Il-17a inhibitors

Abstract

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

Description

IL-17A INHIBITORSBACKGROUND OF THE INVENTION

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

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

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

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

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

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

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

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

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

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

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

[0012] The present invention provides a compound of formula I, wherein R1isHN — > O= / \ -“hv , or a pharmaceutically acceptable salt thereof.

[0013] The present invention provides a compound of formula I, wherein R1is, or a pharmaceutically acceptable salt thereof.

[0014] The present invention provides further embodiments of any of the above embodiments, and particular groups of compounds and / or salts of formula I.

[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 R2isor 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 w embodiments wherein R2isor a pharmaceutically acceptable salt thereof.

[0021] The present invention provides a compound according to any of the above JW I V6 embodiments wherein R2is , or a pharmaceutically acceptable salt thereof.

[0022] The present invention provides a compound according to any of the above embodiments whereinpharmaceutically acceptable salt thereof.Further, the present invention provides a compound selected from the group consisting of:N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)- 5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl- lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)- 5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl- lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)- 5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l- isopropyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l- isopropyl- lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l- methyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l- methyl- lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2- (((3R,5R)-5-methyl-2-oxopiperi din-3-yl)methyl)imidazo[l,2-b][l, 2, 4]tri azin-6- yl)methyl)-l -isopropyl- 1H-1, 2, 4-triazole-5-carboxamide (isomer 1);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2- (((3R,5R)-5-methyl-2-oxopiperi din-3-yl)methyl)imidazo[l,2-b][l, 2, 4]tri azin-6- yl)methyl)-l -isopropyl- 1H-1, 2, 4-triazole-5-carboxamide (isomer 2);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)- 5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl- lH-l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)- 5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl- lH-l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)- 5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l- isopropyl-lH-l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)- 5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l- isopropyl-lH-l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2- (((3R,5R)-5-methyl-2-oxopiperi din-3-yl)methyl)imidazo[l,2-b][l, 2, 4]tri azin-6- yl)methyl)-l-ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2- (((3R,5R)-5-methyl-2-oxopiperi din-3-yl)methyl)imidazo[l,2-b][l, 2, 4]tri azin-6- yl)methyl)-l-ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-isopropyl-lH- l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-isopropyl-lH- l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((3-oxo-2- azabicyclo[3.1.1 ]heptan-4-yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 - isopropyl-lH-l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((3-oxo-2- azabicyclo[3.1.1 ]heptan-4-yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 - isopropyl-lH-l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5R)- 2-oxo-5-(trifluoromethyl)piperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)methyl)-l -isopropyl- 1H-1, 2, 4-triazole-5-carboxamide (isomer 1);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5R)- 2-oxo-5-(trifluoromethyl)piperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)methyl)-l -isopropyl- 1H-1, 2, 4-triazole-5-carboxamide (isomer 2);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2- (((3R,5R)-2-oxo-5-(trifluoromethyl)piperi din-3-yl)methyl)imidazo[l, 2-b][l, 2, 4]tri azin-6- yl)methyl)-l-ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2- (((3R,5R)-2-oxo-5-(trifluoromethyl)piperi din-3-yl)methyl)imidazo[l, 2-b][l, 2, 4]tri azin-6- yl)methyl)-l-ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((3-oxo-2-azabicyclo[3.1.1]heptan- 4-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l- methyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((3-oxo-2-azabicyclo[3.1.1]heptan- 4-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l- methyl-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l- methyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l- methyl-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-l-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)-5,5,5-trifluoro-4,4-dimethylpentyl)-l- methyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-l-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)-5,5,5-trifluoro-4,4-dimethylpentyl)-l- methyl-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((3-oxo-2-azabicyclo[3.1.1]heptan- 4-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l- methyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((3-oxo-2-azabicyclo[3.1.1]heptan- 4-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l- methyl-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-cyclohexyl(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -methyl- lH-pyrazole-5- carboxamide (isomer 1);N-((lS)-cyclohexyl(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -methyl- lH-pyrazole-5- carboxamide (isomer 2);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-l-methyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-l-methyl-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-l-methyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-l-methyl-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3-methylcyclohexyl)methyl)-l- methyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3-methylcyclohexyl)methyl)-l- methyl-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3-methylcyclohexyl)methyl)-l-(2- fluoroethyl)-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3-methylcyclohexyl)methyl)-l-(2- fluoroethyl)-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-l-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)-3-(l- (trifluoromethyl)cyclopropyl)propyl)-l-methyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-l-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)-3-(l- (trifluoromethyl)cyclopropyl)propyl)-l-methyl-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-l-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-3 -(1 -(trifluoromethyl)cyclopropyl)propyl)- 1 - methyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-l-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-3 -(1 -(trifluoromethyl)cyclopropyl)propyl)- 1 - methyl- lH-pyrazole-5-carboxamide (isomer 2);N-((3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)(spiro[2.5]octan-6-yl)m ethyl)- 1 -ethyl- 1H- pyrazole-5-carboxamide;N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-l-isopropyl-lH-l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-l-isopropyl-lH-l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-l-isopropyl-lH-l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-l-isopropyl-lH-l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2- (((3R,5 S)-2-oxo-5-(trifluoromethyl)piperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)methyl)-l-ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2- (((3R,5 S)-2-oxo-5-(trifluoromethyl)piperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)methyl)-l-ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-((R)-3,3-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2- (((3R,5R)-5-methyl-2-oxopiperi din-3-yl)methyl)imidazo[l,2-b][l, 2, 4]tri azin-6- yl)methyl)-l-ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-((R)-3,3-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2- (((3R,5R)-5-methyl-2-oxopiperi din-3-yl)methyl)imidazo[l,2-b][l, 2, 4]tri azin-6- yl)methyl)-l-ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-((R)-3,3-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6- yl)methyl)-l-ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-((R)-3,3-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6- yl)methyl)-l-ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)methyl)-l-ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 1); andN-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5R)- 2-oxo-5-(trifluoromethyl)piperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)methyl)-l-ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 2); or a pharmaceutically acceptable salt thereof.

[0023] 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.

[0024] 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

[0025] Compounds of the present invention are potent inhibitors of IL- 17 A, and upon administration to a patient in need thereof, may provide therapeutic benefits while avoiding certain problems associated with biological IL-17A signaling antagonists, such as IL-17 antibodies. As such, compounds of the present invention are believed to be useful for the treatment of conditions in which excessive IL-17A mediated signaling plays a role, and such as psoriasis, rheumatoid arthritis, spondyloarthritis and multiple sclerosis, including relief of certain immunologically-mediated symptoms. Compounds of the present invention are also believed to be useful in improving disease symptoms in psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, palmoplantar psoriasis, rheumatoid arthritis, multiple sclerosis, systemic sclerosis, psoriatic arthritis, spondyloarthritis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma, non-infectious uveitis, and COPD.

[0026] Further, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0027] In another embodiment, the present invention provides a pharmaceutical composition comprising the compound of formula I, or a pharmaceutically acceptable saltthereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. Furthermore, this embodiment of the invention provides a pharmaceutical composition for treating psoriasis, comprising the compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers, or diluents. In another embodiment the invention provides a pharmaceutical composition for treating rheumatoid arthritis, comprising the compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers, or diluents. In another embodiment the invention provides a pharmaceutical composition for treating multiple sclerosis, comprising the compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers, or diluents.

[0028] Further, the present invention provides a method of treating a disease or disorder selected from the group consisting of psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, palmoplantar psoriasis, rheumatoid arthritis, multiple sclerosis, systemic sclerosis, psoriatic arthritis, spondyloarthritis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma, non-infectious uveitis, and / or COPD, comprising administering to a patient in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. Further, the present invention provides a method of treating psoriasis, comprising administering to a patient in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. Further, the present invention provides a method of treating spondyloarthritis, comprising administering to a patient in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0029] 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.

[0030] 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.

[0031] 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).

[0032] 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.

[0033] 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 tosevere 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.

[0034] "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.

[0035] 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.

[0036] 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 usingchiral synthons or chiral reagents or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.

