compounds

Abstract

The present invention relates to novel compounds and pharmaceutical compositions. More particularly, the present invention provides novel compounds which are useful for the treatment of and prevention of neurodegenerative disorders including, but not limited to, Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), and Nasu-Hakola Disease (NHD).

Description

[0001] PC073167A

[0002] COMPOUNDS

[0003] Field of the Invention

[0004] The present invention relates to novel compounds and pharmaceutical compositions. More particularly, the present invention provides novel compounds which are useful forthe treatment of and prevention of neurodegenerative disorders including, but not limited to, Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), and Nasu-Hakola Disease (NHD).

[0005] Background

[0006] Triggering receptors expressed on myeloid cell-2 (TREM2) is part of the TREM family of type 1 innate immune immunoglobulin (Ig) cell surface receptors that are encoded by a gene cluster on human chromosome 6p21. In addition to TREM2, this cluster encodes the genes for NCR2 (encoding NKp44), TREM1, TREML1 (encoding TREM-like 1), TREML2, and TREML4. TREM2 consists of a single V-type immunoglobulin domain paired with a stalk region and N-terminal leader sequence, a single pass transmembrane domain, and a short non-signaling C-terminal cytoplasmic domain (Colonna, 2023).

[0007] The biological function of TREM2 is in part predicated by its expression in cells of the myeloid lineage. In the periphery, TREM2 is expressed in monocytes, macrophages, and dendritic cells and regulates cellular metabolism, inflammation, and phagocytosis to maintain tissue homeostasis (Colonna, 2023). In the bone, osteoclast expressed TREM2 maintains osteoclastogenesis and bone remodeling (Lee et al., 2021). Perhaps most widely studied in the brain, TREM2 is expressed in microglia and regulates their differentiation and activation to promote survival, proliferation, and phagocytosis; functions that are critical for homeostatic synaptic pruning of neurons and removal of cellular debris and pathological protein aggregates (Colonna, 2023; Deczkowska et al., 2020; Lee & Landreth, 2010; Qin et al., 2022). As a cell type, microglia are specialized brain-resident innate immune cells that respond to a variety of stressors and immune perturbations (Lenz & Nelson, 2018). Microglia can also obtain neuroprotective or inflammatory states in order to respond to localized signals in the brain (Muzio et al., 2021). TREM2 expression has been shown to promote Disease-associated microglia (DAM) and DAMs are found in association with amyloid fibrils and plaque in pre-clinical Alzheimer’s Disease (AD) models (Claes et al., 2021). Genetic ablation of TREM2 in microglia impairs phagocytosis and chemotaxis, as well as clustering around amyloid plaques in vivo (McQuade et al., 2020).

[0008] Several ligands have been characterized to bind TREM2 including bacterial anionic molecules, lipoproteins, sulfatides, apolipoproteins (APOE) and amyloid p (Ap) (Singh et al., 2021). TREM2 ligand binding promotes its association with the TREM2 signaling co-receptor DNAX-activating protein 12 kDA (DAP12) via negatively charged residues in the transmembrane domain of DAP12. Once in complex, SRC kinases phosphorylate immunoreceptor tyrosine-based activation motifs (ITAMs) located in the cytosolic domain of DAP12 in the TREM2 / DAP12 complex. These phosphorylated ITAMs recruit the protein tyrosine kinase SYK to initiate signaling via PI3K / MAPK, for example, to regulate TREM2 dependent cellular processes (Colonna, 2023). Beyond cells that express TREM2, DAP12 is also expressed in granulocytes and activated B and T cell subsets (Paradowska-Gorycka & Jurkowska, 2013).

[0009] In addition to binding ligand, the extracellular domain of TREM2 is cleaved by metalloproteases, such as ADAM10 and ADAM17, resulting in the shedding of soluble TREM2 (sTREM2) (Thornton et al., 2017). The biological function of sTREM2 remains to be fully understood, however, sTREM2 may act to negatively regulate TREM2 signaling, acting as a decoy receptor for natural ligand binding (Filipello et al., 2022). sTREM2 can be detected in plasma and the cerebral spinal fluid (CSF) from myeloid cell expressed TREM2 in the periphery and microglia expressed TREM2 in the CNS, respectively (Lin et al., 2024). Furthermore, CSF sTREM2 levels have been shown to correlate with Alzheimer’s disease (AD) progression and cognitive decline and the presence of sTREM2 in the CSF (Lin et al., 2024). Elevated sTREM2 levels were also found in the CSF of select patients with Parkinson’s Disease (PD), supporting a role for this receptor in neurodegenerative diseases (NDDs) (Wilson et al., 2020).

[0010] TREM2 has gained increased attention as a therapeutic target given the emergence of genetic variants associated with increased risk of developing neurodegenerative diseases (NDDs). In particular, the loss-of-function arginine-47-histidine (R47H) variant (rs75932628-T) is the most common TREM2 disease variant and is associated with risk of developing late-onset Alzheimer’s disease (LOAD) (Andrade-Guerrero et al., 2023). The R47H TREM2 variant has reduced ability to bind endogenous ligand, resulting in the loss of neuroprotective microglial function by decreased response to and uptake of Ap (Jonsson et al., 2013; Kulkarni et al., 2021; Rikos et al., 2024). In pre-clinical AD mice models, TREM2- / - mice and microglia deficient for SYK have reduced capacity to swarm Ap plaques and fail to acquire a DAM signature, resulting in accelerated brain pathology. Moreover, mice expressing the human TREM2 R47H disease variant have impaired microglial responses to Ap due to the impairment in SYK signaling (Wang et al., 2022; Wang et al., 2015). Other rare TREM2 variants associated with increased AD risk have been described and include N68K, D87N, T96K, R98W, and H157Y, among others (Filipello et al., 2022; Guerreiro, Wojtas, et al., 2013). Beyond AD, loss-of-function TREM2 variants have been described and are reported to increase susceptibility to Parkinsons Disease (PD), Amyotrophic Lateral Sclerosis (ALS), Nasu-Hakola Disease (NHD) and Frontotemporal Dementia (FTD). For example, the R47H variant has been associated with increased risk for FTD, PD and ALS (Cady et al., 2014; Rayaprolu et al., 2013). Additional bi-allelic mutations in TREM2 cause NHD (Guerreiro, Bilgic, et al., 2013; Koseoglu et al., 2018; Paloneva et al., 2002).

[0011] Genetic and pre-clinical evidence supports that TREM2 plays a critical role in regulating microglial function. Therapeutic agents that modulate TREM2 signaling and activity may provide treatment for neurodegenerative disorders including, but not limited to, Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), and Nasu-Hakola Disease (NHD).

[0012] References

[0013] Andrade-Guerrero, J., Santiago-Balmaseda, A., Jeronimo-Aguilar, P., Vargas-Rodriguez, I., Cadena-Suarez, A. R., Sanchez-Garibay, C., Pozo-Molina, G., Mendez-Catala, C. F., Cardenas-Aguayo, M. D., Diaz-Cintra, S., Pacheco-Herrero, M., Luna-Munoz, J., & Soto-Rojas, L. O. (2023). Alzheimer's Disease: An Updated Overview of Its Genetics. Int J Mol Sci, 24(4).

[0014] Cady, J., Koval, E. D., Benitez, B. A., Zaidman, C., Jockel-Balsarotti, J., Allred, P., Baloh, R. H., Ravits, J., Simpson, E., Appel, S. H., Pestronk, A., Goate, A. M., Miller, T. M., Cruchaga, C., & Harms, M. B. (2014). TREM2 variant p. R47H as a risk factor for sporadic amyotrophic lateral sclerosis. JAMA Neurol, 71(4), 449-453.

[0015] Claes, C., Danhash, E. P., Hasselmann, J., Chadarevian, J. P., Shabestari, S. K., England, W. E., Lim, T. E., Hidalgo, J. L. S., Spitale, R. C., Davtyan, H., & Blurton-Jones, M. (2021). Plaque-associated human microglia accumulate lipid droplets in a chimeric model of Alzheimer's disease. Mol Neurodegener, 16(1), 50.

[0016] Colonna, M. (2023). The biology of TREM receptors. Nature Reviews Immunology, 23(9), 580-594.

[0017] Deczkowska, A., Weiner, A., & Amit, I. (2020). The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway. Cell, 181(6), 1207-1217.

[0018] Filipello, F., Goldsbury, C., You, S. F., Locca, A., Karch, C. M., & Piccio, L. (2022). Soluble TREM2: Innocent bystander or active player in neurological diseases? Neurobiology of Disease, 165, 105630.

[0019] Guerreiro, R., Bilgic, B., Guven, G., Bras, J., Rohrer, J., Lohmann, E., Hanagasi, H., Gurvit, H., & Emre, M. (2013). Novel compound heterozygous mutation in TREM2 found in a Turkish frontotemporal dementia-like family. Neurobiol Aging, 34(12), 2890. e2891 -2895.

[0020] Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majounie, E., Cruchaga, C., Sassi, C., Kauwe, J. S., Younkin, S., Hazrati, L., Collinge, J., Pocock, J., Lashley, T., Williams, J., Lambert, J. C., Amouyel, P., Goate, A., Rademakers, R.,... Hardy, J. (2013). TREM2 variants in Alzheimer's disease. N Engl J Med, 368(2), 117-127.

[0021] Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P. V., Snaedal, J., Bjornsson, S., Huttenlocher, J., Levey, A. I., Lah, J. J., Rujescu, D., Hampel, H., Giegling, I., Andreassen, O. A., Engedal, K., Ulstein, I., Djurovic, S., Ibrahim-Verbaas, C., Hofman, A.,... Stefansson, K. (2013). Variant of TREM2 Associated with the Risk of Alzheimer's Disease. New England Journal of Medicine, 368(2), 107-116.

[0022] Kbseoglu, E., Tepgeg, F., Yetkin, M. F., Uyguner, O., Ekinci, A., Abdulrezzak, U., & Hanagasi, H. (2018). Nasu Hakola Disease: A Rare Cause of Dementia and Cystic Bone Lesions, Report of a New Turkish Family. Noro Psikiyatr Ars, 55(1), 98-102.

[0023] Kulkarni, B., Kumar, D., Cruz-Martins, N., & Sellamuthu, S. (2021). Role of TREM2 in Alzheimer’s Disease: A Long Road Ahead. Molecular Neurobiology, 58(10), 5239-5252.

[0024] Lee, C. Y., & Landreth, G. E. (2010). The role of microglia in amyloid clearance from the AD brain. J Neural Transm (Vienna), 117(8), 949-960.

[0025] Lee, J.-W., Lee, l.-H., limura, T., & Kong, S. W. (2021). Two macrophages, osteoclasts and microglia: from development to pleiotropy. Bone Research, 9(1), 11.

[0026] Lenz, K. M., & Nelson, L. H. (2018). Microglia and Beyond: Innate Immune Cells As Regulators of Brain Development and Behavioral Function [Review], Frontiers in Immunology, 9.

[0027] Lin, C., Kong, Y., Chen, Q., Zeng, J., Pan, X., & Miao, J. (2024). Decoding STREM2: its impact on Alzheimer's disease - a comprehensive review of mechanisms and implications. Front Aging Neurosci, 16, 1420731.

[0028] McQuade, A., Kang, Y. J., Hasselmann, J., Jairaman, A., Sotelo, A., Coburn, M., Shabestari, S. K., Chadarevian, J. P., Fote, G., Tu, C. H., Danhash, E., Silva, J., Martinez, E., Cotman, C., Prieto, G. A., Thompson, L. M., Steffan, J. S., Smith, I., Davtyan, H.,... Blurton-Jones, M. (2020). Gene expression and functional deficits underlie TREM2-knockout microglia responses in human models of Alzheimer’s disease. Nature Communications, 11(1), 5370.

[0029] Muzio, L., Viotti, A., & Martino, G. (2021). Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy [Review], Frontiers in Neuroscience, 15.

[0030] Paloneva, J., Manninen, T., Christman, G., Hovanes, K., Mandelin, J., Adolfsson, R., Bianchin, M., Bird, T., Miranda, R., Salmaggi, A., Tranebjaerg, L., Konttinen, Y., & Peltonen, L. (2002). Mutations in Two Genes Encoding Different Subunits of a Receptor Signaling Complex Result in an Identical Disease Phenotype. The American Journal of Human Genetics, 71(3), 656-662.

[0031] Paradowska-Gorycka, A., & Jurkowska, M. (2013). Structure, expression pattern and biological activity of molecular complex TREM-2 / DAP12. Human Immunology, 74(6), 730-737.

[0032] Qin, Q., Wang, M., Yin, Y., & Tang, Y. (2022). The Specific Mechanism of TREM2 Regulation of Synaptic Clearance in Alzheimer's Disease. Front Immunol, 13, 845897.

[0033] Rayaprolu, S., Mullen, B., Baker, M., Lynch, T., Finger, E., Seeley, W. W., Hatanpaa, K. J., Lomen-Hoerth, C., Kertesz, A., Bigio, E. H., Lippa, C., Josephs, K. A., Knopman, D. S., White, C. L., 3rd, Caselli, R., Mackenzie, I. R., Miller, B. L., Boczarska-Jedynak, M., Opala, G.,. .. Ross, O. A. (2013). TREM2 in neurodegeneration: evidence for association of the p. R47H variant with frontotemporal dementia and Parkinson's disease. Mol Neurodegener, 8, 19.

[0034] Rikos, D., Siokas, V., Mentis, A.-F. A., Aloizou, A.-M., Liampas, I., Tsouris, Z., Peristeri, E., Stamati, P., Hadjigeorgiou, G. M., & Dardiotis, E. (2024). TREM2 R47H variant and risk for Alzheimer’s disease: assessment in a Greek population and updated meta-analysis.

[0035] International Journal of Neuroscience, 134(7), 786-794.

[0036] Singh, H., Rai, V., Nooti, S. K., & Agrawal, D. K. (2021). Novel ligands and modulators of triggering receptor expressed on myeloid cells receptor family: 2015-2020 updates. Expert Opin TherPat, 31(6), 549-561.

[0037] Thornton, P., Sevalle, J., Deery, M. J., Fraser, G., Zhou, Y., Ståhl, S., Franssen, E. H., Dodd, R. B., Qamar, S., Gomez Perez-Nievas, B., Nicol, L. S. C., Eketjäll, S., Revell, J., Jones, C., Billinton, A., St George-Hyslop, P. H., Chessell, I., & Crowther, D. C. (2017). TREM2 shedding by cleavage at the H157‐ S158 bond is accelerated for the Alzheimer's disease‐associated H157Y variant. EMBO Molecular Medicine, 9(10), 1366-1378.

[0038] Wang, S., Sudan, R., Peng, V., Zhou, Y., Du, S., Yuede, C. M., Lei, T., Hou, J., Cai, Z., Celia, M., Nguyen, K., Poliani, P. L., Beatty, W. L., Chen, Y., Cao, S., Lin, K., Rodrigues, C., Ellebedy, A. H., Gilfillan, S., Colonna, M. (2022). TREM2 drives microglia response to amyloid-p via SYK-dependent and - independent pathways. Cell, 185(22), 4153-4169.e4119.

[0039] Wang, Y., Celia, M., Mallinson, K., Ulrich, J. D., Young, K. L., Robinette, M. L., Gilfillan, S., Krishnan, G. M., Sudhakar, S., Zinselmeyer, B. H., Holtzman, D. M., Cirrito, J. R., & Colonna, M. (2015). TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell, 160(6), 1061-1071.

[0040] Wilson, E. N., Swarovski, M. S., Linortner, P., Shahid, M., Zuckerman, A. J., Wang, Q., Channappa, D., Minhas, P. S., Mhatre, S. D., Plowey, E. D., Quinn, J. F., Zabetian, C. P., Tian, L., Longo, F. M., Cholerton, B., Montine, T. J., Poston, K. L., & Andreasson, K. I. (2020).

[0041] Soluble TREM2 is elevated in Parkinson's disease subgroups with increased CSF tau. Brain, 143(3), 932-943. Summary of the Invention

[0042] The present invention relates to a compound of formula (I) having the structure:

[0043]

[0044] or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein:

[0045] each of Ai, A2, A3, and A4 is selected independently from the group consisting of CH, CR, and N, where R is deuterium, Ci-C8alkyl, Ci-C8haloalkyl, fluoro, cyano, C1-C3 alkoxy, or C1-C3 haloalkoxy;

[0046] X is CH2, CH-(C1-C6alkyl), C-(C1-C6alkyl)2, CH-(C1-C6haloalkyl), C-(C1-C6alkyl)(C1-C6alkyl), C-(Ci-C6haloalkyl)2, CHF, CF2, CF-(CI-C6alkyl), CF-(CI-C6haloalkyl), NH, N-(C1-C6alkyl), O, or S(O)g, where q is 0, 1 or 2;

[0047] R1 is Ci-C6alkyl, C3-C8cycloalkyl, phenyl, a 5- or 6-membered heteroaryl or heterocycloalkyl containing one, two, three or four heteroatoms selected from the group consisting of N, S and O atoms, or an 8-, 9- or 10-membered bicyclic aryl, heteroaryl or heterocycloalkyl containing one, two or three heteroatoms selected from the group consisting of N, S and O atoms; wherein each of said alkyl, cycloalkyl, phenyl, aryl, heteroaryl, or heterocycloalkyl may be unsubstituted or substituted by one or more of halo, cyano, deuterium, hydroxy, oxo, Ci-C8alkyl, Ci-C8haloalkyl, Ci-C8alkoxy, Ci-C8haloalkoxy, phenyl, SF5, -SO2-R’, -CONR’R”, NR’COR”, -NR’CONR’R”, -NR’CO2R”, -(CH2)n-SO2-R’, -NHSO2-R’, -NR”SO2-R’, -SO2NR’R”, NR’R”, -P(O)R’R”, -SOR-’R” or SR’ where each R’ and R” are independently H, C1-Ce alkyl, Ci-Ce haloalkyl or Cs-C8cycloalkyl;

[0048] R2and R2’ are independently selected from the group consisting of H, halo, Ci-C8alkyl, -(CH2)m-(C3-C8cycloalkyl), -(CH2)m-phenyl, a 5- or 6-membered heteroaryl or heterocycloalkyl containing one, two, three or four heteroatoms selected from the group consisting of N, S and O atoms, or an 8-, 9- or 10-membered bicyclic aryl, heteroaryl or heterocycloalkyl containing one, two or three heteroatoms selected from the group consisting of N, S and O atoms; wherein each of said alkyl, cycloalkyl, phenyl, aryl, heteroaryl or heterocycloalkyl may be unsubstituted or substituted by one or more of phenyl, halo, cyano, deuterium, hydroxy, Ci-C6alkyl, Ci-C6 alkoxy, -SO2-R’, -CONR’R”, NR’COR”, -NR’CONR’R”, -NR’CO2R”, -(CH2)„-SO2-R’, -NHSO2-R’, -NR”SO2-R’, -SO2NR’R”, NR’R” or SR’ where R’ and R” are independently H, Ci-C6alkyl or C3-C8cycloalkyl; or,

[0049] R2and R2’ are taken together to form a C3-C8cycloalkyl ring optionally substituted with one or more of halo, Ci-C6alkoxy, or cyano;

[0050] R3is selected from the group consisting of H, deuterium, Ci-C8alkyl, C3-C8cycloalkyl, phenyl, naphthyl, a 5- or 6-membered heteroaryl or heterocycloalkyl containing one, two, three or four heteroatoms selected from the group consisting of N, S and O atoms, and a 8-, 9- or 10-membered bicyclic aryl, heteroaryl or heterocycloalkyl containing one, two or three heteroatoms selected from the group consisting of N, S and O atoms; wherein each of said alkyl, cycloalkyl, phenyl, naphthyl, heteroaryl or heterocycloalkyl may be unsubstituted or substituted by one or more of phenyl, halo, cyano, deuterium, oxo, hydroxy, amino, Ci-C6alkyl optionally substituted with cyano, Ci-C8haloalkyl, Ci-C8alkoxy, Ci-C8alkoxyalkyl, Ci-C8haloalkoxy, Ci-C8hydroxyalkyl, C3-C8cycloalkyl optionally substituted with one or more of cyano or fluoro, 3- to 8-membered heterocycloalkyl, -(CH2)„-(3- to 8-membered heterocycloalkyl), -SO2-R’, NHR’, NR’R”, -CONR’R”, NR’COR”, -NR’CONR’R”, -NR’CO2R”, -(CH2)„-SO2-R’, -(CH2)n-CN, -NHSO2-R’, -NR”SO2-R’, -SO2NR’R”, -(CH2)„-NR’R”, -(CH2)„-NHR’, -P(O)R’R”, or SR’ where R’ and R” are independently H, Ci-C8alkyl, Ci-C8haloalkyl, Ci-C8alkoxy, Ci-C8alkoxyalkyl, Ci-C8hydroxyalkyl, C3-C8cycloalkyl, phenyl, or 5- or 6-membered heteroaryl or heterocycloalkyl containing one, two, three or four heteroatoms selected from the group consisting of N, S and O atoms; or two substituents on each of said alkyl, cycloalkyl, phenyl, naphthyl, heteroaryl or heterocycloalkyl are taken together to form a cyclic group selected from C4-C8cycloalkyl or heterocycloalkyl wherein the cyclic group may be optionally substituted with one or more of deuterium, cyano, oxo, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3alkoxy, C1-C3haloalkoxy, or halo;

[0051] R4and R5are independently selected from the group consisting of H, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C8alkoxy, Ci-C8haloalkoxy, C3-C8cycloalkyl, and NR’R” where R’ and R” are independently H, Ci-C6alkyl or C3-C8cycloalkyl, wherein each of said alkyl and cycloalkyl may be unsubstituted or substituted by halo, cyano, deuterium, hydroxy, Ci-C6alkyl and Ci-C6alkoxy; or

[0052] R4and Rs are taken together to form a C4-C8cycloalkyl or heterocycloalkyl ring optionally substituted with one or more of deuterium, cyano, oxo, Ci-C3alkyl, Ci-C3haloalkyl, or halogen;

[0053] m is 0, 1, 2 or 3; and

[0054] n is 0, 1, 2, or 3. In other aspects, the present invention also provides: pharmaceutical compositions which comprise a pharmaceutically acceptable carrier and a compound of formula I, ora pharmaceutically acceptable salt thereof; and, methods for treating conditions or disorders including:

[0055] The present invention will be further understood from the following description given by way of example only. The present invention is directed to a class of TREM2-modulating compounds. In particular, the present invention is directed to certain compounds useful as TREM2 modulators which have utility in the treatment of certain neurodegenerative diseases. While the present invention is not so limited, an appreciation of various aspects of the invention will be gained through the following discussion and the examples.

[0056] Detailed Description of the Invention

[0057] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the meanings that are commonly understood by those of ordinary skill in the art.

[0058] The phrase “therapeutically effective” is intended to qualify the amount of compound or pharmaceutical composition, or the combined amount of active ingredients in the case of combination therapy. This amount or combined amount will achieve the goal of treating the relevant condition.

[0059] The term “treatment,” as used herein to describe the present invention and unless otherwise qualified, means administration of the compound, pharmaceutical composition or combination to effect preventative, palliative, supportive, restorative, or curative treatment. The term treatment encompasses any objective or subjective improvement in a subject with respect to a relevant condition or disease.

[0060] The term “preventive treatment,” as used herein to describe the present invention, means that the compound, pharmaceutical composition or combination is administered to a subject to inhibit or stop the relevant condition from occurring in a subject, particularly in a subject or member of a population that is significantly predisposed to the relevant condition.

[0061] The term “pharmaceutically acceptable” means the substance (e.g., the compounds of the invention) and any salt thereof, or composition containing the substance or salt of the invention that is suitable for administration to a patient. When referring to a compound of Formula I, unless otherwise stated, it is understood that a pharmaceutically acceptable salt of said compound is also considered.

[0062] The compound(s) of the disclosure refers to the compounds of Formula I. One of ordinary skill in the art will appreciate that the compounds of the disclosure include conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic, diastereomeric and other mixtures of such isomers, tautomers thereof, where they may exist. One of ordinary skill in the art will also appreciate that the compounds of the disclosure include solvates, hydrates, isomorphs, polymorphs, esters, salt forms, prodrugs, and isotopically labelled versions thereof, where they may be formed.

[0063] Compounds of the disclosure can include novel intermediates used in the preparation thereof.

[0064] As used herein, the singular form “a”, “an”, and “the” include plural references unless indicated otherwise. For example, “a” substituent includes one or more substituents. The term “or” means “and / or” unless clearly indicated otherwise.

[0065] As used herein, the term “about” when used to modify a numerically defined parameter means that the parameter may vary by as much as 10% below or above the stated numerical value forthat parameter. For example, a dose of about 5 mg means 5% ± 10%, i.e., it may vary between 4.5 mg and 5.5 mg.

[0066] “Optional" or "optionally" means that the subsequently described event or circumstance may, but need not occur, and the description includes instances where the event or circumstance occurs and instances in which it does not.

[0067] The terms “optionally substituted” and “substituted or unsubstituted” are used interchangeably to indicate that the particular group being described may have no nonhydrogen substituents (i.e., unsubstituted), or the group may have one or more non-hydrogen substituents (i.e., substituted). If not otherwise specified, the total number of substituents that may be present is equal to the number of H atoms present on the unsubstituted form of the group being described. Where an optional substituent is attached via a double bond, such as an oxo (=O) substituent, the group occupies two available valences, so the total number of other substituents that are included is reduced by two. In the case where optional substituents are selected independently from a list of alternatives, the selected groups may be the same or different. Throughout the disclosure, it will be understood that the number and nature of optional substituent groups will be limited to the extent that such substitutions make chemical sense to one of ordinary skill in the art.

[0068] “Halogen” or “halo” refers to fluoro, chloro, bromo and iodo (F, Cl, Br, I).

[0069] “Cyano” refers to a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., -CEN.

[0070] “Hydroxy” refers to an -OH group.

[0071] “Oxo” refers to a double bonded oxygen (=O).

[0072] "Alkyl" refers to a saturated, monovalent aliphatic hydrocarbon radical that has a specified number of carbon atoms, including straight chain or branched chain groups. Alkyl groups may contain, but are not limited to, 1 to 12 carbon atoms (“C1-12 alkyl”), 1 to 8 carbon atoms (“C1-8 alkyl”), 1 to 6 carbon atoms (“Ci-e alkyl”), 1 to 5 carbon atoms (“C1.5 alkyl”), 1 to 4 carbon atoms (“C1.4 alkyl”), 1 to 3 carbon atoms (“C1.3 alkyl”), or 1 to 2 carbon atoms (“C1.2 alkyl”). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, secbutyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, and the like. Alkyl groups may be optionally substituted, unsubstituted or substituted, as further defined herein. In some instances, substituted alkyl groups are specifically named by reference to the substituent group. For example, “haloalkyl” refers to an alkyl group having the specified number of carbon atoms that is substituted by one or more halo substituents, up to the available valence number.

[0073] “Haloalkyl” refers to an alkyl group as defined above containing the specified number of carbon atoms wherein at least one hydrogen atom has been replaced by halogen. Haloalkyl groups may contain, but are not limited to, 1-6 carbon atoms (“Ci_6haloalkyl”), 1-4 carbon atoms (“C1.4 haloalkyl”), or 1-2 carbon atoms (“Ci_2haloalkyl”). More specifically, fluorinated alkyl groups may be specifically referred to as “fluoroalkyl.” Examples of fluoroalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and tetrafluoroethyl. Examples of fully substituted fluoroalkyl groups (also referred to as perfluoroalkyl groups) include trifluoromethyl (-CF3) and pentafluoroethyl (-C2F5).

[0074] “Alkoxy” refers to an alkyl group, as defined herein, that is single bonded to an oxygen atom. The attachment point of an alkoxy radical to a molecule is through the oxygen atom. An alkoxy radical may be depicted as alkyl-O-. Alkoxy groups may contain, but are not limited to, 1 to 8 carbon atoms (“C^g alkoxy”), 1 to 6 carbon atoms (“Cv6alkoxy”), 1 to 4 carbon atoms (“C^ alkoxy”), or 1 to 3 carbon atoms (“Cv3alkoxy”). Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isobutoxy, and the like.

[0075] “Haloalkoxy” refers to an alkoxyl group as defined above containing the specified number of carbon atoms wherein at least one hydrogen atom has been replaced by halogen. Haloalkoxy groups may contain, but are not limited to, 1-6 carbon atoms, (“Ci-e haloalkoxy”), 1-4 carbon atoms (“Ci.4haloalkoxy”), or 1-2 carbon atoms (“Ci.2haloalkoxy”). More specifically, fluorinated alkoxyl groups may be specifically referred to as “fluoroalkoxy.” “Alkoxyalkyl” refers to an alkyl group, as defined herein, that is substituted by an alkoxy group, as defined herein. Examples include, but are not limited to, CH3OCH2- and CH3CH2OCH2-.

[0076] “Hydroxyalkyl” refers to an alkyl group, as defined herein, that is substituted by a hydroxy group, as defined herein. Examples include, but are not limited to, -CH3OH and -CH3CH2OH.

[0077] “Cycloalkyl” refers to a fully or partially saturated hydrocarbon ring system that has the specified number of carbon atoms, which may be a monocyclic, spirocyclic, bridged or fused bicyclic or polycyclic ring system that is connected to the base molecule through a carbon atom of the cycloalkyl ring. “Cycloalkyl” can referto the ring system being a fully saturated hydrocarbon ring system. Cycloalkyl groups may contain, but are not limited to, 3 to 12 carbon atoms (“C3.12cycloalkyl”), 3 to 8 carbon atoms (“C3.8cycloalkyl”), 3 to 6 carbon atoms (“C3.6cycloalkyl”), 3 to 5 carbon atoms (“C3.5cycloalkyl”) or 3 to 4 carbon atoms (“C3.4cycloalkyl”). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantanyl, and the like. Cycloalkyl groups may be optionally substituted, unsubstituted or substituted, as further defined herein.

[0078] “Heterocycloalkyl” refers to a fully or partially saturated ring system containing the specified number of ring atoms and containing at least one heteroatom selected from N, O and S as a ring member, where ring S atoms are optionally substituted by one or two oxo groups (i.e., S(O)q, where q is 0, 1 or 2) and where the heterocycloalkyl ring is connected to the base molecule via a ring atom, which may be C or N. The heterocycloalkyl can refer to the ring system being fully saturated. Heterocycloalkyl rings include rings which are spirocyclic, bridged, or fused to one or more other heterocycloalkyl or carbocyclic rings, where such spirocyclic, bridged, or fused rings may themselves be saturated, partially unsaturated or aromatic to the extent unsaturation or aromaticity makes chemical sense, provided the point of attachment to the base molecule is an atom of the heterocycloalkyl portion of the ring system. Heterocycloalkyl rings may contain 1 to 4 heteroatoms selected from N, O, and S(O)q as ring members, or 1 to 2 ring heteroatoms, provided that such heterocycloalkyl rings do not contain two contiguous oxygen or sulfur atoms.

[0079] Heterocycloalkyl rings may be optionally substituted or unsubstituted, as further defined herein. Such substituents may be present on the heterocyclic ring attached to the base molecule, or on a spirocyclic, bridged or fused ring attached thereto. Heterocycloalkyl rings may include, but are not limited to, 3-8 membered heterocyclyl groups, for example 4-7 or 4-6 membered heterocycloalkyl groups, in accordance with the definition herein.

[0080] “Aryl” or “aromatic” refers to monocyclic, bicyclic (e.g., biaryl, fused) or polycyclic ring systems that contain the specified number of ring atoms, in which all carbon atoms in the ring are of sp2 hybridization and in which the pi electrons are in conjugation. Aryl groups may contain, but are not limited to, 6 to 20 carbon atoms ("C6-20aryl"), 6 to 14 carbon atoms ("C6-14aryl"), 6 to 12 carbon atoms ("C6-12aryl"), or 6 to 10 carbon atoms ("C6-10aryl"). Fused aryl groups may include an aryl ring (e.g., a phenyl ring) fused to another aryl ring. Examples include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, and indenyl. Aryl groups may be optionally substituted, unsubstituted or substituted, as further defined herein.

[0081] Similarly, “heteroaryl” or “heteroaromatic” refer to monocyclic, bicyclic (e.g., heterobiaryl, fused) or polycyclic ring systems that contain the specified number of ring atoms and include at least one heteroatom selected from N, O, and S as a ring member in a ring in which all carbon atoms in the ring are of sp2 hybridization and in which the pi electrons are in conjugation. Heteroaryl groups may contain, but are not limited to, 5 to 20 ring atoms (“5-20 membered heteroaryl”), 5 to 14 ring atoms (“5-14 membered heteroaryl”), 5 to 12 ring atoms (“5-12 membered heteroaryl”), 5 to 10 ring atoms (“5-10 membered heteroaryl”), 5 to 9 ring atoms (“5-9 membered heteroaryl”), or 5 to 6 ring atoms (“5-6 membered heteroaryl”).

[0082] Heteroaryl rings are attached to the base molecule via a ring atom of the heteroaromatic ring. Thus, either 5- or 6-membered heteroaryl rings, alone or in a fused structure, may be attached to the base molecule via a ring C or N atom. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridizinyl, pyrimidinyl, pyrazinyl, benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, purinyl, triazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl and carbazolyl. Examples of 5- or 6-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl rings. Heteroaryl groups may be optionally substituted, unsubstituted or substituted, as further defined herein.

[0083] “Amino” refers to a group -NH2, which is unsubstituted. Where the amino is described as substituted or optionally substituted, the term includes groups of the form -NRxRy, where each of Rxand Ryis defined as further described herein. For example, “alkylamino” refers to a group -NRxRy, wherein one of Rxand Ryis an alkyl moiety and the other is H, and “dialkylamino” refers to -NRxRywherein both of Rx and Ry are alkyl moieties, where the alkyl moieties have the specified number of carbon atoms (e.g., - NH(C1-4alkyl) or -N(C1-4alkyl)2).

[0084] The term “fused bicyclic” refers to a ring system comprising two rings fused together. Specific examples include naphthyl, imidazo[2,1-b][1,3]thiazolyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrrolo[2,3-b]pyridyl, pyrrolo[2,3-c]pyridyl, pyrrolo[3,2-c]pyridyl, pyrrolo[3,2-b]pyridyl, imidazo[4,5-b]pyridyl, imidazo[4,5-c]pyridyl, pyrazolo[4,3-d]pyridyl, pyrazolo[4,3- c]pyridyl, pyrazolo[3,4-c]pyridyl, pyrazolo[3,4-b]pyridyl, isoindolyl, indazolyl, purinyl, indolizinyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrrolo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl, pyrido[3,2- d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazino[2,3-b]pyrazinyl and pyrimido[4,5-d]pyrimidine.

[0085] As used herein, the terms “co-administration”, “co-administered” and “in combination with”, referring to a combination of a compound of formula I and one or more other therapeutic agents, includes the following:

[0086] • simultaneous administration of such a combination of a compound of formula I and a further therapeutic agent to a patient in need of treatment, when such components are formulated together into a single dosage form which releases said components at substantially the same time to said patient,

[0087] • substantially simultaneous administration of such a combination of a compound of formula I and a further therapeutic agent to a patient in need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at substantially the same time by said patient, whereupon said components are released at substantially the same time to said patient,

[0088] • sequential administration of such a combination of a compound of formula I and a further therapeutic agent to a patient in need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at consecutive times by said patient with a significant time interval between each administration, whereupon said components are released at substantially different times to said patient; and

[0089] • sequential administration of such a combination of a compound of formula I and a further therapeutic agent to a patient in need of treatment, when such components are formulated together into a single dosage form which releases said components in a controlled manner.

[0090] The term ’excipient’ is used herein to describe any ingredient other than a compound of formula I.

[0091] The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. The term “excipient” encompasses diluent, carrier or adjuvant.

[0092] The present invention is related to novel compounds which are TREM2 modulators useful for the treatment of diseases and conditions associated with dysregulation of TREM2. The present invention further provides pharmaceutical compositions comprising such TREM2 modulators as well as methods of treating and / or preventing such diseases and conditions. Accordingly, the present invention provides a compound of formula I, as represented above, or a pharmaceutically acceptable salt thereof.

[0093] Described below are a number of embodiments (E) of this first aspect of the invention, where for convenience E1 is identical thereto.

[0094] E1 A compound of formula I as defined above, or a pharmaceutically acceptable salt thereof.

[0095] E2. A compound according to E1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein each of A1, A2, and A3is N; A4is N or CH; X is O; and R2 and R2’ are independently selected from the group consisting of H, fluoro and methyl; or R2and R2’ are taken together to form a C3-C4 cycloalkyl ring optionally substituted with one or more of fluoro.

[0096] E3. A compound according to E1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein each of A1, A2, A3, and A4 is N; X is O; and R2 and R2’ are independently selected from the group consisting of H and methyl. E4. A compound according to E1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein each of A1, A2, A3, and A4is N; X is O; and R4and R5are independently selected from the group consisting of methyl and trifluoromethyl.

