solid. ES / MS (m / z): 657 (M+H).

[0092] The compounds in the following table were prepared essentially as described in Example 59 using the corresponding appropriate amines and carboxylic acids.IL-17A / A HEK-Blue Cell Assay

[0093] The HEK-Blue IL-17A reporter cell line (Fisher #NC1408637) is used for cell- based 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 Act1 adapter molecule, the combination of which, when stimulated by IL-17A / A or IL-17A / F activates a NFαB promoter and drives expression of the recombinant Secreted Alkaline Phosphatase (SEAP) gene. Media from the cells is then added to a development reagent (Quanti-Blue Substrate, Fisher #NC9711613), and read at A630.

[0094] Compounds are dispensed in DMSO to an empty clear 384-well tissue culture plate in a titration ranging from 10 μM to 27 pM, with DMSO added to every well to a final concentration of 0.1%. Cells are then added to the plate (45 μL / well at a concentration of 280,000cells / mL). IL-17A / A (Genscript #Z03228) or IL-17A / F (R&D Systems) is added to the plate to a final concentration of 5 ng / mL and a final well volume of 50 μL. The cells, compound, and IL- 17A / A or IL-17A / F are then incubated for 20 hours before media is removed for SEAP analysis. The resulting inhibition curve is then analyzed using Dotmatics’ integrated 4-parameter fit screening protocol to generate IC50values. Table A includes IC50values 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

[0095] 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. Human Liver Microsomal Stability Studies

[0096] Test compound and control compound (testosterone, diclofenac, propafenone) working solution preparation.5 μL of a compound and control compound stock solution (10 mM in dimethyl sulfoxide (DMSO)) were diluted with 495 μL of acetonitrile (ACN).

[0097] NADPH cofactor preparation. The appropriate amount of NADPH powder was weighed and diluted into a 10 mM MgCl2 solution (working solution concentration: 10 mM; final concentration in reaction system: 1 mM). Materials: NADPH powder: β-Nicotinamide adenine dinucleotide phosphate reduced form, tetrasodium salt; NADPH·4Na (Vendor: BONTAC, Cat. No. BT04).

[0098] Liver Microsome Preparation. The appropriate concentrations of microsome working solutions were prepared in 100 mM potassium phosphate buffer. Materials: Human Liver Microsomes (HLM) Cat No.452117 and Lot No.38298 (Corning)

[0099] Stop solution preparation. Cold (4°C) acetonitrile (ACN) containing 250 nM Tolbutamide and 250 nM Labetalol as internal standards (IS) were used as the stop solution.[000100] Assay Procedure. Empty incubation plates (T60 and NCF60) were warmed for 10 mins prior to use (NCF = No Co-Factor). Liver microsomes were diluted to 0.56 mg / mL in 100 mM phosphate buffer and 445 µL of the microsome working solutions (0.56 mg / mL) were transferred into pre-warmed 'Incubation' plates T60 and NCF60, then 'Incubation' plates T60 and NCF60 were pre-incubated for 10 min at 37°C with constant shaking. Blank plates were prepared by addition of 54 µL liver microsome solution, followed by 6 µL of NAPDH cofactor, and the addition of 180 µL of stop solution to the blank plate. A 5 µL aliquot of compound working solution (100 μM) was added into the 'Incubation' plates (T60 and NCF60) containing microsomes and mixed thoroughly 3 times. To the NCF60 plate 50 µL of buffer was added and mixed 3 times thoroughly. The 'Incubation' plates were placed at 37°C for 60 min while shaking. In the 'Quenching' plate T0, 180 µL of stop solution and 6 µL of NAPDH cofactor were added and the plate was chilled (4°C) to prevent evaporation. The T60 plate was mixed 3 times thoroughly and immediately 54 µL of the mixture was removed for the 0-min time point and added to the 'Quenching' plate T0. Then 44 µL of NAPDH cofactor was added to the 'Incubation' plate T60. The T60 plate was kept at 37°C for 60 min while shaking. ‘Quenching’ plates were prepared by adding 180 µL of stop solution. At 5, 15, 30, 45, and 60 min, the respective incubation sample was mixed once and a 60 µL sample aliquot from the T60 plate was serially transferred per time point to the 'Quenching' plates. For the NCF60 plate, the incubation sample was mixed once and a 60 µL sample aliquot was transferred from the NCF60 incubation to the 'Quenching' plate containing 180 µL of stop solution at the 60-min time point. Final concentrations of each component in the incubation media: microsomes (0.5 mg protein / mL); test compound (1 µM); control compound (1 µM); ACN (0.99%); and DMSO (0.01%). Table B provides reaction plate incubation times. Table B: Reaction Plates Incubation[000101] All 'Quenching' plates were shaken for 10 min, then centrifuged at 4000 rpm for 20 minutes at 4°C. An 80 µL aliquot of supernatant was transferred into 240 µL of HPLC water, and mixed using a plate shaker for 10 min. Each bioanalysis plate was sealed and shaken for 10 minutes prior to LC-MS / MS analysis. [000102] Peak area ratios were calculated by dividing the analyte peak area by the internal standard peak area and the peak area ratios were converted to % parent remaining using tharea ratio at time 0 as 100%. The slope (ke, min-1) was determined from the plot of % parent remaining vs incubation time using first order kinetics (Equation 1). The half-life (T1 / 2, min) and intrinsic clearance (CLint, μL / min / mg protein), was determined using Equation 2 and 3 respectively. Equation 1: Ct= C0* e-(ke*t)Equation 2: T1 / 2= ln(2) / keEquation 3: CLint= (ke* 1000) / (microsome concentration in mg / mL) [000103] Table C shows the human liver microsome intrinsic clearance of selected compounds. Table C. HLM CLint (µL / min / mg protein) of selected compounds at 1 µM[000104] 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