[0037] 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

[0038] The following examples are provided for illustration purposes only. The abbreviations used herein are defined according to Aldrichimica Acta, vol. 17, No. 1, 1984. Other abbreviations are defined as follows: “ACN” refers to acetonitrile; “AcOH” refers to acetic acid; “aq” refers to aqueous; “BOC2O” refers to di- / c / 7-butyl dicarbonate; “CDF’ refers to carbonyldiimidazole; “DCC” refers to N, M-dicyclohexylcarbodiimide; “DCE” refers to dichloroethane; “DCM” refers to dichloromethane; “DDQ” refers to 2,3-dichloro-5,6-dicyano- 1,4-benzoquinone; “DIPEA” refers to diisopropyl ethylamine; “DMAP” refers to 4- dimethylaminopyridine; “DMSO” refers to dimethyl sulfoxide; “EDCI” refers to l-ethyl-3-(3- dimethylaminopropyljcarbodiimide; “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); “KO / Bu” refers to potassium terLbutoxide; “LED” refers to light-emitting diode; “LiHMDS” refers to lithium bis(trimethylsilyl)amide; “MeOH” refers to methanol; “min” refers to minutes; “Pd(dppf)C12” refers to [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); “PE” refers to petroleum ether; “Prep-HPLC” refers to preparatory high performance liquid chromatography; “Prep-TLC” refers to preparatory thin layer chromatography; “Prep-SFC” refers to preparatory supercritical fluid chromatography; “RT” refers to room temperature; “sat”refers to saturated; “TEA” refers to triethylamine; “TFA” refers to trifluoroacetic acid; “THF” refers to tetrahydrofuran; “TMEDA” refers to N, N, N', A'-tetramethylethylenediamine; “TMSQ” refers to trimethyl silyl chloride; “TMSCN” refers to trimethyl silyl cyanide; “TMSI” refers to iodotrimethylsilane; “T4P” refers to 2,4,6-tributyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide; “4DPAIPN” refers to 2,4,5,6-tetrakis(diphenylamino)isophthalonitrile.

[0039] In the schemes below, all substituents unless otherwise indicated, are as previously defined. The reagents and starting materials are either commercially available or may be prepared by methods well known to one of ordinary skill in the art, some of which are presented in the preparations below. Without limiting the scope of the invention, the following schemes, preparations, and examples are provided to further illustrate the invention.

[0040] Scheme 1 depicts the preparation of compounds of the present invention beginning with a suitable aminotriazine (i) and bromoketone (ii). The PG moiety on the amine of the intermediates is a standard amine protecting group well known to the skilled artisan, including carbamate protecting groups. The aminotriazine (i) and bromoketone (ii) are reacted with trimethyl borate, in the presence of an appropriate base, such as DIPEA, in a suitablesolvent, such as THF, at 70 °C for at least 3 h. The imidazotriazine intermediate (iii) is deprotected under acidic conditions, and include reacting intermediate (iii) in a mixture of appropriate acids, such as aq. HC1 and AcOH, at 60 °C for at least 30 min. Alternatively, intermediate (iii) is reacted with TMSI in a suitable solvent, such as DCM, at 20°C for 2 h. Alternatively, the deprotection of intermediate (iii) is accomplished in the presence of Pd / C and ammonium formate or ammonium acetate, in an appropriate solvent, such as MeOH. The deprotected amine (iv) is reacted with a suitable carboxylic acid under standard amide coupling conditions and include an appropriate coupling reagent, such as EDCI or T4P, a suitable base, such as DIPEA or pyridine, in an appropriate solvent, such as DCM, at RT for at least 1 h. The resulting intermediate (v) is reacted with l,3-dioxoisoindolin-2-yl 2,2-dimethyltetrahydro-2H- pyran-4-carboxylate in presence a suitable radical initiator, such as 4DPAIPN, in an appropriate solvent, such as DMSO. The reaction is stirred at RT, under N2 atmosphere, under LED (395-456 nm) irradiation, for 16 h.Scheme 2

[0041] Scheme 2 depicts the preparation of the triazine intermediate (i) beginning with a suitable triazine amine (vi). The triazine amine (vi) is reacted with methylboronic acid under Suzuki coupling conditions in the presence of an appropriate Pd catalyst, such as Pd(dppf)C12, and a suitable base, such as K3PO4, in an appropriate solvent mixture, such as dioxane and H2O, at 100 °C for 12 h. Following the protection of the amine (vii) under conditions well known to the skilled artisan, intermediate (viii) is reacted with l,3,5-trichloro-l,3,5-triazinane-2,4,6-trione, in a suitable solvent, such as DCE, at 70 °C for 12 h. The triazine (ix) and protected lactam (x) are reacted under standard nucleophilic substitution conditions and include a suitable base, such as CS2CO3, in an appropriate solvent, such as THF. Following the deprotection of the amines of intermediate (xi) under acidic conditions well known to the skilled person, the ester (xii) is hydrolyzed in the presence of a suitable base, such as LiOH, in an appropriate mixture ofsolvents, such as THF and H2O. The triazine intermediate (i) is generated under decarboxylation conditions and include reacting (xiii) with NaCl in a suitable solvent, such as DMF, at 100 °C for 12 h.Scheme 3

[0042] Scheme 3 depicts an alternative preparation of the triazine intermediate (i) beginning with a suitable piperidone (xiv). The piperidone (xiv) is reacted in the presence of TMSC1, TMEDA and I2 in an appropriate solvent, such as toluene, at 0 °C for 2 h. The resulting intermediate (xv) is reacted with a suitable phosphite, such as triethyl phosphite, in an appropriate solvent, such as toluene, at 100 °C for 12 h, under N2 atmosphere. The ylide (xvi) and the aldehyde (xvii) are reacted under Wittig-Homer conditions and include a suitable base, such as KOtBu, in an appropriate solvent, such as THF. The olefin intermediate (xviii) is reacted under hydrogenation conditions and include H2, NHi.MeOH and Pd / AhCh, in a suitable mixture of solvents, such as DCM and MeOH. Following the rearomatization of the triazine (xix) into theintermediate (xx), which was deprotected under acidic conditions with an appropriate acid, such as TFA, in a suitable solvent, such as DCM to provide the triazine intermediate (i).PREPARATIONS Preparation 1 (l-(trifluoromethyl)cy cl opropyl)m ethanol

[0043] To the flow reactor 1 was added a solution of 1- (trifluoromethyl)cyclopropanecarboxylic acid (500 g, 3.24 mol) in THF (10 mL) and BH3 THF complex (IM, 6.49 L). The temperature of flow reactor 1 was set at 80 °C. The flow rate of pump 1 was adjusted to 15 mL / min for solution 1. The mixture was collected with a bottle containing aq. NH4CI solution. The reaction mixture was collected after running 180 min. The reaction mixture was diluted with H2O and extracted with EtOAc, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (250 g, 1.78 mol, 55%) as a yellow oil. 'HNMR (400 MHz, CDCI3) d 3.72 (s, 2H), 1.10 - 0.95 (m, 2H), 0.83 - 0.70 (m, 2 H).Preparation 2 l-(trifluoromethyl)cyclopropane-l-carbaldehyde

[0044] To a solution of methyl sulfmylmethane (87.0 g, 1.11 mol, 87 mL) in DCM (9 mL) was added oxalyl dichloride (70.6 g, 556 mmol, 48.7 mL). The mixture was stirred at -70 °C for 0.5 h. Then l-(trifluoromethyl)cyclopropyl)methanol (60.0 g, 428 mmol) in DCM (1 mL) was added and the mixture was stirred at -70 °C for 0.5 h. To the mixture was then added TEA (212 g, 2.10 mol, 292 mL). The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was diluted with H2O and washed with sat. aq. NaCl solution, the organic layers were combined, and dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title product (59.0 g, crude) as a yellow oil. ‘H NMR (400 MHz, CDCI3) d 9.68 (s, 1H), 1.28 - 1.15 (m, 2H), 0.83 - 0.80 (m, 2H).Preparation 3 ethyl 3-(l-(trifluoromethyl)cyclopropyl)acrylate

[0045] A mixture of l-(trifluoromethyl)cyclopropane-l-carbaldehyde (59.0 g, 427 mmol), ethyl 2-(dimethoxyphosphoryl)acetate (92.1 g, 469 mmol), 2, 3, 4, 6,7,8- hexahydropyrrolo[l,2-a]pyrimidine (58.3 g, 469 mmol, 56.2 mL), and LiCl (19.9 g, 469 mmol, 9.63 mL) in DCM (6 mL) was stirred at 20 °C for 4 h. The reaction mixture was diluted with H2O and extracted with EtOAc, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCL, PEZEtOAc) to afford the title product (43.0 g, 206 mmol, 48%) as a yellow oil.JH NMR (400 MHz, CDCI3) d 6.70, (d, J= 16.0 Hz, 1H), 5.88 (d, J= 16.0 Hz, 1H), 4.21 (q, J= 6.8 Hz, 2H), 1.43 - 1.37 (m, 2H), 1.30 (t, J= 7.2 Hz, 3H), 1.07 - 1.01 (m, 2H).Preparation 4 ethyl 3-(l-(trifluoromethyl)cyclopropyl)propanoate