[0097] E5. A compound according to E1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein R3is phenyl, 5- or 6-membered heteroaryl containing one, two, three or four heteroatoms selected from the group consisting of N, S and O atoms, or 8-, 9- or 10-membered bicyclic aryl or heteroaryl containing one, two or three heteroatoms selected from the group consisting of N, S and O atoms; wherein each of said phenyl, aryl or heteroaryl may be unsubstituted or substituted by one or more of phenyl, halo, cyano, deuterium, oxo, hydroxy, amino, C1-C6alkyl optionally substituted with cyano, C1-C6haloalkyl, C1-C6alkoxy, C1-C6alkoxyalkyl, C1-C8haloalkoxy, C1-C8hydroxyalkyl, C3-C8cycloalkyl optionally substituted with one or more of cyano or fluoro, 3- to 8-membered heterocycloalkyl, -(CH2)n-(3- to 8-membered heterocycloalkyl), -SO2-R’, NHR’, NR’R”, -CONR’R”, NR’COR”, -NR’CONR’R”, -NR’CO2R”, -(CH2)„-SO2-R’, -(CH2)n-CN, -NHSO2-R’, -NR”SO2-R’, -SO2NR’R”, -(CH2)„-NR’R”, -(CH2)„-NHR’, -P(O)R’R”, or SR’ where R’ and R” are independently H, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkoxy, C1-C6alkoxyalkyl, C1-C6hydroxyalkyl, C3-C8cycloalkyl, phenyl, or 5- or 6-membered heteroaryl or heterocycloalkyl containing one, two, three or four heteroatoms selected from the group consisting of N, S and O atoms; or two substituents on each of said phenyl, aryl or heteroaryl are taken together to form a cyclic group selected from C4-C8cycloalkyl or heterocycloalkyl wherein the cyclic group may be optionally substituted with one or more of deuterium, cyano, oxo, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3alkoxy, C1-C3haloalkoxy, or halo;

[0098] E6. A compound according to E1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein R1is selected from the group consisting of C3-C8cycloalkyl, phenyl, and a 6-membered heteroaryl; wherein each of said cycloalkyl, phenyl, or heteroaryl may be unsubstituted or substituted by one or more of halo, cyano, deuterium, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

[0099] E7. A compound according to E1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein each of A1, A2, A3, and A4is N; X is O; and R1is selected from the group consisting of C3-C8cycloalkyl, phenyl, and a 6-membered heteroaryl; wherein each of said cycloalkyl, phenyl, or heteroaryl may be unsubstituted or substituted by halo, cyano, deuterium, C1-C8alkyl, C1-C8haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy. E8. A compound according to E1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein each of A1, A2, A3, and A4is N; X is O; and R1is selected from the group consisting of phenyl, and a 6-membered heteroaryl; wherein each of said phenyl or heteroaryl may be unsubstituted or substituted by halo, cyano, deuterium, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

[0100] E9. A compound according to E1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein each of A1, A2, A3, and A4is N; X is O; and R1is C3-C8cycloalkyl unsubstituted or substituted by halo, cyano, deuterium, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

[0101] E10. A compound according to E1 wherein the compound is selected from the group consisting of:

[0102] 1-(4-chloro-2-fluorophenyl)-3-(cis-2-(1-cyclopropyl-1 H-pyrazol-4-yl)-6-methylmorpholino)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1H)-one (single cis stereoisomer, absolute stereochemical configuration not determined);

[0103] 1-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1H)-one;

[0104] 1-(4-chloro-2-fluorophenyl)-3-(2-(4-fluorophenyl)-6-methylmorpholino)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1H)-one;

[0105] 1-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-((S)-2-(4-((R)-S-methylsulfonimidoyl)phenyl)morpholino)pyrazino[2,3-b]pyrazin-2(1 H)-one (single stereoisomer, absolute stereochemical configuration not determined);

[0106] 3-(2-(4-(1H-1,2,4-triazol-1-yl)phenyl)morpholino)-1-(4-chloro-2-fluorophenyl)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1H)-one;

[0107] 1-(4-chloro-2-fluorophenyl)-3-(2-(1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)morpholino)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1H)-one;

[0108] 1-(4,4-difluorocyclohexyl)-6,7-dimethyl-3-(2-(2-(trifluoromethyl)pyridin-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1H)-one;

[0109] 1-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(2-(1-oxo-1,2-dihydroisoquinolin-6-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1H)-one;

[0110] 1-(4-chloro-2-fluorophenyl)-3-(2-(isoquinolin-6-yl)morpholino)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1H)-one;

[0111] 4-(4-(4-(4,4-difluorocyclohexyl)-6,7-dimethyl-3-oxo-3,4-dihydropyrazino[2,3-b]pyrazin-2-yl)morpholin-2-yl)-2-methoxybenzonitrile; 1-(4,4-difluorocyclohexyl)-3-(2-(4-(N,S-dimethylsulfonimidoyl)phenyl)morpholino)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1H)-one;

[0112] 4-(4-(4-(4,4-difluorocyclohexyl)-6,7-dimethyl-3-oxo-3,4-dihydropyrazino[2,3-b]pyrazin-2-yl)morpholin-2-yl)-2-(trifluoromethyl) benzonitrile;

[0113] 3-(2-(4-(cyclopropylsulfonyl)phenyl)morpholino)-1-(4,4-difluorocyclohexyl)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1H)-one;

[0114] 1-(4,4-difluorocyclohexyl)-3-(2-(2-(1,1-difluoroethyl)pyridin-4-yl)morpholino)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1H)-one;

[0115] 1-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)pyrazino[2,3-b]pyrazin-2(1 H)-one (racemic, cis);

[0116] (S)-1-(4,4-difluorocyclohexyl)-6,7-dimethyl-3-(2-(2-methylpyridin-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1H)-one (absolute stereochemical configuration not determined); and,

[0117] rel-(R or S)-1-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1H)-one; or, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt.

[0118] E11. A pharmaceutical composition comprising a compound according to E1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, and a pharmaceutically acceptable excipient.

[0119] E12. A method of treating a disease or condition selected from inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematous, lupus nephritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoidosis, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, brain edema, brain trauma, neurodegeneration, liver disease, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration, glaucoma, diabetes (type 1 and type 2), diabetic neuropathy, viral and bacterial infection, myalgia, endotoxic shock, toxic shock syndrome, osteoporosis, multiple sclerosis, endometriosis, menstrual cramps, vaginitis, candidiasis, cancer, fibrosis, obesity, muscular dystrophy, polymyositis, dermatomyositis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, vitiligo, Alzheimer’s disease, skin flushing, eczema, psoriasis, atopic dermatitis, sunburn, keloid, hypertrophic scar, rheumatic diseases, urticaria, discoid lupus, cutaneous lupus, central nervous system lupus, psoriatic arthritis, asthma, allergic asthma, type I interferonopathies including Aicardi–Goutières syndrome and other mendelian diseases of overexpression of type I interferon, primary progressive multiple sclerosis, relapsing remitting multiple sclerosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, scleroderma, alopecia areata, scarring alopecia, prurigo, prurigo nodularis, CPUO, lichen diseases, lichen planus, Steven’s Johnson’s syndrome, spondylopathy, myositis, vasculitis, pemphigus, lupus, major depression disorder, allergy, dry eye syndrome, transplant rejection, cancer, septic shock, cardiopulmonary dysfunction, acute respiratory disease, ankylosing spondylitis, cachexia, chronic graft-versus-host disease, acute graft-versus-host disease, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, thrombotic thrombocytopenic purpura, myasthenia gravis, Sjogren's syndrome, epidermal hyperplasia, cartilage inflammation, bone degradation, juvenile arthritis, juvenile rheumatoid arthritis, pauciarticular juvenile rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenile enteropathic arthritis, juvenile Reter's Syndrome, SEA Syndrome, juvenile dermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma, juvenile systemic lupus erythematosus, juvenile vasculitis, pauciarticular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemic onset rheumatoid arthritis, enteropathic arthritis, reactive arthritis, Reter's Syndrome, myolitis, polymyolitis, dermatomyolitis, polyarteritis nodosa, Wegener's granulomatosis, arteritis, polymyalgia rheumatica, sarcoidosis, sclerosis, primary biliary sclerosis, sclerosing cholangitis, dermatitis, Still's disease, chronic obstructive pulmonary disease, Guillain-Barre disease, Graves' disease, Addison's disease, Raynaud's phenomenon, psoriatic epidermal hyperplasia, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, an immune disorder associated with or arising from activity of pathogenic lymphocytes, noninfectious uveitis, Behcet’s disease and Vogt–Koyanagi–Harada syndrome, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of E1 to E10, ora pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

[0120] E13. The method according to E12 wherein the compound is administered orally or topically.

[0121] E14. The method according to E12, wherein the compound is administered as a tablet, capsule or lozenge, if administered orally; or, as a cream, ointment, lotion, gel, solution, suspension, foam, aerosol, spray, shampoo, patch or tape, if administered topically.

[0122] E15. A method of treating Alzheimer's Disease, comprising administering to the subject a therapeutically effective amount of a compound according to any one of E1 to E10 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

[0123] E16. The method according to E15, wherein the compound is administered orally. E17. The method according to E15, wherein the compound is administered as a tablet, capsule or lozenge.

[0124] E18. A method of treating a neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Frontotemporal lobar degeneration (FTLD), frontotemporal dementia (FTD), Parkinson's disease, Nasu-Hakola disease, FTLD-like syndrome, Huntington disease, Amyotrophic lateral sclerosis, multiple sclerosis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathies, Charcot-Marie-Tooth disease, prion disease, stroke, a tauopathy, a TDP-43 proteinopathy, a synucleinopathy, dementia, amyloidosis, a demyelinating disorder of the CNS, a demyelinating disorder of the PNS, aeukoencephalopathy, a leukodystrophy, a transmissible spongiform encephalopathy (TSE) and a lysosomal storage disorder (LSD), comprising administering to the subject a therapeutically effective amount of a compound according to any one of E1 to E10 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

[0125] E19. The method according to E18 wherein the compound is administered orally.

[0126] E20. The method according to E18, wherein the compound is administered as a tablet,

[0127] E21. Use of a compound according to any of E1 to E10 for the manufacture of a medicament for the treatment of a condition associated with a loss of function of TREM2.

[0128] E22. Use of a compound according to any of E1 to E10 for the manufacture of a medicament for the treatment a neurodegenerative disease.

[0129] E23. A compound according to any of E1 to E10 for use in the treatment of a disorder for which a modulator of the TREM2 pathway is indicated.

[0130] Compounds of the invention that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers". Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". These stereoisomers are “R” or“S” depending on the configuration of substituents around the chiral carbon atom. The terms “R” and “S” used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30. The enantiomers of the present invention indicated by (R), (S), or * are substantially free of the other enantiomer. “Substantially free” means that the enantiomeric excess is greater than about 90%, preferably greater than about 95%, and more preferably greater than about 99%. Within the context of enantiomeric excess, the term “about” means ±1.0%. The symbol * designates a chiral carbon atom as either (R) or (S) stereochemistry depending on the configuration of substituents around the chiral carbon atom. The present invention contemplates various stereoisomers and mixtures thereof that are specifically included within the scope of this invention. Stereoisomers include enantiomers and mixtures of enantiomers. Individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art. These methods of resolution include, but are not limited to, (1) attachment of a chiral auxiliary to a mixture of enantiomers, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns. Compounds of the present invention not designated (R), (S), or * may exist as racemates (i.e., 50% (R) and 50% (S)) or as a mixture of two enantiomers wherein one enantiomer is in excess. For example, enantiomeric mixtures may include the (R) enantiomer in 51 % and the (S) enantiomer in 49% or vice versa or any combination of (R) and (S) other than the racemic mixture of 50% (R) and 50% (S).

[0131] Included within the scope of the described compounds are all isomers (e.g., cis-, trans-, or diastereomers) of the compounds described herein alone as well as any mixtures. All of these forms, including enantiomers, diastereomers, cis, trans, syn, anti, solvates (including hydrates), tautomers, and mixtures thereof, are included in the described compounds.

[0132] Stereoisomeric mixtures, e.g., mixtures of diastereomers, can be separated into their corresponding isomers in a known manner by means of suitable separation methods.

[0133] Diastereomeric mixtures for example may be separated into their individual diastereomers by means of fractionated crystallization, chromatography, solvent distribution, and similar procedures. This separation may take place either at the level of one of the starting compounds or in a compound of formula I itself. Enantiomers may be separated through the formation of diastereomeric salts, for example by salt formation with an enantiomer-pure chiral acid, or by means of chromatography, for example by HPLC, using chromatographic substrates with chiral ligands. The present invention includes all pharmaceutically acceptable isotopically labelled compounds of formula I or a pharmaceutically acceptable salt thereof, wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.

[0134] Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as2H and3H, carbon, such as11C,13C and14C, chlorine, such as36CI, fluorine, such as18F, iodine, such as123I and125I, nitrogen, such as13N and15N, oxygen, such as150,17O and18O, phosphorus, such as32P, and sulphur, such as35S. Certain isotopically labelled compounds of formula I or a pharmaceutically acceptable salt thereof, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.,3H, and carbon-14, i.e.,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[0135] Substitution with heavier isotopes such as deuterium, i.e.,2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.

[0136] In therapeutic use for treating disorders in a mammal, a compound of the present invention or its pharmaceutical compositions can be administered orally, parenterally, topically, rectally, transmucosally, or intestinally. Parenteral administrations include indirect injections to generate a systemic effect or direct injections to the afflicted area. Topical administrations include the treatment of skin or organs readily accessible by local application, for example, eyes or ears. It also includes transdermal delivery to generate a systemic effect. The rectal administration includes the form of suppositories. The preferred routes of administration are oral and parenteral.

[0137] Pharmaceutically acceptable salts of the compound of formula I or a pharmaceutically acceptable salt thereof, include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.

[0138] Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

[0139] Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

[0140] Pharmaceutically acceptable salts of a compound of formula I ora pharmaceutically acceptable salt thereof, may be prepared, respectively, by one or more of three methods: (i) by reacting the compound of formula I with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound of formula I or by ringopening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by converting one salt of a compound of formula I to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column. All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the resulting salt may vary from completely ionized to almost non-ionized.

[0141] Pharmaceutical compositions of the present invention may be manufactured by methods well known in the art, e.g., by means of conventional mixing, dissolving, granulation, drageemaking, levigating, emulsifying, encapsulating, entrapping, lyophilizing processes or spray drying.

[0142] Pharmaceutical compositions for use in accordance with the present invention may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compound into preparations, which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the instant invention. Such excipients and carriers are described, for example, in Remington’s Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991). The formulations of the invention can be designed to be short-acting, fast-releasing, long-acting, and sustained-releasing. Thus, the pharmaceutical formulations can also be formulated for controlled release or for slow release.

[0143] Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an amount sufficient to achieve the intended purpose, i.e., control or the treatment of disorders or diseases. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms / signs of disease or prolong the survival of the subject being treated.

[0144] The quantity of active component, which is the compound of this invention, in the pharmaceutical composition and unit dosage form thereof, may be varied or adjusted widely depending upon the manner of administration, the potency of the particular compound and the desired concentration. Determination of a therapeutically effective amount is well within the capability of those skilled in the art. Generally, the quantity of active component will range between 0.01% to 99% by weight of the composition. Generally, a therapeutically effective amount of dosage of active component will be in the range of about 0.01 to about 100 mg / kg of body weight / day, preferably about 0.1 to about 10 mg / kg of body weight / day, more preferably about 0.3 to 3 mg / kg of body weight / day, even more preferably about 0.3 to 1.5 mg / kg of body weight / day It is to be understood that the dosages may vary depending upon the requirements of each subject and the severity of the disorders or diseases being treated.

[0145] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.

[0146] Also, it is to be understood that the initial dosage administered may be increased beyond the above upper level in order to rapidly achieve the desired concentration at the site of action. On the other hand, the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose may also be divided into multiple doses for administration, e.g., two to four times per day.

[0147] The invention also includes the following embodiments:

[0148] a compound of I or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate of said compound or salt, as defined in any of the embodiments described herein, for use as a medicament;

[0149] a compound of I or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate of said compound or salt as defined in any of the embodiments described herein, for use in the treatment of selected from inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematous, lupus nephritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoidosis, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, brain edema, brain trauma, neurodegeneration, liver disease, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration, glaucoma, diabetes (type 1 and type 2), diabetic neuropathy, viral and bacterial infection, myalgia, endotoxic shock, toxic shock syndrome, osteoporosis, multiple sclerosis, endometriosis, menstrual cramps, vaginitis, candidiasis, cancer, fibrosis, obesity, muscular dystrophy, polymyositis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, vitiligo, Alzheimer’s disease, skin flushing, eczema, psoriasis, atopic dermatitis, sunburn, keloid, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummular dermatitis, seborrheic dermatitis, seborrhea, oily skin, eyelid dermatitis, diaper dermatitis, dermatomyositis, scleroderma, hypertrophic scar, morphea, frontal fibrosing alopecia, cicatricial alopecia, lichen planus, lichen sclerosis, alopecia areata, vitiligo, rosacea, rosacea-like dermatitis, steroid-induced dermatitis, drug eruptions (including papulopustular drug eruption), epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis, acne (including but not limited to acne vulgaris, nodular acne, nodulocystic acne, cystic acne, conglobate acne, steroid acne), and autoinflammatory syndromes (including but not limited to PAPA, PAPASH, PASS, PASH, SAPHO, PCO, and SH], and acne scar), chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, vogt-koyanagi-harada disease, sutton nevus / nevi, post inflammatory hypopigmentation, senile leukoderma, chemical / drug-induced leukoderma, cutaneous lupus erythematosus, palmoplantar pustulosis, pemphigoid, sweet's syndrome, hidradenitis suppurativa, nail psoriasis, flexural psoriasis, intractable wounds, sebaceous hyperplasia, Fordyce’s condition (Fordyce’s granules; Fordyce’s spots), Fox-Fordyce’s disease, osmidrosis (bromhidrosis), hirsutism, or skin tumors (nevus sebaceous, sebaceous adenoma, sebaceoma, sebaceous epithelioma, steatocytoma simplex, steatocytoma multiplex, Muir-Torre syndrome, sebaceous carcinoma, hypertrophic scar, rheumatic diseases, urticaria, discoid lupus, central nervous system lupus, psoriatic arthritis, asthma, allergic asthma, type I interferonopathies including Aicardi– Goutières syndrome and other mendelian diseases of overexpression of type I interferon, primary progressive multiple sclerosis, relapsing remitting multiple sclerosis, non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, scleroderma, alopecia areata, spondylopathy, myositis, vasculitis, pemphigus, lupus, major depression disorder, allergy, dry eye syndrome, transplant rejection, cancer, septic shock, cardiopulmonary dysfunction, acute respiratory disease, ankylosing spondylitis, cachexia, chronic graft- versus-host disease, acute graft-versus-host disease, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjogren's syndrome, epidermal hyperplasia, cartilage inflammation, bone degradation, juvenile arthritis, juvenile rheumatoid arthritis, pauciarticular juvenile rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenile enteropathic arthritis, juvenile Reter's Syndrome, SEA Syndrome, juvenile dermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma, juvenile systemic lupus erythematosus, juvenile vasculitis, pauciarticular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemic onset rheumatoid arthritis, enteropathic arthritis, reactive arthritis, Reter's Syndrome, myolitis, polymyolitis, dermatomyolitis, polyarteritis nodosa, Wegener's granulomatosis, arteritis, polymyalgia rheumatica, sarcoidosis, sclerosis, primary biliary sclerosis, sclerosing cholangitis, dermatitis, Still's disease, chronic obstructive pulmonary disease, Guillain-Barre disease, Graves' disease, Addison's disease, Raynaud's phenomenon, psoriatic epidermal hyperplasia, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, an immune disorder associated with or arising from activity of pathogenic lymphocytes, noninfectious uveitis, Behcet’s disease or Vogt–Koyanagi–Harada syndrome;

[0150] a method of treating a disease for which an modulator of TREM2 is indicated, in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate of said compound or salt as defined in any of the embodiments described herein;

[0151] the use of a compound of formula I or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate of said compound or salt as defined in any of the embodiments described herein, for the manufacture of a medicament for treating a disease or condition for which a modulator of TREM2 is indicated; and,

[0152] a pharmaceutical composition for the treatment of a disease or condition for which a modulator of TREM2 is indicated, comprising a compound of formula I ora pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate of said compound or salt as defined in any of the embodiments described herein.

[0153] The present invention also provides any of the uses, methods or compositions as defined above wherein the compound of formula I ora pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate of said compound or salt, is used in combination with another pharmacologically active compound, particularly one of the functionally defined classes or specific compounds listed below. These agents may be administered as part of the same or separate dosage forms, via the same or different routes of administration, and on the same or different administration schedules according to standard pharmaceutical practice known to one skilled in the art.

[0154] Suitable agents for use in combination therapy with a compound of formula I or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate of said compound or salt, sulfasalazine, mesalazine, prednisone, azathioprine, infliximab, adalimumab, belimumab, becertolizumab, natalizumab, vedolizumab, hydrocortisone, budesonide, cyclosporin, tacrolimus, fexofenadine, 6-mercaptopurine, methotrexate, ursodeoxycholic acid, obeticholic acid, anti-histamines, rifampin, prednisone, methotrexate, azathioprine, cyclophosphamide, hydroxychloroquine, mofetil, sodium mycophenolate, tacrolimus, leflunomide, chloroquine and quinacrine, thalidomide, rituxan, NSAIDs, solumedrol, depomedrol and dexamethasone.

[0155] Other suitable agents for use in combination therapy with a compound of formula I, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate of said compound or salt, include: a retinoid, antibiotics, benzoyl peroxide, an ITK or TRK inhibitor, a 5-lipoxygenase activating protein (FLAP) antagonist; a leukotriene antagonist (LTRA) such as an antagonist of LTB4, LTC4, LTD4, LTE4, CysLTI orCysLT2, e.g., montelukast or zafirlukast; a histamine receptor antagonist, such as a histamine type 1 receptor antagonist or a histamine type 2 receptor antagonist, e.g., loratidine, fexofenadine, desloratidine, levocetirizine, methapyrilene or cetirizine; an a1 -adrenoceptor agonist or an a2-adrenoceptor agonist, e.g., phenylephrine, methoxamine, oxymetazoline or methylnorephrine; a muscarinic M3 receptor antagonist, e.g. tiotropium or ipratropium; a dual muscarinic M3 receptor antagononist / p2 agonist; a PDE inhibitor, such as a PDE3 inhibitor, a PDE4 inhibitor or a PDE5 inhibitor, e.g., theophylline, sildenafil, vardenafil, tadalafil, ibudilast, cilomilast or roflumilast; sodium cromoglycate or sodium nedocromil; a cyclooxygenase (COX) inhibitor, such as a non-selective inhibitor (e.g., aspirin or ibuprofen) or a selective inhibitor (e.g. celecoxib or valdecoxib); a glucocorticosteroid, e.g., fluticasone, mometasone, dexamethasone, prednisolone, budesonide, ciclesonide or beclamethasone; an anti- inflammatory monoclonal antibody, e.g., infliximab, adalimumab, tanezumab, ranibizumab, bevacizumab or mepolizumab; a p2 agonist, e.g., salmeterol, albuterol, salbutamol, fenoterol or formoterol, particularly a long-acting p2 agonist; an integrin antagonist, e.g., natalizumab; an adhesion molecule inhibitor, such as a VLA-4 antagonist; a kinin B1 or B2 receptor antagonist; an immunosuppressive agent, such as an inhibitor of the IgE pathway (e.g., omalizumab) or cyclosporine; a matrix metalloprotease (MMP) inhibitor, such as an inhibitor of MMP-9 or MMP-12; a tachykinin NK1, NK2 or NK3 receptor antagonist; a protease inhibitor, such as an inhibitor of elastase, chymase or catheopsin G; an adenosine A2a receptor agonist; an adenosine A2b receptor antagonist; a urokinase inhibitor; a dopamine receptor agonist (e.g., ropinirole), particularly a dopamine D2 receptor agonist (e.g., bromocriptine); a modulator of the NFKB pathway, such as an IKK inhibitor; a further modulator of a cytokine signaling pathway such as an inhibitor of JAK kinase, syk kinase, p38 kinase, SPHK-1 kinase, Rho kinase, EGF-R or MK-2; a mucolytic, mucokinetic or anti- tussive agent; an antibiotic; an antiviral agent; a vaccine; a chemokine; an epithelial sodium channel (ENaC) blocker or Epithelial sodium channel (ENaC) inhibitor; a nucleotide receptor agonist, such as a P2Y2 agonist; a thromboxane inhibitor; niacin; a 5-lipoxygenase (5-LO) inhibitor, e.g., Zileuton; an adhesion factor, such as VLAM, ICAM or ELAM; a CRTH2 receptor (DP2) antagonist; a prostaglandin D2 receptor (DP1) antagonist; a haematopoietic prostaglandin D2 synthase (HPGDS) inhibitor; interferon-p; a soluble human TNF receptor, e.g., Etanercept; a HDAC inhibitor; a phosphoinositotide 3-kinase gamma (PI3Ky) inhibitor; a phosphoinositide 3-kinase delta (PI3K6) inhibitor; a CXCR-1 ora CXCR-2 receptor antagonist; an IRAK-4 inhibitor; diacylglycerol acyltransferase-1 (DGAT1) or a diacylglycerol acyltransferase-2 (DGAT2) inhibitor and, a TLR-4 orTLR-9 inhibitor, including the pharmaceutically acceptable salts of the specifically named compounds and the pharmaceutically acceptable solvates of said specifically named compounds and salts. The agents may be administered with another active agent, wherein the second active agent may be administered either orally or topically.

[0156] Accordingly, the invention provides methods of treating or preventing a disease, condition or disorder associated with TREM2 in a subject, such as a human or non-human mammal, comprising administering an effective amount of one or more compounds described herein to the subject in need thereof.

[0157] One way of carrying out the invention is to administer a compound of formula I in the form of a prodrug. Thus, certain derivatives of a compound of formula I which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into a compound of formula I having the desired activity, for example by hydrolytic cleavage, particularly hydrolytic cleavage promoted by an esterase or peptidase enzyme. Such derivatives are referred to as “prodrugs.” Further information on the use of prodrugs may be found in “Pro-drugs as Novel Delivery Systems,” Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and “Bioreversible Carriers in Drug Design,” Pergamon Press, 1987 (Ed.

[0158] E. B. Roche, American Pharmaceutical Association). Reference can also be made to Nature Reviews / Drug Discovery, 2008, 7, 355 and Current Opinion in Drug Discovery and Development, 2007, 10, 550.

[0159] Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula I with certain moieties known to those skilled in the art as ‘pro-moieties’ as described, for example, in ‘Design of Prodrugs’ by H. Bundgaard (Elsevier, 1985). Thus, a prodrug in accordance with the invention is (a) an ester or amide derivative of a carboxylic acid in a compound of formula I; (b) an ester, carbonate, carbamate, phosphate or ether derivative of a hydroxyl group in a compound of formula I; (c) an amide, imine, carbamate or amine derivative of an amino group in a compound form formula I; (d) a thioester, thiocarbonate, thiocarbamate or sulfide derivatives of a thiol group in a compound of formula I; or, (e) an oxime, enol ester or imine derivative of a carbonyl group in a compound of formula I.

[0160] Some specific examples of prodrugs in accordance with the invention include:

[0161] (i) where the compound of formula I contains a carboxylic acid functionality (- COOH), an ester thereof, such as a compound wherein the hydrogen of the carboxylic acid functionality of the compound of formula I is replaced by Ci-C8alkyl (e.g., ethyl) or (Ci-C8alkyl)C(=O)OCH2- (e.g., t-BuC(=O)OCH2-);

[0162] (ii) where the compound of formula I contains an alcohol functionality (-OH), an ester thereof, such as a compound wherein the hydrogen of the alcohol functionality of the compound of formula I is replaced by-CO(Ci-C8alkyl) (e.g., methylcarbonyl) or the alcohol is esterified with an amino acid;

[0163] (iii) where the compound of formula I contains an alcohol functionality (-OH), an ether thereof, such as a compound wherein the hydrogen of the alcohol functionality of the compound of formula I is replaced by (Ci-C8alkyl)C(=O)OCH2- or- CH2OP(=O)(OH)2; (iv) where the compound of formula I contains an alcohol functionality (-OH), a phosphate thereof, such as a compound wherein the hydrogen of the alcohol functionality of the compound of formula I is replaced by-P(=O)(OH)2or-P(=0)(ONa)2or-P(=0)(0-)2Ca2+;

[0164] (v) where the compound of formula I contains a primary or secondary amino functionality (-NH2or -NHR where R ≠ H), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound of formula I is / are replaced by (Ci- Cw)alkanoyl, -COCH2NH2 or the amino group is derivatized with an amino acid;

[0165] (vi) where the compound of formula I contains a primary or secondary amino functionality (-NH2or -NHR where R ≠ H), an amine thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound of formula I is / are replaced by - CH2OP(=O)(OH)2.

[0166] (vii) where the ketone functionality of compound of formula I is replaced by an oxime, an imine or an enol ester.

[0167] Certain compounds of Formula I may themselves act as prodrugs of other compounds of formula I.

[0168] It is also possible for two compounds of formula I to be joined together in the form of a prodrug. In certain circumstances, a prodrug of a compound of formula I may be created by internally linking two functional groups in a compound of formula I, for instance by forming a lactone. References to compounds of formula I are taken to include the compounds themselves and prodrugs thereof. The invention includes such compounds of formula I as well as pharmaceutically acceptable salts of such compounds and pharmaceutically acceptable solvates of said compounds and salts.

[0169] Also included within the scope of the invention are active metabolites of compounds of formula I, that is, compounds formed in vivo upon administration of the drug, often by oxidation, reduction or dealkylation. Some examples of metabolites in accordance with the invention include

[0170] (i) where the compound of formula I contains a methyl group, an hydroxymethyl derivative thereof (-CH3 -> -CH2OH or -CH3 -> -COOH):

[0171] (ii) where the compound of formula I contains an alkoxy group, a hydroxy derivative thereof (- OR -> -OH);

[0172] (iii) where the compound of formula I contains a tertiary amino group, a secondary amino derivative thereof (-NRR’ -> -NHR or -NHR’);

[0173] (iv) where the compound of formula I contains a secondary amino group, a primary derivative thereof (-NHR -> -NH2); (v) where the compound of formula I contains a phenyl moiety, a phenol derivative thereof (- Ph -> -PhOH); and

[0174] (vi) where the compound of formula I contains an amide group, a carboxylic acid derivative thereof (-CONH2-> COOH).

[0175] (vii) where the compound of formula I contains a carbonyl group thereof (-C=O(R)) -> - CHOH(R))

[0176] A compound of formula I can be administered perse, or in the form of a pharmaceutical composition, which, as active constituent contains an efficacious dose of at least one compound of the invention, in addition to customary pharmaceutically innocuous excipients and / or additives.

[0177] Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods fortheir preparation may be found, for example, in Remington’s Pharmaceutical Sciences, 19thEdition (Mack Publishing Company, 1995).

[0178] Compounds of formula I may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays and liquid formulations.

[0179] Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, ora suitable oil, and one or more emulsifying agents and / or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

[0180] Compounds of formula I may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001).

[0181] For tablet dosage forms, depending on dose, the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will comprise from 1 weight % to 25 weight %. In one embodiment of the present invention, the disintegrant will comprise from 5 weight % to 20 weight % of the dosage form. Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray- dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet. Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants generally comprise from 0.25 weight % to 10 weight %. In one embodiment of the present invention, lubricants comprise from 0.5 weight % to 3 weight % of the tablet. Other possible ingredients include anti-oxidants, colorants, flavoring agents, preservatives and taste-masking agents.

[0182] Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.

[0183] Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated. Formulations of tablets are discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

[0184] Consumable oral films for human or veterinary use are typically pliable water-soluble or water- swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula I, a film-forming polymer, a binder, a solvent, a humectant, a plasticizer, a stabilizer or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function. The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %. Other possible ingredients include anti-oxidants, colorants, flavorings and flavor enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents. Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming. Solid formulations for oral administration may be formulated to be immediate and / or modified release. Modified release includes delayed, sustained, pulsed, controlled, targeted and programmed telease. Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line, 25(2), 1-14, by Verma et al (2001). The use of chewing gum to achieve controlled release is described in WOOO / 35298.

[0185] Compounds of formula I may also be administered directly into the blood stream, into muscle, or into an internal organ. Such parenteral administration includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intra-articular and subcutaneous administration. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

[0186] Compounds of formula I may also be administered topically to the skin or mucosa, that is, dermally ortransdermally.

[0187] Parenteral formulations of compounds of the invention are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffers (preferably buffering to a pH of from 3 to 9). Formulations for parenteral administration may also be sterile non-aqueous solutions, or dried (e.g. lyophilized) forms to be administered on reconstitution with a suitable vehicle such as sterile, pyrogen-free water.

[0188] Pharmaceutical compositions for topical ortransdermal administration of a compound of the invention include ointments, pastes, creams, lotions, gels, suppositories, powders, solutions, sprays, drops, inhalants and patches. The compound of the invention is admixed under sterile conditions with a pharmaceutically acceptable topical carrier and any preservatives or buffers as may be required. Compounds that are volatile may require admixture with formulating agents or with packaging materials to assure proper dosage delivery. Compounds of the invention that have poor skin permeability may require one or more permeation enhancers, whereas compounds rapidly absorbed through the skin may require formulation with absorption-retarding agents or barriers.

[0189] The term “pharmaceutically acceptable topical carrier" refers to a carrier medium, suitable for topical application, that provides appropriate delivery of an effective amount of a compound of the invention, such as an inactive liquid orcream vehicle capable of suspending or dissolving the compound. The skilled person will appreciate that this term encompasses carrier materials approved for use in topical cosmetics as well.

[0190] The terms “permeation enhancer” relates to an increase in the permeability of the skin, nail, hair, claw or hoof to the compound of the invention, so as to increase the rate and extent of permeation of the compound. The enhanced permeation can be observed, for example, by measuring the rate of diffusion of the drug through animal or human skin, nail, hair, claw or hoof using a diffusion cell apparatus. A diffusion cell is described by Merritt et al., “Diffusion Apparatus for Skin Penetration,” J. Controlled Release, 1 (1984) pp. 161-162.

[0191] The ointments, pastes, creams, lotions, gels, suppositories, powders, solutions, sprays, drops, inhalants and patches for topical administration may contain, in addition to a compound of the invention, one or more pharmaceutically acceptable excipients, such animal or vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, zinc oxide, preservatives, antioxidants, fragrances, emulsifiers, dyes, inert fillers, anti-irritants, tackifiers, fragrances, opacifiers, antioxidants, gelling agents, stabilizers, surfactants, emollients, coloring agents, preservatives, buffering agents, permeation enhancers. Such excipients should not interfere with the effectiveness of the biological activity of the active agent and not be deleterious to the epithelial cells or their function.

[0192] Transdermal administration may be achieved by means of a transdermal patch. The transdermal patch may be of the ‘reservoir and porous membrane’ type or employ a ‘matrix system’.

[0193] The solubility of compounds of the invention used in the preparation of pharmaceutical compositions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.

[0194] The compounds of formula I can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler, as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or as nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

[0195] Delivery by inhalation is the preferred route of administration for the compounds of the present invention.

[0196] The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound of formula I comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the compound, a propellant as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

[0197] Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying. Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as I- leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

[0198] A suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1pg to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 pl to 10Opl. A typical formulation may comprise a compound of formula I propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.

[0199] Suitable scents, such as a fruit or floral aroma may be added to those formulations of the invention intended for intranasal administration. Formulations for intranasal administration may be formulated to be immediate and / or modified release using, for example, PGLA.

[0200] Modified release includes delayed, sustained, pulsed, controlled, targeted and programmed release.

[0201] Compounds of formula I may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Compounds of formula I may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste, bioavailability and / or stability when using any of the aforementioned modes of administration. Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.

[0202] As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e., as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in international patent publications WO91 / 11172, WO94 / 02518 and WO98 / 55148.

[0203] In as much as it may be desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound of formula I may conveniently be combined in the form of a kit suitable for coadministration of the compositions. Thus, a kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula I and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like. Such a kit is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid.

[0204] The compounds of the invention may be prepared by any method known in the art for the preparation of compounds of analogous structure. In particular, the compounds of the invention can be prepared by the procedures described by reference to the Schemes that follow, or by the specific methods described in the Examples, or by processes similar to either.

[0205] The skilled person will appreciate that the experimental conditions set forth in the protocols that follow are illustrative of suitable conditions for effecting the transformations shown, and that it may be necessary or desirable to vary the precise conditions employed for the preparation of compounds of formula I. It will be further appreciated that it may be necessary or desirable to carry out the transformations in a different order from that described, or to modify one or more of the transformations, to provide the desired compound of the invention.