CLAIMS What is claimed is:

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

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

3. The compound according to claim 1 or 2 wherein R1isor a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 or 2 wherein R1ispharmaceutically acceptable salt thereof.

5. The compound according to claim 1 or 2 wherein R1ispharmaceutically acceptable salt thereof.

6. The compound according to any one of claims 2 to 5 wherein pharmaceutically acceptable salt thereof.

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

8. The compound according to any one of claims 2 to 5 whereinpharmaceutically acceptable salt thereof. The compound according to any one ofpharmaceutically acceptable salt thereof. The compound according to any onepharmaceutically acceptable salt thereof.

11. The compound according to any one of claims 2 to 5 wherein R3ispharmaceutically acceptable salt thereof.

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

13. The compound according to any one of claims 2 to 5 wherein pharmaceutically acceptable salt thereof.

14. The compound of claim 1 selected from the group consisting of: 1-methyl-N-((1S)-((1r,4S)-4-methylcyclohexyl)(2-((3-oxomorpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1H-pyrazole-5- carboxamide (isomer 1); 1-methyl-N-((1S)-((1r,4S)-4-methylcyclohexyl)(2-((3-oxomorpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1H-pyrazole-5- carboxamide (isomer 2); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)- 3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H- pyrazole-5-carboxamide (isomer 1); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)- 3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H- pyrazole-5-carboxamide (isomer 2); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)- 3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H- pyrazole-5-carboxamide (isomer 3); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)- 3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H- pyrazole-5-carboxamide (isomer 4); N-((1S)-(4,4-difluorocyclohexyl)(2-((6-methyl-3-oxomorpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H- pyrazole-5-carboxamide (isomer 1); N-((1S)-(4,4-difluorocyclohexyl)(2-((6-methyl-3-oxomorpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H- pyrazole-5-carboxamide (isomer 2);N-((1S)-(4,4-difluorocyclohexyl)(2-((6-methyl-3-oxomorpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H- pyrazole-5-carboxamide (isomer 3); N-((1S)-(4,4-difluorocyclohexyl)(2-((6-methyl-3-oxomorpholin-2-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H- pyrazole-5-carboxamide (isomer 4); 1-methyl-N-((1S)-(2-((6-methyl-3-oxomorpholin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H-pyrazole-5- carboxamide (isomer 1); 1-methyl-N-((1S)-(2-((6-methyl-3-oxomorpholin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H-pyrazole-5- carboxamide (isomer 2); 1-methyl-N-((1S)-(2-((6-methyl-3-oxomorpholin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H-pyrazole-5- carboxamide (isomer 3); 1-methyl-N-((1S)-(2-((6-methyl-3-oxomorpholin-2-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H-pyrazole-5- carboxamide (isomer 4); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)- 3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-methyl-1H- pyrazole-5-carboxamide (isomer 1); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)- 3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-methyl-1H- pyrazole-5-carboxamide (isomer 2); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)- 3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-methyl-1H- pyrazole-5-carboxamide (isomer 3); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)- 3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-methyl-1H- pyrazole-5-carboxamide (isomer 4);N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)- 3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-4-methyl-1,2,5- oxadiazole-3-carboxamide (isomer 1); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)- 3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-4-methyl-1,2,5- oxadiazole-3-carboxamide (isomer 2); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)- 3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-4-methyl-1,2,5- oxadiazole-3-carboxamide (isomer 3); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)- 3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-4-methyl-1,2,5- oxadiazole-3-carboxamide (isomer 4); N-((1S)-((S)-3,3-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1- ethyl-1H-pyrazole-5-carboxamide (isomer 1); N-((1S)-((S)-3,3-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1- ethyl-1H-pyrazole-5-carboxamide (isomer 