[0046] To a solution of Pd / C (5.11 g, 4.80 mmol, 10.0 % purity) in THF (2 mL) was added ethyl 3-(l-(trifluoromethyl)cyclopropyl)acrylate (20.0 g, 96.0 mmol). The mixture was stirred at 20 °C under H2 atmosphere for 3 h. The reaction mixture was filtered and the cake was washed with MeOH. The filtrate was concentrated under reduced pressure to afford the title product (12.0 g, 57.0 mmol, 59%) as a white oil. 'HNMR (400 MHz, CDCI3) d 4.14 (q, J= 7.2 Hz, 2H), 2.49 (t, J= 7.6 Hz, 2H), 1.90 (t, J= 8.0 Hz, 2H), 1.27 (t, J= 7.2 Hz, 3H), 1.00 - 0.96 (t, J= 5.6 Hz, 2H), 0.65 - 0.62 (m, 2H).Preparation 53 -( 1 -(trifluoromethyl)cy clopropyl)propan- 1 -ol

[0047] Ethyl 3-(l-(trifluoromethyl)cyclopropyl)propanoate (20.0 g) was dissolved in THF (240 mL) (solution 1). LAH (2.50 M, 7.22 g) (solution 2). The solution 1 was pumped by pump 1 {SI, Pl, 22.5 mL / min} to flow reactor 1 {FLR1, PF A, Coils reactor, 3.175 (1 / 8”) mm, 60 mL, 25 °C}. The solution 2 was pumped by pump 2 {S2, P2, 7.492 mL / min} to flow reactor 1 {FLR1, PF A, Coils reactor, 3.175 (1 / 8”) mm, 60 mL, 25 °C}. The residence time of flow reactor 1 was 2 min. The mixture was collected with a bottle containing Na2SO4 • 10 FEO. Pump 2 was started, after 2 min Pump 1 was started, the total reaction time was 30 min. The reaction mixture was filtered and the cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to afford the title product (15.0 g, 89.2 mmol, 94%) as a white oil.JH NMR (400 MHz, CDC13) d 3.65 (t, J= 6.0 Hz, 2H), 1.75 - 1.63 (m, 4H), 0.98 - 0.92 (m, 2H), 0.65 - 0.58 (m, 2H).Preparation 6 3-(l-(trifluoromethyl)cyclopropyl)propanal

[0048] To a solution of methyl sulfinylmethane (19.3 g, 247 mmol, 19.3 mL) in DCM(160 mL) was added oxalyl dichloride (15.7 g, 123 mmol, 10.8 mL) at -70 °C and stirred at -70 °C for 0.5 h. A solution of 3-(l-(trifluoromethyl)cyclopropyl)propan-l-ol (16.0 g, 95.1 mmol) in DCM (40 mL) was then added at -70 °C and the mixture was stirred for 0.5 h. Finally, TEA was added (47.1 g, 466 mmol, 64.8 mL) at -70 °C and the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was diluted with H2O. The organic layers were washed with H2O, dried over anhydrous ISfeSCU, and concentrated under reduced pressure to afford the title product (15.8 g, 95.1 mmol, 100%) as a yellow oil. 'HNMR (400 MHz, CDCI3) d 9.80 (s, 1H), 2.68 (t, J= 7.6 Hz, 2H), 1.92 - 1.88 (m, 2H), 1.00 - 0.97 (m, 2H), 0.63 - 0.52 (m, 2H).Preparation 7(S,E)-2-methyl-N-(3-(l-(trifluoromethyl)cyclopropyl)propylidene)propane-2-sulfinamide

[0049] To a solution of 3-(l-(trifluoromethyl)cyclopropyl)propanal (15.0 g, 90.2 mmol) in DCE (150 mL) and DCM (150 mL) was added CuSCU (43.2 g, 270 mmol, 41.5 mL) and (S)-2- methylpropane-2-sulfmamide (21.8 g, 180 mmol). The mixture was stirred at 60 °C for 8 h. The reaction mixture was filtered and washed with EtOAc. The filtrate was diluted with H2O and extracted with EtOAc, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PEZEtOAc) to afford the title product (13.0 g, 48.2 mmol, 53%) as a yellow oil.JH NMR (400 MHz, CDCI3) d 8.08 (t, J = 4.0 Hz, 1H), 2.74 - 2.67 (m, 2H), 1.93 - 1.87 (m, 2H), 1.20 - 1.17 (m, 9H), 1.03 - 0.99 (m, 2H), 0.66 - 0.56 (m, 2H).Preparation 8(S)-N-((S)- 1 -cyano-3 -( 1 -(trifluoromethyl)cyclopropyl)propyl)-2-methylpropane-2-sulfmamide

[0050] A mixture of (S,E)-2-methyl-N-(3-(l- (trifluoromethyl)cyclopropyl)propylidene)propane-2-sulfmamide (13.0 g, 48.2 mmol), TMSCN (19.1 g, 193 mmol, 24.1 mL, 4.01 eq), H2O (1.74 g, 96.5 mmol, 1.74 mL, 2.00 eq) and CsF (1.47 g, 9.65 mmol) in DCM (130 mL) was degassed and purged with N2 for 3 times at 0 °C, and then the mixture was stirred at 25 °C under N2 atmosphere for 12 h. The reaction mixture was diluted with H2O and extracted with EtOAc, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PEZEtOAc) to afford the title product (10.0 g, 31.1 mmol, 65%) as a yellow oil.1H NMR (400 MHz, CDCI3) d 4.22 - 4.21 (m, 1H), 4.18 (d, J= 7.2 Hz, 1H), 2.14 - 2.06 (m, 2H), 1.83 - 1.70 (m, 2H), 1.26 - 1.25 (m, 9H), 1.03 (s, 2H), 0.67 - 0.60 (m, 2H).Preparation 9 (S)-2-amino-4-(l-(trifluoromethyl)cyclopropyl)butanoic acid

[0051] A solution of (S)-N-((S)-l-cyano-3-(l-(trifluoromethyl)cyclopropyl)propyl)-2- methylpropane-2-sulfmamide (10.0 g, 31.1 mmol) in HC1 (1 mL) and AcOH (10 mL) was stirred at 80 °C for 3.5 h. The reaction mixture was concentrated under reduced pressure to afford the title product (7.00 g, crude, HC1) as a yellow oil. ES / MS (m / z): 212 (M+H).Preparation 10(S)-2-(((benzyloxy)carbonyl)amino)-4-(l-(trifluoromethyl)cyclopropyl)butanoic acid

[0052] A mixture of (S)-2-amino-4-(l-(trifluoromethyl)cyclopropyl)butanoic acid (6.40 g, 30.3 mmol), benzyl (2,5-dioxopyrrolidin-l-yl) carbonate (11.3 g, 45.4 mmol), K2CO3 (12.5 g, 90.9 mmol) and H2O (20 mL) in THF (1 mL) was stirred at 20 °C under N2 atmosphere for 1 h. The reaction mixture was quenched by IM aq. HC1 (50 mL) at 0 °C, and then diluted with H2O and extracted with EtOAc. The combined organic layers were dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, which was purified by prep- HPLC (column: Phenomenex luna C18 (250^70 mm, 10 um); mobile phase: [H2O (FA) - ACN]; gradient: 34% - 64% B over 20 min) to afford the title product (8.00 g, 22.5 mmol, 78% yield) as a yellow solid. ES / MS (m / z): 346 (M+H).Preparation 11 benzyl (S)-(l-(dimethyl(oxo)-16-sulfaneylidene)-2-oxo-5-(l-(trifluoromethyl)cyclopropyl)pentan-3-yl)carbamate

[0053] Trimethylsulfoxoniumiodide (2.78 g, 12.6 mmol) in THF (30 mL) was added to a solution of KO / Bu (IM, 12.6 mL) and the resulting mixture was stirred at 25 °C for 1 h to obtain a first mixture. To (S)-2-(((benzyloxy)carbonyl)amino)-4-(l-(trifluoromethyl)cyclopropyl)butanoic acid (3.00 g, 8.44 mmol) in THF (30 mL) was added CDI (1.78 g, 10.9 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for 1 h. The suspension was then filtered and the filtrate was cooled to 25 °C to obtain a second mixture. The second mixture was added to the first at 25 °C. The resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCh, PEZEtOAc) and then was purified by prep-HPLC (column: Phenomenex luna C 18 (250^70 mm, 10 um); mobile phase: [H2O (FA) - ACN]; gradient: 40% - 70% B over 30 min). Then residue was purified by prep-SFC (column: DAICEL CHIRALPAK AD (250 mmx30 mm, 10 um); mobile phase: [CO2- EtOH (0.1% NH3H2O)]; B%:45%, isocratic elution mode ) to afford the title product (2.80 g, 6.43 mmol, 61%) as a yellow solid. ES / MS (m / z): 420 (M+H).Preparation 12 benzyl (S)-(l-bromo-2-oxo-5-(l-(trifluoromethyl)cyclopropyl)pentan-3-yl)carbamate