[0206] In addition, the skilled person will appreciate that it may be necessary or desirable at any stage in the synthesis of compounds of the invention to protect one or more sensitive groups, so as to prevent undesirable side reactions. In particular, it may be necessary or desirable to protect amino or carboxylic acid groups. The protecting groups used in the preparation of the compounds of the invention may be used in conventional manner. See, for example, those described in Protective Groups in Organic Synthesis by Theodora W Greene and Peter G M Wuts, 3rd edition, (John Wiley and Sons, 1999), in particular, chapters 7 (“Protection for the Amino Group”) and 5 (“Protection for the Carboxyl Group”), incorporated herein by reference, which also describes methods for the removal of such groups.

[0207] Experimental Procedures

[0208] The compounds and intermediates described below were named using the naming convention provided with ChemDraw version 20.1.1.123. The naming convention provided with ChemDraw version 20.1.1.123 is well known by those skilled in the art and it is believed that the naming convention generally comports with the IUPAC (International Union for Pure and Applied Chemistry) recommendations on Nomenclature of Organic Chemistry and the CAS Index rules. Unless noted otherwise, all reactants were obtained commercially without further purifications or were prepared using methods known in the literature.

[0209] The following illustrates the synthesis of various compounds of the present invention. Additional compounds within the scope of this invention may be prepared using the methods illustrated in these Examples, either alone or in combination with techniques generally known in the art. All starting materials in these Preparations and Examples are either commercially available or can be prepared by methods known in the art or as described herein.

[0210] Commercial solvents and reagents were generally used without further purification. Anhydrous solvents were employed where appropriate, generally ACROSEALTM products from Acros Organics, Aldrich SURE / SEAL™ from Sigma- Aldrich, or DRISOLVTM products from EMD Chemicals. Commercial solvents and reagents were used without further purification.

[0211] Experiments were generally carried out under inert atmosphere (nitrogen or argon), particularly in cases where oxygen- or moisture-sensitive reagents or intermediates were employed.

[0212] Unless otherwise noted, chemical reactions were performed at room temperature (about 23 degrees Celsius).

[0213] The terms “concentrated,” “evaporated,” and “concentrated in vacuo” refer to the removal of solvent at reduced pressure on a rotary evaporator with a bath temperature less than 60 °C.

[0214] For syntheses referencing procedures in other Examples or Methods, reaction conditions (reaction time and temperature) may vary. In general, reactions were followed by thin-layer chromatography (TLC) or mass spectrometry (MS) and subjected to work-up when appropriate.

[0215] Purifications may vary between experiments: in general, solvents and the solvent ratios used for eluents / gradients were chosen to provide appropriate retention times.

[0216] Reaction progress was monitored using thin layer chromatography (TLC), liquid chromatography-mass spectrometry (LCMS) and high-performance liquid chromatography (HPLC), analyses. TLC was performed on pre-coated silica gel plates with a fluorescence indicator (254 nm excitation wavelength) and visualized under UV light and / or with 12, KMnO4, CoCI2, phosphomolybdic acid, or ceric ammonium molybdate stains.

[0217] LCMS data were acquired on an Agilent 1100 Series instrument with a Leap Technologies autosampler, Gemini C18 columns or Atlantis dC18 columns, ACN / water gradients, and either TFA, formic acid, or ammonium hydroxide modifiers or similar equipment. The column eluent was analyzed using Waters ZQ mass spectrometer scanning in both positive and negative ion modes from 100 to 1200 Da. Other similar instruments were also used. Mass spectrometry data are reported from LCMS analyses.

[0218] HPLC data were acquired on an Agilent 1100 Series, C-830 or C-850 instrument using Gemini, Sunfire, Boston Prime, Sepacore, Welch Xtimate, Phenomenex Gemini NX orXBridge C18 columns, as well as, WePure Biotech XP tC18 columns, ACN / water gradients, and either TFA, formic acid or ammonium hydroxide modifiers and comparable equipment. Purifications were performed by medium performance liquid chromatography (MPLC) using Isco CombiFlash Companion, AnaLogix I ntel I iFlash 280, Biotage SP1, or Biotage Isolera One instruments and pre-packed Isco RediSep or Biotage Snap silica cartridges and the like. Commercial benchtop photoreactors such as the Penn OC Photoreactor M2, Acceled Photoreactor M2 and Lumidox II with 24-well block were utilized with 450 or 445 nanometer (nm) light-emitting diode (LED).

[0219] Racemic compounds are indicated either by the absence of drawn or described stereochemistry.

[0220] In some examples, chiral separations were carried out to separate enantiomers or diastereomers of certain compounds of the disclosure. Chiral purifications were performed by ChiralPAK-AD, -AS, -IC, Chiralcel-OD, or-OJ, Pirkle Covalent (R, R) Whelk-O1, Phenomenex Cellulose-1 columns; and CO2 mixtures with MeOH, EtOH, isopropyl alcohol, or MeCN, alone or modified using TFA, formic acid or isopropylamine. UV detection was used to trigger fraction collection.

[0221] Proton nuclear magnetic resonance (1H NMR) spectra were recorded, referenced to residual peaks from the deuterated solvents employed. The deuterated solvents employed were as follows: CDCI3 is deuterated chloroform; CD3OD is deuterated methanol; (CD3)2SO is deuterated dimethyl sulfoxide. The peak shapes are described as follows: d is doublet; dd is doublet of doublets; ddd is doublet of doublet of doublets; dt is doublet of triplets, dq is doublet of quartets; m is multiplet, s is singlet, t is triplet, td is triplet of doublets; tt is triplet of triplets; q is quartet; quin is quintet and brs is broad singlet. Proton nuclear magnetic spectroscopy (1H NMR) chemical shifts are expressed in parts per million (ppm, d) referenced to the deuterated solvent residual peaks (CDCI3, 7.26 ppm; (CD3)2SO, 3.33 or 2.50 ppm; CD3OD is 4.87 or 3.31 ppm). Proton nuclear magnetic spectroscopy (1H NMR) chemical shifts are given in parts per million downfield from tetramethylsilane and were recorded on 300, 400, 500, or 600 MHz (where MHz is megahertz) Varian, Bruker, or Jeol spectrometers.

[0222] Products were generally dried under vacuum before being carried on to further reactions or submitted for biological testing.

[0223] In the experimental sections that follow the following abbreviations may be used. A is angstrom; AcOH is acetic acid; Ac2O is acetic anhydride; AdBrettPhos Pd G3 is [2-(di-1 -adamantylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxybiphenyl][2-(2'-amino-1, T-biphenyl)]palladium(l I) methanesulfonate; NH4HCO2 is ammonium formate; BOC2O is di-terf-butyl dicarbonate; BrettPhos Pd G3 is [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1, T -biphenyl)]palladium(l I) methanesulfonate methanesulfonate; brine is highly concentrated water solution of sodium chloride; °C is degrees Celsius; CO2is carbon dioxide; Cs2CO3is cesium carbonate; CsF is cesium fluoride; Cui is copper(l) iodide; Cu(OTf)2is copper(ll) triflate; DCE is 1,2-dichloroethane; DCM is dichloromethane; DMSO is dimethyl sulfoxide; DIPEA is A / , / V-diisopropylethylamine; DIAD is diisopropyl azodicarboxylate; DMA is dimethylacetamide; DMAP is 4-(dimethylamino)pyridine; DMF is dimethylformamide; EDCI is 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride; EtOAc is ethyl acetate; EtOH is ethanol; Fe is iron; g is gram; h is hour; HCI is hydrochloric acid; H2O is water; HPLC is high performance liquid chromatography; / PrOAc is isopropyl acetate; K2CO3is potassium carbonate; [lr(dF(Me)ppy)2(dtbbpy)]PF6is Iridium(lll) bis[2-(2,4-difluorophenyl)-5-methylpyridine-N, C2o]-4,40-di-te / Y-butyl-2,20-bipyridine hexafluorophosphate; KOtBu is potassium te / Y-butoxide; LCMS is liquid chromatography mass spectrometry; LED is light-emitting diode; LiCI is lithium chloride; LiHMDS is lithium bis(trimethylsilyl)amide; M is molar; M+ is mass ion; mg is milligram; MgSO4 is magnesium sulfate; MeCN is acetonitrile; min is minute; MeOH is methanol; mL is milliliter; mL / min is milliliter per minute; mm is millimeter; mM is millimolar; mmol is millimole; mol is mole; MPa is megapascal; mW is megawatts; pm is micrometer; pmol is micromole; pL is microliter; N is normal; N2is nitrogen; NaOH is sodium hydroxide; n-BuOH is 1 -butanol; nm is nanometer; NaBH(OAc)3is sodium triacetoxyborohydride; NaHCO3is sodium bicarbonate; Na2CO3is sodium carbonate; NaOtBu is sodium tert-butoxide; Na2SO4is sodium sulfate; NBS is N-bromosuccinimide; NFLHCOs is ammonium bicarbonate; NH4CI is ammonium chloride; NH4OH is ammonium hydroxide; NFLHCOs is ammonium bicarbonate; NiBr2.dtbbpy is [4,4'-bis(te / Y-butyl)-2,2'-bipyridine]nickel dibromide; NiCI2.glyme is Nickel(ll) chloride ethylene glycol dimethyl ether complex; O2is oxygen; Pd / AI2O3is palladium on alumina; Pd / C is palladium on carbon; Pd(OH)2 / C is palladium hydroxide on carbon; PdCI2(PPh3)2is bis(triphenylphosphine )palladium(l I) dichloride; Pd(dppf)CI2is [1,1'-is(diphenylphosphino)ferrocene] dichloropalladium(ll) complex with dichloromethane; PPh3is triphenylphosphine; PSI is pounds per square inch; PyBOP is (benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate; PyHBr3is pyridinium tribromide; r / min is revolutions per minute; SOCI2is thionyl chloride; Pd2(dba)3is tris(dibenzylideneacetone)dipalladium(0), rac-BINAP-Pd-G3 is [2'-(amino-K / \ / )[1,1'-biphenyl]-2-yl-KC][[2'-(diphenylphosphino)[1,1'-binaphthalen]-2-yl]diphenylphosphine-KP](methanesulfonato-KO)- palladium; TEA is triethylamine; TFA is trifluoroacetic acid; THF is tetrahydrofuran; TMG is 1,1,3,3-tetramethylguanidine; fBuXPhos Pd G3 is [(2-di-te / Y-butylphosphino-2',4',6'-triisopropyl-1,1 '-biphenyl)-2-(2'-amino-1,1 '-biphenyl)] palladiu m(l I) methanesulfonate; W is watt; wt% is weight percent; Xantphos is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; XantPhos Pd G3 is [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1, T-biphenyl)]palladium(ll) methanesulfonate; XantPhos Pd G4 is (SP-4-3)-[[5-(diphenylphosphino)-9,9-dimethyl-9 / 7-xanthen-4-yl]diphenylphosphine-KP](methanesulfonato-KO)[2'-(methylamino-KA / )[1,1 '-biphenyl]-2-yl-KC]- palladium; XPhos Pd G3 is (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1, T-biphenyl)]palladium(ll) methanesulfonate. Preparation P1

[0224] / V2-(4-Chloro-2-fluorophenyl)-5,6-dimethylpyrazine-2,3-diamine hydrochloride (P1 )

[0225]

[0226] Step 1. Preparation of 3-chloro- / V-(4-chloro-2-fluorophenyl)-5,6-dimethylpyrazin-2-amine (C1) To a 300-mL EasyMax reactor with a temperature probe and reflux condenser was added a solution of 2,3-dichloro-5,6-dimethylpyrazine (CAS: 32493-79-1; 20.0 g, 113 mmol) in THF (98 mL). To the solution was added 4-chloro-2-fluoroaniline (CAS: 57946-56-2; 17.3 g, 119 mmol) and KOfBu (19.0 g, 169 mmol) slowly. After the addition, the reaction mixture changed to a dark red color. The reaction mixture was stirred at 65 °C for 2.5 h then cooled to room temperature. To the suspension was added H2O (1080 mL) dropwise which resulted in precipitation of solids. The slurry was stirred at room temperature overnight then was filtered and rinsed with H2O. The filter cake was dried under a flow of N2gas then collected to provide C1 (22.2 g, 68.6% yield) as a light-brown solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+2H)+= 288.2.1H NMR (400 MHz, (CD3)2SO) 6 8.38 (s, 1 H), 7.61 (t, 1H), 7.47 (dd, 1H), 7.29-7.24 (m, 1H), 2.32 (s, 3H), 2.26 (s, 3H).

[0227] Step 2. Preparation of / V-(4-chloro-2-fluorophenyl)-3-((diphenylmethylene)amino)-5,6-dimethylpyrazin-2-amine (C2)

[0228] To a 300-mL EasyMax reactor with a temperature probe was added a solution of C1 (8.45 g, 29.5 mmol), benzophenone imine (CAS: 1013-88-3; 6.42 g, 35.4 mmol) and rac-BINAP-Pd-G3 (1.46 g, 1.48 mmol) in 1,4-dioxane (84 mL). To the solution was added NaOfBu (7.09 g, 73.8 mmol). The reaction solution was stirred at 60 °C for 2.5 h which caused the dark red solution to change to a dark purple. The reaction mixture was filtered through a silica plug (~1 inch) in a 1000 mL fritted glass funnel, eluting with 20% EtOAc in heptane (1000 mL). The filtrate was concentrated in vacuo. The residue was dissolved in DCM then purified through a silica plug (~1 inch) in a fritted glass funnel (500 mL), eluting with 20% EtOAc in heptane (1000 mL). The filtrate was concentrated in vacuo to form C2 (11.6 g, 91.5% yield) as a yellow orange solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 431.6.1H NMR (400 MHz, CDCI3) 6 8.67-8.59 (m, 1 H), 7.91-7.81 (m, 2H), 7.56-7.27 (m, 7H), 7.20-7.06 (m, 4H), 2.37 (s, 3H), 2.08 (s, 3H). Step 3. Preparation of N2-(4-chloro-2-fluorophenyl)-5,6-dimethylpyrazine-2,3-diamine hydrochloride (P1)

[0229] To a dark yellow solution of C2 (0.25 g, 0.58 mmol) in THF (2.9 mL) was added 1M HCI (1.2 mL) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc then rinsed with a saturated aqueous solution of NaHCOs (3 x5 mL). The organic layer was dried with MgSO4then filtered and concentrated in vacuo to form a yellow oil. The yellow oil was suspended in heptane (20 mL) and heated with a heat gun until a homogenous light-yellow solution formed. The solution was cooled to room temperature while stirring which caused precipitates to form. The slurry was stirred for 1 h at room temperature then filtered and rinsed with cold heptane (1 mL). The filter cake was dried under high vacuum then collected to provide P1 (0.13 g, 72% yield) as an off-white crystalline solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 267.2.1H NMR (400 MHz, CDCl3) 67.89 (t, 1H), 7.15-7.04 (m, 2H), 6.32 (s, 1H), 4.45 (s, 2H), 2.35 (d, 6H).

[0230] Preparation P2

[0231] 2-(2-Ethylpyridin-4-yl)morpholine hydrochloride (P2)

[0232]

[0233] Step 1. Preparation ofte / Y-butyl 2-(2-ethylpyridin-4-yl)morpholine-4-carboxylate (C3)

[0234] A reaction mixture of 4-bromo-2-ethylpyridine (CAS: 156761-88-5; 0.200 g, 1.07 mmol), 4-(te / Y-butoxycarbonyl)morpholine-2-carboxylic acid (CAS: 189321-66-2; 0.373 g, 1.61 mmol), [lr(dF(Me)ppy)2(dtbbpy)]PF6(10.9 mg, 0.0107 mmol), NiBr2.dtbbpy (26.2 mg, 0.0537 mmol) phthalimide (CAS: 85-41-6; 36.4 mg, 0.247 mmol), TMG (0.248 g, 2.15 mmol) in DMSO (10.7 mL) was degassed with N2gas for 2 min. The reaction vessel was sealed then irradiated with a photoreactor (fan speed: 5000 r / min; stirred speed: 1000 r / min; 100% 450 nm LED) and stirred at room temperature for 16 h. The reaction mixture was diluted with H2O (10 mL) and EtOAc (10 mL). The suspension was extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with H2O, dried with Na2SO4then concentrated in vacuo. The residue was dissolved in MeOH (0.2 mL) then purified by reverse phase HPLC (WePure Biotech XP tCi8150 mm x40 mm x 7 pm, H2O (0.05% NH4OH + 10 mM NH4HCO3) / MeCN, 28-68% MeCN in 9 min, flow rate= 60 mL / min) to provide C3 (0.115 g, 36.6% yield) as a yellow oil. (LC / MS) m / z (M+2H)+= 294.1.1H NMR (400 MHz, CD3OD) 68.43-8.37 (m, 1H), 7.36 (s, 1H), 7.30-7.24 (m, 1H), 4.48 (dt, 1H), 4.15-3.98 (m, 2H), 3.96-3.88 (m, 1H), 3.67 (tt, 1H), 3.15-3.00 (m, 1H), 2.87-2.77 (m, 3H), 1.51-1.46 (m, 9H), 1.33-1.25 (m, 3H). Step 2. Preparation of 2-(2-ethylpyridin-4-yl)morpholine hydrochloride (P2)

[0235] To a solution of C3 (0.060 g, 0.21 mmol) in DCM (1 mL) was added HCI in 1,4-dioxane (4 mL). The resulting mixture was stirred at room temperature for 2.5 h. The suspension was concentrated in vacuo then lyophilized to provide P2 (0.060 g, >95% yield) as a colorless gum. The gum was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 193.1.

[0236] Preparation P3

[0237] 2-Methyl-6-(2-methylpyridin-4-yl)morpholine (P3)

[0238]

[0239] Step 1. Preparation of 2-(benzyl(2-hydroxypropyl)amino)-1-(2-methylpyridin-4-yl)ethan-1-one (C4)

[0240] To a reaction mixture of 2-bromo-1-(2-methylpyridin-4-yl)ethan-1-onehydrobromide (CAS: 1187669-34-6; 24 g, 81 mmol) in THF (300 mL) was added 1-(benzylamino)-2-propanol (CAS: 27159-32-6; 16 g, 98 mmol) and DIPEA (53 g, 0.41 mol) dropwise. The orange suspension was stirred at room temperature for 18 h then filtered. The filtrate was diluted with EtOAc (200 mL) and washed with H2O (200 mL). The organic phase was dried with Na2SO4then concentrated in vacuo to form a brown liquid. The liquid was purified with a silica plug and eluted with / PrOAc (2 L). The filtrate was concentrated in vacuo to provide C4 (23 g, 95% yield) as a yellow oil. (LC / MS) m / z (M+H)+= 299.2.

[0241] Step 2. Preparation of 4-benzyl-2-methyl-6-(2-methylpyridin-4-yl)-3,4-dihydro-2 / 7-1,4-oxazine (C5)

[0242] To a solution of C4 (23 g, 77 mmol) in DCE (200 mL) was added trimethylsilyl trifluoromethanesulfonate (CAS: 26607-77-8; 50 mL) dropwise. The suspension was stirred at 80 °C for 16 h before another portion of trimethylsilyl trifluoromethanesulfonate (CAS: 26607-77-8; 50 mL) was added. The reaction mixture was stirred at 100 °C for 16 h then poured into saturated NaHCOs solution (1 L). The suspension was diluted with DCE. The organic layer was separated then dried with Na2SO4and concentrated in vacuo to provide C5 (22 g, >95% yield) as a yellow oil. The oil was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 281.2.

[0243] Step 3. Preparation of 2-methyl-6-(2-methylpyridin-4-yl)morpholine (P3)

[0244] To a solution of C5 (13.6 g, 48.5 mmol) in MeOH (200 mL) was added NH4HCO2 (CAS: 540-69-2; 14.0 g, 0.222 mol) and Pd(OH)2 / C (CAS: 12135-22-7; 13.6 g, 20 wt%, 48.5 mmol). The reaction mixture was stirred at 65 °C for 16 h then filtered over Celite. The filtrate was concentrated in vacuo to provide a residue. The residue was purified by column chromatography (silica gel, 0-20% MeOH / DCM) to provide P3 (3.80 g, 41.7% yield). (LC / MS) m / z (M+H)+= 193.2.1H NMR (400 MHz, CD3OD) 6 8.38 - 8.33 (m, 1 H), 7.34 - 7.20 (m, 2H), 4.54 (dd, 1 H), 3.81 - 3.71 (m, 1 H), 3.03 (dd, 1 H), 2.95 - 2.86 (m, 1 H), 2.54 - 2.50 (m, 3H), 2.49 - 2.41 (m, 2H), 1.21 (d, 3H).

[0245] Preparation P4

[0246] (2R,6S)-2-Methyl-6-(2-methylpyridin-4-yl)morpholine hydrochloride and (2S,6R)-2-Methyl-6-(2- methylpyridin-4-yl)morpholine hydrochloride (racemic, cis) (P4)

[0247]

[0248] Step 1. Preparation ofte / Y-butyl (2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholine-4-carboxylate and te / Y-butyl (2S,6 / ?)-2-methyl-6-(2-methylpyridin-4-yl)morpholine-4-carboxylate (racemic, cis) (C6)

[0249] To a solution of P3 (20. g, 0.10 mol) in MeCN (400 mL) was added BOC2O (25 g, 0.11 mol) and DMAP (1.3 g, 0.010 mol). The reaction mixture was stirred at room temperature 1 h then concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-20% / PrOAc / heptane). The residue was purified again by column chromatography (silica gel, 0-20% / PrOAc / heptane) to provide C6 (8.2 g, 27% yield) as a yellow oil. (LC / MS) m / z (M+H)+= 293.2.1H NMR (400 MHz, CDCl3) 6 8.47-8.42 (m, 1 H), 7.19-7.15 (m, 1H), 7.10-7.05 (m, 1 H), 4.48-4.37 (m, 1H), 4.23-3.84 (m, 2H), 3.74-3.62 (m, 1H), 2.66-2.55 (m, 2H), 2.55-2.51 (m, 3H), 1.50-1.44 (m, 9H), 1.28-1.22 (m, 3H).

[0250] Step 2. Preparation of (2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholine hydrochloride and (2S,6R)-2-Methyl-6-(2-methylpyridin-4-yl)morpholine hydrochloride (racemic, cis) (P4) The same procedure was followed from Preparation P2, step 2 with C6 (0.045 g, 0.15 mmol) to provide P4 (0.030 g, >95% yield) as a yellow oil. The oil was used directly in the next step without further purification.

[0251] Preparation P5

[0252] 2-(2,6-Dimethylpyridin-4-yl)morpholine hydrochloride (P5)

[0253]

[0254] Step 1. Preparation of te / Y-butyl 2-(2,6-dimethylpyridin-4-yl)morpholine-4-carboxylate formate (C7)

[0255] The same procedure was followed from Preparation P2, step 1 with 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (CAS: 189321-66-2; 0.466 g, 2.02 mmol) and 4-bromo-2,6-dimethylpyridine (CAS: 5093-70-9; 0.250 g, 1.34 mmol) with a photoreactor (450 nm light, fan speed 5200 r / min; stir rate: 1000 r / min; and 100% LED). The crude residue was purified by reverse phase HPLC (WePure Biotech XP tC18150 mm x 40 mm x 7 μm, H2O (0.225% formic acid) / MeCN, 1-41% MeCN in 9 min, flow rate= 60 mLZ min) to provide C7 (0.190 g, 41.8% yield) as a colorless gum. (LC / MS) m / z (M+H)+= 293.3.1H NMR (400 MHz, CDCl3) 68.22 (s, 1H), 7.06 (s, 2H), 4.42-4.35 (m, 1H), 4.25-3.88 (m, 3H), 3.66 (td,1H), 3.08-2.99 (m, 1H), 2.79-2.65 (m, 1H), 2.58 (s, 6H), 1.49 (s, 9H).

[0256] Step 2. Preparation of 2-(2,6-dimethylpyridin-4-yl)morpholine hydrochloride (P5)

[0257] The same procedure was followed from Preparation P2, step 2 with C7 (0.070 g, 0.21 mmol) to provide P5 (0.065 g, >95% yield) as a yellow solid. The solid was used directly in the next step without further purification.

[0258] Preparation P6

[0259]

[0260] Step 1. Preparation ofte / Y-butyl 2-(3-methylisothiazol-5-yl)morpholine-4-carboxylate (C8)

[0261] The same procedure was followed from Preparation P2, step 1 with 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (CAS: 189321-66-2; 0.390 g, 1.68 mmol) and 5- bromo-3-methylisothiazole (CAS: 20493-60-1; 0.200 g, 1.12 mmol) and utilized a photoreactor (445 nm, 255 mW) with a fan. The purification conditions were altered. The crude residue was purified by reverse phase HPLC (WePure Biotech XP tC18150 mm x 40 mm x 7 μm, H2O (0.05% NH4OH + 10 mM NH4HCO3) / MeCN, 29-69% MeCN in 9 min, flow rate= 60 mL / min) to provide C8 (0.104 g, 32.7% yield) as a yellow oil. (LC / MS) m / z (M+H)+= 285.0.1H NMR (400 MHz, CD3OD) 6 7.08 (s, 1H), 4.21— 4.12 (m, 1H), 4.02-3.94 (m, 1H), 3.92-3.84 (m, 1H), 3.75-3.63 (m, 1 H), 3.38-3.34 (m, 1H), 3.17-2.88 (m, 2H), 2.48-2.44 (m, 3H), 1.52-1.48 (m, 9H). Step 2. Preparation of 2-(3-methylisothiazol-5-yl)morpholine hydrochloride (P6)

[0262] The same procedure was followed from Preparation P2, step 2 with C8 (0.070 g, 0.25 mmol) to provide P6 (0.070 g, >95% yield) as a yellow solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 185.0.

[0263] Preparation P7

[0264] 1-(4-(Morpholin-2-yl)pyridin-2-yl)cyclobutane-1 -carbonitrile trifluoroacetate (P7)

[0265]

[0266] Step 1. Preparation of 4-(te / Y-butyl) 2-(1,3-dioxoisoindolin-2-yl) morpholine-2,4-dicarboxylate (C9)

[0267] To a solution of 4-(te / Y-butoxycarbonyl)morpholine-2-carboxylic acid (CAS: 189321-66-2; 3.00 g, 13.0 mmol) in DCM (65 mL) was added / V-hydroxyphthalimide (CAS: 524-38-9; 1.90 g, 11.7 mmol), EDCI (2.49 g, 13.0 mmol) and DMAP (0.158 g, 1.30 mmol). The reaction mixture was stirred at room temperature for 16 h then filtered with a silica gel plug. The filter cake was rinsed with DCM (3 x 50 mL). The filtrate was concentrated in vacuo to provide C9 (3.10 g, 63.5% yield) as a white solid.1H NMR (400 MHz, CDCI3) 6 7.93-7.87 (m, 2H), 7.83-7.78 (m, 2H), 4.54 (dd, 1 H), 4.32-4.01 (m, 2H), 3.82-3.63 (m, 2H), 3.57-3.41 (m, 1H), 3.26 (ddd, 1H), 1.49 (s, 9H).

[0268] Step 2. Preparation of te / Y-butyl 2-(2-(1-cyanocyclobutyl)pyridin-4-yl)morpholine-4-carboxylate (C10)

[0269] To a reaction mixture of NiCl2.glyme (13 mg, 0.060 mmol) and 5-methoxypicolinimidamide (CAS: 1179532-65-0; 9.1 mg, 0.060 mmol) in DMA (1 mL) was stirred at room temperature for 5 min before C9 (0.16 g, 0.42 mmol) and 1-(4-bromopyridin-2-yl)cyclobutane-1 -carbonitrile (CAS: 1163707-59-2; 71 mg, 0.30 mmol) were added. The suspension was stirred for 5 min then tetrabutylammonium iodide (0.11 g, 0.30 mmol), zinc (0.12 g, 1.8 mmol) and TFA (17 mg, 0.15 mmol) were added. The reaction mixture was stirred at room temperature for 16 h then diluted with H2O (3 mL) and EtOAc (5 mL). The suspension was extracted with EtOAc (2 x5 mL). The combined organic layers were washed with H2O then dried with Na2SO4and concentrated in vacuo. The residue was dissolved in MeOH (0.2 mL) and purified by reverse phase HPLC (Welch Xtimate C18150 mm x 30 mm x 5 μm, H2O (0.05% NH4OH + 10 mM NH4HCO3) / MeCN, 39-79% MeCN in 9 min, flow rate= 25 mL / min) to provide C10 (0.038 g, 37% yield) as a yellow gum.1H NMR (400 MHz, CD3OD) 68.59-8.57 (m, 1H), 7.61 (s, 1H), 7.41-7.37 (m, 1H), 4.57-4.51 (m, 1H), 4.19-4.01 (m, 2H), 3.96-3.88 (m, 1H), 3.72-3.64 (m, 1H), 3.50-3.45 (m, 1H), 3.15-3.08 (m, 1H), 2.90-2.72 (m, 4H), 2.47-2.34 (m, 1H), 2.18-2.07 (m, 1H), 1.48 (s, 9H).

[0270] Step 3. Preparation of 1-(4-(morpholin-2-yl)pyridin-2-yl)cyclobutane-1 -carbonitrile trifluoroacetate (P7)

[0271] To a reaction mixture of C10 (38 mg, 0.11 mmol) in DCM (1 mL) was added TFA (0.5 mL) then stirred at room temperature for 2 h. The suspension was concentrated in vacuo and lyophilized to form P7 (0.040 g, >95% yield) as a colorless gum. (LC / MS) m / z (M+H)+= 244.0.

[0272] Preparation P8

[0273] 2-(2-(Difluoromethoxy)pyridin-4-yl)morpholine hydrochloride (P8)

[0274]

[0275] Step 1. Preparation ofte / Y-butyl 2-(2-(difluoromethoxy)pyridin-4-yl)morpholine-4-carboxylate (C11)

[0276] The same procedure was followed from Preparation P2, step 1 with 4- tert-butoxycarbonyl)morpholine-2-carboxylic acid (CAS: 189321-66-2; 0.477 g, 2.06 mmol) and 4-bromo-2-(difluoromethoxy)pyridine (CAS: 832735-56-5; 0.308 g, 1.38 mmol) and utilized the photoreactor (fan speed: 5200 r / min; stirring speed: 1200 r / min; 100% 450 nm LED). The purification conditions were altered. The crude residue was purified by reverse phase HPLC (Welch Xtimate C18150 mm x 30 mm x 5 μm, H2O (NH4OH-NH4HCO3) / MeCN, 39-79% MeCN in 9 min, 100% MeCN hold 2 min, flow rate= 25 mL / min) to provide C11 (0.173 g, 38.1% yield) as a yellow oil. (LC / MS) m / z (M+H)+= 331.1.1H NMR (400 MHz, CDCI3) 68.16 (d, 1H), 7.46 (s, 1 H), 7.08 (d, 1 H), 6.94 (s, 1H), 4.43 (dd, 1H), 4.22-3.86 (m, 3H), 3.66 (td, 1 H), 3.09-2.95 (m, 1H), 2.82-2.66 (m, 1H), 1.49 (s, 9H).

[0277] Step 2. Preparation of 2-(2-(difluoromethoxy)pyridin-4-yl)morpholine hydrochloride (P8)

[0278] The same procedure was followed from Preparation P2, step 2 with C11 (0.070 g, 0.23 mmol) to provide P8 (0.057 g, >95% yield) as a yellow solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 231.1.

[0279] Preparation P9

[0280] / V, / V-Dimethyl-4-(morpholin-2-yl)pyridin-2-amine hydrochloride (P9)

[0281]

[0282] Step 1. Preparation ofte / Y-butyl 2-(2-(dimethylamino)pyridin-4-yl)morpholine-4-carboxylate (C12)

[0283] The same procedure was followed from Preparation P7, step 2 with C9 (0.606 g, 1.61 mmol) and 4-bromo- / V, / V-dimethylpyridin-2-amine (CAS: 946000-27-7; 0.231 g, 1.15 mmol). The purification conditions were altered. The crude residue was purified by reverse phase HPLC (C18150 mm x 40 mm x 5 μm, H2O (NH4OH-NH4HCO3) / MeCN, 29-69% MeCN in 9 min, 100% MeCN hold 2 min, flow rate= 60 mL / min) to provide C12 (0.180 g, 50.9% yield) as a colorless gum. (LC / MS) m / z (M+H)+= 308.1.1H NMR (400 MHz, CDCl3) 6 8.13 (d, 1H), 6.55-6.49 (m, 2H), 4.37-4.30 (m, 1 H), 4.24-3.85 (m, 3H), 3.69-3.61 (m, 1 H), 3.09 (s, 6H), 3.05-2.97 (m, 1 H), 2.84-2.72 (m, 1H), 1.49 (s, 9H).

[0284] Step 2. Preparation of / V, / V-dimethyl-4-(morpholin-2-yl)pyridin-2-amine hydrochloride (P9)

[0285] The same procedure was followed from Preparation P2, step 2 with C12 (0.070 g, 0.23 mmol) to provide P9 (0.056 g, >95% yield) as a white solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 208.2.

[0286] Preparation P10

[0287] 2-(2-Methylthiazol-5-yl)morpholine hydrochloride (P10)

[0288]

[0289] Step 1. Preparation ofte / Y-butyl 2-(2-methylthiazol-5-yl)morpholine-4-carboxylate (C13) The same procedure was followed from Preparation P2, step 1 with 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (CAS: 189321-66-2; 0.390 g, 1.68 mmol) and 5-bromo-2-methylthiazole (CAS: 57268-16-3; 0.200 g, 1.12 mmol) and utilized the photoreactor (fan speed: 5000 r / min; stirred speed: 1000 r / min; 100% 450 nm LED). The purification conditions were altered. The crude residue was purified by reverse phase HPLC (Welch Xtimate C18150 mm x 30 mm x 5 μm, H2O (0.225% formic acid) / MeCN, 17-57% MeCN in 9 min, flow rate= 25 mLZ min) to provide C13 (41.6 mg, 13.0% yield) as a yellow oil. (LC / MS) m / z (M+H)+= 285.1.1H NMR (400 MHz, CDCl3) 6 7.53 (s, 1 H), 4.67 (dd, 1 H), 4.27-3.79 (m, 3H), 3.74-3.58 (m, 1H), 3.14-2.95 (m, 2H), 2.72-2.68 (m, 3H), 1.48 (s, 9H).

[0290] Step 2. Preparation of 2-(2-methylthiazol-5-yl)morpholine hydrochloride (P10)

[0291] At 0 °C, to a solution of C13 (0.041 g, 0.15 mmol) in 1,4-dioxane (1 mL) was added HCI in 1,4-dioxane (4 mL) then stirred at room temperature for 2 h. The suspension was concentrated in vacuo then lyophilized to provide P10 (0.041 g, >95% yield) as a light-yellow solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 185.2.

[0292] Preparation P11

[0293] 2-(2-Methoxypyridin-4-yl)morpholine hydrochloride (P11)

[0294]

[0295] Step 1. Preparation ofte / Y-butyl 2-(2-methoxypyridin-4-yl)morpholine-4-carboxylate (C14) The same procedure was followed from Preparation P2, step 1 with 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (CAS: 189321-66-2; 0.369 g, 1.60 mmol) and 4-bromo-2-methoxypyridine (CAS: 100367-39-3; 0.200 g, 1.06 mmol) and utilized the photoreactor (fan speed: 5000 r / min; stirred speed: 1000 r / min; 100% 450 nm LED). The purification conditions were altered. The crude residue was purified by reverse phase HPLC (WePure Biotech XP tC18150 mm x 40 mm x 7 μm, H2O (0.05% NH4OH + 10 mM NH4HCO3) / MeCN, 30-70% MeCN in 9 min, flow rate= 60 mL / min) and lyophilized again to provide C14 (189 mg, 60.5% yield) as a brown oil. (LC / MS) m / z (M+H)+= 295.1.1H NMR (400 MHz, CDCl3) 6 8.14 (d, 1 H), 6.89-6.85 (m, 1 H), 6.76 (s, 1H), 4.41-4.35 (m, 1H), 4.23-3.98 (m, 3H), 3.93 (s, 3H), 3.65 (td, 1H), 3.09-2.96 (m, 1 H), 2.83-2.67 (m, 1H), 1.49-1.46 (m, 9H). Step 2. Preparation of 2-(2-methoxypyridin-4-yl)morpholine hydrochloride (P11)

[0296] At 0 °C, to a solution of C14 (0.070 g, 0.24 mmol) in 1,4-dioxane (1 mL) was added HCI in 1,4-dioxane (4 mL) then stirred at room temperature for 2 h. The suspension was concentrated in vacuo then lyophilized to provide P11 (0.074 g, >95% yield) as a light-yellow solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 195.2.