2); N-((1S)-((S)-3,3-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1- ethyl-1H-pyrazole-5-carboxamide (isomer 3); N-((1S)-((S)-3,3-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1- ethyl-1H-pyrazole-5-carboxamide (isomer 4); 1-ethyl-N-((1S)-((1r,4S)-4-methylcyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1H- pyrazole-5-carboxamide (isomer 1); 1-ethyl-N-((1S)-((1r,4S)-4-methylcyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1H- pyrazole-5-carboxamide (isomer 2);1-ethyl-N-((1S)-((1r,4S)-4-methylcyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1H- pyrazole-5-carboxamide (isomer 3); 1-ethyl-N-((1S)-((1r,4S)-4-methylcyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1H- pyrazole-5-carboxamide (isomer 4); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)- 3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-1,2,4- triazole-5-carboxamide (isomer 1); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)- 3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-1,2,4- triazole-5-carboxamide (isomer 2); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)- 3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-1,2,4- triazole-5-carboxamide (isomer 3); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)- 3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-1,2,4- triazole-5-carboxamide (isomer 4); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)- 3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl-1H- 1,2,4-triazole-5-carboxamide (isomer 1); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)- 3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl-1H- 1,2,4-triazole-5-carboxamide (isomer 2); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)- 3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl-1H- 1,2,4-triazole-5-carboxamide (isomer 3); N-((1S)-(4,4-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2-yl)methyl)- 3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl-1H- 1,2,4-triazole-5-carboxamide (isomer 4);N-((1S)-((S)-3,3-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1- isopropyl-1H-1,2,4-triazole-5-carboxamide (isomer 1); N-((1S)-((S)-3,3-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1- isopropyl-1H-1,2,4-triazole-5-carboxamide (isomer 2); N-((1S)-((S)-3,3-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1- isopropyl-1H-1,2,4-triazole-5-carboxamide (isomer 3); N-((1S)-((S)-3,3-difluorocyclohexyl)(2-((3-oxo-6-(trifluoromethyl)morpholin-2- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1- isopropyl-1H-1,2,4-triazole-5-carboxamide (isomer 4); 1-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H- pyrazole-5-carboxamide; 1-(2-fluoroethyl)-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4- methylcyclohexyl)methyl)-1H-pyrazole-5-carboxamide; 1-(2-fluoroethyl)-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1R,3S)-3- methylcyclohexyl)methyl)-1H-pyrazole-5-carboxamide; 1-ethyl-N-((S)-1-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)-3-(1-(trifluoromethyl)cyclopropyl)propyl)- 1H-pyrazole-5-carboxamide; N-((S)-cyclohexyl(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)-1,4-dihydroimidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-4-ethyl-1,2,5- oxadiazole-3-carboxamide; N-((S)-cyclohexyl(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-methyl-1H-pyrazole-5- carboxamide;N-((S)-cycloheptyl(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-1,2,4-triazole-5- carboxamide; N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)-1,4-dihydroimidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1- isopropyl-1H-1,2,4-triazole-5-carboxamide; N-((S)-((R)-3,3-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)- 3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H-1,2,4- triazole-5-carboxamide; N-((1S)-((S)-3,3-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)- 3-(tetrahydro-2H-pyran-4-yl)octahydroimidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl- 4,5-dihydro-1H-1,2,4-triazole-5-carboxamide; 1-isopropyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H- 1,2,4-triazole-5-carboxamide; 2-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-2,5- dihydro-1H-1,2,4-triazole-3-carboxamide; N-((R)-((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1- isopropyl-1H-1,2,4-triazole-5-carboxamide; N-((S)-((1R,4s,7S)-bicyclo[5.1.0]octan-4-yl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1,5-dihydroimidazo[1,2-b][1,2,4]triazin-6- yl)methyl)-1-isopropyl-1H-1,2,4-triazole-5-carboxamide (Isomer 1); N-((S)-((1R,4s,7S)-bicyclo[5.1.0]octan-4-yl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-1,5-dihydroimidazo[1,2-b][1,2,4]triazin-6- yl)methyl)-1-isopropyl-1H-1,2,4-triazole-5-carboxamide (Isomer 