[0054] To a solution of benzyl (S)-(l-(dimethyl(oxo)-16-sulfaneylidene)-2-oxo-5-(l- (trifluoromethyl)cyclopropyl)pentan-3-yl)carbamate (1.80 g, 4.13 mmol) in THF (20 mL) was added HBr (1.01 g, 4.13 mmol, 680 pL, 33.0% purity). The mixture was stirred at 55 °C for 2 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure togive a residue, which was purified by column chromatography (SiO2, PE / EtOAc) to afford the title product (1.74 g, 4.12 mmol, 97% yield) as a yellow solid. ES / MS (m / z): 422 (M+H).Preparation 13 6-vinyl- 1 , 2, 4-tri azin-3 -amine

[0055] To a solution of 6-bromo-l,2,4-triazin-3-amine (200 g, 1.14 mol) and 4, 4,5,5- tetramethyl-2-vinyl-l,3,2-dioxaborolane (193 g, 1.26 mol, 213 mL) in dioxane (1200 mL) and H2O (62 mL) was added Pd(dppf)C12 (41.8 g, 57.1 mmol) and K3PO4 (509 g, 2.40 mol). The mixture was stirred at 80 °C for 3 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PEZEtOAc) to afford the title product (139 g, crude) as a white solid.JH NMR (400 MHz, CDCI3) d 8.34 (s, 1H), 6.99 - 6.77 (m, 1H), 6.08 (d, J = 16.0 Hz, 1H), 5.71 - 5.41 (m, 3H).

[0056] The compound in the following table was prepared essentially as described in Preparation 13 using the appropriate triazine amine.Preparation 15 / c V-biityl (6-vinyl- 1, 2, 4-triazin-3-yl)carbamate

[0057] To a solution of 6-vinyl- 1, 2, 4-triazin-3 -amine (100 g, 818 mmol) in THF (300 mL) was added LiHMDS (IM, 1.15 L) at -65 °C for 1 h. Then Boc2O (232 g, 1.06 mol, 244 mL)in THF (200 mL) was added at -65 °C for 1 h. The mixture was stirred at -65 °C for 1 h under N2 atmosphere. The reaction mixture was diluted with sat. aq. NH4CI and extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PEZEtOAc) to afford the title product (100 g, crude) as a white solid. ES / MS (m / z): 123 (M-99).Preparation 16 tert-butyl (6-formyl-l,2,4-triazin-3-yl)carbamate

[0058] To a solution of tert-butyl (6-vinyl-l,2,4-triazin-3-yl)carbamate (100 g, 449 mmol) in THF (1750 mL) and H2O (1150 mL) was added OsC (3.50 g, 13.7 mmol, 714 pL) at 0 °C and stirred for 10 min. Then NalC was added (240 g, 1.12 mol, 62.3 mL) at 0 °C in four portions, the reaction mixture was stirred at 0 °C for another 4 h under N2 atmosphere. The reaction mixture was filtered, and then filtrate was quenched by FeCh solution, then stirred for another 0.5 h. The mixture was extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCh, PEZEtOAc) to afford the title product (80.0 g, 338 mmol, 75% yield) as a yellow oil. ES / MS (m / z): 223 (M-H).Preparation 17 3 -iodopiperidin-2-one

[0059] TMSC1 (219 g, 2.02 mol, 256 mL) was added dropwise to a solution cooled to 0 °C of piperidin-2-one (100 g, 1.01 mol) and TMEDA (351 g, 3.03 mol, 456 mL) in toluene (1000 mL) under N2 atmosphere, the mixture was stirred at 0 °C for 0.5 h, then I2 (307 g, 1.21 mol, 243 mL) was introduced in three portions. The reaction mixture was stirred at 0 °C for 2 h. Thereaction mixture was quenched by addition of sat. aq. NaHCCh at 0 °C. The reaction mixture was diluted with H2O and extracted with DCM. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCh, PEZEtOAc) to afford the title product (177 g, crude) as a white solid.JH NMR (400 MHz, CDCI3) d 7.32 (s, 1H), 4.76 (t, J = 4.0 Hz, 1H), 3.30 - 3.20 (m, 2H), 2.17 - 1.99 (m, 2H), 1.94 - 1.80 (m, 1H), 1.75 - 1.73 (s, 1H).

[0060] The compound in the following table was prepared essentially as described in Preparation 17 using the appropriate piperidone.Preparation 19 diethyl (2-oxopiperi din-3 -yl)phosphonate

[0061] A solution of 3-iodopiperidin-2-one (177 g, 786 mmol) and triethyl phosphite (653 g, 3.93 mol, 674 mL) in toluene (600 mL) was stirred at 100 °C for 12 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography ( Si O2, PEZEtOAc then DCM / MeOH) to afford the title product (150 g, crude) as a white solid. 'HNMR (400 MHz, CDCI3) d 6.47 (s, 1H), 4.34 - 4.00 (m, 4H), 3.44 - 3.26 (m, 2H), 3.11 - 2.88 (m, 1H), 2.30 - 1.96 (m, 3H), 1.88 - 1.66 (m, 1H), 1.41 - 1.28 (m, 6H).

[0062] The compound in the following table was prepared essentially as described in Preparation 19 using the appropriate iodopiperidone.Preparation 21 ter -butyl (E)-(6-((2-oxopiperi din-3 -ylidene)m ethyl)- 1, 2, 4-triazin-3-yl)carbamate

[0063] To a solution of diethyl (2-oxopiperi din-3 -yl)phosphonate (55.9 g, 237 mmol) in THF (500 mL) was added KO / Bu (IM, 246 mL) at 0 °C for 1 h. tert-Butyl (6-formyl- 1,2,4- triazin-3-yl)carbamate (41.0 g, 182 mmol) in THF (250 mL) was added. The mixture was stirred at 25°C for 1 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCL, DCM / MeOH) to afford the title product (45.0 g, 147 mmol, 81%) as a white solid. ES / MS (m / z): 306 (M+H).

[0064] The compound in the following table was prepared essentially as described in Preparation 21 using the appropriate piperidone phosphonate.Preparation 23 tert-butyl (6-((2-oxopiperi din-3 -yl)m ethyl)- 1,6-dihydro-l, 2, 4-triazin-3-yl)carbamate

[0065] To a mixture of tert-butyl (E)-(6-((2-oxopiperi din-3 -ylidene)methyl)- 1,2, 4-triazin- 3-yl)carbamate (45.0 g, 147 mmol) and NHLMeOH (7M, 63.1 mL) in MeOH (2000 mL) was stirred at 20 °C until becoming clear solution. The H2 back pressure regulator was adjusted to 0 MPa, the flow rate of H2 to 95 mL / min, heated the fixed bed Pd / AhCL (30.0 g, 147 mmol, 5% purity) to 20 °C. Then the solution was pumped into the reactor at a flow rate of 3 mL / min, for 25 h in total. After the reaction was finished, the tubing was washed with MeOH (400 mL), all the reaction solution was collected for analysis. The reaction mixture was concentrated under reduced pressure to give a residue, which was triturated with DCM at 25 °C for 10 min to afford the title product (40.0 g, crude) as a white solid. ES / MS (m / z): 310 (M+H).

[0066] The compound in the following table was prepared essentially as described in Preparation 23 using the appropriate piperidone triazine.Preparation 25 tert-butyl (6-((2-oxopiperidin-3-yl)methyl)-l,2,4-triazin-3-yl)carbamate

[0067] To a solution of tert-butyl (6-((2-oxopiperi din-3 -yl)m ethyl)- 1,6-dihydro-l, 2,4- triazin-3-yl)carbamate (49.0 g, 158 mmol) in THF (500 mL) was added DDQ (35.9 g, 158 mmol)at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by addition of sat. aq. NaHCCL at 0 °C, and then extracted with DCM / MeOH (10: 1). The combined organic layers were washed with aq. NaHCCL, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, which was triturated with PEZEtOAc (1 : 1) at 25 °C for 20 min to afford the title product (40.0 g, crude) as a white solid. ES / MS (m / z): 308 (M+H).

[0068] The compound in the following table was prepared essentially as described in Preparation 25 using the appropriate dihydrotriazine.Preparation 27 3-((3-amino-l,2,4-triazin-6-yl)methyl)piperidin-2-one (isomer 2)

[0069] To a solution of tert-butyl (6-((2-oxopiperi din-3 -yl)m ethyl)- 1, 2, 4-triazin-3- yl)carbamate (40.0 g, 130 mmol) in DCM (300 mL) was added TFA (230 g, 2.02 mol, 150 mL) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue, then the pH of the residue was adjusted to 8 by addition of NHs / MeOH (7M) and concentrated under reduced pressure to give a residue. Single stereoisomers were isolated by chiral SFC purification (column: DAICEL CHIRALPAK AY (250 mm * 50 mm, 10 um); mobile phase: [CCh-ACN / zPrOH (0.1% NH3H2O)]; B%:50%, isocratic elution mode) and reversed-phase HPLC (column: Welch Ultimate XB-NH2 250 * 50 * 10 um; mobile phase: [Hexane-EtOH 0.1% NH3.H2O ]; gradient:25%-65% B over 15 min). The second eluting isomer (8.00 g, 34.7 mmol, 27%, 89.9% purity) was obtained as a white solid. ES / MS (m / z): 208 (M-55).