[0297] Preparation P12

[0298] (4-(Morpholin-2-yl)pyridin-2-yl)methanol hydrochloride (P12)

[0299]

[0300] Step 1. Preparation of tert-butyl 2-(2-(hydroxymethyl)pyridin-4-yl)morpholine-4-carboxylate (C15)

[0301] The same reaction was conducted in two batches then combined for purification as follows: A reaction mixture of 4-(fert-butoxycarbonyl)morpholine-2-carboxylic acid (CAS:

[0302] 189321-66-2; 0.37 g, 1.6 mmol), (4-bromopyridin-2-yl)methanol (CAS: 131747-45-0; 0.20 g, 1.1 mmol), [lr(dF(Me)ppy)2(dtbbpy)]PF6(11 mg, 0.011 mmol), NiBr2.dtbbpy (26 mg, 0.053 mmol) phthalimide (CAS: 85-41-6; 0.16 g, 1.1 mmol) and TMG (0.24 g, 2.1 mmol) in DMSO (11 mL) was degassed with N2gas for 2 min to form the first batch. The reaction vessel of the first batch was sealed then irradiated with photoreactor (445 nm, 255 mW) and stirred at room temperature for 48 h.

[0303] The second batch of the same reaction was conducted with 4-(fert-butoxycarbonyl)morpholine-2-carboxylic acid (CAS: 189321-66-2; 92 mg, 0.40 mmol) and (4-bromopyridin-2-yl)methanol (CAS: 131747-45-0; 0.050 g, 0.27 mmol) and utilized the photoreactor (445 nm, 255 mW). The two batches were combined and diluted with H2O (15 mL) and EtOAc (15 mL). The suspension was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with H2O, dried with Na2SO4then concentrated in vacuo. The residue was purified by reverse phase HPLC (C18150 mm x 40 mm x 7 μm, H2O (NH4OH-NH4HCO3) / MeCN, 12-52% MeCN in 9 min, 100% MeCN hold for 2 min, flow rate= 60 mL / min) and lyophilized again to provide C15 (0.12 g, 31% yield) as a colorless gum.1H NMR (400 MHz, CDCl3) 68.54 (d, 1H), 7.31 (s, 1H), 7.25-7.21 (m, 1H), 4.80-4.76 (m, 3H), 4.48-4.42 (m, 1H), 4.26-3.87 (m, 3H), 3.72-3.63 (m, 1H), 3.11-2.96 (m, 1H), 2.80-2.66 (m, 1H), 1.49 (s, 9H). Step 2. Preparation of (4-(morpholin-2-yl)pyridin-2-yl)methanol hydrochloride (P12)

[0304] At 0 °C, to a solution of C15 (0.060 g, 0.20 mmol) in 1,4-dioxane (1 mL) was added HCI in 1,4-dioxane (4 mL) then stirred at room temperature for 2 h. The suspension was concentrated in vacuo then lyophilized to provide P12 (0.052 g, >95% yield) as a light-yellow solid. The solid was used directly in the next step without further purification.

[0305] Preparation P13

[0306] 2-(2-(Methoxymethyl)pyridin-4-yl)morpholinel hydrochloride (P13)

[0307]

[0308] Step 1. Preparation of tert-butyl 2-(2-(methoxymethyl)pyridin-4-yl)morpholine-4-carboxylate (C16)

[0309] The same procedure was followed from Preparation P2, step 1 with 4- tert-butoxycarbonyl)morpholine-2-carboxylic acid (CAS: 189321-66-2; 0.10 g, 0.45 mmol) and 4-bromo-2-(methoxymethyl)pyridine (CAS: 864412-04-4; 61 mg, 0.30 mmol) and utilized the photoreactor (445 nm, 255mW). The purification conditions were altered. The crude residue was purified by reverse phase HPLC (Welch Xtimate C18150 mm x 30 mm x 5 μm, H2O (0.05% formic acid) / MeCN, 9-49% MeCN in 9 min, 100% MeCN for 2 min, flow rate= 25 mL / min) to provide C16 (23 mg, 25% yield) as a colorless oil. (LC / MS) m / z (M+H)+= 309.2.1H NMR (400 MHz, CDCl3) 68.55 (d, 1H), 7.46 (s, 1H), 7.23-7.20 (m, 1H), 4.59 (s, 2H), 4.47-4.41 (m, 1H), 4.11-3.88 (m, 3H), 3.72-3.63 (m, 1H), 3.51-3.48 (m, 3H), 3.10-2.98 (m, 1H), 2.85-2.70 (m, 1H), 1.50-1.47 (m, 9H).

[0310] Step 2. Preparation of 2-(2-(methoxymethyl)pyridin-4-yl)morpholine hydrochloride (P13)

[0311] The same procedure was followed from Preparation P2, step 2 with C16 (0.023 g, 0.075 mmol) to provide P13 (0.024 g, >95% yield) as a colorless gum. The gum was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 209.0. Preparation P14

[0312] 2-(5-Chloropyridin-3-yl)morpholine hydrochloride (P14)

[0313]

[0314] p Step 1. Preparation ofte / Y-butyl 2-(5-chloropyridin-3-yl)morpholine-4-carboxylate (C17)

[0315] The same procedure was followed from Preparation P2, step 1 with 4-(tert- butoxycarbonyl)morpholine-2-carboxylic acid (CAS: 189321-66-2; 0.390 g, 1.68 mmol) and 3- bromo-5-chloropyridine (CAS: 73583-39-8; 0.216 g, 1.12 mmol) and utilized the photoreactor (fan speed: 5000 r / min; stirred speed: 1000 r / min; 100% 450 nm LED). The purification conditions were altered. The crude residue was purified by reverse phase HPLC (WePure Biotech XP tC18150 mm x 40 mm x 7 μm, H2O (0.05% NH4OH + 10 mM NH4HCO3) / MeCN, 31-71% MeCN in 9 min, flow rate= 60 mL / min) to provide C17 (85.1 mg, 25.4% yield) as a yellow oil. (LC / MS) m / z (M+H)+= 299.0.1H NMR (400 MHz, CD3OD) 68.54-8.50 (m, 2H), 7.94 (t, 1H), 4.61-4.54 (m, 1H), 4.14-3.99 (m, 2H), 3.96-3.89 (m, 1H), 3.72-3.64 (m, 1H), 3.16-3.03 (m, 1H), 2.98-2.76 (m, 1H), 1.49 (s, 9H).

[0316] Step 2. Preparation of 2-(5-chloropyridin-3-yl)morpholine hydrochloride (P14)

[0317] At 0 °C, to a solution of C17 (0.060 g, 0.20 mmol) in 1,4-dioxane (1 mL) was added HCI in 1,4-dioxane (4 mL) then stirred at room temperature for 2 h. The suspension was concentrated in vacuo then lyophilized to provide P14 (0.058 g, 92% yield) as a light-yellow solid. The solid was used directly in the next step without further purification.

[0318] Preparation P15

[0319] 2-(2-Morpholinopyridin-4-yl)morpholine hydrochloride (P15)

[0320]

[0321] Step 1. Preparation ofte / Y-butyl 2-(2-morpholinopyridin-4-yl)morpholine-4-carboxylate (C18) The same procedure was followed from Preparation P7, step 2 with C9 (542 mg, 1.44 mmol) and 4-(4-bromopyridin-2-yl)morpholine (CAS: 1040377-12-5; 0.250 g, 1.03 mmol). The purification conditions were altered. The crude residue was purified by reverse phase HPLC (WePure Biotech XP tC18150 mm x 40 mm x 7 μm, H2O (0.05% NH4OH + 10 mM NH4HCO3) / MeCN, 27-67% MeCN in 9 min, flow rate= 60 mL / min) to provide C18 (0.160 g, 44.5% yield) as a colorless gum. (LC / MS) m / z (M+H)+= 350.3.1H NMR (400 MHz, CDCI3) 6 8.16 (d, 1H), 6.71- 6.58 (m, 2H), 4.43-4.30 (m, 1H), 4.20-3.89 (m, 3H), 3.82 (t, 4H), 3.71-3.60 (m, 1H), 3.52 (t, 4H), 3.10-2.96 (m, 1 H), 2.82-2.69 (m, 1H), 1.49-1.47 (m, 9H).

[0322] Step 2. Preparation of 2-(2-morpholinopyridin-4-yl)morpholine hydrochloride (P15)

[0323] At 0 °C, to a solution of C18 (0.060 g, 0.17 mmol) in 1,4-dioxane (1 mL) was added HCI in 1,4-dioxane (4 mL) then stirred at room temperature for 2 h. The suspension was concentrated in vacuo then lyophilized to provide P15 (0.055 g, 89% yield) as a light-yellow solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 250.2.

[0324] Preparation P16

[0325] 4-(Morpholin-2-yl)pyridin-2(1 / 7)-one hydrochloride (P16)

[0326]

[0327] Step 1. Preparation ofte / Y-butyl 2-(2-oxo-1,2-dihydropyridin-4-yl)morpholine-4-carboxylate (C19)

[0328] The same procedure was followed from Preparation P7, step 2 with C9 (0.61 g, 1.6 mmol) and 4-bromopyridin-2(3 / 7)-one (CAS: 36953-37-4; 0.20 g, 1.1 mmol). The purification conditions were altered. The crude residue was purified by reverse phase HPLC (Welch Xtimate C18150 mm x 30 mm x 5 μm, H2O (NH4OH-NH4HCO3) / MeCN, 8-48% MeCN in 9 min, 100% MeCN hold 2 min, flow rate= 25 mL / min) to provide C19 (25 mg, 7.8% yield) as a white solid. (LC / MS) m / z (M-fert-butyl group)+ = 225.1.1H NMR (400 MHz, CDCI3) 6 7.33 (d, 1H), 6.59 (s, 1H), 6.36-6.26 (m, 1 H), 4.27 (dd, 1H), 4.16-3.85 (m, 3H), 3.68-3.59 (m, 1H), 3.09- 2.93 (m, 1 H), 2.83-2.63 (m, 1 H), 1.48 (s, 9H).

[0329] Step 2. Preparation of 2-(2-morpholinopyridin-4-yl)morpholine hydrochloride (P16)

[0330] At 0 °C, to a solution of C19 (0.035 g, 0.12 mmol) in 1,4-dioxane (1 mL) was added HCI in 1,4-dioxane (4 mL) then stirred at room temperature for 2 h. The suspension was concentrated in vacuo then lyophilized to provide P16 (0.032 g, 76% yield) as a light-yellow solid. The solid was used directly in the next step without further purification. Preparation P17

[0331] 2-(4-(Morpholin-2-yl)pyridin-2-yl)acetonitrile trifluoroacetate (P17)

[0332]

[0333] Step 1. Preparation of tert-butyl 2-(2-(cyanomethyl)pyridin-4-yl)morpholine-4-carboxylate (C20) The same procedure was followed from Preparation P7, step 2 with C9 (0.500 g, 1.33 mmol) and 2-(4-bromopyridin-2-yl)acetonitrile (CAS: 312325-73-8; 0.200 g, 1.02 mmol). The purification conditions were altered. The crude residue was purified by HPLC (Welch Xtimate C18150 mm x 30 mm x 5 μm, H2O (0.225% formic acid) / MeCN, 15-55% MeCN in 9 min, flow rate= 25 mLZ min) to provide C20 (39.1 mg, 12.7% yield) as a yellow oil. (LC / MS) m / z (M+H)+= 304.1.1H NMR (400 MHz, CDCl3) 68.56 (d, 1H), 7.48 (s, 1H), 7.27-7.26 (m, 1H), 4.50-4.42 (m,1H), 4.30-3.99 (m, 3H), 3.95 (s, 2H), 3.72-3.63 (m, 1H), 3.14-2.96 (m, 1H), 2.82-2.67 (m, 1H), 1.49 (s, 9H).

[0334] Step 2. Preparation of 2-(4-(morpholin-2-yl)pyridin-2-yl)acetonitrile trifluoroacetate (P17)

[0335] To a reaction mixture of C20 (0.046 g, 0.15 mmol) in DCM (1 mL) was added TFA (0.5 mL) then stirred at room temperature for 2 h. The suspension was concentrated in vacuo and lyophilized to form P17 (0.060 g, 93% yield) as a yellow gum. (LC / MS) m / z (M+H)+= 204.1.

[0336] Preparation P18

[0337] 2-(Imidazo[1,2-a]pyridin-7-yl)morpholine hydrochloride (P18)

[0338]

[0339] Step 1. Preparation of tert-butyl 2-(imidazo[1,2-a]pyridin-7-yl)morpholine-4-carboxylate (C21) A reaction mixture of C9 (0.43 g, 1.1 mmol), 7-bromoimidazo[1,2-a]pyridine (CAS:

[0340] 808744-34-5; 0.15 g, 0.76 mmol), NiCl2.glyme (0.17 g, 0.76 mmol), 5-methoxypicolinimidamide (CAS: 1179532-65-0; 0.14 g, 0.76 mmol), tetrabutylammonium iodide (0.28 g, 0.76 mmol) and zinc (0.50 g, 7.6 mmol) were put under high vacuum then degassed with N2gas (3x). The reaction mixture was suspended in DMA (2 mL) and stirred at room temperature for 2 h. The suspension was filtered through Celite (2x) then the filter cake was washed with EtOAc. The filtrate was concentrated in vacuo to give a brown gum. To the gum was added 1 M HCI then the pH was adjusted to pH>7 with saturated NaHCO3. The residue was purified by column chromatography (silica gel, 0-7% MeOH / DCM) then lyophilized to give a yellow gum. The gum was diluted with EtOAc (15 mL) then washed with NaHCOs (3 x 10 mL), brine (3 x 10 mL). The organic layer was dried with Na2SO4then concentrated in vacuo to provide C21 (55 mg, 24% yield) as a colorless gum. (LC / MS) m / z (M+H)+= 304.1.1H NMR (400 MHz, (CD3)2SO) 6 8.53 (d, 1H), 7.93 (s, 1H), 7.55 (d, 2H), 6.91 (dd, 1H), 4.48 (dd, 1 H), 4.07-3.88 (m, 2H), 3.79 (d, 1H), 3.62-3.50 (m, 1H), 3.06-2.76 (m, 2H), 1.43-1.42 (m, 9H).

[0341] Step 2. Preparation of 2-(imidazo[1,2-a]pyridin-7-yl)morpholine hydrochloride (P18)

[0342] At 0 °C, to a solution of C21 (0.050 g, 0.16 mmol) in DCM (0.5 mL) was added HCI in 1,4-dioxane (1 mL) then stirred at room temperature for 2 h. The suspension was concentrated in vacuo then lyophilized to provide P18 (0.045 g, >95% yield) as a yellow solid. The solid was used directly in the next step without further purification.1H NMR (400 MHz, (CD3)2SO) 6 9.97- 9.83 (m, 1H), 8.94 (d, 1 H), 8.37 (d, 1H), 8.22 (d, 1H), 7.94-7.91 (m, 1H), 7.52-7.49 (m, 1H), 5.13-5.07 (m, 1H), 4.21 (dd, 1H), 4.09-3.55 (m, 1 H), 3.69-3.56 (m, 1H), 3.30-3.25 (m, 1H), 3.20-3.10 (m, 1H), 3.04-2.91 (m, 1H).

[0343] Preparation P19

[0344] 2-(1-Cyclopropyl-1 / 7-pyrazol-4-yl)morpholine hydrochloride (P19)

[0345]

[0346] Step 1. Preparation ofte / Y-butyl 2-(1-cyclopropyl-1 / 7-pyrazol-4-yl)morpholine-4-carboxylate (C22)

[0347] The same reaction was conducted in two batches then combined for purification as follows: A reaction mixture of 4-bromo-1-cyclopropyl-1 / 7-pyrazole (CAS: 1151802-23-1; 4.50 g, 24.1 mmol), 4-(terf-butoxycarbonyl)morpholine-2-carboxylic acid (CAS: 189321-66-2; 11.1 g, 48.1 mmol), [Ir(dF(Me)ppy)2(dtbbpy)]PF6(0.270 g, 0.241 mmol), NiBr2.dtbbpy (958 mg, 2.41 mmol) phthalimide (CAS: 85-41-6; 7.08 g, 48.1 mmol), TMG (5.54 g, 48.1 mmol) in DMSO (300 mL) was degassed with N2gas for 30 min to form the first batch. The reaction solution of the first batch was pumped by Pump 1 (flow rate= 60 mL / min) to the flow reactor (FLR1, PFA, Coils reactor, 3.175(1 / 8”) mm, 100 mL, room temperature) with 450 nm LED light (2400 W). The reaction mixture of the first batch was continuously circulating for (FLR1, 360 min) then the tubing was washed with solvent. The peristaltic pump was turned off then the tubing was washed with solvent again.

[0348] The second batch of the same reaction was conducted with 4-bromo-1-cyclopropyl-1 / 7- pyrazole (CAS: 1151802-23-1; 0.500 g, 2.67 mmol) and 4-(te / Y-butoxycarbonyl)morpholine-2- carboxylic acid (CAS: 189321-66-2; 0.618 g, 2.67 mmol). The two batches were combined then diluted with DCM (100 mL) and H2O (600 mL). The suspension was extracted with EtOAc (5 x 100 mL). The combined organic layers were washed with H2O then dried with Na2SO4. The residue was suspended in MeOH then filtered. The filtrate was concentrated in vacuo then dissolved in (1:1) DMSO: MeOH (50 mL). The solution was purified by reverse phase HPLC (C18150 mm x 40 mm x 5 μm, H2O (0.05% formic acid) / MeCN, 17-57% MeCN in 9 min, 100% MeCN hold for 2 min, flow rate= 60 mL / min) and lyophilized then dried further under high vacuum to provide C22 (1.90 g, 24.2% yield) as a yellow oil. (LC / MS) m / z (M+H)+= 294.3.1H NMR (400 MHz, CDCl3) 6 7.46 (s, 2H), 4.45-4.36 (m, 1H), 4.13-3.81 (m, 3H), 3.68-3.51 (m, 2H), 3.11-2.87 (m, 2H), 1.47 (s, 9H), 1.12-1.05 (m, 2H), 1.03-0.95 (m, 2H).

[0349] Step 2. Preparation of 2-(1-cyclopropyl-1 / 7-pyrazol-4-yl)morpholine hydrochloride (P19)

[0350] To a solution of C22 (0.046 g, 0.16 mmol) in DCM (1 mL) was added HCI (0.40 g, 4.0 mmol) then stirred at room temperature for 3 h. The light-yellow reaction mixture was concentrated in vacuo to provide P19 (0.036 g, >95% yield) as a light-yellow gum. The gum was used directly in the next step without further purification.

[0351] Preparation P20

[0352] 2-(2,3-Dimethylpyridin-4-yl)morpholine hydrochloride (P20)

[0353]

[0354] p Step 1. Preparation ofte / Y-butyl 2-(2,3-dimethylpyridin-4-yl)morpholine-4-carboxylate (C23) The same procedure was followed from Preparation P2, step 1 with 4- tert-butoxycarbonyl)morpholine-2-carboxylic acid (CAS: 189321-66-2; 0.373 g, 1.61 mmol) and 4-bromo-2,3-dimethylpyridine (CAS: 259807-91-5; 0.200 g, 1.07 mmol) and utilized the photoreactor (fan speed: 5000 r / min; stirred speed: 1000 r / min; 100% 450 nm LED). The purification conditions were altered. The crude residue was purified by reverse phase HPLC (Welch Xtimate C18150 mm x 30 mm x 5 μm, H2O (NH4OH-NH4HCO3) / MeCN, 25-65% MeCN in 9 min, 100% MeCN hold 2 min, flow rate= 25 mL / min) to provide C23 (66.3 mg, 21.1% yield) as a white solid. (LC / MS) m / z (M+H)+= 293.0.1H NMR (400 MHz, CD3OD) 6 8.23 (d, 1 H), 7.38 (d, 1H), 4.67 (dd, 1 H), 4.16-3.92 (m, 3H), 3.71 (td, 1 H), 3.17-3.00 (m, 1 H), 2.78-2.62 (m, 1H), 2.52 (s, 3H), 2.31 (s, 3H), 1.49 (s, 9H). Step 2. Preparation of 2-(2,3-dimethylpyridin-4-yl)morpholine hydrochloride (P20)

[0355] The same procedure was followed from Preparation P2, step 2 with C23 (0.046 g, 0.16 mmol) to provide P20 (0.052 g, >95% yield) as a white solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 193.2.

[0356] Preparation P21

[0357]

[0358] p Step 1. Preparation ofte / Y-butyl 2-(2-methyl-2 / 7-1,2,3-triazol-4-yl)morpholine-4-carboxylate (C24)

[0359] The same procedure was followed from Preparation P2, step 1 with 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (CAS: 189321-66-2; 0.43 g, 1.8 mmol) and 4-bromo-2-methyl-2 / 7-1,2,3-triazole (CAS: 16681-67-7; 0.20 g, 1.2 mmol) and utilized the photoreactor (445 nm, 255 mW). The purification conditions were altered. The crude residue was purified by reverse phase HPLC (Welch Xtimate C18150 mm x 30 mm x 5 μm, H2O (0.05% formic acid) / MeCN, 18-58% MeCN in 9 min, 100% MeCN hold 2 min, flow rate= 25 mL / min) to provide C24 (35 mg, 11 % yield) as a colorless oil. (LC / MS) m / z (M+H)+= 269.1.1H NMR (400 MHz, CDCl3) 67.55 (s, 1H), 4.62-4.55 (m, 1H), 4.18 (s, 3H), 4.10-3.85 (m, 3H), 3.74-3.61 (m, 1H), 3.16-3.00 (m, 2H), 1.48 (s, 9H).

[0360] Step 2. Preparation of 2-(2-methyl-2 / 7-1,2,3-triazol-4-yl)morpholine hydrochloride (P21)

[0361] The same procedure was followed from Preparation P2, step 2 with C24 (0.035 g, 0.13 mmol) to provide P21 (0.028 g, 77% yield) as a yellow solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 169.1.

[0362] Preparation P22

[0363] 1-Methyl-4-(morpholin-2-yl)pyridin-2(1 / 7)-one hydrochloride (P22)

[0364]

[0365] p Step 1. Preparation ofte / Y-butyl 2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)morpholine-4-carboxylate (C25) The same procedure was followed from Preparation P2, step 1 with 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (CAS: 189321-66-2; 0.33 g, 1.4 mmol) and 4-bromo-1-methylpyridin-2(1 / - / )-one (CAS: 214342-63-9; 0.18 g, 0.96 mmol) and utilized the photoreactor (445 nm, 255 mW). The purification conditions were altered. The crude residue was purified by reverse phase HPLC (Ci8150 mm x 40 mm x 7 pm, (NH4OH-NH4HCO3) / MeCN, 10-50% MeCN in 9 min, 100% MeCN hold 2 min, flow rate= 60 mL / min) to provide C25 (87 mg, 23% yield) as a yellow solid. (LC / MS) m / z (M+H)+= 295.1.1H NMR (400 MHz, CD3OD) 6 7.63 (d, 1H), 6.58 (s, 1H), 6.40 (dd, 1H), 4.33 (dd, 1H), 4.13-3.96 (m, 2H), 3.93-3.85 (m, 1 H), 3.63 (td, 1 H), 3.55 (s, 3H), 3.08-2.97 (m, 1H), 2.84-2.59 (m, 1 H), 1.48 (s, 9H).

[0366] Step 2. Preparation of 1-methyl-4-(morpholin-2-yl)pyridin-2(1 / 7)-one hydrochloride (P22)

[0367] The same procedure was followed from Preparation P2, step 2 with C25 (0.040 g, 0.14 mmol) to provide P22 (0.047 g, >95% yield) as a white solid. The solid was used directly in the next step without further purification.

[0368] Preparation P23

[0369] 2-(5,6-Dimethylpyridin-3-yl)morpholine hydrochloride (P23)

[0370]

[0371] [Ir(dF(Me)ppy)2(dtbbpy)]PF6C26 P23

[0372] DMSO

[0373]

[0374] 450 nm LED photoreactor

[0375] Step 1. Preparation ofte / Y-butyl 2-(5,6-dimethylpyridin-3-yl)morpholine-4-carboxylate (C26) The same procedure was followed from Preparation P2, step 1 with 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (CAS: 189321-66-2; 0.477 g, 2.06 mmol) and 5-bromo-2,3-dimethylpyridine (CAS: 27063-90-7; 0.256 g, 1.38 mmol) and utilized the photoreactor (fan speed: 5200 r / min; stirring speed: 1200 r / min; 100% 450 nm LED). The purification conditions were altered. The crude residue was purified by reverse phase HPLC (Cis 150 mm x40 mm x 7 pm, (NH4OH-NH4HCO3) / MeCN, 35-55% MeCN in 9 min, 100% MeCN hold 2 min, flow rate= 60 mL / min) then concentrated in vacuo. The residue was basified with NH4OH to pH~8. The suspension was extracted with EtOAc (2 x 20 mL). The combined organic layers were concentrated in vacuo to provide C26 (173 mg, 43.0% yield) as a colorless oil. (LC / MS) m / z (M+H)+= 293.0.1H NMR (400 MHz, CDCI3) 6 8.33-8.29 (m, 1H), 7.44 (s, 1H), 4.43-4.36 (m, 1H), 4.17-3.88 (m, 3H), 3.67 (td, 1H), 3.11-2.97 (m, 1 H), 2.88-2.74 (m, 1H), 2.49 (s, 3H), 2.28 (s, 3H), 1.47 (s, 9H). Step 2. Preparation of 2-(5,6-dimethylpyridin-3-yl)morpholine hydrochloride (P23)

[0376] The same procedure was followed from Preparation P2, step 2 with C26 (0.060 g, 0.21 mmol) to provide P23 (0.065 g, >95% yield) as a colorless gum. The gum was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 193.1.

[0377] Preparation P24

[0378] 2-(2-Cyclopropylpyridin-4-yl)morpholine hydrochloride (P24)

[0379]

[0380] p Step 1. Preparation ofte / Y-butyl 2-(2-cyclopropylpyridin-4-yl)morpholine-4-carboxylate (C7) The same procedure was followed from Preparation P2, step 1 with 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (CAS: 189321-66-2; 0.350 g, 1.51 mmol) and 4-bromo-2-cyclopropylpyridine (CAS: 1086381-28-3; 0.200 g, 1.01 mmol) and utilized the photoreactor (fan speed: 5000 r / min; stirring speed: 1000 r / min; 100% 450 nm LED). The purification conditions were altered. The crude residue was purified by reverse phase HPLC (Cis 150 mm x40 mm x 7 pm, (NH4OH-NH4HCO3) / MeCN, 32-72% MeCN in 9 min, 100% MeCN hold 2 min, flow rate= 60 mL / min) to provide C7 (0.140 g, 45.5% yield) as a light-yellow gum. (LC / MS) m / z (M+H)+= 305.1.1H NMR (400 MHz, CD3OD) 68.32 (d, 1H), 7.25-7.23 (m, 1H), 7.19-7.15 (m, 1H), 4.45 (dd, 1H), 4.11-3.98 (m, 2H), 3.95-3.87 (m, 1H), 3.66 (td, 1H), 3.15-3.01 (m, 1H), 2.88-2.68 (m, 1H), 2.15-2.05 (m, 1H), 1.50-1.48 (m, 9H), 1.07-1.00 (m, 2H), 0.97-0.92 (m, 2H).

[0381] Step 2. Preparation of 2-(2-cyclopropylpyridin-4-yl)morpholine hydrochloride (P24)

[0382] The same procedure was followed from Preparation P2, step 2 with C27 (0.070 g, 0.23 mmol) to provide P24 (0.056 g, >95% yield) as a white solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 205.2. Preparation P25

[0383] (2R,6S)-2-(1-cyclopropyl-1 / 7-pyrazol-4-yl)-6-methylmorpholine hydrochloride and (2S,6R)-2-(1- Cyclopropyl-1 / 7-pyrazol-4-yl)-6-methylmorpholine hydrochloride (racemic, cis) (P25)

[0384]

[0385] racemic mixture racemic mixture

[0386] of cis isomers of cis isomers

[0387] Step 1. Preparation of 2-chloro-1-(1-cyclopropyl-1 / 7-pyrazol-4-yl)ethan-1-one (C28)

[0388] Under N2gas, in a flame dried 3-neck flask, to a solution of 1-cyclopropyl-4-iodo-1 / 7-pyrazole (CAS: 1239363-40-6; 10. g, 43 mmol) in THF (200 mL) was added 2M isopropylmagnesium chloride (CAS: 1068-55-9; 32 mL) dropwise. The reaction mixture was stirred at -70 °C for 3 h and 20 min. The resulting solution was quenched with saturated aqueous NH4CI. The suspension was stored in the freezer overnight then filtered. The filtrate was extracted with EtOAc then the organic layer was dried with Na2SO4and concentrated in vacuo to give an orange oil. The oil was diluted with EtOAc, which caused the precipitation of white solids. The suspension was filtered then the filter cake was collected to provide C28 (1.0 g) as a white solid.

[0389] The filtrate was purified by column chromatography (silica gel, 0-100% EtOAc / heptane) to provide C28 (3.2 g). The batches of product were combined to obtain C28 (4.2 g, 53% yield). (LC / MS) m / z (M+H)+= 185.1.

[0390] Step 2. Preparation of 2-(benzyl(2-hydroxypropyl)amino)-1-(1-cyclopropyl-1 / 7-pyrazol-4-yl)ethan-1-one (C29)

[0391] To a solution of C28 (9.2 g, 50. mmol) in MeCN (0.17 L) was added 1-benzylamino-2-propanol (CAS: 27159-32-6; 7.3 mL) followed by DIPEA (40 mL) dropwise. The reaction mixture was stirred at 90 °C for 6 h then was cooled to room temperature and diluted with H2O. The suspension was extracted with EtOActhen the organic layer was dried with Na2SO4and concentrated in vacuo to give an orange oil. The oil was purified by column chromatography (silica gel, 0-100% EtOAc / heptane) to provide C29 (7.5 g, 51% yield) as a yellow oil. (LC / MS) m / z (M+H)+= 314.3.

[0392] Step 3. Preparation of 4-benzyl-6-(1-cyclopropyl-1 / 7-pyrazol-4-yl)-2-methyl-3,4-dihydro-2 / 7-1,4-oxazine (C30)

[0393] A solution of C29 (7.5 g, 24 mmol) in DCE (61 mL) was added trimethylsilyl trifluoromethanesulfonate (CAS: 26607-77-8; 17 mL) dropwise which changed the reaction to an orange solution. The solution was stirred at 80 °C for 3 h which caused the precipitation of grey solids. The reaction mixture was cooled to room temperature then saturated aqueous NaHCOs was added. The suspension was extracted with DCE then the organic layer was dried with Na2SO4and concentrated in vacuo to give C30 (6.2 g, 77 % yield) as an orange oil.

[0394] (LC / MS) m / z (M+H)+= 296.3.

[0395] Step 4. Preparation of 2-(1-cyclopropyl-1 / 7-pyrazol-4-yl)-6-methylmorpholine (C31)

[0396] To a solution of C30 (6.2 g, 21 mmol) in MeOH (0.10 L) was added ammonium formate (5.8 g, 92 mmol) then Pd(OH)2 / C (5.6 g, 20 wt%, 21 mmol). The reaction mixture was stirred at 65 °C for 4 h then cooled to room temperature. The suspension was filtered over Celite. The filtrate was concentrated in vacuo to provide C31 (4.1 g, 94% yield) as a green oil. The oil was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 208.60.

[0397] Step 5. Preparation ofte / Y-butyl (2R,6S)-2-(1-cyclopropyl-1 / 7-pyrazol-4-yl)-6-methylmorpholine-4-carboxylate and te / Y-butyl (2S,6R)-2-(1-cyclopropyl-1 / 7-pyrazol-4-yl)-6-methylmorpholine-4-carboxylate (racemic, cis) (C32)

[0398] To a solution of C31 (4.1 g, 20. mmol) in MeCN (76 mL) was added BOC2O (5 mL) and DMAP (0.24 g, 2.0 mmol). The solution was stirred at room temperature for 7 h then concentrated in vacuo to give a brown oil. A portion of the oil (0.10 g) was purified by reverse phase HPLC (Sepacore 40 g, H2O / MeCN, 20-70% MeCN over 60 min then 70-100% MeCN over 5 min, flow rate= 50 mL / min) to give C32 as an oil. The rest of the oil (5.9 g) was purified by reverse phase HPLC (Sepacore 330 g, H2O / MeCN, 0-45% MeCN over 60 min then 45-100% MeCN over 0 min and hold at 100% MeCN for 16 min, flow rate= 140 mL / min) to give C32 as an oil. The two batches of product were combined and lyophilized to provide C32 (1.5 g, 25% yield) as a yellow oil. (LC / MS) m / z (M+H)+= 308.2.1H NMR (400 MHz, CDCl3) 67.52-7.43 (m, 2H), 4.48-4.40 (m, 1H), 4.20-3.80 (m, 2H), 3.73-3.50 (m, 2H), 2.86-2.69 (m, 1H), 2.63-2.45 (m, 1 H), 1.51 -1.46 (m, 9H), 1.24-1.19 (m, 3H), 1.14-1.06 (m, 2H), 1.04-0.95 (m, 2H). Step 6. Preparation of (2 / ?,6S)-2-(1-cyclopropyl-1 / 7-pyrazol-4-yl)-6-methylmorpholine hydrochloride and (2S,6 / ?)-2-(1-Cyclopropyl-1 / 7-pyrazol-4-yl)-6-methylmorpholine hydrochloride (racemic, cis) (P25)

[0399] The same procedure was followed from Preparation P2, step 2 with C32 (0.10 g, 0.32 mmol) to provide P25 (0.067 g, >95% yield) as a yellow gum. The gum was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 308.1.

[0400] Preparation 26

[0401] 2-(1 / 7-Pyrazol-4-yl)morpholine (P26)

[0402]

[0403] Step 1. Preparation of 2-bromo-1-(1-methyl-1 / 7-pyrazol-4-yl)ethan-1-one (C33)

[0404] To a solution of 1-(1-methyl-1 / 7-pyrazol-4-yl)ethan-1-one (CAS: 37687-18-6; 25 g, 0.20 mol) in DCM (350 mL) and EtOH (88 mL) was added PyHBr3(64 g, 0.20 mol). The reaction mixture was stirred at room temperature for 18 h then was diluted with H2O (400 mL). The suspension was extracted with DCM (4 x 400 mL). The combined organic layers were dried with Na2SO4and concentrated in vacuo. The residue was diluted with petroleum ether then stirred for about 30 min which caused the precipitation of solids. The suspension was filtered, and the filter cake was collected to provide C33 (35 g, 85% yield) as a yellow solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+2H)+= 205.0.

[0405] Step 2. Preparation of 2-(benzyl(2-hydroxyethyl)amino)-1-(1-methyl-1 / 7-pyrazol-4-yl)ethan-1-one (C34)

[0406] To a solution of C33 (34.4 g, 169 mmol) in MeCN (400 mL) was added N-benzylethanolamine (CAS: 104-63-2; 25.6 g, 169 mmol) and K2CO3(58.5 g, 424 mmol). The reaction mixture was stirred at 80 °C for 16 h then was filtered. The filtrate was concentrated in vacuo then diluted with H2O (300 ml). The suspension was extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with brine (150 mL) then dried with Na2SO4. The mixture was filtered, and the filtrate was concentrated in vacuo to give a yellow gum. The gum was purified by column chromatography (silica gel, 0-10% MeOH / DCM) to give C34 (26.8 g, 57.9% yield) as a yellow gum. (LC / MS) m / z (M+H)+= 274.1.

[0407] Step 3. Preparation of 4-benzyl-2-(1-methyl-1 / 7-pyrazol-4-yl)morpholine (C35)

[0408] At 0 °C, to the solution of C34 (125 g, 458 mmol) in TFA (300 mL) was added triethylsilane (80 mL). The reaction mixture was stirred at 0 °C for 10 min then heated to 100 °C and stirred for 16 h. The suspension was diluted with ice water (1000 mL) then extracted with EtOAc (2 x 500 mL). The combined organic layers were discarded. The aqueous phase was adjusted pH=11 with 1N NaOH then extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine (500 mL) then dried over with Na2SO4and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silica gel, 0-100% EtOAc / hexane) to give C35 (91.2 g, 77.4%) as a yellow oil.1H NMR (400 MHz, CDCl3) 6 7.43 (s, 1H), 7.36-7.25 (m, 5H), 7.26-7.22 (m,1H), 4.56 (dd, 1H), 3.94-3.88 (m, 1 H), 3.85 (s, 3H), 3.78 (td, 1H), 3.54 (s, 2H), 2.88 (dt, 1H), 2.71 (dq, 1 H), 2.31-2.16 (m, 2H).