2);N-((S)-cyclohexyl(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)-1,5-dihydroimidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-isopropyl-1H-1,2,4- triazole-5-carboxamide; N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-3-(4- methylpiperazin-1-yl)benzamide; 1-ethyl-4-fluoro-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4- methylcyclohexyl)methyl)-1H-pyrazole-5-carboxamide; 4-fluoro-1-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4- methylcyclohexyl)methyl)-1H-pyrazole-5-carboxamide; 4-cyclopropyl-N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1,2,5- oxadiazole-3-carboxamide; N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-4-ethyl-1,2,5- oxadiazole-3-carboxamide; N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-4-ethyl-1l3,2l2,5- oxadiazole-3-carboxamide (Isomer 1); N-((S)-(4,4-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-4-ethyl-1l3,2l2,5- oxadiazole-3-carboxamide (Isomer 2); N-((S)-((R)-3,3-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)- 3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-1-ethyl-1H- pyrazole-5-carboxamide; N-((S)-((S)-3,3-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-2-ethyl-4H-2l4- pyrazole-3-carboxamide;4-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1,2,5- oxadiazole-3-carboxamide; 4-ethyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1,2,5- oxadiazole-3-carboxamide; 1-methyl-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H- pyrazole-5-carboxamide; N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1r,4S)-4-methylcyclohexyl)methyl)-1H-pyrazole-5- carboxamide; 1-(2-fluoroethyl)-N-((S)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((1S,3R)-3- methylcyclohexyl)methyl)-1H-pyrazole-5-carboxamide; 2-ethyl-N-((S)-5,5,5-trifluoro-4,4-dimethyl-1-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)pentyl)-1l2,2l4- pyrazole-3-carboxamide; 1-methyl-N-((S)-5,5,5-trifluoro-4,4-dimethyl-1-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)pentyl)-1H- pyrazole-5-carboxamide; 1-methyl-N-((S)-1-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)-3-(1-(trifluoromethyl)cyclopropyl)propyl)- 1H-pyrazole-5-carboxamide; 4-cyclopropyl-N-((1R)-1-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)-3,4-dihydroimidazo[1,2-b][1,2,4]triazin-6-yl)-2-((1,1,1- trifluoro-2-methylpropan-2-yl)oxy)ethyl)-1,2,5-oxadiazole-3-carboxamide; 4-ethyl-N-((R)-1-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)-2-((1,1,1-trifluoro-2-methylpropan-2- yl)oxy)ethyl)-1,2,5-oxadiazole-3-carboxamide;1-ethyl-N-((R)-1-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)-1,5-dihydroimidazo[1,2-b][1,2,4]triazin-6-yl)-2-((1,1,1-trifluoro-2- methylpropan-2-yl)oxy)ethyl)-1H-pyrazole-5-carboxamide; 1-methyl-N-((1R,2S)-1-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)-2-((1,1,1-trifluoro-2- methylpropan-2-yl)oxy)propyl)-1H-pyrazole-5-carboxamide (Isomer 1); 1-methyl-N-((1S,2R)-2-methyl-1-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)-3-(1- (trifluoromethyl)cyclopropyl)propyl)-1H-pyrazole-5-carboxamide (Isomer 1); 1-methyl-N-((1S,2R)-2-methyl-1-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)-3-(1- (trifluoromethyl)cyclopropyl)propyl)-1H-pyrazole-5-carboxamide (Isomer 2); 1-ethyl-N-((1S,2R)-2-methyl-1-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)-1,5-dihydroimidazo[1,2-b][1,2,4]triazin-6-yl)-3-(1- (trifluoromethyl)cyclopropyl)-propyl)-1H-pyrazole-5-carboxamide (Isomer 1); 1-ethyl-N-((1S,2R)-2-methyl-1-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3- (tetrahydro-2H-pyran-4-yl)-1,5-dihydroimidazo[1,2-b][1,2,4]triazin-6-yl)-3-(1- (trifluoromethyl)cyclopropyl)-propyl)-1H-pyrazole-5-carboxamide (Isomer 2); 1-ethyl-N-((R)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)((R)-tetrahydro-2H-pyran-2-yl)methyl)-1H- pyrazole-5-carboxamide (Isomer 2); and N-((S)-cyclohexyl(2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,2-b][1,2,4]triazin-6-yl)methyl)-2-ethyl-3H-2l4-pyrazole-3- carboxamide; or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

16. 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 14, or a pharmaceutically acceptable salt thereof.

17. A method of treating psoriasis according to claim 16 comprising administering to a patient in need thereof an effective amount of a compound according to claim 14, or a pharmaceutically acceptable salt thereof.

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

19. A compound according to any one of claims 1 to 14, 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.

20. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for use in the treatment of psoriasis.

21. Use of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating psoriasis.

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