[0070] The compound in the following table was prepared essentially as described in Preparation 27 using the appropriate piperidone triazine.Preparation 29 tert-butyl (terZ-butoxycarbonyl)(6-methyl-l,2,4-triazin-3-yl)carbamate

[0071] To a solution of 6-methyl-l,2,4-triazin-3-amine (60.0 g, 544 mmol) in DCM (400 mL) was added BOC2O (297 g, 1.36 mol, 312 mL) and DMAP (53.2 g, 435 mmol). The mixturewas stirred at 25 °C for 12 h. The mixture was concentrated to afford the title product (40.0 g, 128 mmol, 24%) as a yellow solid. ES / MS (m / z): 311 (M+H).Preparation 30 tert-butyl (tert-butoxycarbonyl)(6-(chloromethyl)-l,2,4-triazin-3-yl)carbamate

[0072] To a solution of tert-butyl A-tert-butoxycarbonyl-N-(6-methyl-l,2,4-triazin-3- yl)carbamate (40.0 g, 128 mmol) in DCE (400 mL) was added l,3,5-trichloro-l,3,5-triazinane- 2, 4, 6-trione (20.9 g, 90.2 mmol). The mixture was stirred at 70 °C for 12 h. The mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiCh, PEZEtOAc) to afford the title product (16.0 g, 46.4 mmol, 36%) as yellow oil. ES / MS (m / z): 245 (M-99)Preparation 312-(tert-butyl) 4-methyl 4-((3-(bis(tert-butoxycarbonyl)amino)-l,2,4-triazin-6-yl)methyl)-3-oxo- 2-azabicyclo[3.1.1 ]heptane-2,4-dicarboxylate

[0073] To a solution of 2-(tert-butyl) 4-methyl 3-oxo-2-azabicyclo[3.1.1]heptane-2,4- dicarboxylate (10.3 g, 38.2 mmol) in THF (150 mL) was added CS2CO3 (22.6 g, 69.6 mmol) at 0 °C under N2 atmosphere. The mixture was stirred at 0°C for 1 h, then was added tert-butyl (tert- butoxycarbonyl)(6-(chloromethyl)-l,2,4-triazin-3-yl)carbamate (12.0 g, 34.8 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was partitioned between H2O and EtOAc. The organic phase was separated, washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4,filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, PE / EtOAc) to afford the title product (18.0 g, 31.1 mmol, 90%) as yellow oil. ES / MS (m / z): 578 (M+H).Preparation 32 methyl 4-((3-amino-l,2,4-triazin-6-yl)methyl)-3-oxo-2-azabicyclo[3.1.1]heptane-4-carboxylate;TFA

[0074] To a solution of 2-( / c / 7-butyl) 4-methyl 4-((3-(bis(tert-butoxycarbonyl)amino)- l,2,4-triazin-6-yl)methyl)-3-oxo-2-azabicyclo[3.1.1]heptane-2,4-dicarboxylate (18.0 g, 31.1 mmol) in DCM (180 mL) was added TFA (35.5 g, 311 mmol, 23.1 mL). The mixture was stirred at 25 °C for 12 h. The residue was concentrated to afford the title product (12.0 g, 30.6 mmol, 98%, TFA) as yellow oil. ES / MS (m / z): 278 (M+H).Preparation 334-((3-amino-l,2,4-triazin-6-yl)methyl)-3-oxo-2-azabicyclo[3.1.1]heptane-4-carboxylic acid

[0075] To a solution of methyl 4-((3-amino-l,2,4-triazin-6-yl)methyl)-3-oxo-2- azabicyclo[3.1.1]heptane-4-carboxylate; TFA (12.0 g, 30.6 mmol) in THF (120 mL) and H2O (20.0 mL) was added LiOH.H2O (3.86 g, 92.0 mmol). The mixture was stirred at 25 °C for 12 h. The residue was adjusted with IM aq HC1 to pH = 6, the mixture was concentrated to the title product (8.00 g, 30.3 mmol, 99%) as yellow oil. ES / MS (m / z): 264 (M+H).Preparation 344-((3-amino-l,2,4-triazin-6-yl)methyl)-2-azabicyclo[3.1.1]heptan-3-one

[0076] To a solution of 4-((3-amino-l,2,4-triazin-6-yl)methyl)-3-oxo-2- azabicyclo[3.1.1]heptane-4-carboxylic acid (4.00 g, 10.6 mmol) in DMF (50.0 mL) was added NaCl (1.24 g, 21.2 mmol). The mixture was stirred at 100 °C for 12 h. The mixture was filtered and concentrated to give a residue. The residue was purified by reversed-phase HPLC (column: Welch Ultimate XB > C18 20 - 40pm; 120 A; mobile phase: [H2O (NH4HCO3) - ACN]; B%: 30 - 50% 45min; % min) to afford the title product (1.20 g, 5.47 mmol, 52%) as a yellow solid. ES / MS (m / z): 220 (M+H).Preparation 354-((3 -amino- 1 ,2,4-triazin-6-yl)methyl)-2-azabicyclo[3.1.1 ]heptan-3 -one (isomer 1 ) Preparation 364-((3 -amino- 1 ,2,4-triazin-6-yl)methyl)-2-azabicyclo[3.1.1 ]heptan-3 -one (isomer 2)

[0077] The mixture of stereoisomers of 4-((3-amino-l,2,4-triazin-6-yl)methyl)-2- azabicyclo[3.1.1]heptan-3-one was purified by prep-SFC (column: DAICEL CHIRALPAK IG (250 mm * 30 mm, 10 urn); mobile phase: [CO2- ACN / EtOH (0.1% NH3H2O)]; B%: 70%, isocratic elution mode). The first eluting isomer (1.20 g, 5.47 mmol, 55%) was obtained as yellow solid. ES / MS (m / z): 220 (M+H). The second eluting isomer (1.30 g, 5.93 mmol, 59%) was obtained as yellow solid. ES / MS (m / z): 220 (M+H).Preparation 37 l,3-dioxoisoindolin-2-yl 2,2-dimethyltetrahydro-2H-pyran-4-carboxylate

[0078] A mixture of 2,2-dimethyltetrahydro-2H-pyran-4-carboxylic acid (1.00 g, 6.32 mmol), 2-hydroxyisoindoline-l,3-dione (1.13 g, 6.95 mmol), DCC (1.57 g, 7.59 mmol, 1.53 mL), and DMAP (77.2 mg, 632 pmol) in THF (30.0 mL) was stirred at 20 °C for 2 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, PEZEtOAc) to afford the title product (1.50 g, 4.95 mmol, 78%) as a white solid. 'H NMR (400 MHz, CDCI3) 8 7.92 - 7.88 (m, 2H), 7.83 - 7.79 (m, 2H), 3.90 - 3.83 (m, 1H), 3.74 (d, J = 2.4 Hz, 1H), 3.17 - 3.07 (m, 1H), 2.06 - 1.72 (m, 4H), 1.30 (d, J = 7.1 Hz, 6H).Preparation 38 benzyl (3-(dimethyl(oxo)-16-sulfaneylidene)-2-oxo-l-(spiro[2.5]octan-6-yl)propyl)carbamate (isomer 1)Preparation 39 benzyl (3-(dimethyl(oxo)-16-sulfaneylidene)-2-oxo-l-(spiro[2.5]octan-6-yl)propyl)carbamate (isomer 2)

[0079] 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 - MeOH (0.1% NH3H2O)]; B%: 45%, isocratic elution mode) (740 mg, 1.76 mmol, 34%, 93.1% purity) was obtained as a white solid. ES / MS (m / z): 392 (M+H). 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 - MeOH (0.1% NH3H2O)]; B%: 45%, isocratic elution mode)(730 mg, 1.82 mmol, 36% yield, 97.4% purity) was obtained as a white solid. ES / MS (m / z): 392 (M+H).Preparation 40 benzyl (3-bromo-2-oxo-l-(spiro[2.5]octan-6-yl)propyl)carbamate