[0409] Step 4. Preparation of 2-(1 / 7-pyrazol-4-yl)morpholine (P26)

[0410] A solution (labeled S1) was prepared of C35 (98 g, 0.38 mol) in MeOH (970 mL) then was set aside. The flow reactor had a fixed bed (named FLR1, volume= 50 mL) which was completely packed with granular catalyst 5% Pd / Al2O3 (WXC1035, 33 g, 0.31 mmol). The H2back pressure regulator was adjusted to 1.0 MPa, and the flow rate of H2was 100 mL / min. The solution, S1, was pumped by Pump 1 (S1, P1, 1.5 mL / min) to fixed bed (FLR1, SS, Fixed bed, 12.7(1 / 2”) mm, 50 mL, 60 °C). The reaction mixture was collected from the reactor output then was filtered through Celite. The filtrate was concentrated in vacuo to provide P26 (58 g, 91% yield) as a yellow oil. (LC / MS) m / z (M+H)+= 168.1.1H NMR (400 MHz, (CD3)2SO) 6 7.59 (s, 1H), 7.32 (s, 1 H), 4.29 (dd, 1H), 3.77 (s, 3H), 3.76-3.71 (m, 2H), 3.56-3.47 (m, 1 H), 2.85 (dd, 1 H), 2.70-2.64 (m, 2H), 2.61-2.55 (m, 1H).

[0411] Preparation P27 and P28

[0412] (S)-2-(1 / 7-Pyrazol-4-yl)morpholine and (R)-2-(1 / 7-Pyrazol-4-yl)morpholine (P27 and P28),

[0413] absolute stereochemical configuration not determined

[0414]

[0415] Step 1. Preparation of (S)-2-(1 / 7-pyrazol-4-yl)morpholine and (R)-2-(1 / 7-pyrazol-4-yl)morpholine (P27 and P28), absolute stereochemical configuration not determined

[0416] P26 (15 g, 86 mmol) was purified by SFC [Column: Chiral Technologies AD-H 250 mm x 50 mm x 5 pm; Mobile phase: 65% CO2 / 35% (MeOH + 0.2% [7N ammonia in MeOH]); flow rate= 250 mL / min; backpressure= 100 bar, temperature= 40 °C] which provided first eluting isomer as P27 (3.568 min, 7.17 g, 49.6% yield) as a yellow solid. The second eluting isomer as P28 (3.987 min, 6.97 g, 48.3% yield) as an orange oil. Absolute stereochemical configuration of P27 and P28 was not determined.

[0417] P27:1H NMR (500 MHz, (CD3)2SO) 6 7.58 (s, 1 H), 7.32 (s,1 H), 4.31 - 4.27 (m, 1 H), 3.79 - 3.76 (m, 3H), 3.76 - 3.71 (m, 1 H), 3.55 - 3.48 (m, 1 H), 2.85 (d, 1 H), 2.71 - 2.65 (m, 2H), 2.62 - 2.55 (m, 1H).

[0418] P28:1H NMR (500 MHz, (CD3)2SO) 6 7.59 (s, 1 H), 7.32 (s,1 H), 4.32 - 4.27 (m, 1 H), 3.79 - 3.76 (m, 3H), 3.75 - 3.71 (m, 1 H), 3.55 - 3.48 (m, 1 H), 2.85 (d, 1 H), 2.70 - 2.65 (m, 2H), 2.62 - 2.55 (m, 1 H).

[0419] Preparation P29

[0420] Ethyl 2-((te / Y-butyldimethylsilyl)oxy)-2-(diethoxyphosphoryl)acetate (P29)

[0421]

[0422] Step 1. Preparation of ethyl 2-(diethoxyphosphoryl)-2-hydroxyacetate (C36)

[0423] A solution of diethyl phosphite (CAS: 762-04-9; 5.50 g, 39.8 mmol), ethyl 2-oxoacetate (CAS: 924-44-7; 8.13 g, 39.8 mmol), 4A molecular sieves (15.0 g) and TsOH (75.8 mg, 0.398 mmol) in toluene (90 mL) was stirred at reflux (oil bath 120 °C) for 16 h. The reaction mixture was cooled to room temperature and concentrated to in vacuo. The residue was purified by column chromatography (silica gel, 1:10, MeOH: EtOAc) to provide C36 (4.00 g, 41.8%) as a yellow oil.1H NMR (400 MHz, CDCl3) 64.58-4.49 (m, 1H), 4.40-4.29 (m, 2H), 4.26-4.08 (m, 4H), 3.32 (t, 1 H), 1.40-1.23 (m, 9H).

[0424] Step 2. Preparation of ethyl 2-((te / Y-butyldimethylsilyl)oxy)-2-(diethoxyphosphoryl)acetate (P29) At 0 °C, to a solution of C36 (4.00 g, 16.6 mmol) in DCM (100 mL) were added imidazole (1.81 g, 26.6 mmol) and TBSCI (3.01 g, 20.0 mmol). The reaction mixture was stirred to room temperature for 16 h. The suspension was quenched with aqueous NH4CI (50 mL) and extracted with DCM (2 x 80 mL). The organic layer was washed with brine (80 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, (1:1) EtOAc: hexane) to provide P29 (5.02 g, 70.9% yield) as a yellow oil. (LC / MS) m / z (M+H)+= 355.1.1H NMR (400 MHz, CDCl3) 64.59 (d, 1 H), 4.32-4.10 (m, 6H), 1.43-1.24 (m, 9H), 0.93 (s, 9H), 0.11 (d, 6H). Preparation P30

[0425] Ethyl 2-(2-(1-cyclopropyl-1 / 7-pyrazol-4-yl)tetrahydro-2 / 7-pyran-4-yl)-2-oxoacetate (P30)

[0426]

[0427] Step 1. Preparation of 4-(4-bromo-5,6-dihydro-2 / 7-pyran-2-yl)-1-cyclopropyl-1 / 7-pyrazole (C37) At -35 °C, to a solution of 1-cyclopropyl-1 / 7-pyrazole-4-carbaldehyde (CAS: 1082066-00-9; 2.50 g, 18.4 mmol) and 3-bromobut-3-en-1-ol (CAS: 76334-36-6; 3.33 g, 22.0 mmol) in DCE (90 mL) was added TfOH (5.51 g, 36.7 mmol) slowly. The reaction mixture was stirred at –35 °C for 2 h, then 0 °C for 1 h, and room temperature for 18 h. The suspension was cooled to 0 °C then quenched with NaHCO3 (60 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with NaHCO3 (50 mL) then brine (50 mL), dried with Na2SO4, and concentration in vacuo. The residue was purified by column chromatography (silica gel, 1:4, EtOAc: hexane) to provide C37 (2.90 g, 58.7% yield) as a yellow oil. (LC / MS) m / z (M+H)+= 269.1.1H NMR (400 MHz, CDCl3) 6 7.46-7.42 (m, 2H), 6.16-6.09 (m, 1 H), 4.75-4.60 (m, 1 H), 4.34-4.17 (m, 2H), 3.61-3.51 (m, 1H), 2.92-2.74 (m, 1 H), 2.68-2.58 (m, 1 H), 1.14-0.95 (m, 4H).

[0428] Step 2. Preparation of 2-(1-cyclopropyl-1 / 7-pyrazol-4-yl)tetrahydro-4 / 7-pyran-4-one (C38)

[0429] To a solution of C37 (2.3 g, 8.5 mmol), morpholine (1.1 g, 13 mmol), and NaOfBu (1.6 g, 17 mmol) in toluene (30 mL) were added BINAP (0.53 g, 0.85 mmol) and Pd(OAc)2(96 mg, 0.43 mmol). The reaction mixture was degassed with N2gas for 3 min, then stirred at 80 °C for 16 h. After cooling to room temperature, the pH was adjusted to pH=3-4 with 1 M HCI then stirred for 30 min. The pH was adjusted to pH=9 with Na2CO3then extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (100 mL), dried with Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 1:10, MeOH: EtOAc) to provide C38 (0.80 g, 45% yield) as a brown oil. (LC / MS) m / z (M+H)+= 207.0.

[0430] 1H NMR (400 MHz, CDCI3) 6 7.46 (d, 2H), 4.75-4.65 (m, 1H), 4.33-4.25 (m, 1 H), 3.86-3.76 (m, 1 H), 3.60-3.53 (m, 1H), 2.71-2.58 (m, 3H), 2.47-2.39 (m, 1H), 1.15-0.94 (m, 4H).

[0431] Step 3. Preparation of ethyl (2E)-{[te / 'f-butyldi(methyl)silyl]oxy}[2-(1-cyclopropyl-1 / - / -pyrazol-4-yl)oxan-4-ylidene]acetate (C39)

[0432] At -70 °C, to a solution of P29 (0.284 g, 0.800 mmol) in THF (3 mL) was slowly added LiHMDS (146 mg, 0.873 mmol, 0.873 mL) under argon gas. The reaction mixture was stirred for 30 min then a solution of C38 (0.150 g, 0.727 mmol) in THF (1 mL) was added dropwise over 1 min. The suspension was stirred at -70 °C for 30 min, then at room temperature for 2.5 h. The reaction mixture was cooled to 0 °C then quenched with NH4CI (10 mL). The suspension was extracted with EtOAc (3 x 10 mL). The combined organic layer was washed with brine (15 mL), dried with Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 1:3, EtOAc:hexane) to provide C39 (0.185 g, 62.6% yield) as a brown oil. (LC / MS) m / z (M+H)+= 407.4.1H NMR (400 MHz, CDCl3) 6 7.45 (dd, 2H), 4.42-4.31 (m, 1H), 4.27-4.16 (m, 2H), 4.14-4.02 (m, 1 H), 3.61-3.44 (m, 2H), 3.26-3.03 (m, 1H), 2.79 (d, 1H), 2.48-2.31 (m, 1 H), 2.20-2.09 (m, 1H), 1.38-1.28 (m, 3H), 1.12-1.04 (m, 2H), 1.04-0.89 (m, 12H), 0.14-0.07 (m, 6H).

[0433] Step 4. Preparation of ethyl (E)-2-((te / Y-butyldimethylsilyl)oxy)-2-(2-(1-cyclopropyl-1 / 7-pyrazol-4-yl)tetrahydro-4 / 7-pyran-4-ylidene)acetate (P30)

[0434] At 0 °C, to a solution of C39 (0.18 g, 0.45 mmol) and AcOH (0.14 g, 2.3 mmol) in MeCN (5 mL) was added CsF (0.14 g, 0.91 mmol) under a N2gas. The reaction mixture was stirred at 0 °C for 30 min, then at room temperature for 20 h. The suspension was quenched with NaHCO3(10 mL) then extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with NaHCO3(15 mL), brine (15 mL), then dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 1:1, EtOAc: hexane) to provide P30 (0.090 g, 68% yield) as a brown gum. (LC / MS) m / z (M+H)+= 293.1.1H NMR (400 MHz, CDCl3) 6 7.46-7.41 (m, 2H), 4.43 (d, 1H), 4.41-4.29 (m, 2H), 4.21-4.07 (m, 1H), 3.74-3.62 (m, 1 H), 3.59-3.50 (m, 1H), 3.48-3.38 (m, 1H), 2.21-2.01 (m, 1 H), 1.98-1.82 (m, 1 H), 1.79-1.63 (m, 2H), 1.42-1.30 (m, 3H), 1.14-0.93 (m, 4H).

[0435] Preparation P31

[0436] Ethyl 2-(2-(1-methyl-1 / 7-pyrazol-4-yl)tetrahydro-2 / 7-pyran-4-yl)-2-oxoacetate (P31)

[0437]

[0438] Step 1. Preparation of 4-(4-bromo-5,6-dihydro-2 / 7-pyran-2-yl)-1-methyl-1 / 7-pyrazole (C40) At -35 °C, to a solution of 1-methyl-1 / 7-pyrazole-4-carbaldehyde (CAS: 25016-11-9; 5.50 g, 49.9 mmol) and 3-bromobut-3-en-1-ol (CAS: 76334-36-6; 9.05 g, 59.9 mmol) in DCE (150 mL) was added TfOH (15.0 g, 99.9 mmol) slowly. The reaction mixture was stirred at -35 °C for 1 h, followed by 0 °C for 1 h, then room temperature for 18 h. The suspension was cooled to 0 °C and quenched with NaHCO3 (100 mL). The mixture was extracted with EtOAc (3 x 150 mL). The combined organic layer was washed with NaHCO3(100 mL) and brine (150 mL), then dried with Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (silica gel, (1:20) MeOH: EtOAc) to provide C40 (8.00 g, 65.9% yield) as a yellow oil. (LC / MS) m / z (M+H)+= 245.2.1H NMR (400 MHz, CDCl3) 6 7.49-7.44 (m, 1H), 7.39-7.33 (m, 1H), 6.15-6.11 (m, 1H), 4.67 (dd, 1H), 4.34-4.18 (m, 2H), 3.91-3.81 (m, 3H), 2.88-2.76 (m, 1 H), 2.69-2.56 (m, 1H).

[0439] Step 2. Preparation of 2-(1-methyl-1 / 7-pyrazol-4-yl)tetrahydro-4 / 7-pyran-4-one (C41)

[0440] To a solution of C40 (3.0 g, 12 mmol), morpholine (1.6 g, 18 mmol), and NaOfBu (2.4 g, 25 mmol) in 1,4-dioxane (50 mL) were added BINAP (0.77 g, 1.2 mmol) and Pd(OAc)2(0.14 g, 0.62 mmol). The reaction mixture was degassed with N2gas for 3 min and then stirred at 80 °C for 16 h. The suspension was cooled to room temperature and adjusted to pH 3-4 with 1 N HCI then stirred for 30 min. The reaction mixture was adjusted to pH= 9 with Na2CO3then extracted with EtOAc (3 x 150 mL). The combined organic layer was washed with brine (150 mL), dried with Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, (1:10) MeOH: EtOAc) to provide C41 (1.9 g, 64% yield) as a brown oil. (LC / MS) m / z (M+H)+= 181.2.1H NMR (400 MHz, CDCI3) 6 7.49-7.46 (m, 1H), 7.37-7.34 (m, 1H), 4.74 (dd, 1 H), 4.32-4.24 (m, 1H), 3.89 (s, 3H), 3.86-3.79 (m, 1 H), 2.72-2.58 (m, 3H), 2.47-2.39 (m, 1H).

[0441] Step 3. Preparation of ethyl (E)-2-((te / Y-butyldimethylsilyl)oxy)-2-(2-(1-methyl-1 / - / -pyrazol-4-yl)tetrahydro-4 / 7-pyran-4-ylidene)acetate (C42)

[0442] At -70 °C, to solution of P29 (2.1 g, 5.9 mmol) in THF (20 mL) was added LiHMDS (1.1 g, 6.4 mmol) slowly under argon gas. After stirring for 30 minutes, a solution of C41 (1.2 g, 5.3 mmol) in THF (6 mL) was added dropwise over 1 min. The reaction mixture was stirred at -70 °C for 30 min, then at room temperature for 2 h. The suspension was cooled to 0 °C then quenched with NH4CI (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine (50 mL), dried with Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100% EtOAc) to provide C42 (1.8 g, 89%) as a colorless oil. (LC / MS) m / z (M+H)+= 381.1.1H NMR (400 MHz, CDCI3) 6 7.46 (d, 1 H), 7.35 (d, 1 H), 4.43-4.33 (m, 1H), 4.32-4.15 (m, 2H), 4.15-4.02 (m, 1H), 3.87 (d, 3H), 3.62-3.44 (m, 1H), 3.29-3.04 (m, 1 H), 2.84-2.74 (m, 1 H), 2.46-2.31 (m, 1H), 2.23-2.09 (m, 1 H), 1.38-1.22 (m, 3H), 0.98-0.94 (m, 9H), 0.14-0.05 (m, 6H).

[0443] Step 4. Preparation of ethyl 2-(2-(1-methyl-1 / 7-pyrazol-4-yl)tetrahydro-2 / 7-pyran-4-yl)-2-oxoacetate (P31)

[0444] At 0 °C under N2gas, to a solution of C42 (1.8 g, 3.5 mmol) and AcOH (1.1 g, 18 mmol) in MeCN (30 mL) was added CsF (1.1 g, 7.1 mmol). The reaction mixture was stirred at 0 °C for 30 min, then stirred at room temperature 20 h. The suspension was quenched with NaHCO3(20 mL) then extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with NaHCO3(30 mL), brine (50 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100% EtOAc) to provide P31 (0.72 g, 76% yield) as a yellow oil. (LC / MS) m / z (M+H)+= 267.1.1H NMR (400 MHz, CDCI3) 6 7.48-7.44 (m, 1 H), 7.38-7.33 (m, 1H), 4.47-4.40 (m, 1H), 4.39-4.28 (m, 2H), 4.22-4.12 (m, 1H), 3.89-3.86 (m, 3H), 3.75-3.63 (m, 1H), 3.58-3.39 (m, 1H), 2.19-2.01 (m, 1 H), 1.97-1.81 (m, 2H), 1.79-1.65 (m, 1 H), 1.40-1.34 (m, 3H).

[0445] Preparation P32

[0446] 2-(2-M

[0447]

[0448]

[0449] flow chemistry

[0450] Step 1. Preparation ofte / Y-butyl 2-(2-methylpyridin-4-yl)morpholine-4-carboxylate (C43)

[0451] The same reaction was conducted in two batches then combined for work-up and purification. A reaction mixture of 4-bromo-2-methylpyridine (CAS: 22282-99-1; 10.0 g, 58.1 mmol), 4-(te / Y-butoxycarbonyl)morpholine-2-carboxylic acid (CAS: 189321-66-2; 26.9 g, 116 mmol), [lr(dF(CF3)ppy)2(dtbbpy)]PF6(CAS: 870987-63-6; 0.652 g, 0.581 mmol), (4,4'-dtbbpy)NiCI2(CAS: 1034901-50-2; 2.31 g, 5.81 mmol) phthalimide (CAS: 85-41-6; 17.1 g, 116 mmol), TMG (13.4 g, 116 mmol) in DMSO (150 mL) was degassed with N2gas for 30 min to form the first batch. The solution of the first batch (100 mL) was pumped into the flow reactor through perfluoroalkoxy Coils (3.175(1 / 8”) mm) with 450 nm LED light (2400 W). The reaction mixture of the first batch was continuously circulating for 240 min. The tubing was washed with solvent. The 450 nm LED light (2400 W) was turned on and the reaction mixture of the first batch was collected. The 450 nm LED light and peristaltic pump were turned off then the tubing was washed again with solvent.

[0452] A second batch of the same reaction was conducted with 4-bromo-2-methylpyridine (CAS: 22282-99-1; 10.0 g, 58.1 mmol) then the two batches were combined. The combined reaction mixture was diluted with ice water (500 mL) and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (5 x200 mL). The combined organic layers were washed with H2O and dried with Na2SO4. The residue was purified by column chromatography (silica gel, 0-30% EtOAc: hexane) to provide C43 (19.0 g, 59.4% yield) as a yellow oil. (LC / MS) m / z (M+H)+= 279.1.1H NMR (400 MHz, (CD3)2SO) 6 8.41 (d, 1 H), 7.25 (s, 1H), 7.17 (d, 1 H), 4.42 (dd, 1 H), 4.06-3.92 (m, 2H), 3.79 (d, 1H), 3.61-3.50 (m, 1H), 3.00-2.95 (m, 1H), 2.69-2.65 (m, 1 H), 2.46 (s, 3H), 1.42 (s, 9H). Step 2. Preparation of 2-(2-methylpyridin-4-yl)morpholine hydrochloride (P32) To a solution of C43 (25.9 g, 93.0 mmol) in DCM (50 mL) was added HCI in 1,4-dioxane (200 mL). The resulting mixture was stirred at room temperature for 16 h. The suspension was concentrated in vacuo then lyophilized to provide P32 (20.5 g, >95% yield) as a yellow solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 179.1.1H NMR (400 MHz, (CD3)2SO) 6 10.41-10.23 (m, 2H), 8.78 (d, 1H), 7.96 (d, 1H), 7.86 (d, 1H), 5.19 (dd, 1H), 4.19 (dd, 1H), 4.14-4.03 (m, 1H), 3.69-3.61 (m, 1H), 3.26 (d, 1H), 3.10-3.06 (m, 1H), 2.99-2.90 (m, 1H), 2.77 (s, 3H).

[0453] Preparation P33

[0454] Methyl 2-(2-methoxypyridin-4-yl)tetrahydro-2 / 7-pyran-4-carboxylate (P33)

[0455] Z^N (SP-4-2)-[4, 4'-bis( 1, 1 -d i methylethyl )-2, 2'-bipyridine-K / \ / 1]K / 1 ']di bromo-nickel v— O N e tetra-n-butylammonium decatungstate '

[0456]

[0457] rj+K3PO4, MeCN °W o

[0458]

[0459] 0 °C- room temperature — o ' —Br450 nm LED photoreactor P33

[0460] Step 1. Preparation of methyl 2-(2-methoxypyridin-4-yl)tetrahydro-2 / 7-pyran-4-carboxylate (P33) A reaction mixture of methyl tetrahydro-2 / 7-pyran-4-carboxylate (CAS: 110238-91-0; 0.721 g, 5.00 mmol), 4-bromo-2-methoxypyridine (0.188 g, 1.00 mmol), tetra-n-butylammonium decatungstate (CAS: 68109-03-5; 33.2 mg, 0.0100 mmol) and (SP-4-2)-[4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-KN1, KN1']dibromo-nickel (CAS: 1894189-67-3; 24.3 mg, 0.0500 mmol) was dried via heat gun dried under vacuum. To the reaction mixture were added K3PO4(233 mg, 1.10 mmol) and MeCN (10 mL). The solution was sonicated under N2 gas for 2 min then sparged with N2gas for 10 min at 0 °C. The reaction vial was then sealed with parafilm and irradiated with 395 nm blue LED light in a photoreactor for 24 h at room temperature then sat at room temperature for 48 h. The suspension was filtered through Celite and concentrated in vacuo. The residue was purified with column chromatography (silica gel, 0-20% EtOAc: heptane) to provide (2:1) (P33 (0.220 g): methyl tetrahydro-2 / 7-pyran-4-carboxylate (~0.110 g)). The crude was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 252.2.

[0461] Example 1

[0462] rel-(R or S)-1-(4-Chloro-2-fluorophenyl)-6,7-dimethyl-3-(2-(1-methyl-1 / 7-pyrazol-4- yl)morpholino)pyrazino[2,3-b]pyrazin-2(1 / - / )-one (1), absolute stereochemical configuration not determined

[0463]

[0464] Step 1. Preparation of A / 2-(4-chloro-2-fluorophenyl)-5,6-dimethylpyrazine-2,3-diamine (C44) Under N2gas, 4-chloro-2-fluoroaniline (CAS: 57946-56-2; 0.432 g, 2.97 mmol), 3-bromo-5,6-dimethylpyrazin-2-amine (CAS: 6294-69-5; 0.500 g, 2.47 mmol), AdBrettPhos Pd G3 (CAS: 1445972-29-1; 0.125 g, 0.124 mmol) and CS2CO3 (2.42 g, 7.42 mmol) were dissolved in 1,4-dioxane (9.9 mL) then stirred at 80 °C for 19 h. The reaction mixture was filtered then the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-80% EtOAc / heptane) to provide C44 (0.192 g, 29.1% yield). (LC / MS) m / z (M+H)+= 267.4.1H NMR (400 MHz, (CD3)2SO) 67.85 (t, 1H), 7.66 (s, 1H), 7.41 (dd, 1H), 7.22-7.16 (m, 1H), 5.99 (s, 2H), 2.18 (d, 6H).

[0465] Step 2. Preparation of 1-(4-chloro-2-fluorophenyl)-6,7-dimethyl-1,4-dihydropyrazino[2,3-b]pyrazine-2, 3-dione (C45)

[0466] Under N2gas, C44 (0.190 g, 0.712 mmol) and diethyl oxalate (CAS: 95-92-1; 3.12 g, 21.4 mmol) was added then stirred at 120 °C for 2.5 h. The yellow suspension became a brown solution during heating then the precipitation of solids occurred. The brown reaction mixture was cooled to room temperature then diluted with heptane (9 mL) and the slurry was stirred overnight at room temperature. The suspension was filtered then washed with heptane. The filter cake was collected to provide C45 (0.171 g, 74.8% yield) as a grey solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 321.5.1H NMR (400 MHz, (CD3)2SO) 6 12.75 (s, 1H), 7.75-7.70 (m, 1H), 7.54-7.47 (m, 2H), 2.42 (s, 3H), 2.26 (s, 3H).

[0467] Step 3. Preparation of 3-chloro-1-(4-chloro-2-fluorophenyl)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1H)-one (C46)

[0468] To a solution of C45 (5.10 g, 15.9 mmol) in DCE (150 mL) and DMF (10 mL) was added SOCI2 (1.89 g, 15.9 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 1 h then was concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-16% EtOAc / petroleum ether) to provide C46 (4.90 g, 90.9% yield) as a yellow solid. (LC / MS) m / z (M+H)+= 339.0.1H NMR (400 MHz, CDCI3) 6 7.37-7.32 (m, 2H), 7.30-7.26 (m, 1 H), 2.66 (s, 3H), 2.51 (s, 3H).

[0469] Step 4. Preparation of rel-(R or S)-1-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1 / 7)-one (1 )

[0470] To a solution of C46 (0.340 g, 1.00 mmol) in MeCN (10 mL) was added DIPEA (0.259 g, 2.01 mmol) and P27 (0.335 g, 2.01 mmol). The reaction mixture was stirred at 50 °C for 15 min then concentrated under a flow of N2 gas. The residue was purified by column chromatography (silica gel, 0-100% EtOAc / heptane) to provide 1 (0.277 g, 58.9% yield) as an off-white solid. (LC / MS) m / z (M+H)+= 470.6.1H NMR (400 MHz, (CD3)2SO) δ 7.77–7.71 (m, 2H), 7.61-7.54 (m, 1H), 7.53-7.48 (m, 1 H), 7.45-7.43 (m, 1 H), 5.04-4.77 (m, 2H), 4.60 (dt, 1H), 4.00-3.96 (m, 1H), 3.81 (s, 3H), 3.78-3.69 (m, 1 H), 3.30-3.18 (m, 2H), 2.47 (s, 3H), 2.31 (s, 3H).

[0471] Example 24

[0472] 1-(4-Chloro-2-fluorophenyl)-6,7-dimethyl-3-(2-(1-methyl-1 / 7-pyrazol-4- yl)morpholino)pyrazino[2,3-b]pyrazin-2(1 / 7)-one (24)

[0473]

[0474] Step 1. Preparation of 1-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(2-(1-methyl-1 / 7-pyrazol-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1 / 7)-one (24)

[0475] To a solution of C46 (0.014 g, 0.041 mmol) in MeCN (1 mL) was added P26 (0.020 g, 0.083 mmol) followed by DIPEA (21 mg, 0.17 mmol). The reaction mixture was stirred at 50 °C for 1 h. To the suspension was added DMSO (1 mL) then purified by reverse phase HPLC (XBridge Ci8100 mm x 19 mm x 5 pm, H2O (0.05% TFA) / MeCN (0.05% TFA), 5-95% MeCN over 9 min, 95% hold 1 min, flow rate = 25 mL / min) to provide 24 (6.3 mg, 33% yield). (LC / MS) m / z (M+H)+= 470.3;1H NMR (600 MHz, (CD3)2SO) 6 7.77-7.73 (m, 2H), 7.60-7.55 (m, 1 H), 7.52 (dd, 1H), 7.45 (d, 1H), 5.02-4.80 (m, 2H), 4.61 (dt, 1H), 4.01 (d, 1H), 3.82 (s, 3H), 3.78-3.72 (m, 1 H), 3.31-3.17 (m, 2H), 2.48 (s, 3H), 2.32 (s, 3H). Example 1 Alternate Procedure and Example 27

[0476] (S)-1 -(4-Chloro-2-fluorophenyl)-6,7-dimethyl-3-(2-(1 -methyl-1 / - / -pyrazol-4- yl)morpholino)pyrazino[2,3-b]pyrazin-2(1 / 7)-one and (R)-1 -(4-Chloro-2-fluorophenyl)-6,7- dimethyl-3-(2-(1 -methyl-1 / 7-pyrazol-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1 / 7)-one (1 and 27), absolute stereochemical configuration not determined

[0477]

[0478] Step 1. Preparation of (S)-1 -(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(2-(1 -methyl-1 / - / -pyrazol-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1 / 7)-one and (R)-1 -(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(2-(1 -methyl-1 / 7-pyrazol-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1 / 7)-one (1 and 27), absolute stereochemical configuration not determined

[0479] Example 24 (23.4 mg, 0.0498 mmol) was dissolved in MeOH then purified by SFC [Pirkle Covalent (R, R) Whelk-O1 250 mm x 21.1 mm x 5 pm, Mobile phase= 85% CO2 / 15% (MeOH (0.2% NH4OH)), isocratic over 10 min, flow rate= 75 mL / min; backpressure: 120 bar] and lyophilized to provide the first eluting isomer as Example 27 (1.91 min, 5.10 mg, 21.8% yield) and the second eluting isomer as Example 1 (2.17 min, 6.20 mg, 26.5% yield).

[0480] 27:1H NMR (600 MHz, DMSO) 6 7.76 - 7.74 (m, 2H), 7.58 (td, 1 H), 7.54 - 7.51 (m, 1 H), 7.45 (d, 1 H), 5.01 - 4.79 (m, 2H), 4.61 (dt, 1 H), 4.01 (d, 1 H), 3.83 (s, 3H), 3.79 - 3.72 (m, 1 H), 3.31 - 3.21 (m, 2H), 2.48 (s, 3H), 2.32 (s, 3H).

[0481] 1:1H NMR (600 MHz, (CD3)2SO) 6 7.76-7.72 (m, 2H), 7.59-7.54 (m, 1H), 7.51 (dd, 1H), 7.44 (d, 1H), 5.04-4.76 (m, 2H), 4.60 (dt, 1 H), 3.99 (d, 1H), 3.81 (s, 3H), 3.77-3.71 (m, 1H), 3.30-3.18 (m, 2H), 2.47 (s, 3H), 2.31 (s, 3H). Example 2

[0482] 1-(4-Chloro-2-fluorophenyl)-6,7-dimethyl-3-(2-(2-methylpyridin-4-yl)morpholino)pyrazino[2,3- b]pyrazin-2(1 / 7)-one (2)

[0483]

[0484] Step 1. Preparation of / V-(4-chloro-2-fluorophenyl)-5,6-dimethylpyrazin-2-amine (C47)

[0485] Under N2gas, to a reaction mixture of 5-chloro-2,3-dimethylpyrazine (CAS: 59489-32-6; 5.00 g, 35.1 mmol), 4-chloro-2-fluoroaniline (CAS: 57946-56-2; 4.85 g, 33.3 mmol), Brettphos (0.471 g, 0.877 mmol) and CS2CO3 (34.3 g, 105 mmol) in 1,4-dioxane (150 mL) was added Brettphos Pd G3 (1.50 g, 1.75 mmol). The reaction mixture was stirred at 50 °C for 6h then was concentrated in vacuo. The residue was purified by column chromatography (silica gel, 18% EtOAc / petroleum ether) to provide C47 (6.60 g, 74.8% yield) as a light-green solid.1H NMR (400 MHz, CDCI3) 68.23-8.16 (m, 1H), 7.96 (s, 1H), 7.16-7.08 (m, 2H), 6.48 (s, 1H), 2.46 (d, 6H).

[0486] Step 2. Preparation of 3-bromo- / V-(4-chloro-2-fluorophenyl)-5,6-dimethylpyrazin-2-amine (C48) At 0 °C, to the reaction mixture of C47 (7.3 g, 29 mmol) in MeCN (300 mL) and DMF (50 mL) was added NBS (5.2 g, 29 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h. After the stir, the reaction mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with NaHCO3(2 x 100 mL) then dried with Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-8% EtOAc / petroleum ether) to provide C48 (8.3 g, 86% yield) as a yellow solid. (LC / MS) m / z (M+H)+= 331.8.1H NMR (400 MHz, CDCl3) 68.49-8.43 (m, 1H), 7.25-7.21 (m, 1H), 7.17-7.10 (m, 2H), 2.44 (d, 6H).

[0487] Step 3. Preparation of / V-(4-chloro-2-fluorophenyl)-3-((diphenylmethylene)amino)-5,6-dimethylpyrazin-2-amine (C2)

[0488] A reaction mixture of C48 (8.29 g, 25.1 mmol), benzophenone imine (CAS: 1013-88-3; 4.54 g, 25.1 mmol) and Cs2CO3(24.5 g, 75.2 mmol) in 1,4-dioxane (250 mL) was purged with N2gas (3x) before Pd2(dba)3(0.689 g, 0.752 mmol) and Xantphos (0.871 g, 1.50 mmol) were added. The reaction mixture was purged with N2gas (3x) then stirred at 90 °C for 16 h. The suspension was filtered through a silica gel pad then the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, 5% EtOAc / n-hexane) to provide C2 (9.52 g, 88.1% yield) as a brown solid. (LC / MS) m / z (M+H)+= 431.6.1H NMR (400 MHz, CDCI3) 6 8.67-8.59 (m, 1 H), 7.91-7.81 (m, 2H), 7.56-7.27 (m, 7H), 7.20-7.06 (m, 4H), 2.37 (s, 3H), 2.08 (s, 3H).

[0489] Step 4. Preparation of A / 2-(4-chloro-2-fluorophenyl)-5,6-dimethylpyrazine-2,3-diamine (C49) To a solution of C2 (9.52 g, 22.1 mmol) in EtOAc (150 mL) was added aqueous 1M HCI (150 mL) then stirred at room temperature for 2 h. The reaction solution was basified slowly with 1M Na2CO3to pH~8 then extracted with EtOAc (3 x200 mL). The combined organic layers were dried with Na2SO4then concentrated in vacuo to give a light-yellow solid. The solid was purified by column chromatography (silica gel, 0-37% EtOAc / petroleum ether) to provide C49 (6.20 g, >95.0% yield) as a yellow solid. (LC / MS) m / z (M+H)+= 267.4.1H NMR (400 MHz, (CD3)2SO) 6 7.85 (t, 1H), 7.66 (s, 1 H), 7.41 (dd, 1H), 7.22-7.16 (m, 1H), 5.99 (s, 2H), 2.18 (d, 6H).

[0490] Step 5. Preparation of 1-(4-chloro-2-fluorophenyl)-6,7-dimethyl-1,4-dihydropyrazino[2,3-b]pyrazine-2, 3-dione (C50)

[0491] The same procedure was followed from Example 1, step 2 with C50 (0.190 g, 0.712 mmol) to provide C49 (0.171 g, 74.8% yield) as a grey solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 321.5.1H NMR (400 MHz, (CD3)2SO) 6 12.75 (s, 1H), 7.75-7.70 (m, 1 H), 7.54-7.47 (m, 2H), 2.42 (s, 3H), 2.26 (s, 3H).

[0492] Step 6. Preparation of 3-chloro-1-(4-chloro-2-fluorophenyl)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1H)-one (C51)

[0493] The same procedure was followed from Example 1, step 3 with C50 (5.10 g, 15.9 mmol) to provide C51 (4.90 g, 90.9% yield) as a yellow solid. (LC / MS) m / z (M+H)+ = 339.0.1H NMR (400 MHz, CDCI3) 67.37-7.32 (m, 2H), 7.30-7.26 (m, 1 H), 2.66 (s, 3H), 2.51 (s, 3H).

[0494] Step 7. Preparation of 1-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(2-(2-methylpyridin-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1 / 7)-one (2)

[0495] A reaction mixture of C51 (32 mg, 0.094 mmol), 2-(2-methylpyridin-4-yl)morpholine (CAS: 1211523-01-1; 0.020 g, 0.11 mmol) and DIPEA (61 mg, 0.47 mmol) in MeCN (2 mL) was stirred at 50 °C for 2 h then concentrated in vacuo. The residue was purified by reverse phase HPLC (Cis 150 mm x 30 mm x 5 pm, H2O (NH4OH-NH4HCO3) / MeCN, 35-75% MeCN over 9 min, 100% hold 2 min, flow rate = 30 mL / min) and lyophilized to provide 2 (8.7 mg, 19% yield) as a white solid. (LC / MS) m / z (M+H)+= 481.0.1H NMR (400 MHz, CDCI3) 6 8.47 (d, 1 H), 7.37- 7.27 (m, 2H), 7.25-7.14 (m, 3H), 5.35 (s, 1 H), 5.14 (s, 1H), 4.66 (dd, 1H), 4.19 (d, 1H), 3.97- 3.87 (m, 1 H), 3.40-3.30 (m, 1H), 3.13-3.01 (m, 1H), 2.57 (d, 6H), 2.40 (s, 3H).

[0496] Example 3

[0497] 1 -(4-Fluorophenyl)-6,7-dimethyl-3-(2-(1 -methyl-1 / 7-pyrazol-4-yl)morpholino)pyrazino[2,3- b]pyrazin-2(1 / - / )-one (3)

[0498]

[0499] Step 1. Preparation of / V, / V-(5,6-dimethylpyrazine-2,3-diyl)bis(1,1-diphenylmethanimine) (C52) A solution of 2,3-dichloro-5,6-dimethylpyrazine (CAS: 32493-79-1; 8.50 g, 48.0 mmol), benzophenone imine (CAS: 1013-88-3; 26.1 g, 144 mmol) and CS2CO3 (46.9 g, 144 mmol) in 1,4-dioxane (160 mL) was purged with N2gas (3x), followed by addition of Pd2(dba)3(1.32 g, 1.44 mmol) and Xantphos (1.67 g, 2.88 mmol). The reaction mixture was sparged with N2gas (3x) then stirred at 90 °C for 16 h. The reaction mixture was filtered, and the filter cake was washed with EtOAc (3 x 50 mL). The filtrate was concentrated in vacuo to give an orange gum. The gum was purified by column chromatography (silica gel, 0-25% EtOAc / petroleum ether) to provide C52 (15.3, 68.4% yield) as yellow solid. (LC / MS) m / z (M+H)+= 467.1.1H NMR (400 MHz, (CD3)2SO) 6 7.65-7.56 (m, 4H), 7.53-7.48 (m, 2H), 7.47-7.41 (m, 4H), 7.38-7.28 (m, 6H), 6.97 (d, 4H), 2.14 (s, 6H).

[0500] Step 2. Preparation of 5,6-dimethylpyrazine-2,3-diamine (C53)

[0501] To a solution of C52 (15.3 g, 32.8 mmol) in EtOAc (50 mL) was added 1 M HCI (60 mL) then stirred at room temperature for 2 h. The organic layer was set aside, and the aqueous layer was extracted with EtOAc (30 mL). The combined organic layers were discarded, and the aqueous layer was lyophilized to give a yellow solid. The solid was diluted with H2O (80 mL) followed by addition of 1M Na2CO3until pH 8 was reached, which resulted in the precipitation of solids. The suspension was filtered, and the filter cake was collected, then lyophilized to provide C53 as a solid. The filtrate was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried with Na2SO4then concentrated in vacuo to provide C53 as a light-yellow solid. The two batches of final product were combined to provide C53 (4.10 g, 90.4% yield) as a light-yellow solid. (LC / MS) m / z (M+H)+= 139.0.1H NMR (400 MHz, (CD3)2SO) 65.78 (s, 4H), 2.09 (s, 6H).

[0502] Step 3. Preparation of 6, 7-dimethyl-1,4-dihydropyrazino[2,3-b]pyrazine-2, 3-dione (C54)

[0503] A solution of C53 (3.10 g, 22.4 mmol) in diethyl oxalate (CAS: 95-92-1; 30 mL) was degassed with N2gas for 3 min then stirred at 120 °C for 24 h. The reaction mixture was filtered then the filter cake was washed with EtOAc (3 x 10 mL). The filter cake was collected to provide C54 (4.10 g, 95.1% yield) as a yellow solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 193.2.1H NMR (400 MHz, (CD3)2SO) 6 12.38 (s, 2H), 2.39 (s, 6H).

[0504] Step 4. Preparation of 6,7-dimethyl-3-(2-(1-methyl-1 / 7-pyrazol-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1 / - / )-one (C55)

[0505] Under N2gas, to a solution of C54 (1.00 g, 5.20 mmol) and P26 (1.04 g, 6.24 mmol) in DMSO (20 mL) was added PyBOP (5.42 g, 10.4 mmol) and DIPEA (2.02 g, 15.6 mmol). The reaction mixture was stirred at 50 °C for 16 h then poured into ice water (80 mL). The diluted reaction mixture was extracted with EtOAc (5 x20 mL). The combined organic layers were washed with brine (80 mL), dried over Na2SO4and concentrated in vacuo to give a brown oil. The oil was purified by column chromatography (silica gel, 0-13% MeOH / DCM) to provide an impure C55 as an orange oil. The oil was purified again by column chromatography (silica gel.

[0506] 0-100% EtOAc / hexane then 0-15% MeOH / DCM) which resulted in an orange oil. The oil was dissolved in (4:1) (petroleum ether: DCM) then stirred for 5 min at room temperature then set aside without stirring for 5 min. The supernatant liquid was removed and discarded. The residual oil was dissolved in (3:1) (petroleum ether: DCM) and stirred vigorously for 5 min which resulted in precipitation of brown solids. The suspension was filtered and the solid was collected. The solid was suspended in (1:1) (petroleum ether: DCM) and stirred for 5 min then filtered. The solid was collected to provide C55 (1.06 g, 59.4% yield) as a yellow solid. (LC / MS) m / z (M+H)+= 342.1.1H NMR (400 MHz, (CD3)2SO) 6 12.65 (s, 1H), 7.74 (s, 1H), 7.44 (s, 1H), 5.05-4.93 (m, 1H), 4.92-4.80 (m, 1H), 4.56 (dd, 1H), 4.01-3.92 (m, 1H), 3.82 (s, 3H), 3.75-3.66 (m, 1H), 3.28-3.16 (m, 2H), 2.45 (s, 6H).

[0507] Step 5. Preparation of 1-(4-fluorophenyl)-6,7-dimethyl-3-(2-(1-methyl-1 / 7-pyrazol-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1 / 7)-one (3)

[0508] To a solution of C55 (0.070 g, 0.21 mmol) and (4-fluorophenyl)boronic acid (CAS: 1765-93-1; 43 mg, 0.31 mmol) in DMF (1 mL) was added Cu(OTf)2(74 mg, 0.20 mmol) and pyridine (49 mg, 0.62 mmol) at room temperature. The reaction mixture was stirred at 60 °C under O2 gas for 16 h. The suspension was diluted with H2O (10 mL) then extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL) then dried with Na2SO4and concentrated in vacuo to give a yellow gum. The gum was dissolved in MeOH (2 mL) then purified by reverse phase HPLC (Boston Prime C18150 mm x 30 mm x 5 μm, H2O (0.05% NH4OH) / MeCN, 23-53% MeCN over 10 min, flow rate = 35 mL / min) then lyophilized to provide 3 (38 mg, 42% yield). (LC / MS) m / z (M+H)+= 436.2.1H NMR (400 MHz, (CD3)2SO) 6 7.74 (s, 1H), 7.45-7.33 (m, 5H), 5.05-4.93 (m, 1H), 4.90-4.77 (m, 1 H), 4.58 (dd, 1 H), 4.02-3.96 (m, 1H), 3.81 (s, 3H), 3.77-3.69 (m, 1 H), 3.29-3.17 (m, 2H), 2.45 (s, 3H), 2.28 (s, 3H).

[0509] Example 4

[0510] 6,7-Dimethyl-3-(2-(1 -methyl-1 / 7-pyrazol-4-yl)morpholino)-1-(3,3,3-trifluoropropyl)pyrazino[2,3-

[0511]

[0512] Step 1. Preparation of 6,7-dimethyl-3-(2-(1-methyl-1 / 7-pyrazol-4-yl)morpholino)-1 -(3,3,3-trifluoropropyl)pyrazino[2,3-b]pyrazin-2(1 / 7)-one (4)

[0513] Under N2gas, to a solution of C55 (0.030 g, 0.088 mmol), 1,1,1-trifluoro-3-iodopropane (CAS: 460-37-7; 39 mg, 0.18 mmol) in DMF (1 mL) was added K2CO3(36 mg, 0.26 mmol). The reaction mixture was stirred at room temperature for 16 h then was diluted with H2O (5 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 1 / 10, MeOH / EtOAc) to provide an impure 4 (28 mg) as a colorless oil. The oil was lyophilized then purified by reverse phase HPLC (WePure Biotech XP tC18150 mm x 40 mm x 7 μm, H2O (0.05% NH4OH + 10 mM NH4HCO3) / MeCN, 30-70% MeCN in 9 min, flow rate= 60 mL / min) and lyophilized again to provide 4 (6.2 mg, 16% yield) as a white solid. (LC / MS) m / z (M+H)+= 438.2.1H NMR (400 MHz, CDCI3) 6 7.52 (s, 1H), 7.42 (s, 1 H), 5.27-5.14 (m, 1H), 5.11-4.98 (m, 1H), 4.72-4.62 (m, 3H), 4.11—4.03 (m, 1H), 3.89 (s, 3H), 3.87-3.82 (m, 1H), 3.42-3.25 (m, 2H), 2.64-2.56 (m, 8H) Example 5

[0514] 6,7-Dimethyl-3-(2-(1 -methyl-1 / 7-pyrazol-4-yl)morpholino)-1-(spiro[2.5]octan-6-yl)pyrazino[2,3- b]pyrazin-2(1 / 7)-one (5)

[0515]

[0516] Step 1. Preparation of 6,7-dimethyl-3-(2-(1-methyl-1 / 7-pyrazol-4-yl)morpholino)-1-(spiro[2.5]octan-6-yl)pyrazino[2,3-b]pyrazin-2(1 / 7)-one (5)

[0517] To a reaction mixture of C55 (0.050 g, 0.15 mmol), spiro[2.5]octan-6-ol (CAS: 22428-83-7; 28 mg, 0.22 mmol) and PPh3(77 mg, 0.29 mmol) in THF (1.5 mL) was added DIAD (89 mg, 0.44 mmol) slowly. The reaction mixture was stirred at room temperature for 3 h then quenched with H2O (1 mL) and concentrated in vacuo. The residue was purified by reverse phase HPLC (WePure Biotech XP tC18150 mm x 40 mm x 7 μm, H2O (0.05% NH4OH + 10mM NH4HCO3) / MeCN, 20-60% MeCN in 9 min, flow rate= 60 mL / min) then lyophilized to provide 5 (16 mg, 24% yield) as a white solid. (LC / MS) m / z (M+H)+= 450.2.1H NMR (400 MHz, (CD3)2SO) 6 7.74 (s, 1 H), 7.44 (s, 1 H), 5.38-5.26 (m, 1H), 4.96-4.85 (m, 1H), 4.82-4.71 (m, 1 H), 4.56 (dd, 1H), 4.00-3.93 (m, 1H), 3.81 (s, 3H), 3.75-3.67 (m, 1H), 3.23-3.12 (m, 2H), 2.83-2.68 (m, 2H), 2.51 (s, 3H), 2.45 (s, 3H), 1.92-1.82 (m, 2H), 1.61-1.53 (m, 2H), 0.95 (d, 2H), 0.38-0.25 (m, 4H).

[0518] Example 6

[0519] 1-(4-Chloro-2-fluorophenyl)-3-(2-(2-ethylpyridin-4-yl)morpholino)-6,7-dimethylpyrazino[2,3- b]pyrazin-2(1 / 7)-one (6)

[0520]

[0521] Step 1. Preparation of 1-(4-chloro-2-fluorophenyl)-3-(2-(2-ethylpyridin-4-yl)morpholino)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1 / 7)-one (6) To a reaction mixture of C45 (0.030 g, 0.088 mmol), 4A molecular sieves (0.10 g) and P2 (29 mg, 0.097 mmol) in MeCN (0.8 mL) was added DIPEA (0.080 g, 0.62 mmol) at room temperature. The suspension was stirred at 50 °C for 1.5 h then purified by reverse phase HPLC (Phenomenex Gemini NX C18150 mm x 40 mm x 5 μm, H2O (0.05% NH4OH) / MeCN, 50-70% MeCN in 10 min, flow rate = 60 mL / min) and lyophilized to provide 6 (25 mg, 57% yield) as a white solid. (LC / MS) m / z (M+H)+= 495.2.1H NMR (400 MHz, (CD3)2SO) 6 8.49 (d, 1 H), 7.75 (ddd, 1H), 7.62-7.49 (m, 2H), 7.29 (s, 1 H), 7.22 (d, 1H), 5.18— 4.99 (m, 1H), 4.96-4.84 (m, 1H), 4.71 (d, 1 H), 4.17-4.11 (m, 1H), 3.88-3.79 (m, 1H), 3.32-3.27 (m, 1 H), 3.17-3.04 (m, 1 H), 2.77 (q, 2H), 2.48 (s, 3H), 2.32 (s, 3H), 1.23 (t, 3H).

[0522] Example 7

[0523] 1-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-((2S,6 / ?)-2-methyl-6-(2-methylpyridin-4- yl)morpholino)pyrazino[2,3-b]pyrazin-2(1 / 7)-one and 1 -(4-chloro-2-fluorophenyl)-6,7-dimethyl-3- ((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1 / - / )-one (racemic, cis) (7)

[0524]

[0525] racemic mixture of cis isomers

[0526] Step 1. Preparation of 1-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1 / - / )-one and 1-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1 / 7)-one (racemic, cis) (7)

[0527] A reaction mixture of C46 (0.037 g, 0.11 mmol), P4 (25 mg, 0.13 mmol) and DIPEA (0.070 g, 0.54 mmol) in MeCN (2 mL) was stirred at 50 °C for 2 h then purified by reverse phase HPLC (C18150 mm x 40 mm x 5 μm, H2O (0.05% formic acid) / MeCN, 20-60% MeCN in 9 min, flow rate = 60 mL / min) and lyophilized to provide 7 (12 mg, 23% yield) as a white solid. (LC / MS) m / z (M+H)+= 495.1.1H NMR (400 MHz, CD3OD) 6 8.40 (d, 1 H), 7.52-7.32 (m, 5H), 5.34 (s, 1H), 5.24-5.13 (m, 1H), 4.81-4.75 (m, 1H), 4.00-3.90 (m, 1H), 3.03-2.90 (m, 2H), 2.55 (d, 6H), 2.39 (s, 3H), 1.34 (d, 3H). Examples 8 and 9

[0528] 6,7-Dimethyl-3-(2-(1-methyl-1 / 7-pyrazol-4-yl)morpholino)-1-(3- (trifluoromethyl)cyclobutyl)pyrazino[2,3-b]pyrazin-2(1 / 7)-one (racemic, separated cis and trans isomers) (8 and 9), cis / trans configuration not assigned

[0529]

[0530] Step 1. Preparation of 5,6-dimethyl-A / 2-(3-(trifluoromethyl)cyclobutyl)pyrazine-2,3-diamine (C56) A mixture of BrettPhos Pd G3 (14 mg, 0.016 mmol) and 3-(trifluoromethyl)cyclobutan-1-amine hydrochloride (CAS: 1803601-06-0; 6.1 mg, 0.38 mmol) were purged with N2gas (2x) then a solution of 3-chloro-5,6-dimethylpyrazin-2-amine (CAS: 39213-71-3; 0.050 g, 0.32 mmol) in THF (0.79 mL) was added. The reaction mixture was degassed with N2gas for 1 min before 1 M LiHMDS (1.1 mL) was added dropwise. The suspension was stirred at 65 °C for 24 h then cooled to room temperature and quenched with saturated aqueous NH4CI (1 mL). The suspension was diluted with EtOAc and H2O then stirred vigorously for 2 h. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2x). The organic layers were combined then washed with brine. The organic layer was filtered through a plug of cotton and Celite, then the filtrate was concentrated in vacuo to provide C56 (0.083 g, >95.0% yield) as a gum. The gum was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 261.7.

[0531] Step 2. Preparation of 6,7-dimethyl-1-(3-(trifluoromethyl)cyclobutyl)-1,4-dihydropyrazino[2,3-b]pyrazine-2, 3-dione (C57)

[0532] A solution of C56 (0.083 g, 0.32 mmol) in diethyl oxalate (CAS: 95-92-1; 2.7 g, 18 mmol) was stirred at 100 °C for 24 h. The solution was concentrated under N2gas to provide C57 (0.10 g, >95.0% yield) as a gum. The gum was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 315.3.

[0533] Step 3. Preparation of 3-chloro-6,7-dimethyl-1-(3-(trifluoromethyl)cyclobutyl)pyrazino[2,3-b]pyrazin-2(1 / - / )-one (C58) To a solution of C57 (0.100 g, 0.318 mmol) in DCE (3.0 mL) and DMF (0.03 mL) was added SOCI2(0.568 g, 4.77 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 2 h then was concentrated under N2gas to form C58 (0.11 g, >95.0% yield) as a brown gum. The gum was used directly in the next step without further purification. (LC / MS) m / z (M+H)+ = 333.3.

[0534] Step 4. Preparation of c / s and trans diastereomers of 6,7-dimethyl-3-(2-(1-methyl-1 / 7-pyrazol-4-yl)morpholino)-1-(3-(trifluoromethyl)cyclobutyl)pyrazino[2,3-b]pyrazin-2(1 / 7)-one (8 and 9) To a solution of C58 (0.11 g, 0.32 mmol) in MeCN (2 mL) was added a solution of P26 (0.11 g, 0.64 mmol) in MeCN (1 mL) then DIPEA (0.17 g, 1.3 mmol). The reaction mixture was stirred at room temperature for 2 h then concentrated in vacuo. The residue was diluted with EtOAc and H2O then acidified with 1N HCI. The acidic reaction mixture was stirred vigorously for 15 min then filtered through a Celite-packed filter funnel and rinsed with EtOAc. The organic layer was collected, and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried with Na2SO4, filtered then concentrated in vacuo. The residue was suspended in DMSO then filtered with a syringe filter. The solution was purified by reverse phase HPLC (Sunfire C18100 mm x 19 mm x 5 μm, H2O (0.05% TFA) / MeCN (0.05% TFA), 30-70% MeCN over 9 min, 95% hold 1 min, flow rate = 25 mL / min) to provide the first eluting isomer as 8 (2.39 min, 22 mg, 15% yield): (LC / MS) m / z (M+H)+= 464.4. The second eluting isomer as 9 (2.59 min, 7.0 mg, 4.7% yield): (LC / MS) m / z (M+H)+= 464.4. [LCMS method (Atlantis dC1850mm x 4.6 0mm x 5um, H2O (0.05% TFA) / MeCN (0.05% TFA), 5 to 95% over 5 min).

[0535] 8:1H NMR (600 MHz, (CD3)2SO) 6 7.75 (s, 1 H), 7.45 (s, 1H), 5.53-5.43 (m, 1 H), 4.90-4.73 (m, 2H), 4.57 (dd, 1 H), 4.00-3.95 (m, 1H), 3.83 (s, 3H), 3.71 (td, 1H), 3.28-3.17 (m, 2H), 3.15-3.09 (m, 3H), 2.58-2.54 (m, 2H), 2.51-2.49 (m, 3H), 2.47 (s, 3H).

[0536] 9:1H NMR (600 MHz, (CD3)2SO) 6 7.75 (s, 1H), 7.45 (s, 1 H), 5.99-5.81 (m, 1 H), 4.95-4.72 (m, 2H), 4.57 (dd, 1 H), 4.01-3.96 (m, 1H), 3.84-3.80 (m, 3H), 3.75-3.69 (m, 1H), 3.46-3.37 (m, 1H), 3.28-3.01 (m, 5H), 2.52 (s, 3H), 2.48-2.34 (m, 4H). Example 10

[0537] 1-(4-Chloro-2-fluorophenyl)-7-methyl-3-(2-(1-methyl-1 / 7-pyrazol-4-yl)morpholino)pyrazino[2,3-

[0538]

[0539] Step 1. Preparation of methyl 2-((3-bromo-5-methylpyrazin-2-yl)amino)-2-oxoacetate (C59) A solution of 3-bromo-5-methylpyrazin-2-amine (CAS: 74290-65-6; 1.00 g, 5.32 mmol) and TEA (1.08 g, 10.6 mmol) in DCM (27 mL) was cooled in an ice-water bath and methyl 2-chloro-2-oxoacetate (CAS: 5781-53-3; 0.977 g, 7.98 mmol) was added slowly. The reaction mixture was warmed to room temperature and stirred for 2 h. The suspension was filtered through Celite and eluted with DCM (50 mL). The filtrate was concentrated in vacuo then the residue was purified by column chromatography (silica gel, 0-50% EtOAc / petroleum ether) to provide C59 (0.451 g, 30.9% yield) as a brown solid. (LC / MS) m / z (M+H)+= 275.9.1H NMR (400 MHz, (CD3)2SO) 6 11.29 (s, 1 H), 8.48 (s, 1H), 3.85 (s, 3H), 2.52-2.50 (m, 3H).

[0540] Step 2. Preparation of A / 2-(4-chloro-2-fluorophenyl)-6-methylpyrazine-2,3-diamine (C60)

[0541] Under N2gas, to a stirred solution of C59 (0.370 g, 1.35 mmol) in 1,4-dioxane (13.5 mL) was added 4-chloro-2-fluoroaniline (CAS: 57946-56-2; 0.295 g, 2.03 mmol), Cs2CO3(1.32 g, 4.05 mmol) and XantPhos Pd G3 (0.139 g, 0.135 mmol). The reaction mixture was purged with N2gas (3x) then stirred at 90 °C for 16 h. The suspension was filtered through Celite then the filter cake was washed with EtOAc (2 x 10 mL). The filtrate was concentrated in vacuo to give a brown gum. The gum was purified by column chromatography (silica gel, 0-50% THF / petroleum ether) to provide C60 (90.0 mg, 21.7% yield) as a yellow solid. (LC / MS) m / z (M+H)+= 252.9.1H NMR (400 MHz, (CD3)2SO) 6 7.87-7.81 (m, 2H), 7.44 (dd, 1H), 7.30 (s, 1H), 7.24-7.20 (m, 1H), 6.05 (s, 2H), 2.12 (s, 3H).

[0542] Step 3. Preparation of 1-(4-chloro-2-fluorophenyl)-7-methyl-1,4-dihydropyrazino[2,3-b]pyrazine-2, 3-dione (C61)

[0543] A reaction mixture of C60 (0.050 g, 0.20 mmol) in diethyl oxalate (CAS: 95-92-1; 1.0 mL) was degassed with N2gas for 3 min. The reaction mixture was stirred at 120 °C for 8 h then filtered. The filter cake was washed with hexane (3 x3 mL). The filter cake was collected for provide C61 (35 mg, 58% yield) as a light pink solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 307.0.1H NMR (400 MHz, (CD3)2SO 6 12.85-12.80 (m, 1H), 8.07 (s, 1 H), 7.77-7.70 (m, 1H), 7.56-7.46 (m, 2H), 2.28 (s, 3H).

[0544] Step 4. Preparation of 1-(4-chloro-2-fluorophenyl)-7-methyl-3-(2-(1-methyl-1 / 7-pyrazol-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1 / 7)-one (10)

[0545] Under N2 gas, to a solution of C61 (35 mg, 0.11 mmol) and P26 (23 mg, 0.14 mmol) in DMSO (1 mL) was added PyBOP (0.12 g, 0.23 mmol) and DIPEA (44 mg, 0.34 mmol). The reaction mixture was stirred at 50 °C for 16 h then quenched with 1 drop of H2O and diluted with MeOH. The solution was purified by reverse phase HPLC (Boston Prime C18150 mm x 40 mm x 5 μm, H2O (0.05% NH4OH + 10 mM NH4HCO3) / MeCN, 40-60% MeCN in 10 min, flow rate: 35 mL / min) and lyophilized to provide 10 (22 mg, 43% yield) as a white solid. (LC / MS) m / z (M+H)+=456.1.1H NMR (400 MHz, (CD3)2SO) 68.26 (s, 1H), 7.76-7.69 (m, 2H), 7.59-7.48 (m, 2H), 7.43-7.42 (m, 1 H), 5.05—4.91 (m, 1H), 4.91-4.77 (m, 1H), 4.66-4.58 (m, 1H), 4.05-3.97 (m, 1H), 3.84-3.79 (m, 3H), 3.79-3.71 (m, 1 H), 3.30-3.23 (m, 2H), 2.36-2.31 (m, 3H).

[0546] Example 11

[0547] 1-(4-Chloro-2-fluorophenyl)-3-(3-(1 -cyclopropyl-1 / 7-pyrazol-4-yl)-4-methylpiperazin-1-yl)-6,7- dimethylpyrazino[2,3-b]pyrazin-2(1 / 7)-one (11 )

[0548]

[0549] Step 1. Preparation ofte / Y-butyl 4-(4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-oxo-3,4-dihydropyrazino[2,3-b]pyrazin-2-yl)-2-(1-cyclopropyl-1 / 7-pyrazol-4-yl)piperazine-1 -carboxylate (C62)

[0550] A reaction mixture of C46 (0.420 g, 1.24 mmol), 1,1 -dimethylethyl 2-(1-cyclopropyl-1 H-pyrazol-4-yl)-1 -piperazinecarboxylate (CAS: 2863568-43-6; 0.436 g, 1.49 mmol) and DIPEA (0.800 g, 6.19 mmol) in MeCN (10 mL) was stirred at 50 °C for 2 h then concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-36% THF / petroleum ether) to provide C62 (0.320 g, 43.4% yield) as a yellow solid. (LC / MS) m / z (M+H)+= 595.2.

[0551] Step 2. Preparation of 1 -(4-chloro-2-fluorophenyl)-3-(3-(1 -cyclopropyl-1 / 7-pyrazol-4-yl)piperazin-1 -yl)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1 / 7)-one (C63)

[0552] To a mixture of C62 (0.32 g, 0.54 mmol) in 0.054 M HCI in 1,4-dioxane ( 10 mL) was stirred at room temperature for 2 h then concentrated in vacuo to provide C63 (0.27 g, >95% yield) as a yellow solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 495.1.

[0553] Step 3. Preparation of 1-(4-chloro-2-fluorophenyl)-3-(3-(1 -cyclopropyl-1 / 7-pyrazol-4-yl)-4-methylpiperazin-1 -yl)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1 / 7)-one (11 )

[0554] To a solution of C63 (0.090 g, 0.18 mmol) in toluene (3 mL) was added formaldehyde (27 mg, 0.91 mmol) and AcOH (33 mg, 0.55 mmol). The reaction mixture was stirred at 100 °C for 2 h before NaBH(OAc)3(0.12 g, 0.55 mmol) was added. The suspension was stirred for an additional 16 h at 100 °C then concentrated in vacuo. The residue was dissolved in DMF then purified by reverse phase HPLC (WePure Biotech XP tC18150 mm x 40 mm x 7 μm, H2O (0.05% NH4OH + 10 mM NH4HCO3) / MeCN, 35-75% MeCN in 9 min, flow rate= 60 mL / min) and lyophilized to provide 11 (33 mg, 36% yield) as light-yellow solid. (LC / MS) m / z (M+H)+= 509.3.1H NMR (400 MHz, CD3OD) 6 7.73 (s, 1 H), 7.57-7.36 (m, 4H), 5.06 (d, 2H), 3.66 (tt, 1H), 3.57-3.41 (m, 1H), 3.32-3.20 (m, 2H), 3.13-2.97 (m, 1H), 2.53 (s, 3H), 2.47 (td, 1H), 2.38 (s, 3H), 2.18 (s, 3H), 1.16-0.96 (m, 4H).

[0555] Example 13

[0556] 1-(4-Chlorophenyl)-6,7-dimethyl-3-(2-(1-methyl-1 / 7-pyrazol-4-yl)morpholino)pyrazino[2,3- b]pyrazin-2(1 / 7)-one (13)

[0557]

[0558] Step 1. Preparation of 3-chloro- / V-(4-chlorophenyl)-5,6-dimethylpyrazin-2-amine (C64) A mixture of 3-chloro-5,6-dimethylpyrazin-2-amine (CAS: 39213-71-3; 0.200 g, 1.27 mmol), Cs2CO3(1.03 g, 3.17 mmol) and / BuXPhos Pd G3 (0.120 g, 0.127 mmol) was purged with N2 gas (3x). The reaction mixture was suspended in toluene (6.3 mL) and 1-chloro-4-iodobenzene (CAS: 637-87-6; 0.605 g, 2.54 mmol). The suspension was stirred at 100 °C for 18 h then cooled to room temperature and extracted with EtOAc (3x). The combined organic layers were dried over MgSO4, filtered then concentrated in vacuo to give a brown oil. The oil was purified by column chromatography (silica gel, 0-50% EtOAc / heptane) to provide C64 (0.209 g, 61.4% yield) as a white solid. (LC / MS) m / z (M+H)+= 268.4.

[0559] Step 2. Preparation of 1-(4-chlorophenyl)-6,7-dimethyl-1,4-dihydropyrazino[2,3-b]pyrazine-2,3-dione (C65)

[0560] A mixture of C64 (0.250 g, 0.932 mmol), ethyl 2-amino-2-oxoacetate (CAS: 617-36-7; 0.328 g, 2.80 mmol), Cs₂CO₃ (1.22 g, 3.73 mmol) and XPhos Pd G3 (78.9 mg, 93.2 μmol) was purged with N2gas (3x). The mixture was suspended in 1,4-dioxane (9.3 mL) then stirred at 90 °C for 4.5 h. The suspension was filtered through Celite, and the filter cake was rinsed with a mixture of MeOH and DCM. The filter cake was collected then suspended in (1:1) MeOH / DCM (20 mL) and stirred for 30 min. The suspension was filtered and rinsed with (1:1) MeOH / DCM. The filtrate was concentrated in vacuo then dissolved in MeOH / DCM and purified by column chromatography (silica gel, 0-10% MeOH / DCM) to provide C65 (60.0 mg, 18.5% yield) as a white solid. (LC / MS) m / z (M+H)+= 303.3.

[0561] Step 3. Preparation of 3-chloro-1-(4-chlorophenyl)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1 / 7)-one (C66)

[0562] To a solution of C65 (0.060 g, 0.020 mmol) in DCE (2.00 mL) and DMF (0.01 mL) was added SOCI2(0.24 g, 2.0 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 1.5 h then was cooled to room temperature. To the suspension was added toluene then the solution was concentrated in vacuo (3x) to provide C66 (64 mg, >95% crude). The residue was used directly in the next step without further purification.

[0563] Step 4. Preparation of 1-(4-chlorophenyl)-6,7-dimethyl-3-(2-(1-methyl-1 / 7-pyrazol-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1 / 7)-one (13)

[0564] A reaction mixture of C66 (64 mg, 0.20 mmol), P26 (67 mg, 0.40 mmol) and DIPEA (52 mg, 0.40 mmol) in MeCN (2 mL) was stirred at 50 °C for 2.5 h then concentrated in vacuo. The residue was suspended in DMSO then filtered and purified by reverse phase HPLC (Sunfire C18100 mm x 19 mm x 5 μm, H2O (0.05% TFA) / MeCN (0.05% TFA), 30-95% MeCN over 9 min, 95% hold 1 min, flow rate = 25 mL / min) to provide 13 (37 mg, 41% yield). (LC / MS) m / z (M+H)+= 452.3.1H NMR (600 MHz, (CD3)2SO) 67.74 (s, 1H), 7.62-7.59 (m, 2H), 7.44 (s, 1H), 7.40- 7.37 (m, 2H), 5.05-4.80 (m, 2H), 4.58 (dd, 1H), 3.99 (d, 1H), 3.81 (s, 3H), 3.76-3.70 (m, 1H), 3.29-3.19 (m, 2H), 2.45 (s, 3H), 2.29 (s, 3H). Example 14

[0565] 4-(6,7-Dimethyl-3-(2-(1-methyl-1 / 7-pyrazol-4-yl)morpholino)-2-oxopyrazino[2,3-b]pyrazin-1(2 / 7)- yl)-3-fluorobenzonitrile (14)

[0566]

[0567] Step 1. Preparation of 4-((3-amino-5,6-dimethylpyrazin-2-yl)amino)-3-fluorobenzonitrile (C67) A mixture of 3-chloro-5,6-dimethylpyrazin-2-amine (CAS: 39213-71-3; 0.15 g, 0.95 mmol), 4-amino-3-fluorobenzonitrile (CAS: 63069-50-1; 0.19 g, 1.4 mmol), Cs2CO3(0.93 g, 2.9 mmol) and fBuXPhos Pd G3 (38 mg, 48 μmol) in 1,4-dioxane (3 mL) was degassed with N2gas (3x). The suspension was stirred at 90 °C for 21 h then filtered through Celite and eluted with EtOAc. The filtrate was concentrated in vacuo then purified by column chromatography (silica gel, 0-5% MeOH / DCM) to provide C67 (0.091 g, 37% yield) as a yellow solid. (LC / MS) m / z (M+H)+= 258.8.1H NMR (400 MHz, (CD3)2SO) 68.09-8.06 (m, 1 H), 7.97 (t, 1 H), 7.78 (dd, 1H), 7.57-7.52 (m, 1H), 6.10 (s, 2H), 2.51 (s, 3H), 2.25-2.21 (m, 3H).

[0568] Step 2. Preparation of 4-(6,7-dimethyl-2,3-dioxo-3,4-dihydropyrazino[2,3-b]pyrazin-1 (2 / 7)-yl)-3-fluorobenzonitrile (C68)

[0569] A mixture of C67 (0.050 g, 0.19 mmol) in 1,4-dioxane (0.97 mL) was degassed with N2gas (3x). To the suspension was added TEA (79 mg, 0.78 mmol) then oxalyl chloride (0.030 g, 0.23 mmol). The reaction mixture was stirred at 65 °C for 8 h then another portion of oxalyl chloride (12 mg, 0.097 mmol) was added. The suspension was stirred at 65 °C for 20 h then was concentrated in vacuo. The brown residue was dissolved in DCM and washed with H2O then brine. The organic layer was concentrated in vacuo then dried further under high vacuum. The residue was dissolved in 1,4-dioxane (0.97 mL) then TEA (79 mg, 0.78 mmol) and oxalyl chloride (0.030 g, 0.23 mmol) was added. The reaction mixture was stirred at 90 °C for 2 h then purified by column chromatography (silica gel, 40-100% EtOAc / DCM) to provide C68 (11 mg, 18% yield) as an orange solid.

[0570] Step 3. Preparation of 4-(3-chloro-6,7-dimethyl-2-oxopyrazino[2,3-b]pyrazin-1(2 / 7)-yl)-3-fluorobenzonitrile (C69)

[0571] To a solution of C68 (11 mg, 0.035 mmol) in DCE (0.31 mL) and DMF (0.9 pL) was added SOCI2(42 mg, 0.35 mmol) at room temperature. The reaction mixture was degassed with N2gas then stirred at 50 °C for 2 h. To the suspension was concentrated in vacuo to provide C69 (12 mg, >95.0% yield). The residue was used directly in the next step without further purification.

[0572] Step 4. Preparation of 4-(6,7-dimethyl-3-(2-(1-methyl-1 / 7-pyrazol-4-yl)morpholino)-2-oxopyrazino[2,3-b]pyrazin-1 (2 / 7)-yl)-3-fluorobenzonitrile (14)

[0573] To a mixture of C69 (11 mg, 0.033 mmol) and P26 (7.0 mg, 0.040 mmol) in MeCN (0.37 mL) was added DIPEA (13 mg, 0.10 mmol). The reaction mixture was degassed with N2gas then stirred at 50 °C for 3 h. Another portion of P26 (2.9 mg, 0.017 mmol) and DIPEA (4.3 mg, 0.033 mmol) were added then the suspension was stirred at 50 °C for 1 h. The reaction mixture was concentrated in vacuo then dried further under high vacuum. The residue was purified by reverse phase HPLC (Sunfire C18100 mm x 19 mm x 5 μm, H2O (0.05% TFA) / MeCN (0.05% TFA), 30-95% MeCN over 9 min, 95% hold 1 min, flow rate= 25 mL / min) to provide 14 (4.7 mg, 31% yield). (LC / MS) m / z (M+H)+= 461.4.1H NMR (600 MHz, (CD3)2SO) 6 8.19-8.16 (m, 1H), 7.96-7.92 (m, 1H), 7.81-7.76 (m, 1H), 7.75-7.72 (m, 1H), 7.44 (d, 1H), 5.03-4.73 (m, 2H), 4.60 (dt, 1 H), 4.00 (d, 1 H), 3.81 (s, 3H), 3.78-3.70 (m, 1H), 3.30-3.19 (m, 2H), 2.47 (s, 3H), 2.30 (s, 3H).

[0574] Example 15

[0575] 6,7-Dimethyl-3-(2-(1 -methyl-1 / 7-pyrazol-4-yl)morpholino)-1 -(p-tolyl)pyrazino[2,3-b]pyrazin- 2(1H)-one (15)

[0576]

[0577] Step 1. Preparation of S.e-dimethyl-A^-Qo-tolyOpyrazine^. S-diamine hydrochloride (C70)

[0578] To a reaction mixture of 3-chloro-5,6-dimethylpyrazin-2-amine (CAS: 39213-71-3; 0.050 g, 0.32 mmol), p-toluidine (0.034 g, 0.32 mmol) in EtOH (0.13 mL) and H2O (0.87 mL) was added 12.1M HCI (0.05 mL) in a microwave vial. The suspension was stirred at 175 °C for 1 h in a microwave reactor then set aside at room temperature for 72 h. The reaction mixture was centrifuged using a Genevac centrifugal evaporator, then the aqueous layer was removed and discarded. The organic layer was diluted with H2O (1 mL) then mixed by vortex and centrifuged by Genevac again. The aqueous layer was discarded. The remaining solid was collected and dried under N2gas to provide C70 (39 mg, 33% yield) as a solid. The solid was used directly in the next step without further purification.