[0080] To a solution of benzyl (R)-(3-(dimethyl(oxo)-16-sulfaneylidene)-2-oxo-l- (spiro[2.5]octan-6-yl)propyl)carbamate (730 mg, 1.86 mmol) in THF (8.00 mL) was added LiBr (194 mg, 2.24 mmol, 56.1 pL) and methanesulfonic acid (215 mg, 2.24 mmol, 159 pL). The mixture was stirred at 45 °C for 1 h. The residue was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiCE, PEZEtOAc) to afford the title product (540 mg, 1.37 mmol, 73%) as a white solid.JH NMR (400 MHz, CDCI3) 8 7.37 (s, 5H), 5.35 (d, J = 7.2 Hz, 1H), 5.12 (d, J = 3.6 Hz, 2H), 4.16 - 4.05 (m, 1H), 3.70 - 3.40 (m, 2H), 2.02 - 1.80 (m, 4H), 1.57 - 1.33 (m, 2H), 1.29 - 1.16 (m, 1H), 0.97 - 0.81 (m, 2H), 0.36 - 0.12 (m, 4H).Preparation 41 benzyl ((S)-(4, 4-difluorocy cl ohexyl)(2-((2-oxopiperi din-3 -yl)methyl)imidazo[ 1,2- b] [ 1 ,2,4]triazin-6-yl)methyl)carbamate

[0081] To a solution of 3-((3-amino-l,2,4-triazin-6-yl)methyl)piperidin-2-one (1.40 g, 6.76 mmol) and benzyl (S)-(3-bromo-l-(4,4-difluorocyclohexyl)-2-oxopropyl)carbamate (isomer 2) (3.28 g, 8.11 mmol) in THF (20.0 mL) was added trimethyl borate (3.51 g, 33.7 mmol, 3.82 mL) and DIPEA (4.37 g, 33.7 mmol, 5.88 mL). The mixture was stirred at 75 °C for 1 h. The residue was diluted with H2O and extracted with EtOAc, dried over ISfeSCU, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, PEZEtOAc) to afford the title product (2.30 g, 4.49 mmol, 55%) as a yellow solid. ES / MS (m / z): 513 (M+H).

[0082] The compounds in the following table were prepared essentially as described in Preparation 41 using the appropriate triazine and alkyl halide.Preparation 57 benzyl ((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5- methyl -2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l, 2, 4]triazin-6-yl)methyl)carbamate

[0083] To a solution of benzyl ((S)-(4,4-difluorocyclohexyl)(2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)carbamate (450 mg, 854 pmol), l,3-dioxoisoindolin-2-yl 2,2-dimethyltetrahydro-2H-pyran-4-carboxylate (518 mg, 1.71 mmol) and 4DPAIPN (34.0 mg, 42.7 pmol) in DMSO (5 mL) was added TFA (194 mg, 1.71 mmol, 126 pL). The reaction mixture was degassed and purged with N2. The reaction mixture was stirred at RT for 16 h while irradiating with a LED (395-456 nm). 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 ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, and the residue was purified by prep-HPLC (column: Phenomenex luna C 18 150 * 25 mm * 10 um; mobile phase: [H2O (HC1) - ACN]; gradient: 45% - 75% B over 9 min) to afford the title product (390 mg, 610 pmol, 71%) as a yellow solid. ES / MS (m / z): 639 (M+H).

[0084] The compound in the following table was prepared essentially as described in Preparation 57 using the appropriate imidazotriazine.Preparation 59 3-((6-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2-b][l,2,4]triazin-2- yl)methyl)piperidin-2-one

[0085] A solution of benzyl ((S)-(4, 4-difluorocy cl ohexyl)(2-((2-oxopiperi din-3 - yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)carbamate (2.30 g, 4.49 mmol) in 12M aq. HC1 (20.0 mL) and AcOH (2.00 mL) was stirred at 50 °C for 0.5 h. The residue was diluted with H2O and extracted with EtOAc, the aqueous phase was adjusted with sat. aq. ISfeCCh solution to pH = 8 at 0 °C and extracted with EtOAc, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title product (1.35 g, 3.57 mmol, 80%) as a yellow solid. ES / MS (m / z): 379 (M+H).

[0086] The compounds in the following table were prepared essentially as described in Preparation 59 using the appropriate protected amine.Preparation 73 (3R,5S)-3-((6-((S)-amino(4,4-difluorocyclohexyl)methyl)-3-(2,2-dimethyltetrahydro-2H-pyran- 4-yl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-2-yl)methyl)-5-methylpiperidin-2-one

[0087] To a solution of benzyl ((S)-(4,4-difluorocyclohexyl)(3-((S)-2,2- dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)carbamate (340 mg, 532 pmol) in MeOH (5.00 mL) were added Pd / C (100 mg, 93.9 mol, 10% purity) and NH4CO2H (268 mg, 4.26 mmol). The mixture was stirred at 20 °C for 0.5 h under H2 (15 Psi). The reaction mixture was filtered with MeOH (150 mL) and the filtrate was concentrated under reduced pressure to give aresidue. The residue was diluted with H2O, and adjusted pH = 8 with sat. aq. NaHCCh solution, and extracted with DCM. The combined organic dried over ISfeSCU, filtered, and concentrated under reduced pressure to afford the title product (260 mg, 515 pmol, 97%) as a white solid. ES / MS (m / z): 505 (M+H).Preparation 74(3R,5 S)-3 -((6-amino(spiro[2.5]octan-6-yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-2-yl)methyl)-5- methylpiperidin-2-one

[0088] To a solution of benzyl ((R)-(2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)(spiro[2.5]octan-6-yl)methyl)carbamate (160 mg, 309 pmol) in MeOH (3.00 mL) was added NH4OAC (97.6 mg, 1.55 mmol) and Pd / C (65.9 mg, 61.9 pmol, 10.0% purity) under N2 atmosphere. The mixture was stirred at 50 °C for 1 h. The mixture was filtered with MeOH and the filtrate was concentrated to give a residue, then the residue was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Phenomenex luna C18 150 * 25 mm * 10 um; mobile phase: [H2O (FA) - ACN]; gradient: 10% - 40% B over 10 min) to afford the title product (30.0 mg, 78.4 pmol, 25%) as a white solid. ES / MS (m / z): 383 (M+H)Preparation 75 l-methyl-N-((S)-((lr,4S)-4-methylcyclohexyl)(2-((2-oxopiperidin-3-yl)methyl)imidazo[l,2- b][l,2,4]triazin-6-yl)methyl)-lH-pyrazole-5-carboxamide

[0089] A solution of 3-((6-((S)-amino((lr,4S)-4-methylcyclohexyl)methyl)imidazo[l,2- b][l,2,4]triazin-2-yl)methyl)piperidin-2-one (150 mg, 421 pmol), l-methyl-lH-pyrazole-5- carboxylic acid (159 mg, 1.26 mmol), and EDCI (161 mg, 842 pmol) in pyridine (2 mL) were stirred at RT for 1 h. The reaction mixture was then diluted with H2O and extracted with EtOAc. The combined organic layers were washed with H2O then sat. aq. NaCl solution, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, and the residue was purified by prep-TLC (column: Phenomenex luna Cl 8 150 * 25 mm * 10 um; mobile phase: [H2O (FA) - ACN]; gradient: 33% - 63% B over 10 min) to afford the title product (130 mg, 280 pmol, 67%) as a yellow solid. ES / MS (m / z): 465 (M+H).

[0090] The compounds in the following table were prepared essentially as described in Preparation 75 using the appropriate amine and carboxylic acid.

[0091] The compounds in the following table were prepared essentially as described in Preparation 75 using the appropriate amine and carboxylic acid. ES / MS (m / z): 477 (M+H). a: Isomer 1 was isolated as the first eluting, single stereoisomer by prep-SFC (column: DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 urn); mobile phase: [CO2 - iPrOH (0.1% NH3H2O)]; B%: 35%, isocratic elution mode) (270 mg, 566 pmol, 47%) was obtained as yellow solid, b: Isomer 2 was isolated as the second eluting, single stereoisomer by prep-SFC (column: DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 urn); mobile phase: [CO2- zPrOH (0.1%NH3H2O)]; B%: 35%, isocratic elution mode) (270 mg, 566 pmol, 47%) was obtained as yellow solid. ES / MS (m / z): 477 (M+H)Preparation 86 N-((S)-(4,4-difluorocyclohexyl)(2-((2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l, 2, 4]tri azin-6- yl)m ethyl)- 1 -isopropyl- 1H- 1 ,2,4-triazole-5-carboxamide

[0092] To a solution of 3-((6-((S)-amino(4,4-difluorocyclohexyl)methyl)imidazo[l,2- b][l,2,4]triazin-2-yl)methyl)piperidin-2-one (200 mg, 528 pmol) and lithium 1 -isopropyl- 1H- l,2,4-triazole-5-carboxylate (102 mg, 634 pmol) in DCM (2.00 mL) were added T4P (1.14 g, 1.59 mmol, 50% purity) and DIPEA (204 mg, 1.59 mmol). The mixture was stirred at 25 °C for 2 h. The residue was diluted with sat. aq. ISfeCCh solution and extracted with EtOAc, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCh, DCM / MeOH) to afford the title product (0.180 g, 349 pmol, 66%) as a yellow solid. ES / MS (m / z): 516 (M+H).

[0093] The compounds in the following table were prepared essentially as described in Preparation 86 using the appropriate amine and carboxylic acid.EXAMPLESExample 1N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5- methyl-2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -ethyl- 1H- pyrazole-5-carboxamide (isomer 1) Example 2N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5- methyl-2-oxopiperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -ethyl- 1H- pyrazole-5-carboxamide (isomer 2)

[0094] A solution of (3R,5S)-3-((6-((S)-amino(4,4-difluorocyclohexyl)methyl)-3-(2,2- dimethyltetrahydro-2H-pyran-4-yl)imidazo[l,2-b][l,2,4]triazin-2-yl)methyl)-5-methylpiperidin- 2-one (60.0 mg, 118 mol), l-ethyl-lH-pyrazole-5-carboxylic acid (20.0 mg, 142 mol), and EDCI (45.5 mg, 237 pmol) in pyridine (1 mL) were stirred at RT for 1 h. The reaction mixture was then diluted with H2O and extracted with EtOAc. The combined organic layers were washed with H2O then sat. aq. NaCl solution, dried over anhydrous ISfeSCU, filtered, and concentrated under reduced pressure to give a residue, and the residue was purified by prep-TLC (SiCh, EtOAc / MeOH) to afford a mixture of stereoisomers. Single stereoisomers were isolated by prep- SFC (column: REGIS (S, S) WHELK-01 (250 mm * 25 mm, 10 um); mobile phase: [CO2 - ACN / zPrOH (0.1% NH3H2O)]; B%:30%, isocratic elution mode). The first eluting isomer (14.89 mg, 22.8 pmol, 24%, 96.3% purity) was obtained as a white solid. ES / MS (m / z): 627 (M+H). The second eluting isomer (19.5 mg, 30.58 pmol, 32%, 98.3% purity) was obtained as a white solid. ES / MS (m / z): 627 (M+H).

[0095] 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 7

[0096] N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5R)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l- isopropyl-lH-l,2,4-triazole-5-carboxamide (isomer 1)Example 8

[0097] N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5R)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l- isopropyl-lH-l,2,4-triazole-5-carboxamide (isomer 2)

[0098] To a solution of (3R,5R)-3-((6-((S)-amino((S)-3,3-difluorocyclohexyl)methyl)-3- (2,2-dimethyltetrahydro-2H-pyran-4-yl)imidazo[l,2-b][l,2,4]triazin-2-yl)methyl)-5- methylpiperidin-2-one (80.0 mg, 158 pmol) and lithium l-isopropyl-lH-l,2,4-triazole-5- carboxylate (38.3 mg, 237 mol), in DCM (1 mL) was added DIPEA (81.9 mg, 634 mol, 110 pL) and T4P (50% EtOAc solution, 342 mg, 475 pmol) were stirred at RT for 2 h. The reaction mixture was then diluted with H2O and extracted with EtOAc. The combined organic layers were washed with H2O then sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, and the residue was purified by prep-HPLC (column: Phenomenex luna C18 150 * 25 mm * 10 um; mobile phase: [H2O (FA)-ACN]; gradient: 48%-78% B over 10 min) to afford a mixture of stereoisomers. Single stereoisomers were isolated by prep-SFC (basic condition; column: DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 um); mobile phase: [CO2 - zPrOH (0.1%NH3H2O)]; B%: 35%, isocratic elution mode). The first eluting isomer (22.83 mg, 35.08 pmol, 32%, 98.6% purity) was obtained as an off-white solid. ES / MS (m / z): 642 (M+H). The second eluting isomer (28.95 mg, 43.8 pmol, 40%, 97.1% purity) was obtained as an off-white solid. ES / MS (m / z): 642 (M+H).

[0099] The compounds in the following table were prepared essentially as described in Example 7 using the corresponding appropriate reagents, bases and solvents with the reaction time adjusted to reach completion.Example 15[000100] N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-oxopiperi din-3 -yl)methyl)imidazo[l, 2-b][l , 2, 4]triazin-6-yl)m ethyl)- 1 -isopropyl- 1H-1, 2,4- triazole-5-carboxamide (isomer 1)Example 16[000101] N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-oxopiperi din-3 -yl)methyl)imidazo[l, 2-b][l, 2, 4]triazin-6-yl)m ethyl)- 1 -isopropyl- 1H-1, 2,4- triazole-5-carboxamide (isomer 2)[000102] To an 8.00 mL vial equipped with a stir bar were added N-((S)-(4,4- difluorocy cl ohexyl)(2-((2-oxopiperi din-3 -yl)methyl)imidazo[l,2-b][ 1,2, 4]triazin-6-yl)m ethyl)- 1- isopropyl-lH-l,2,4-triazole-5-carboxamide (150 mg, 290 pmol), l,3-dioxoisoindolin-2-yl 2,2- dimethyltetrahydro-2H-pyran-4-carboxylate (176 mg, 581 pmol), 4DPAIPN (11.5 mg, 14.5 pmol) and TFA (33.1 mg, 290 pmol, 21.6 pL) in DMSO (3.00 mL). The vial was sealed and placed under N2 atmosphere. The reaction was stirred and irradiated with a 34 W 395mn LED lamp (7 cm away), with cooling fan to keep the temperature at 25 °C for 0.5 h. The residue wasdiluted with H2O and extracted with EtOAc, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex luna C18 150 * 25 mm * 10 um; mobile phase: [H2O (FA) - ACN]; gradient: 40% - 60% B over 8 min) to afford a mixture of stereoisomers (60.0 mg, 95.5 pmol) as a white solid. Single stereoisomers were isolated by prep-SFC (neutral condition, column: DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 um); mobile phase: [CO2- zPrOH (0.1%NH3H2O)]; B%: 30%, isocratic elution mode). The first eluting isomer (14.97 mg, 22.0 pmol, 23.0%, 92.4% purity) was obtained as a white solid. ES / MS (m / z): 628 (M+H). The second eluting isomer (14.42 mg, 22.8 pmol, 23.9% yield, 99.5% purity) was obtained as a white solid. ES / MS (m / z): 628 (M+H).[000103] The compounds in the following table were prepared essentially as described in Example 15 using the corresponding appropriate reagents, bases and solvents with the reaction time adjusted to reach completion.IL-17 A / A HEK-Blue Cell Assay[000104] The HEK-Blue IL-17A reporter cell line (Fisher #NC1408637) is used for cellbased IL-17A / A inhibition assays. Cells are grown and prepared for assays according to the manufacturer’s instructions. This cell line consists of HEK 293 cells that are designed to expressed IL-17RA, IL-17RC, and the Actl adapter molecule, the combination of which, when stimulated by IL-17A / A or IL17A / F activates a NFaB promoter and drives expression of the recombinant Secreted Alkaline Phosphatase (SEAP) gene. Media from the cells is then added to a development reagent (Quanti-Blue Substrate, Fisher #NC9711613), and read at Aeso.[000105] Compounds are dispensed in DMSO to an empty clear 384-well tissue culture plate in a titration ranging from 10 pM to 27 pM, with DMSO added to every well to a final concentration of 0.1%. Cells are then added to the plate (45 pL / well at a concentration of 280,000 cells / mL). IL17A / A (Genscript #Z03228) or IL17A / F (R&D Systems) is added to the plate to a final concentration of 5 ng / mL and a final well volume of 50 pL. The cells, compound, and IL-17A / A or IL17A / F are then incubated for 20 hours before media is removed for SEAP analysis. The resulting inhibition curve is then analyzed using Dotmatics’ integrated 4-parameter fit screening protocol to generate IC50 values. Table A includes IC50 values for IL-17A / A and IL- 17A / F inhibition of selected compounds.Table A: IL-17 A / A and IL-17 A / F Inhibition Data for selected compounds[000106] The data provided for selected examples in Table A demonstrate inhibition of ILI A / A and / or IL-17 A / F mediated signaling in the HEK-Blue Cell Assay.Rat Intravenous Half-life and Oral Bioavailability[000107] The test compound was administered as a solution (1 mg / mL) to fasted male Sprague Dawley rats intravenously (IV) at 1 mg / kg and orally (PO) by gavage at 5 mg / kg using a vehicle composed of 10% DMA (Dimethylacetamide), 50% Polyethylene Glycol 400, and 40% purified water. Three animals were dosed IV and 3 animals were dosed PO. Serial blood collections occurred at 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 h post IV bolus dose administration, and 0.25, 0.5, 1, 2, 4, 8 and 24 h post oral dose administration. Blood samples were collected into sample tubes containing K2EDTA anticoagulant. These samples were processed for plasma by centrifugation, then frozen and stored at -70 °C until analysis by LC-MS / MS. Test article concentration was determined in plasma and pharmacokinetics parameters were determined by non-compartmental analysis using Phoenix WinNonlin Version 8.3.5 and using individual plasma concentration time profiles. The following parameters were calculated:[000108] The terminal rate constant, <z(h-1) was determined by linear regression on a semilog concentration-time plot with a minimum of 3 data points.[000109] Half-life (ti / 2) was determined according to ti / 2 = 0.693 / kzAUC(o-t) is the area under the curve from the time of dosing to the last measurable concentration and was calculated using the linear / log trapezoidal rule.AUC(o-°o) was determined as AUC(o-°°) = AUC(o-t) + Ciast / V[000110] Oral Bioavailability (%F) was calculated using AUC(o-°°) if both the IV and POAUCextrapoiated was <20% or AUC(o-t) if either the IV and / or the PO AUCextrapoiated was >20% and was determined as %F = (AUCP0x DoseiV) / (AUCiVX DosePO) x 100[000111] Table B shows the rat intravenous half-life of selected compounds and Table C shows the rat oral bioavailability of selected compounds.Table B. Rat Intravenous Half-life (ti / 2) at 1 mg / kg of selected compoundsTable C. Rat Oral Bioavailability (%F) at 5 mg / kg of selected compounds[000112] The data provided in Table B and Table C illustrate that the selected compounds of the invention exhibit a range of pharmacologically advantageous pharmacokinetics properties as exemplified by their IV half-life and oral bioavailability.[000113] Compounds of the present invention provide novel inhibitors of IL-17A mediated signaling and demonstrate an advantageous combination of pharmacological properties such as potent inhibition of IL-17A binding to and signaling through the IL- 17 receptor and oral bioavailability. As such, compounds of the present invention, in particular the compounds of Formula I, and the examples provided herein, are believed to be useful in the treatment of psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, palmoplantar psoriasis, rheumatoid arthritis, multiple sclerosis, systemic sclerosis, psoriatic arthritis, spondyloarthritis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma, non-infectious uveitis, and COPD.