[0579] Step 2. Preparation of ethyl 2-((5,6-dimethyl-3-(p-tolylamino)pyrazin-2-yl)amino)-2-oxoacetate (C71)

[0580] To a reaction mixture of C70 (47 mg, 0.13 mmol) in DCE (2 mL) and DIPEA (49 mg, 0.38 mmol) was added ethyl 2-chloro-2-oxoacetate (17 mg, 0.13 mmol) at room temperature. The suspension was stirred overnight then concentrated in vacuo to provide C71 (41 mg, >95.0% yield) as an oil. The oil was used directly in the next step without further purification. Step 3. Preparation of 6, 7-dimethyl-1 -(p-tolyl)-l,4-dihydropyrazino[2,3-b]pyrazine-2, 3-dione (C72)

[0581] C71 (0.040 g, 0.12 mmol) was suspended in MeCN (1.5 mL) and filtered with a syringe filter. The filtrate was transferred to 0.5-2.0 mL microwave vial. To the solution was added AcOH (160 pL) which resulted in the precipitation of solids. The reaction mixture was stirred at 150 °C in a microwave for 1 h then concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-6% MeOH / DCM) to give an impure C72 as a tan solid. The solid was suspended in toluene then concentrated in vacuo. The residue was purified again by column chromatography (silica gel, 0-8% MeOH / DCM) to provide C72 (0.020 g, 58% yield) as a tan solid. (LC / MS) m / z (M+H)+= 283.4.1H NMR (400 MHz, CDCI3) 6 8.90-8.83 (m, 1H), 7.35 (d, 2H), 7.16-7.12 (m, 2H), 2.48 (s, 3H), 2.45 (s, 3H), 2.35 (s, 3H).

[0582] Step 4. Preparation of 3-chloro-6,7-dimethyl-1-(p-tolyl)pyrazino[2,3-b]pyrazin-2(1 / 7)-one (C73) To a solution of C72 (0.020 g, 0.071 mmol) in DCE (1 mL) and 1 drop of DMF was added SOCI2(50 pL). The reaction mixture was stirred at 50 °C then diluted with toluene (3 mL) and concentrated in vacuo to provide C73 (0.020 g, 94% yield) as an off-white solid. The solid was used directly in the next step without further purification.

[0583] Step 5. Preparation of 6, 7-dimethyl-3-(2-(1 -methyl-1 / 7-pyrazol-4-yl)morpholino)-1 -(p-tolyl)pyrazino[2,3-b]pyrazin-2(1 / 7)-one (15)

[0584] To a solution of C73 (0.020 g, 0.067 mmol) in MeCN (1 mL) was added P26 (17 mg, 0.10 mmol) followed by DIPEA (17 mg, 0.13 mmol). The reaction mixture was stirred at 50 °C for 1.5 h. To the suspension was added DMSO (1 mL) then purified by reverse phase HPLC (Sunfire C18100 mm x 19 mm x 5 μm, H2O (0.05% TFA) / MeCN (0.05% TFA), 30-70% MeCN over 9 min, 95% hold 1 min, flow rate = 25 mL / min) to provide 15 (10.6 mg, 36.5% yield).

[0585] (LC / MS) m / z (M+H)+= 432.3.1H NMR (600 MHz, (CD3)2SO) 6 7.74 (s, 1 H), 7.43 (s, 1H), 7.32 (d, 2H), 7.20-7.17 (m, 2H), 4.98 (s, 1H), 4.84 (s, 1H), 4.59 (dd, 1H), 4.02-3.95 (m, 1 H), 3.81 (s, 3H), 3.73 (td, 1H), 3.31-3.18 (m, 2H), 2.45 (s, 3H), 2.40 (s, 3H), 2.27 (s, 3H).

[0586] Example 16

[0587] 1 -(4-Chloro-2-fluorophenyl)-6-ethyl-7-methyl-3-(2-(1 -methyl-1 / - / -pyrazol-4- yl)morpholino)pyrazino[2,3-b]pyrazin-2(1 / - / )-one (16)

[0588]

[0589] Step 1. Preparation of 1-(4-chloro-2-fluorophenyl)-6-ethyl-7-methyl-1,4-dihydropyrazino[2,3-b]pyrazine-2, 3-dione (C74)

[0590] The same reaction was conducted in two batches then combined for purification as follows: A reaction mixture of C61 (0.10 g, 0.33 mmol), propanoic acid (0.24 g, 3.3 mmol) and ammonium persulfate (0.30 g, 1.3 mmol) in DMSO (9.3 mL) and H2O (15.5 pL) was stirred at 40 °C for 16 h to form the first batch.

[0591] A second batch of the same reaction was conducted with C61 (0.030 g, 0.098 mmol). The two batches were combined then poured into ice water (20 mL). The mixture was extracted with EtOAc (2 x 15 mL). The combined organic layers were dried over Na2SO4then concentrated in vacuo to give an orange gum. The gum was purified by column chromatography (silica gel, 0-50% EtOAc / hexane) to provide C74 (0.020 g, 14% yield) as a light-yellow solid. (LC / MS) m / z (M+H)+= 334.9.

[0592] Step 2. Preparation of 1-(4-chloro-2-fluorophenyl)-6-ethyl-7-methyl-3-(2-(1-methyl-1 / 7-pyrazol-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1 / 7)-one (16)

[0593] Under N2gas, to a solution of C74 (0.020 g, 0.060 mmol) and P26 (12 mg, 0.072 mmol) in DMSO (1 mL) was added PyBOP (62 mg, 0.12 mmol) and DIPEA (23 mg, 0.18 mmol). The reaction mixture was stirred at 50 °C for 18 h then quenched with 1 drop of H2O and diluted with MeOH. The solution was purified by reverse phase HPLC (Boston Prime C 150 mm x40 mm x 5 pm, H2O (0.05% NH4OH + 10 mM NH4HCO3) / MeCN, 50-70% MeCN in 10 min, flow rate = 60 mL / min) and lyophilized to form 16 (5.2 mg, 18% yield) as a white solid. (LC / MS) m / z (M+H)+= 484.2.1H NMR (400 MHz, (CD3)2SO) δ 7.77–7.71 (m, 2H), 7.60-7.48 (m, 2H), 7.46-7.43 (m, 1H), 5.05-4.77 (m, 2H), 4.62-4.57 (m, 1H), 4.04-3.97 (m, 1H), 3.83-3.79 (m, 3H), 3.78-3.70 (m, 1H), 3.27-3.26 (m, 2H), 2.83-2.75 (m, 2H), 2.33 (s, 3H), 1.26-1.19 (m, 3H).

[0594] Example 17

[0595] 1 -(4-Chloro-2,5-difluorophenyl)-6,7-dimethyl-3-(2-(1 -methyl-1 / - / -pyrazol-4- yl)morpholino)pyrazino[2,3-b]pyrazin-2(1 / - / )-one (17)

[0596]

[0597] Step 1. Preparation of A / 2-(4-chloro-2,5-difluorophenyl)-5,6-dimethylpyrazine-2,3-diamine (C75) A reaction mixture of 3-chloro-5,6-dimethylpyrazin-2-amine (CAS: 39213-71-3; 0.200 g, 1.27 mmol),4-chloro-2,5-difluoroaniline (CAS: 2613-30-1; 0.311 g, 1.90 mmol) and Cs2CO3(1.24 g, 3.81 mmol) in 1,4-dioxane (4 mL) was degassed with N2gas for 3 min. To the suspension was added / BuXPhos Pd G3 (71.9 mg, 0.0888 mmol) at room temperature under N2gas. The reaction mixture was stirred at 90 °C for 16 h then diluted with H2O (20 mL) and extracted with EtOAc (3 x20 mL). The combined organic layers were washed with brine (20 mL) then dried with Na2SO4and concentrated in vacuo to give a yellow gum. The gum was purified by column chromatography (silica gel, 0-40% EtOAc / hexane) to provide C75 (0.140 g, 38.8% yield) as a yellow solid. (LC / MS) m / z (M+H)+= 285.0.1H NMR (400 MHz, CDCI3) 6 8.06 (dd, 1H), 7.14 (dd, 1H), 6.29-6.22 (m, 1H), 4.27-4.09 (m, 2H), 2.39 (s, 3H), 2.36 (s, 3H).

[0598] Step 2. Preparation of 1-(4-chloro-2,5-difluorophenyl)-3-hydroxy-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1 / - / )-one (C76)

[0599] A solution of C75 (0.14 g, 0.49 mmol) and diethyl oxalate (CAS: 95-92-1; 2.0 mL) was degassed with N2gas for 1 min then stirred at 120 °C for 16 h. The suspension was filtered then the filter cake was washed with EtOAc (3 x2 mL). The filter cake was collected to provide C76 (95 mg, 57% yield) as a green solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 339.0.1H NMR (400 MHz, (CD3)2SO) 6 12.95-12.76 (m, 1H), 8.12-7.92 (m, 1 H), 7.76-7.57 (m, 1H), 2.47-2.40 (m, 3H), 2.35-2.25 (m, 3H).

[0600] Step 3. Preparation of 1-(4-chloro-2,5-difluorophenyl)-6,7-dimethyl-3-(2-(1-methyl-1 / 7-pyrazol-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1 / 7)-one (17)

[0601] Under N2gas, to a solution of C76 (95 mg, 0.28 mmol) and P26 (56 mg, 0.34 mmol) in DMSO (1.2 mL) was added PyBOP (0.29 g, 0.56 mmol) and DIPEA (0.11 g, 0.84 mmol). The reaction mixture was stirred at 50 °C for 16 h then purified by reverse phase HPLC (WePure Biotech XP tC 150 mm x40 mm x 7 pm, H2O (0.05% NH4OH) / MeCN, 45-65% MeCN in 10 min, flow rate= 60 mL / min) and lyophilized to form 17 (0.050 g, 37% yield) as a white solid. (LC / MS) m / z (M+H)+= 488.3.1H NMR (400 MHz, (CD3)2SO) 6 8.00 (dd, 1H), 7.80-7.73 (m, 2H), 7.45 (d, 1 H), 5.01-4.92 (m, 1H), 4.89-4.79 (m, 1 H), 4.61 (dd, 1 H), 4.05-3.98 (m, 1 H), 3.82 (s, 3H), 3.79-3.70 (m, 1 H), 3.29-3.21 (m, 2H), 2.48 (s, 3H), 2.34 (s, 3H).

[0602] Example 18

[0603] 5-(4-Chlorophenyl)-2,3-dimethyl-7-(2-(1 -methyl-1 / 7-pyrazol-4-yl)morpholino)pyrido[2,3- b]pyrazin-6(5 / - / )-one (18)

[0604]

[0605] Step 1. Preparation of 5-bromo-6-methoxy-3-nitropyridin-2-amine (C77)

[0606] To a solution of 6-methoxy-3-nitropyridin-2-amine (CAS: 73896-36-3; 10.0 g, 59.1 mmol) in AcOH (200 mL) was added NBS (11.6 g, 65.0 mmol). The reaction mixture was stirred at 65 °C for 1 h then concentrated in vacuo. The residue was suspended in H2O (100 mL) then filtered. The filter cake was collected to obtain C77 (9.00 g, 61.4% yield) as an orange solid. (LC / MS) m / z (M+H)+= 247.8.1H NMR (400 MHz, (CD3)2SO) 6 8.43 (s, 1H), 8.22 (s, 2H), 3.93 (s, 3H).

[0607] Step 2. Preparation of 5-bromo-6-methoxypyridine-2,3-diamine (C78)

[0608] The same reaction was conducted in two batches then combined for purification as follows: To a solution of C77 (8.00 g, 32.2 mmol) in EtOH (80 mL) and H2O (25 mL) was added NH4CI (13.8 g, 258 mmol) and Fe (14.4 g, 258 mmol) to form the first batch. The reaction mixture of the first batch was stirred at 50 °C for 1 h.

[0609] A second batch of the same reaction was conducted with C77 (1.00 g, 4.03 mmol). The batches were combined then filtered and the filtrate was concentrated in vacuo. The residue was washed with H2O (3 x200 mL) then extracted with EtOAc (2 x200 mL). The combined organic layers were dried with Na2SO4then concentrated in vacuo to provide C78 (7.50 g, 94.8% yield) as a black oil. (LC / MS) m / z (M+H)+= 217.9.

[0610] Step 3. Preparation of 7-bromo-6-methoxy-2,3-dimethylpyrido[2,3-b]pyrazine (C79) To a solution of C78 (3.00 g, 13.8 mmol) in EtOH (30 mL) was added 2,3-butanedione (CAS: 431-03-8; 1.40 g, 16.2 mmol) and AcOH (3.30 g, 55.0 mmol). The reaction mixture was stirred at 70 °C for 2 h then concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-50% EtOAc / petroleum ether) to provide C79 (3.10 g, 84.0% yield) as an orange solid. (LC / MS) m / z (M+H)+= 267.8.1H NMR (400 MHz, (CD3)2SO) 6 8.66 (s, 1 H), 4.08 (s, 3H), 2.66 (d, 6H).

[0611] Step 4. Preparation of 4-(6-methoxy-2,3-dimethylpyrido[2,3-b]pyrazin-7-yl)-2-(1-methyl-1 / 7-pyrazol-4-yl)morpholine (C80)

[0612] A reaction mixture of C79 (2.00 g, 7.46 mmol), P26 (1.31 g, 7.83 mmol), Cs2CO3(4.86 g, 14.9 mmol) and XPhos Pd G3 (0.631 g, 0.746 mmol) in 1,4-dioxane (50 mL) was stirred at 90 °C for 12 h. The solution was concentrated in vacuo then purified by column chromatography (silica gel, 0-10% EtOAc / hexane) to provide C80 (0.180 g, 68.1% yield) as a yellow solid. (LC / MS) m / z (M+H)+= 355.5.1H NMR (400 MHz, (CD3)2SO) 6 7.75 (s, 1H), 7.58 (s, 1 H), 7.46 (s, 1 H), 4.65 (dd, 1 H), 4.06 (s, 3H), 4.03-3.95 (m, 1H), 3.87-3.82 (m, 1H), 3.80 (s, 3H), 3.70-3.64 (m, 1 H), 3.58-3.52 (m, 1H), 2.93-2.81 (m, 2H), 2.61 (d, 6H).

[0613] Step 5. Preparation of 2,3-dimethyl-7-(2-(1-methyl-1 / 7-pyrazol-4-yl)morpholino)pyrido[2,3-b]pyrazin-6(5 / - / )-one (C81)

[0614] To a solution of C80 (1.70 g, 4.80 mmol) in AcOH (10.2 mL) was added 0.25M HCI in H2O (3.4 mL). The reaction mixture was stirred at 80 °C under N2gas for 2 h. The suspension was basified to pH=8 with 1N NaOH then extracted with n-BuOH (2 x 10 mL). The combined organic layers were concentrated in vacuo to give a yellow solid. The solid was washed with EtOAc (3 x 30 mL) then concentrated in vacuo to give a yellow solid. The solid was washed with DCM (3 x 30 mL) then concentrated in vacuo to provide C81 (1.30 g, 79.6% yield) as a yellow solid. (LC / MS) m / z (M+H)+= 341.1.1H NMR (400 MHz, (CD3)2SO) 6 7.71 (s, 1H), 7.41 (s, 1H), 6.94 (s, 1 H), 4.60-4.58 (m, 1 H), 4.04-3.86 (m, 2H), 3.79-3.72 (m, 5H), 2.76-2.66 (m, 2H), 2.42 (s, 6H).

[0615] Step 6. Preparation of 5-(4-chlorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1 / - / -pyrazol-4-yl)morpholino)pyrido[2,3-b]pyrazin-6(5 / - / )-one (18)

[0616] The same reaction was conducted in two batches then combined for purification as follows: A reaction mixture of C81 (0.050 g, 0.15 mmol), 1-chloro-4-iodobenzene (38 mg, 0.16 mmol) and K2CO3(51 mg, 0.37 mmol) in DMSO (1.5 mL) was degassed with N2gas for 3 min. To the suspension was added Cui (28 mg, 0.15 mmol) and 8-quinolinol (21 mg, 0.15 mmol) then degassed again with N2gas for 3 min to form the first batch. The suspension of the first batch was stirred at 120 °C for 3 h.

[0617] A second batch of the same reaction was conducted with C81 (0.020 g, 0.060 mmol). The two batches were combined then filtered and washed with MeOH (3 x 3 mL). The filtrate was concentrated in vacuo to form a brown oil. The oil was purified by reverse phase HPLC (Boston Prime C18150 mm x 30 mm x 5 μm, H2O (NH4OH-NH4HCO3) / MeCN, 43-63% MeCN over 10 min, 100% hold 2 min, flow rate= 35 mL / min) and lyophilized to provide 18 (4.5 mg, 6.8% yield) as a white solid. (LC / MS) m / z (M+H)+= 451.1.1H NMR (400 MHz, CD3OD) 6 7.68 (s, 1 H), 7.58-7.51 (m, 3H), 7.28-7.24 (m, 3H), 4.77 (dd, 1H), 4.08-4.02 (m, 1 H), 3.98-3.90 (m, 2H), 3.87 (s, 3H), 3.72-3.67 (m, 1 H), 3.05-2.89 (m, 2H), 2.56 (s, 3H), 2.40 (s, 3H).

[0618] Example 19

[0619] 5-Cyclohexyl-2,3-dimethyl-7-(2-(1-methyl-1 / 7-pyrazol-4-yl)morpholino)pyrido[2,3-b]pyrazin- 6(5 / 7)-one (19)

[0620]

[0621] Step 1. Preparation of 5-cyclohexyl-2,3-dimethyl-7-(2-(1-methyl-1 / - / -pyrazol-4-yl)morpholino)pyrido[2,3-b]pyrazin-6(5 / - / )-one (19)

[0622] To a reaction mixture of C81 (0.050 g, 0.15 mmol), cyclohexanol (22 mg, 0.22 mmol) and PPh3(77 mg, 0.29 mmol) in THF (1.5 mL) was added DIAD (89 mg, 0.44 mmol) slowly. The suspension was quenched with 1 drop of H2O then concentrated in vacuo. The residue was diluted with DMSO and MeOH then purified by reverse phase HPLC (Boston Prime C18150 mm x 40 mm x 5 μm, H2O (0.05% NH4OH +10mM NH4HCO3) / MeCN, 53-73% MeCN in 10 min, flow rate= 35 mL / min) and lyophilized to provide 19 (11 mg, 18% yield) as a white solid.

[0623] (LC / MS) m / z (M+H)+=423.3.1H NMR (400 MHz, (CD3)2SO) 6 7.74 (s, 1 H), 7.44 (s, 1H), 7.09 (s, 1H), 5.50-5.36 (m, 1H), 4.61 (dd, 1H), 3.98-3.84 (m, 2H), 3.82-3.73 (s, 4H), 3.69-3.63 (m, 1 H), 2.86-2.61 (m, 4H), 2.54 (s, 3H), 2.51-2.50 (m, 3H), 1.87-1.79 (m, 2H), 1.72-1.64 (m, 1 H), 1.59-1.51 (m, 2H), 1.43-1.18 (m, 3H).

[0624] Example 20

[0625] 4-(4-Chloro-2-fluorophenyl)-6,7-dimethyl-2-(2-(1-methyl-1 / 7-pyrazol-4-yl)morpholino)pyrido[2,3- b]pyrazin-3(4 / - / )-one trifluoroacetate (20)

[0626]

[0627] Step 1. Preparation of 3-bromo-N-(4-chloro-2-fluorophenyl)-5,6-dimethylpyridin-2-amine (C82) A reaction mixture of 3-bromo-5,6-dimethylpyridin-2-amine (CAS: 161091-49-2, 0.300 g, 1.49 mmol), Cs2CO3(0.729 g, 2.24 mmol) and XantPhos Pd G3 (0.142 g, 0.149 mmol) was put under high vacuum then degassed with N2gas (3x). To the reaction mixture was added toluene (10 mL) and 4-chloro-2-fluoro-1-iodobenzene (CAS: 6797-79-1; 0.421 g, 1.64 mmol). The suspension was stirred at 90 °C for 17 h then cooled to room temperature and extracted with EtOAc (3x). The combined organic layers were dried with MgSO4then filtered and concentrated in vacuo to give a yellow oil. The oil was purified by column chromatography (silica gel, 0-80% EtOAc / heptane.) to provide C82 (0.285 g, 58.0% yield) as an orange solid. (LC / MS) m / z (M+H)+= 331.3.1H NMR (400 MHz, CDCl3) δ 8.64–8.57 (m, 1 H), 7.50 (s, 1 H), 7.15-7.08 (m, 3H), 2.40 (s, 3H), 2.19 (s, 3H).

[0628] Step 2. Preparation of tert-butyl (2-((4-chloro-2-fluorophenyl)amino)-5,6-dimethylpyridin-3-yl)carbamate (C83)

[0629] A mixture of C82 (0.240 g, 0.728 mmol), Cs2CO3(0.593 g, 1.82 mmol) and XPhos Pd G3 (0.123 g, 0.146 mmol) was put under high vacuum then degassed with N2gas (3x). To the reaction mixture was added toluene (3.64 mL) and tert-butyl carbamate (CAS: 4248-19-5; 0.256 g, 2.18 mmol). The suspension was stirred at 120 °C for 6 h before another portion of Cs2CO3(0.593 g, 1.82 mmol), XPhos Pd G3 (61.6 mg, 72.8 μmol) and tert-butyl carbamate (CAS: 4248-19-5; 0.128 g, 1.09 mmol) were added. The reaction mixture was stirred at 120 °C for 1 h then stirred at room temperature for 16 h. The suspension was diluted with H2O then extracted with EtOAc (3x). The combined organic layers were dried with MgSO4then filtered and concentrated in vacuo to give a black oil. The oil was diluted with DCM and purified by column chromatography (silica gel, 0-50% EtOAc / heptane) to provide C83 (89.0 mg, 33.5% yield) as a gray solid. (LC / MS) m / z (M+H)+= 366.3.1H NMR (400 MHz, CDCl3) 67.97-7.88 (m, 1H), 7.51- 7.38 (m, 1H), 7.07 (dd, 1H), 7.05-6.99 (m, 1H), 6.71 (d, 1H), 6.25-6.14 (m, 1H), 2.40 (s, 3H), 2.21 (s, 3H), 1.51 (s, 9H). Step 3. Preparation of N2-(4-chloro-2-fluorophenyl)-5,6-dimethylpyridine-2,3-diamine (C84) To a solution of C83 (89 mg, 0.24 mmol) in DCM (1.2 mL) was added TFA (1.2 mL). The reaction mixture was stirred at room temperature for 2 h then concentrated in vacuo to provide C84 (0.11 g, >95% yield) as a brown oil. The oil was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 267.3.

[0630] Step 4. Preparation of ethyl 2-((2-((4-chloro-2-fluorophenyl)amino)-5,6-dimethylpyridin-3-yl)amino)-2-oxoacetate (C85)

[0631] At 0 °C, to a reaction mixture of C84 (64 mg, 0.24 mmol) in DCE (2.4 mL) and DIPEA (0.16 g, 1.2 mmol) was added ethyl 2-chloro-2-oxoacetate (36 mg, 0.26 mmol). The brown solution was stirred at room temperature for 2 h and 45 min then was quenched with MeOH (1 mL). The quenched solution was concentrated in vacuo to provide C85 (88 mg, >95% yield) as a residue. The residue was used directly in the next step without further purification.

[0632] Step 5. Preparation of 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2, 3-dione (C86)

[0633] In a microwave vial, to a solution of C85 (88 mg, 0.24 mmol) in MeCN (2.4 mL) was added AcOH (0.29 g, 4.8 mmol). The reaction mixture was stirred at 150 °C in a microwave for 1 h then concentrated in vacuo. The residue was dissolved in toluene (3 mL) then concentrated in vacuo (3x). The residue was purified by column chromatography (silica gel, 0-10% MeOH / DCM) to provide C86 (54 mg, 70% yield) as a tan solid. (LC / MS) m / z (M+H)+= 320.4. 1H NMR (400 MHz, CDCl3) δ 12.04 (s, 1H), 7.52 (s, 1H), 7.34-7.28 (m, 2H), 2.28 (d, 6H).

[0634] Step 6. Preparation of 2-chloro-4-(4-chloro-2-fluorophenyl)-6,7-dimethylpyrido[2,3-b]pyrazin-3(4H)-one (C87)

[0635] To a reaction mixture of C86 (54 mg, 0.17 mmol) in DCE (1.7 mL) and DMF (0.01 mL) was added SOCI2(0.20 g, 1.7 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 1 h then was cooled to room temperature and concentrated in vacuo. To the residue was added toluene then concentrated in vacuo (3x) to provide C87 (57 mg, >95% yield) as an orange solid. The solid was used directly in the next step without further purification.

[0636] Step 7. Preparation of 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-(2-(1-methyl-1 / 7-pyrazol-4-yl)morpholino)pyrido[2,3-b]pyrazin-3(4H)-one trifluoroacetate (20)

[0637] To a solution of C87 (57 mg, 0.17 mmol) in MeCN (1.7 mL) was added P26 (57 mg, 0.34 mmol) followed by DIPEA (44 mg, 0.34 mmol). The solution was stirred at 50 °C for 1.5 h then concentrated in vacuo. The residue was suspended in DMSO (1 mL), filtered and purified by reverse phase HPLC (Sunfire C18100 mm x 19 mm x 5 μm, H2O (0.05% TFA) / MeCN (0.05% TFA), 15-55% MeCN over 9 min, 95% hold 1 min, flow rate= 25 mL / min) to provide 20 (51 mg, 64% yield). (LC / MS) m / z (M+H)+=469.4;1H NMR (600 MHz, (CD3)2SO) δ 7.75–7.69 (m, 3H), 7.59-7.47 (m, 2H), 7.43 (s, 1 H), 4.77 (m, 1H), 4.65 (d, 1 H), 4.60 (m, 1H), 3.98 (m, 1 H), 3.82 (s, 3H), 3.74 (m, 1H), 3.26-3.08 (m, 2H), 2.27 (s, 3H), 2.25 (s, 3H).

[0638] Example 21

[0639] 1-(4-Chloro-2-fluorophenyl)-6,7-dimethyl-3-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[2,3-b]pyrazin-2(1H)-one (21)

[0640]

[0641] Step 1. Preparation of N3-(4-chloro-2-fluorophenyl)-5,6-dimethylpyridine-2,3-diamine (C88) A reaction mixture of 3-bromo-5,6-dimethylpyridin-2-amine (CAS: 161091-49-2, 0.10 g, 0.50 mmol), 4-chloro-2-fluoroaniline (CAS: 57946-56-2; 0.11 g, 0.75 mmol), Cs2CO3(0.49 g, 1.5 mmol) in 1,4-dioxane (2.5 mL) was degassed with N2gas for 5 min. To the suspension was added XPhos Pd G3 (42 mg, 0.050 mmol) then stirred at 90 °C for 20 h. The suspension was cooled to room temperature then concentrated by N2gas. The residue was purified by column chromatography (silica gel, 10-100% EtOAc / heptane) to provide C88 (0.050 g, 38% yield). Step 2. Preparation of 1-(4-chloro-2-fluorophenyl)-6,7-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2, 3-dione (C89)

[0642] At 0 °C, to a solution of C88 (25 mg, 0.094 mmol) in DCM (1 mL) was added TEA (0.020 g, 0.20 mmol) then 2M oxalyl chloride in DCM (52 pL). The reaction mixture was warmed to room temperature and stirred for 2 h then set aside overnight. Another portion of TEA (0.020 g, 0.20 mmol) then 2M oxalyl chloride in DCM (52 pL) were added then stirred overnight. The suspension was diluted with H2O then extracted with EtOAc. The organic layer was dried with Na2SO4, filtered and concentrated in vacuo to provide C89 (0.020 g, 66% yield) as a gum. The gum was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 320.2. Step 3. Preparation of 3-chloro-1-(4-chloro-2-fluorophenyl)-6,7-dimethylpyrido[2,3-b]pyrazin-2(1H)-one (C90)

[0643] To a solution of C89 (0.020 g, 0.063 mmol) in DCE (0.3 mL) and DMF (2.0 pL) was added SOCI2(74 mg, 0.63 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 1.5 h then was concentrated in vacuo to form C90 (0.021 mg, >95% yield) as a gum. The gum was used directly in the next step without further purification.

[0644] Step 4. Preparation of 1-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[2,3-b]pyrazin-2(1H)-one (21)

[0645] To a solution of C90 (21 mg, 0.062 mmol) in MeCN (0.5 mL) was added P26 (13 mg, 0.075 mmol) followed by DIPEA (24 mg, 0.19 mmol). The solution was stirred at 50 °C for 2 h then concentrated in vacuo. The residue was purified by reverse phase HPLC (Sunfire C18100 mm x 19 mm x 5 μm, H2O (0.05% TFA) / MeCN (0.05% TFA), 70-80% MeCN over 9 min, 95% hold 1 min, flow rate= 25 mL / min) to provide 21 (4.8 mg, 16% yield). (LC / MS) m / z (M+H)+= 469.5.

[0646] Example 22

[0647] 1-(4-Chloro-2-fluorophenyl)-7-ethyl-6-methyl-3-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1H)-one (22)

[0648]

[0649] Step 1. Preparation of 5-methyl-6-vinylpyrazin-2-amine (C91)

[0650] To a solution of 6-bromo-5-methylpyrazin-2-amine (CAS: 74290-68-9; 3.89 g, 20.7 mmol), CsF (9.43 g, 62.1 mmol) and vinylboronic acid pinacol ester (CAS: 75927-49-0; 4.78 g, 31.0 mmol) in 1,4-dioxane (36 mL) and H2O (18 mL) was added PdCI2(PPh3)2(1.45 g, 2.07 mmol). The reaction mixture was stirred for 16 h at 80 °C under N2gas then concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-20% EtOAc / heptane) to provide C91 (3.70 g, 70.0% yield, 53% Purity) as a light-yellow oil. (LC / MS) m / z (M+H)+= 136.1.

[0651] Step 2. Preparation of 6-ethyl-5-methylpyrazin-2-amine (C92)

[0652] Under N2gas, to a solution of C91 (3.7 g, 15 mmol) in MeOH (41 mL) was added Pd / C (0.77 g, 10 wt%, 0.73 mmol). The reaction mixture was stirred under hydrogen pressure for 3 h then filtered through Celite. The filtrate was concentrated in vacuo then purified by column chromatography (silica gel, 0-20% MeOH / DCM) to provide C92 (2.2 g, >95% yield) as a lightyellow solid. (LC / MS) m / z (M+H)+= 138.1.

[0653] Step 3. Preparation of 3-bromo-6-ethyl-5-methylpyrazin-2-amine (C93)

[0654] At 0 °C, to a solution of C92 (1.29 g, 8.46 mmol) in DMF (28.2 mL) was added NBS (1.51 g, 8.46 mmol) portion-wise. The reaction solution was stirred at 0 °C for 72 h then poured into H2O (70 mL). The reaction mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with a solution of sodium thiosulfate, 3% LiCI and brine. The organic layer was dried with Na2SO4, filtered the concentrated in vacuo to give a dark powder. The powder was dissolved in DCM and purified by column chromatography (silica gel, 0-20% EtOAc / heptane) to provide C93 (0.647 g, 35.4% yield) as a yellow crystalline solid. (LC / MS) m / z (M+H)+= 216.1.1H NMR (400 MHz, CDCl3) δ 4.81 (s, 2H), 2.73-2.58 (q, 2H), 2.40-2.39 (m, 3H), 1.24-1.19 (m, 3H).

[0655] Step 4. Preparation of 3-bromo-N-(4-chloro-2-fluorophenyl)-6-ethyl-5-methylpyrazin-2-amine (C94)

[0656] A solution of C93 (0.426 g, 1.97 mmol) and 4-chloro-2-fluoro-1-iodobenzene (CAS: 6797-79-1; 1.01 g, 3.94 mmol) in toluene (9.9 mL) was degassed with N2gas then XantPhos Pd G4 (37.9 mg, 0.0394 mmol) and NaOtBu (0.473 g, 4.93 mmol) were added. The reaction mixture was stirred at 70 °C for 16 h then cooled to room temperature. The suspension was poured into H2O (30 mL) then extracted with EtOAc (3 x 50 mL). The combined organic layers were dried with Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in DCM then purified by column chromatography (silica gel, 0-20% EtOAc / heptane) to provide C94 (0.265 g, 39.0 %) as a yellow solid. (LC / MS) m / z (M+H)+= 346.1.

[0657] Step 5. Preparation of N-(4-chloro-2-fluorophenyl)-3-((diphenylmethylene)amino)-6-ethyl-5-methylpyrazin-2-amine (C95)

[0658] A reaction mixture of C94 (0.230 g, 0.667 mmol), benzophenone imine (CAS: 1013-88-3; 0.121 g, 0.667 mmol) and Cs2CO3(0.652 g, 2.00 mmol) in 1,4-dioxane (3.3 mL) was degassed with N2gas before Pd2(dba)3(42.8 mg, 0.0467 mmol) and Xantphos (27.0 mg, 0.467 mmol) were added. The reaction mixture was degassed with N2gas (3x) then stirred at 90 °C for 16 h. The suspension was filtered through a silica gel pad then the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-20% EtOAc / heptane) to provide C95 (0.265 g, 89.1% yield) as a dark yellow solid.

[0659] Step 6. Preparation of N2-(4-chloro-2-fluorophenyl)-6-ethyl-5-methylpyrazine-2,3-diamine (C96) To a solution of C95 (0.264 g, 0.595 mmol) in EtOAc (3.8 mL) was added 1M HCI (3.8 mL). The reaction mixture was stirred at room temperature for 49 h then basified slowly with 1 M Na2CO3to pH=8. The suspension was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried with Na2SO4and concentrated in vacuo to give an off-white solid. The solid was purified by column chromatography (silica gel, 0-20% EtOAc / heptane) to provide C96 (0.134 g, 80.2% yield) as an off-white solid. (LC / MS) m / z (M+H)+= 281.1.

[0660] Step 7. Preparation of 1-(4-chloro-2-fluorophenyl)-7-ethyl-6-methyl-1,4-dihydropyrazino[2,3-b]pyrazine-2, 3-dione (C97)

[0661] Under N2gas, a solution of C96 (0.134 g, 0.477 mmol) in diethyl oxalate (CAS: 95-92-1; 1.9 mL) was stirred at 120 °C overnight. The reaction mixture was cooled to room temperature and EtOAc was added which resulted in precipitation of solids. The suspension was filtered then the filter cake was washed with EtOAc. The filter cake was collected to provide C97 (0.118 g, 73.8% yield) as an off-white solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 335.2.

[0662] Step 8. Preparation of 1-(4-chloro-2-fluorophenyl)-7-ethyl-6-methyl-3-(2-(1-methyl-1 / 7-pyrazol-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1 / 7)-one (22)

[0663] Under N2gas, to a solution of C97 (0.12 g, 0.35 mmol) and P26 (71 mg, 0.42 mmol) in DMSO (3.6 mL) was added PyBOP (0.37 g, 0.70 mmol) and DIPEA (0.14 g, 1.1 mmol). The solution was stirred at 50 °C for overnight then filtered. The filter cake was washed with DMSO. The filtrate was purified twice by reverse phase HPLC (C18, H2O (2% MeCN) / MeCN, 25-95% MeCN over 25 min, 95% hold 5 min, flow rate= 30 mL / min) to provide 22 (0.070 g, 41% yield) as a light-yellow solid. (LC / MS) m / z (M+H)+=484.2.1H NMR (400 MHz, CDCl3) 67.48 (s, 1H), 7.39 (s, 1H), 7.36-7.18 (m, 4H), 5.24-5.18 (m, 1H), 5.03 (s, 1H), 4.65 (dt, 1H), 4.09-4.00 (m, 1H), 3.80-3.88 (m, 4H), 3.46-3.21 (m, 2H), 2.74-2.63 (m, 2H), 2.56 (s, 3H), 1.04 (t, 3H). Example 23

[0664] 1-(4-Chloro-2-fluorophenyl)-7-methoxy-6-methyl-3-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1H)-one (23)

[0665]

[0666]

[0667] Step 1. Preparation of 5-bromo-6-methoxypyrazin-2-amine (C98)

[0668] Under N2gas, to 5-bromo-6-methoxypyrazin-2-amine (CAS: 1245649-92-6; 3.0 g, 15 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (CAS: 823-96-1; 7.4 g, 50 wt%, 29 mmol) in 1,4-dioxane (50 mL) were added K2CO3(4.1 g, 29 mmol) and Pd(dppf)CI2(2.4 g, 2.9 mmol). The reaction mixture was stirred at 100 °C overnight then was diluted with H2O (10 mL). The suspension was extracted with DCM (20 mL) then the organic layer was washed with H2O (2x). The organic layer was dried with Na2SO4, filtered then concentrated in vacuo to give a red oil. The oil was dissolved in DCM and purified by column chromatography (silica gel, 0-20% MeOH / DCM) to provide C98 (2.0 g, >95% yield).