Claims

CLAIMSWhat is claimed is:

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

2. The compound according to claim 1 wherein R1isor a pharmaceutically acceptable salt thereof.The compound according to claim 1 wherein R1isor a pharmaceutically acceptable salt thereof.The compound according to claim 1 wherein R1isacceptable salt thereof.The compound according to claim 1 wherein R1ispharmaceutically acceptable salt thereof.The compound according to any of claims 2 to 5 whereinpharmaceutically acceptable salt thereof.

7. The compound according to any of claims 2 to 5 whereinpharmaceutically acceptable salt thereof.The compound according to any of claims 2 to 5 whereinpharmaceutically acceptable salt thereof.The compound according to any of claims 2 to 5 wherein R2isor a pharmaceutically acceptable salt thereof.

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

11. The compound according to any of claims 2 to 5 wherein R2ispharmaceutically acceptable salt thereof.

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

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

14. The compound of claim 1 selected from the group consisting of:N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)- 5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl- lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)- 5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl- lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)- 5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l- isopropyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)- 5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l- isopropyl-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l- methyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l- methyl- lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2- (((3R,5R)-5-methyl-2-oxopiperi din-3-yl)methyl)imidazo[l,2-b][l, 2, 4]tri azin-6- yl)methyl)-l -isopropyl- 1H-1, 2, 4-triazole-5-carboxamide (isomer 1);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2- (((3R,5R)-5-methyl-2-oxopiperi din-3-yl)methyl)imidazo[l,2-b][l, 2, 4]tri azin-6- yl)methyl)-l -isopropyl- 1H-1, 2, 4-triazole-5-carboxamide (isomer 2);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)- 5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl- lH-l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)- 5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-ethyl- lH-l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)- 5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l- isopropyl-lH-l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)- 5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l- isopropyl-lH-l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2- (((3R,5R)-5-methyl-2-oxopiperi din-3-yl)methyl)imidazo[l,2-b][l, 2, 4]tri azin-6- yl)methyl)-l-ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2- (((3R,5R)-5-methyl-2-oxopiperi din-3-yl)methyl)imidazo[l,2-b][l, 2, 4]tri azin-6- yl)methyl)-l-ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-isopropyl-lH- l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)methyl)-l-isopropyl-lH- l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((3-oxo-2- azabicyclo[3.1.1 ]heptan-4-yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 - isopropyl-lH-l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((3-oxo-2- azabicyclo[3.1.1 ]heptan-4-yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 - isopropyl-lH-l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5R)- 2-oxo-5-(trifluoromethyl)piperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)methyl)-l -isopropyl- 1H-1, 2, 4-triazole-5-carboxamide (isomer 1);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5R)- 2-oxo-5-(trifluoromethyl)piperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)methyl)-l -isopropyl- 1H-1, 2, 4-triazole-5-carboxamide (isomer 2);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2- (((3R,5R)-2-oxo-5-(trifluoromethyl)piperi din-3-yl)methyl)imidazo[l, 2-b][l, 2, 4]tri azin-6- yl)methyl)-l-ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2- (((3R,5R)-2-oxo-5-(trifluoromethyl)piperi din-3-yl)methyl)imidazo[l, 2-b][l, 2, 4]tri azin-6- yl)methyl)-l-ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((3-oxo-2-azabicyclo[3.1.1]heptan- 4-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l- methyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((3-oxo-2-azabicyclo[3.1.1]heptan- 4-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l- methyl-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l- methyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l- methyl-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-l-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)-5,5,5-trifluoro-4,4-dimethylpentyl)-l- methyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-l-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)-5,5,5-trifluoro-4,4-dimethylpentyl)-l- methyl-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((3-oxo-2-azabicyclo[3.1.1]heptan- 4-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l- methyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((3-oxo-2-azabicyclo[3.1.1]heptan- 4-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4-methylcyclohexyl)methyl)-l- methyl-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-cyclohexyl(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -methyl- lH-pyrazole-5- carboxamide (isomer 1);N-((lS)-cyclohexyl(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)methyl)- 1 -methyl- lH-pyrazole-5- carboxamide (isomer 2);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-l-methyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-l-methyl-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-l-methyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-l-methyl-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3-methylcyclohexyl)methyl)-l- methyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3-methylcyclohexyl)methyl)-l- methyl-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3-methylcyclohexyl)methyl)-l-(2- fluoroethyl)-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3-methylcyclohexyl)methyl)-l-(2- fluoroethyl)-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-l-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)-3-(l- (trifluoromethyl)cyclopropyl)propyl)-l-methyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-l-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)-3-(l- (trifluoromethyl)cyclopropyl)propyl)-l-methyl-lH-pyrazole-5-carboxamide (isomer 2);N-((lS)-l-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-3 -(1 -(trifluoromethyl)cyclopropyl)propyl)- 1 - methyl-lH-pyrazole-5-carboxamide (isomer 1);N-((lS)-l-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-3 -(1 -(trifluoromethyl)cyclopropyl)propyl)- 1 - methyl- lH-pyrazole-5-carboxamide (isomer 2);N-((3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3- yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)(spiro[2.5]octan-6-yl)m ethyl)- 1 -ethyl- 1H- pyrazole-5-carboxamide;N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-l-isopropyl-lH-l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lr,4S)-4- methylcyclohexyl)methyl)-l-isopropyl-lH-l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-l-isopropyl-lH-l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2- oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6-yl)((lS,3R)-3- methylcyclohexyl)methyl)-l-isopropyl-lH-l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2- (((3R,5 S)-2-oxo-5-(trifluoromethyl)piperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)methyl)-l-ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-((S)-3,3-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2- (((3R,5 S)-2-oxo-5-(trifluoromethyl)piperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)methyl)-l-ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-((R)-3,3-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2- (((3R,5R)-5-methyl-2-oxopiperi din-3-yl)methyl)imidazo[l,2-b][l, 2, 4]tri azin-6- yl)methyl)-l-ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-((R)-3,3-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2- (((3R,5R)-5-methyl-2-oxopiperi din-3-yl)methyl)imidazo[l,2-b][l, 2, 4]tri azin-6- yl)methyl)-l-ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-((R)-3,3-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2- (((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6- yl)methyl)-l-ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 1);N-((lS)-((R)-3,3-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5S)-5-methyl-2-oxopiperidin-3-yl)methyl)imidazo[l,2-b][l,2,4]triazin-6- yl)methyl)-l-ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 2);N-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5R)-2-oxo-5-(trifluoromethyl)piperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)methyl)-l-ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 1); andN-((lS)-(4,4-difluorocyclohexyl)(3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((3R,5R)- 2-oxo-5-(trifluoromethyl)piperi din-3 -yl)methyl)imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6- yl)methyl)-l-ethyl-lH-l,2,4-triazole-5-carboxamide (isomer 2); 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 13 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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