[0669] Step 2. Preparation of 3-bromo-6-methoxy-5-methylpyrazin-2-amine (C99)

[0670] At 0 °C, to a solution of C98 (2.0 g, 14 mmol) in DMF (48 mL) was added NBS (2.6 g, 14 mmol) portion-wise. The reaction solution was warmed to room temperature and stirred for 15 h then quenched with 1 M sodium thiosulfate (50 mL). The suspension was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried with Na2SO4, filtered then concentrated in vacuo to give a brown oil. The oil was dissolved in DCM and purified by column chromatography (silica gel, 0-20% MeOH / DCM) to provide C99 (2.1 g, 68% yield) as a yellow oil. (LC / MS) m / z (M+H)+= 218.0. Step 3. Preparation of 3-bromo-N-(4-chloro-2-fluorophenyl)-6-methoxy-5-methylpyrazin-2-amine (C100)

[0671] The same procedure was followed from Example 22, step 4 with C99 (0.330 g, 1.51 mmol) to provide C100 (0.225 g, 42.9% yield) as a yellow solid.

[0672] Step 4. Preparation of N-(4-chloro-2-fluorophenyl)-3-((diphenylmethylene)amino)-6-methoxy-5-methylpyrazin-2-amine (C101)

[0673] The same procedure was followed from Example 22, step 5 with C100 (0.225 g, 0.649 mmol) to provide C101 (0.503 g, 68.8% yield) as an orange solid. (LC / MS) m / z (M+H)+= 447.3.

[0674] Step 5. Preparation of N2-(4-chloro-2-fluorophenyl)-6-methoxy-5-methylpyrazine-2,3-diamine (C102)

[0675] The same procedure was followed from Example 22, step 6 with C101 (0.503 g, 1.13 mmol) to provide C102 (0.113 g, >95% yield) as an orange solid. (LC / MS) m / z (M+H)+= 283.1. Step 6. Preparation of 1-(4-chloro-2-fluorophenyl)-7-methoxy-6-methyl-1,4-dihydropyrazino[2,3-b]pyrazine-2, 3-dione (C103)

[0676] The same procedure was followed from Example 22, step 7 with C102 (0.133 g, 0.470 mmol) to provide C103 (0.076 g, 48% yield) as a solid. The solid was used directly in the next step without further purification. (LC / MS) m / z (M+H)+= 337.2.

[0677] Step 7. Preparation of 1-(4-chloro-2-fluorophenyl)-7-methoxy-6-methyl-3-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1H)-one (23)

[0678] Under N2gas, to a solution of C103 (76 mg, 0.27 mmol) and P26 (45 mg, 0.27 mmol) in DMSO (2.3 mL) was added PyBOP (0.23 g, 0.45 mmol) and DIPEA (88 mg, 0.68 mmol). The solution was stirred at 50 °C for overnight then filtered. The filter cake was washed with DMSO. The filtrate was purified by reverse phase HPLC (C18, NH4HCO3 / MeCN, 30-95% MeCN over 20 min, 95% hold 10 min, flow rate = 30 mL / min) to provide 23 (0.081 g, >95% yield) as a yellow solid. (LC / MS) m / z (M+H)+=486.2.1H NMR (400 MHz, (CD3)2SO) δ 7.77–7.71 (m, 2H), 7.62 (td, 1H), 7.51 (dd, 1H), 7.43-7.42 (m, 1H), 4.81 (d, 1H), 4.67 (d, 1 H), 4.59 (dt, 1 H), 4.01-3.95 (m, 1H), 3.81 (s, 3H), 3.74 (tt, 1 H), 3.59 (s, 3H), 3.28-3.11 (m, 2H), 2.38 (s, 3H).

[0679] Example 97

[0680] 1-(4-Chloro-2-fluorophenyl)-3-(2-(1,1-dioxidothiochroman-6-yl)morpholino)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1H)-one (97)

[0681]

[0682] Step 1. Preparation of 4-(4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-oxo-3,4-dihydropyrazino[2,3-b]pyrazin-2-yl)morpholine-2-carboxylic acid (C104)

[0683] To a solution of C45 (1.40 g, 4.13 mmol) in MeCN (10.3 mL) was added DIPEA (1.60 g, 12.4 mmol) and morpholine-2-carboxylic acid hydrochloride (CAS: 878010-24-3; 1.04 g, 6.19 mmol). The solution was stirred at room temperature for 17 h then diluted with H2O (20 mL). The suspension was extracted with EtOAc (1 x 30 mL, 1 x20 mL) then 10% MeOH: DCM (20 mL). The combined organic layer was dried with Na2SO4and concentrated in vacuo to provide C104 (2.11 g, crude). (LC / MS) m / z (M+H)+=434.4;1H NMR (400 MHz, (CD3)2SO) δ 12.5 (br s, 1 H), 7.78-7.70 (m, 1 H), 7.61-7.47 (m, 2H), 4.83-4.76 (m, 1 H), 4.50 (s, 1 H), 4.13-4.09 (m, 1 H), 3.99 (d, 1 H), 3.69-3.60 (m, 1H), 3.54-3.44 (m, 1H), 3.33-3.29 (m, 1H), 2.81-2.77 (m, 1 H), 2.47 (s, 3H), 2.31 (s, 3H).

[0684] Step 2. Preparation of 1-(4-chloro-2-fluorophenyl)-3-(2-(1,1-dioxidothiochroman-6-yl)morpholino)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1H)-one (97)

[0685] To a reaction mixture of C104 (0.030 g, 0.069 mmol), 6-bromothiochromane 1,1-dioxide (CAS: 1784147-12-1; 0.020 g, 0.076 mmol), NiBr2·glyme (1.1 mg, 3.5 pmol), 4,4'-di-terf-butyl-2,2'-dipyridyl (1.1 mg, 4.1 pmol), (lr[dF(CF3)ppy]2(dtbpy))PF6(0.68 mg, 0.69 pmol) and phthalimide (CAS: 85-41-6; 0.010 g, 3.5 pmol) in DMSO (1.0 mL) was added TMG (16 mg, 0.14 mmol). The suspension was degassed with N2gas for 15 min. The reaction vessel was sealed then irradiated with a photoreactor (fan speed: 5320 r / min; stirred speed: 1500 r / min; 100% 450 nm LED) and stirred at room temperature for ~16 h. The reaction mixture concentrated via flow of N2to half the volume then filtered. The filtrate was purified by reverse phase HPLC (Sunfire C18100 mm x 19 mm x 5 μm, H2O (0.05% TFA) / MeCN (0.05% TFA), 20-60% MeCN over 10 min, flow rate = 25 mL / min) to provide 97 (4.4 mg, 11% yield). (LC / MS) m / z (M+H)+= 570.3.

[0686] Example 100

[0687] 1-(4,4-Difluorocyclohexyl)-6,7-dimethyl-3-(2-(2-methylpyridin-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1H)-one (100)

[0688]

[0689] Step 1. Preparation of N2-(4,4-difluorocyclohexyl)-5,6-dimethylpyrazine-2,3-diamine (C105) The same procedure was followed from Example 8 and 9, step 1 with 3-chloro-5,6-dimethylpyrazin-2-amine (CAS: 39213-71-3; 0.50 g, 3.2 mmol) and 4,4-difluorocyclohexan-1-amine (CAS: 458566-84-2; 0.51 g, 3.8 mmol). The work-up and purification were altered. The reaction mixture was quenched with NH4CI (15 mL) then diluted with EtOAc and stirred at room temperature for 1 h. The aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine, dried with MgSO4, filtered and concentrated under a stream of N2gas. The residue was purified by column chromatography (silica gel, 0-10% MeOH: DCM) to provide C105 (0.40 g, 50% yield) as a brown gum. (LC / MS) m / z (M+H)+= 257.1.1H NMR (400 MHz, (CD3)2SO) δ 5.52 (s, 2H), 5.46 (d, 1H), 3.97-3.81 (m, 1H), 2.05 (s, 3H), 2.01 (s, 3H), 1.94-1.77 (m, 6H), 1.52-1.40 (m, 2H).

[0690] Step 2. Preparation of 1 -(4,4-difluorocyclohexyl)-6,7-dimethyl-1,4-dihydropyrazino[2,3-b]pyrazine-2, 3-dione (C106)

[0691] A solution of C105 (0.40 g, 1.6 mmol) in diethyl oxalate (CAS: 95-92-1; 4.0 mL) was degassed with N2gas for 1 min. The reaction mixture was stirred at 80 °C for 16 h then 120 °C for 6 h. The suspension was filtered then washed with (1:10, EtOAc: hexane, 3 x2 mL). The filtrate was concentrated in vacuo then purified by column chromatography (silica gel, 1:10, MeOH: DCM) to provide C106 (0.21 g, 53% yield) as a brown solid. (LC / MS) m / z (M+H)+= 311.0.

[0692] Step 3. Preparation of 3-chloro-1-(4,4-difluorocyclohexyl)-6,7-dimethylpyrazino[2,3-b]pyrazin- 2(1H)-one (C107) To a solution of C106 (0.10 g, 0.29 mmol) in DCE (3.0 mL) and DMF (0.2 mL) was added SOCI2(0.34 g, 2.9 mmol) at room temperature. The reaction mixture was stirred at 40 °C for 2 h then stirred at room temperature for ~24 h and concentrated in vacuo. To the residue was added (1:10, EtOAc: heptane, 10 mL) then stirred for 30 min. and filtered. The filter cake was collected to provide C107 (0.080 g, 84% yield) as a brown solid. (LC / MS) m / z (M+H)+ = 328.9.

[0693] Step 4. Preparation of 1-(4,4-difluorocyclohexyl)-6,7-dimethyl-3-(2-(2-methylpyridin-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1 / 7)-one (100)

[0694] To a reaction mixture of C107 (0.040 g, 0.12 mmol), 4A molecular sieves (0.10 g), P32 (29 mg, 0.13 mmol) in MeCN (1 mL) was added DIPEA (0.11 g, 0.85 mmol). The reaction mixture was stirred at 50 °C for 1.5 h then quenched with 1 drop of H2O. The suspension was purified by reverse phase HPLC (Boston Prime C18150 mm x 40 mm x 5 μm, H2O (0.05% NH4OH + 10 mM NH4HCO3) / MeCN, 48-68% MeCN in 10 min, flow rate: 35 mL / min) and lyophilized to provide 100 (27 mg, 47% yield) as a white solid. (LC / MS) m / z (M+H)+ = 471.3.1H NMR (400 MHz, (CD3)2SO) 6 8.47 (d, 1H), 7.30 (s, 1 H), 7.22 (d, 1H), 5.46-5.42 (m, 1 H), 5.07-4.79 (m, 2H), 4.68 (dd, 1H), 4.17-4.08 (m, 1 H), 3.87-3.76 (m, 1H), 3.31-3.19 (m, 1H), 3.02 (dd, 1H), 2.94-2.87 (m, 2H), 2.53-2.52 (m, 6H), 2.49 (s, 3H), 2.22-1.95 (m, 4H), 1.73 (d, 2H).

[0695] Example 103

[0696] 1-(4-Chloro-2-fluorophenyl)-6,7-dimethyl-3-(2-(phthalazin-6-yl)morpholino)pyrazino[2,3- b]pyrazin-2(1 / 7)-one (103)

[0697]

[0698] Step 1. Preparation of 1,3-dioxoisoindolin-2-yl 4-(4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-oxo-3, 4-dihydropyrazino[2,3-b]pyrazin-2-yl)morpholine-2-carboxylate (C108)

[0699] A reaction mixture of C104 (0.200 g, 0.461 mmol), 2-hydroxyisoindoline-1,3-dione (CAS: 19064-74-5; 75.2 mg, 0.461 mmol), EDCI (97.2 mg, 0.507 mmol) and DMAP (5.63 mg, 46.1 pmol) in DCM (2.3 mL) was stirred at room temperature for 18 h then poured into 10% citric acid (10 mL) and extracted with DCM. The organic layer was washed with NaHCO3which caused precipitate to form in the organic layer. The organic layer was filtered, and the filter cake was collected to provide C108 (0.242 g, 90.8% yield) as a solid. (LC / MS) m / z (M+H)+=579.2;1H NMR (400 MHz, (CD3)2SO) 68.06-7.89 (m, 4H), 7.78-7.70 (m, 1 H), 7.60-7.48 (m, 2H), 5.17-5.06 (m, 1 H), 4.89-4.75 (m, 1H), 4.48-4.24 (m, 1H), 4.22-3.98 (m, 2H), 3.94-3.79 (m, 1H), 3.74-3.51 (m, 1H), 3.30-3.28 (m, 3H), 2.34-2.30 (m, 3H).

[0700] Step 2. Preparation of 1-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(2-(phthalazin-6-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1 / 7)-one (103)

[0701] A reaction mixture of 6-bromophthalazine (CAS: 19064-74-5; 18 mg, 86 pmol), C108 (0.050 g, 86 pmol), 5-methylpicolinimidamide hydrochloride (CAS: 875293-96-2; 16 mg, 86 pmol), NiCI2.glyme (19 mg, 86 pmol) and zinc (56 mg, 0.86 mmol) was degassed with N2gas (3x). The mixture was suspended in DMA (0.17 mL) then stirred at room temperature for 1.5 h. The reaction mixture was diluted with EtOAc then filtered. The filter cake was washed with EtOAc and MeOH. The filtrate was concentrated in vacuo. The residue was purified by reverse phase HPLC (Sunfire C18100 mm x 19 mm x 5 μm, H2O (0.05% TFA) / MeCN (0.05% TFA), 25-95% MeCN over 10 min, flow rate = 25 mL / min) to provide 103 (1.8 mg, 4.0% yield). (LC / MS) m / z (M+H)+= 518.2.

[0702] Example 110

[0703] 1-(4-Chloro-2-fluorophenyl)-6,7-dimethyl-3-(2-(1-methyl-1 / 7-pyrazol-4-yl)tetrahydro-2 / 7-pyran-4- yl)pyrazino[2,3-b]pyrazin-2(1 / - / )-one (racemic, cis) (110)

[0704]

[0705] racemic mixture

[0706] of cis isomers

[0707] Step 1. Preparation of 1-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(2-(1-methyl-1 / 7-pyrazol-4-yl)tetrahydro-2 / 7-pyran-4-yl)pyrazino[2,3-b]pyrazin-2(1 / - / )-one (racemic, cis) (110)

[0708] Under N2gas, a reaction mixture of C49 (50 mg, 0.19 mmol), P31 (71 mg, 0.19 mmol), and AcOH (56 mg, 0.94 mmol) in EtOH (0.5 mL) was stirred at 120 °C for 5 h in a microwave reactor. The suspension was then concentrated in vacuo. The brown gum was purified by reverse phase HPLC (WePure Biotech XP tC18150 mm x 40 mm x 7 μm column; Mobile Phase A: H2O (0.05% NH4OH and 10 mM NH4HCO3) / Mobile Phase B: MeCN; gradient: 45-75% of Mobile Phase B over 10 min; flow rate: 60 mL / min) then lyophilized to provide 110 (14 mg, 16%) as a white solid. (LC / MS) m / z (M+H)+= 469.2.1H NMR (400 MHz, (CD3)2SO) 6 7.80-7.75 (m, 1 H), 7.66 (s, 1H), 7.62-7.51 (m, 2H), 7.38 (s, 1H), 4.50 (d, 1H), 4.11-4.03 (m, 1H), 3.79 (s, 3H), 3.74-3.56 (m, 2H), 2.67-2.53 (m, 3H), 2.43 (s, 3H), 2.12 (d, 1H), 2.00-1.74 (m, 3H).

[0709] Example 112

[0710] 1-(4-Chloro-2-fluorophenyl)-3-((2S,4R)-2-(1-cyclopropyl-1 / 7-pyrazol-4-yl)tetrahydro-2 / 7-pyran-4- yl)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1 / - / )-one (racemic, cis) (112)

[0711]

[0712] racemic mixture

[0713] of cis isomers

[0714] Step 1. Preparation of 1-(4-chloro-2-fluorophenyl)-3-((2S,4R)-2-(1-cyclopropyl-1 / 7-pyrazol-4-yl)tetrahydro-2 / 7-pyran-4-yl)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1 / 7)-one (racemic, cis)

[0715] Under N2gas, a reaction mixture of C49 (50 mg, 0.19 mmol), P30 (82 mg, 0.28 mmol), and AcOH (34 mg, 0.56 mmol) in EtOH (0.5 mL) was stirred at 120 °C for 6 h in a microwave reactor. The suspension was then concentrated in vacuo. The brown gum was purified by reverse phase HPLC (WePure Biotech XP tC18150 mm x 40 mm x 7 μm column; Mobile Phase A: H2O (0.05% NH4OH and 10 mM NH4HCO3) / Mobile Phase B: MeCN; gradient: 24-54% of Mobile Phase B over 15 min; flow rate: 60 mL / min) then lyophilized to provide 112 (25 mg, 27%) as a white solid. (LC / MS) m / z (M+H)+= 495.2.1H NMR (400 MHz, (CD3)2SO) 6 7.80-7.75 (m, 1H), 7.73 (s, 1 H), 7.63-7.50 (m, 2H), 7.37 (s, 1H), 4.48 (d, 1 H), 4.13-4.02 (m, 1H), 3.75-3.54 (m, 3H), 2.60-2.52 (m, 3H), 2.43 (s, 3H), 2.16-2.06 (m, 1 H), 1.93-1.71 (m, 3H), 1.05-0.85 (m, 4H).

[0716] Example 113 and 114

[0717] 1-(4-Chloro-2-fluorophenyl)-3-((2S,4R)-2-(1-cyclopropyl-1 / 7-pyrazol-4-yl)tetrahydro-2 / 7-pyran-4- yl)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1 / 7)-one and 1 -(4-Chloro-2-fluorophenyl)-3-((2R,4S)-2- (1-cyclopropyl-1 / 7-pyrazol-4-yl)tetrahydro-2 / 7-pyran-4-yl)-6,7-dimethylpyrazino[2,3-b]pyrazin- 2(1H)-one (113 and 114) (single stereoisomer, absolute stereochemical configuration not determined)

[0718]

[0719] single stereoisomers, absolute stereochemical configurations not determined Step 1. Preparation of 1-(4-chloro-2-fluorophenyl)-3-((2S,4R)-2-(1-cyclopropyl-1 / 7-pyrazol-4-yl)tetrahydro-2 / 7-pyran-4-yl)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1 / 7)-one and 1 -(4-chloro-2-fluorophenyl)-3-((2R,4S)-2-(1 -cyclopropyl-1 / 7-pyrazol-4-yl)tetrahydro-2 / 7-pyran-4-yl)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1H)-one (113 and 114), (single stereoisomer, absolute stereochemical configuration not determined)

[0720] Example 112 (0.140 g, 0.283 mmol) was separated into its component isomers using SFC purification (DAICEL CHIRALPAK IG, 250 mm x 30 mm x 10 pm column; Mobile phase A: CO2; Mobile phase B: EtOH with 0.1% of NH4OH; isocratic 60% of Mobile Phase B; flow rate: 80 g / min; column temperature: 40 °C; backpressure: 100 bar) and lyophilized to provide The Example 112: peak 2 (10.6 mg, 7.60% yield) as a white solid and Example 113: peak 3 (19.8 mg, 14.1% yield) as a white solid. The chiral purity was determined using SFC analytical method on Chiralpak IG-3 50 mm x 4.6 mm x 3 pm column; Mobile phase A: CO2; Mobile phase B: EtOH with 0.2% of NH3; isocratic: 40% of Mobile Phase B; flow rate: 4.0 mL / min; backpressure: 1500 psi; column temperature: 35 °C to provide Example 113: peak 1 as a mixture of atropisomers ((SFC-MS) m / z (M+H)+= 495.38 at retention time: 1.130 min, 49.49% ee, (SFC-MS) m / z (M+H)+= 495.37 at retention time: 1.564 min, 50.51% ee)) and Example 114: peak 2 as a mixture of atropisomers ((SFC-MS) m / z (M+H)+= 495.38 at retention time: 2.225 min, 50.52% ee, (SFC-MS) m / z (M+H)+= 495.38 at retention time: 3.258 min, 49.14% ee). Example 113: (LC / MS) m / z (M+H)+= 495.2.1H NMR (400 MHz, (CD3)2SO) 6 7.79-7.74 (m, 1H), 7.73 (s, 1H), 7.62-7.50 (m, 2H), 7.37 (s, 1H), 4.48 (d, 1H), 4.16-3.99 (m, 1 H), 3.75-3.50 (m, 3H), 2.57 (s, 3H), 2.43 (s, 3H), 2.21-2.05 (m, 1 H), 1.92-1.73 (m, 3H), 1.06-0.81 (m, 4H).

[0721] Example 114: (LC / MS) m / z (M+H)+= 495.2.1H NMR (400 MHz, (CD3)2SO) 6 7.81-7.76 (m, 1H), 7.74 (s, 1H), 7.63-7.51 (m, 2H), 7.38 (s, 1H), 4.49 (d, 1H), 4.14-4.04 (m, 1 H), 3.77-3.56 (m, 3H), 2.58 (s, 3H), 2.44 (s, 3H), 2.23-2.04 (m, 1 H), 1.99-1.75 (m, 3H), 1.09-0.85 (m, 4H).

[0722] Example 116

[0723] 1-(4,4-Difluorocyclohexyl)-3-((2R,4S)-2-(2-methoxypyridin-4-yl)tetrahydro-2 / 7-pyran-4-yl)-6,7- dimethylpyrazino[2,3-b]pyrazin-2(1 / - / )-one (racemic, cis) (116)

[0724]

[0725] Step 1. Preparation of methyl 4-(4-(4,4-difluorocyclohexyl)-6,7-dimethyl-3-oxo-3,4-dihydropyrazino[2,3-b]pyrazin-2-yl)-2-(2-methoxypyridin-4-yl)tetrahydro-2 / 7-pyran-4-carboxylate (C109)

[0726] To a solution of P33 (0.115 g, 0.458 mmol) in toluene (2.28 mL) was added 1 M LiHMDS in THF (0.46 mL). The reaction mixture was stirred at 0 °C for 15 min then C107 (75.0 mg, 0.228 mmol) was added and stirred for 40 min at room temperature. The suspension was pipetted into cold NH4CI solution (10 mL saturated NH4CI with 2 pieces of ice). The aqueous layer was extracted with DCM (3x) then dried with MgSO4and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-100% EtOAc: heptane) to provide C109 (44.7 mg, 36.0% yield). (LC / MS) m / z (M+H)+= 544.3.1H NMR (400 MHz, CDCI3) 6 8.07 (d, 1H), 6.88 (dd, 1 H), 6.77-6.69 (m, 1 H), 5.41 (t, 1H), 4.99 (dd, 1 H), 4.20-4.00 (m, 2H), 3.89 (s, 3H), 3.73 (s, 3H), 3.12-2.97 (m, 2H), 2.68-2.51 (m, 7H), 2.54-2.40 (m, 1H), 2.33-2.16 (m, 3H), 2.02-1.82 (m, 3H), 1.76-1.63 (m, 2H).

[0727] Step 2. Preparation of 1-(4,4-difluorocyclohexyl)-3-((2R,4S)-2-(2-methoxypyridin-4-yl)tetrahydro-2 / 7-pyran-4-yl)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1 / 7)-one (racemic, cis) (116) A reaction mixture of C109 (44.7 mg, 0.0822 mmol) and DABCO (0.138 g, 1.23 mmol) in toluene (0.82 mL) was stirred at 110 °C for 41.5 h then concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-100% EtOAc: heptane) to provide 116 (27.3 mg, 68.4% yield) as a solid. (LC / MS) m / z (M+H)+= 486.3.1H NMR (600 MHz, CDCI3) 6 8.04 (d, 1H), 6.83 (d, 1H), 6.70 (s, 1H), 5.50-5.35 (m, 1H), 4.44 (dd, 1H), 4.30-4.19 (m, 1H), 3.86 (s, 3H), 3.78-3.63 (m, 2H), 3.04 (q, 2H), 2.58 (d, 6H), 2.25-2.15 (m, 2H), 2.14-2.08 (m, 1 H), 2.01 - 1.78 (m, 5H), 1.66 (d, 2H).

[0728] Example 117 and C110

[0729] 1-(4,4-Difluorocyclohexyl)-3-((2R,4S)-2-(2-methoxypyridin-4-yl)tetrahydro-2 / 7-pyran-4-yl)-6,7- dimethylpyrazino[2,3-b]pyrazin-2(1 / 7)-one and 1 -(4,4-Difluorocyclohexyl)-3-((2S,4R)-2-(2- methoxypyridin-4-yl)tetrahydro-2 / 7-pyran-4-yl)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1 / - / )-one (117 and C110) (single stereoisomer, absolute stereochemical configuration not determined)

[0730]

[0731] single stereoisomers, absolute stereochemical configurations not determined Step 1. Preparation of 1-(4,4-difluorocyclohexyl)-3-((2R,4S)-2-(2-methoxypyridin-4-yl)tetrahydro-2 / 7-pyran-4-yl)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1 / 7)-one and 1 -(4,4-difluorocyclohexyl)-3-((2S,4R)-2-(2-methoxypyridin-4-yl)tetrahydro-2 / 7-pyran-4-yl)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1 / 7)-one (single stereoisomer, absolute stereochemical configuration not determined) (117 and C110)

[0732] 116 (24 mg, 0.049 mmol) was purified by SFC [Column: Chiral Technologies OD-H, 250 mm x 21 mm x 5 pm; Mobile phase A: CO2; Mobile phase B: MeOH; isocratic 80% of Mobile Phase B over 20 min; flow rate: 75 mL / min; backpressure: 120 bar] which provided the first eluting isomer as Example 117 (7.0 mg, 29% yield) and the second eluting isomer (6.6 mg, 27% yield). The chiral purity was determined using SFC analytical method on Chiral Technologies OD-H 100 mm x 4.6 mm x 3 pm column; Mobile phase A: CO2; Mobile phase B: MeOH; isocratic: 75% of Mobile Phase B over 10 min; flow rate: 5.0 mL / min; backpressure: 120 bar to provide Example 117: peak 1 ((SFC-MS) m / z (M+H)+= 486.2 at retention time: 2.60 min) and C110: peak 2 ((SFC-MS) m / z (M+H)+= 486.2 at retention time: 4.39 min).

[0733] 117: (LC / MS) m / z (M+H)+= 486.2.

[0734] C110: (LC / MS) m / z (M+H)+= 486.2

[0735] Examples 25-118

[0736] The compounds in Table 1 can be prepared using similar chemistry from the Examples described above by utilizing compounds that are commercially available or that can be synthesized by literature methods to form the resultant compounds of the disclosure.

[0737]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760]

[0761]

[0762]

[0763]

[0764]

[0765]

[0766] *= chiral purification data listed below

[0767] Example 13a: The SNAr was altered in Example 13. To a 100 mL round bottom flask with reflux condenser was added 2,3-dichloro-5,6-dimethylpyrazine (CAS: 32493-79-1; 0.50 g, 2.8 mmol), 4-chloro-3-fluoroaniline (CAS: 367-22-6; 0.49 g, 3.4 mmol), 1M KOtBu in THF (5.6 mL) and toluene (14.1 mL). The reaction mixture was stirred at 85 °C then cooled to room temperature and diluted with H2O. The suspension was extracted with EtOAc (x3). The combined organic layers were dried with MgSO4, filtered, concentrated in vacuo. The red brown oil was dissolved in DCM and purified by column chromatography (silica gel, 0-50% EtOAc / heptane) to provide 3-chloro- / V-(4-chloro-3-fluorophenyl)-5,6-dimethylpyrazin-2-amine (0.29 g, 36% yield) as an orange solid.

[0768] Example 17a: The Palladium Coupling was altered in Example 17. The same procedure was followed from Example 8 and 9, step 1 with 3-chloro-5,6-dimethylpyrazin-2-amine (CAS: 39213-71-3; 0.50 g, 3.2 mmol) and 4,4-difluorocyclohexan-1-amine (CAS: 458566-84-2; 0.51 g, 3.8 mmol). The work-up and purification were altered. The reaction mixture was quenched with NH4Cl (15 mL) then diluted with EtOAc and stirred at room temperature for 1 h. The aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine, dried with MgSO4, filtered and concentrated under a stream of N2gas. The residue was purified by column chromatography (silica gel, 0-10% MeOH: DCM) to provide C105 (0.40 g, 50% yield) as a brown gum.

[0769] The utility of the compounds of the present invention in the treatment and / or prevention of diseases related to TREM2 may be demonstrated by the activity in the in vitro assays described below. The following protocols may of course be varied by those skilled in the art. Such assays also provide a means whereby the activities of the compounds of the present invention can be compared with the activities of other known compounds. Chiral Purification Data:

[0770] Example 93*: A mixture was separated into its component isomers using SFC purification (DAICEL CHIRALPAK IC, 250 mm x 30 mm x 5 pm column; Mobile phase A: CO2; Mobile phase B: EtOH with 0.1 % of NH4OH; isocratic 50% of Mobile Phase B over 40 min; flow rate: 150 g / min). The chiral purity was determined using SFC analytical method on Chiralpak IC-3 100 mm x 4.6 mm x 3 pm column; Mobile phase A: CO2; Mobile phase B: EtOH with 0.2% of NH3; isocratic: 40% of Mobile Phase B; flow rate: 2.8 mL / min; backpressure: 1500 psi; column temperature: 35 °C to provide peak 1 ((SFC-MS) m / z (M+H)+= 510.46 at retention time: 2.214 min, 100% ee) and Example 93: peak 2 as a mixture of atropisomers ((SFC-MS) m / z (M+H)+= 510.47 at retention time: 3.761 min, 48% ee), (SFC-MS) m / z (M+H)+= 510.45 at retention time: 3.928 min, 51% ee).

[0771] Example 115*: A mixture was separated into its component isomers using SFC purification (Chiral Technologies IH, 250 mm x 21 mm x 5 pm column; Mobile phase A: CO2; Mobile phase B: MeOH with 0.1% of NH4OH; isocratic 90% of Mobile Phase B over 10 min; flow rate: 75 mL / min; backpressure: 120 bar). The chiral purity was determined using SFC analytical method on Chiral Technologies AD-H 100 mm x 4.6 mm x 3 pm column; Mobile phase A: CO2; Mobile phase B: MeOH with 0.2% of NH3; isocratic: 80% of Mobile Phase B over 5 min; flow rate: 5.0 mL / min; backpressure: 120 barto provide peak 1 ((SFC-MS) m / z (M+H)+= 471.3 at retention time: 1.67 min) and Example 115: peak 2 ((SFC-MS) m / z (M+H)+= 471.3 at retention time: 1.93 min)

[0772] The utility of the compounds of the present invention in the treatment and / or prevention of diseases related to TREM2 may be demonstrated by the activity in the in vitro assays described below. The following protocols may of course be varied by those skilled in the art. Such assays also provide a means whereby the activities of the compounds of the present invention can be compared with the activities of other known compounds.

[0773] In vitro pharmacology assay

[0774] Cellular phosphorylation of Spleen Tyrosine Kinase (SYK) assays for the in vitro measurement of TREM2 activity

[0775] Pharmacological measurements of TREM2 activity through the Spleen Tyrosine Kinase (SYK) signaling pathway were made by measuring phosphorylated-SYK on Tyrosine 525 / 526 (pSYK). The measurements were made using with a stably transfected HEK293 clonal cell line expressing human TREM2 and DAP12, and pSYK was measured using the AlphaLISA Surefire Ultra Human and Mouse Phospho-SYK (Tyr525 / 526) Detection Kit from Revvity (Catalog # ALSU-PSYK-A50K). The reporter cells were cultured in a growth media comprised of DMEM High Glucose, 10% heat inactivated fetal bovine serum (HI FBS), 1% 100x Glutamax, and 100 U / mL Penicillinstreptomycin (units of penicillin in 1 mL of streptomycin). Thirty thousand cells were plated in 40 microliter (pL) per well in a 384-well, white bottom, poly-d-lysine coated tissue culture plate. Cells were cultured overnight at 37 °C. The next day, test compounds (solubilized and serially diluted in DMSO, in an 11 point, 4-fold dilution series in duplicate) were spotted, 90 nanoliters (nL) per well, into a 384 well v-bottom polypropylene plate. Thirty pL per well of 37 °C dosing media (Dulbecco's modified eagle medium (DMEM) High Glucose, no calcium, no glutamine, no phenol red and no FBS) was added to the compound plate. Growth media was removed from the cell plate, and the cells were washed with HBSS. Twenty pL per well of compounds diluted in dosing media were transferred from the compound plate to the cell plate. Compounds were incubated on cells for 45 min. Compound containing media was then removed and the cells were washed once with HBSS and lysed with 1X AlphaLisa Lysis Buffer (Rewity) Supplemented with 1X Phosphatase Inhibitor (Halt Protease and Phosphatase Inhibitor Cocktail, EDTA-free from ThermoFisher). After 30 min, ten pL of cell lysate was then transferred to a white low volume 384 well plate and cell lysate were assayed for pSYK using the AlphaLISA Surefire Ultra Human and Mouse Phospho-SYK (Tyr525 / 526) Detection Kit from Revvity (Catalog # ALSU-PSYK-A50K). Data was acquired by reading the plates with the EnVision 2105 multilabel reader (PerkinElmer). EC50(half maximal effective concentration) values were determined from this data using a 4-parameter fit algorithm and are provided in the table below, the EC50values are the statistical mean values of n number of samples as denoted by n(EC50).

[0776] Table 2

[0777]

[0778]

[0779]

[0780]

[0781] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application for all purposes.

[0782] It will be apparent to those skilled in the art that various modifications and variations can be made without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims

Claims1. A compound of formula (I) having the structure:or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein:each of Ai, A2, A3, and A4 is selected independently from the group consisting of CH, CR, and N, where R is deuterium, Ci-C6alkyl, Ci-C6haloalkyl, fluoro, cyano, C1-C3 alkoxy, or Ci-C3haloalkoxy;X is CH2, CH-(C1-C6alkyl), C-(Ci-C6alkyl)2, CH-(Ci-Cehaloalkyl), C-(C1-C6alkyl)(C1-C6alkyl), C-(C1-C6haloalkyl)2, CHF, CF2, CF-(C1-C6alkyl), CF-(C1-C6haloalkyl), NH, N-(C1-C6alkyl), O, or S(O)q, where q is 0, 1 or 2;R1 is Ci-C6alkyl, C3-C8cycloalkyl, phenyl, a 5- or 6-membered heteroaryl or heterocycloalkyl containing one, two, three or four heteroatoms selected from the group consisting of N, S and O atoms, or an 8-, 9- or 10-membered bicyclic aryl, heteroaryl or heterocycloalkyl containing one, two or three heteroatoms selected from the group consisting of N, S and O atoms; wherein each of said alkyl, cycloalkyl, phenyl, aryl, heteroaryl, or heterocycloalkyl may be unsubstituted or substituted by one or more of halo, cyano, deuterium, hydroxy, oxo, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, phenyl, SF5, -SO2-R’, -CONR’R”, NR’COR”, -NR’CONR’R”, -NR’CC>2R”, -(CH2)n-SO2-R’, -NHSO2-R’, -NR”SC>2-R’, -SO2NR’R”, NR’R”, -P(O)R’R”, -SOR-’R” or SR’ where each R’ and R” are independently H, Ci-C6alkyl, Ci-C6haloalkyl or C3-C8cycloalkyl;R2 and R2’ are independently selected from the group consisting of H, halo, Ci-C8alkyl, -(CH2)m-(C3-C8cycloalkyl), -(CH2)m-phenyl, a 5- or 6-membered heteroaryl or heterocycloalkyl containing one, two, three or four heteroatoms selected from the group consisting of N, S and O atoms, or an 8-, 9- or 10-membered bicyclic aryl, heteroaryl or heterocycloalkyl containing one,two or three heteroatoms selected from the group consisting of N, S and O atoms; wherein each of said alkyl, cycloalkyl, phenyl, aryl, heteroaryl or heterocycloalkyl may be unsubstituted or substituted by one or more of phenyl, halo, cyano, deuterium, hydroxy, Ci-C6alkyl, Ci-C6alkoxy, -SO2-R’, -CONR’R”, NR’COR”, -NR’CONR’R”, -NR’CO2R”, -(CH2)„-SO2-R’, -NHSO2-R’, -NR”SO2-R’, -SO2NR’R”, NR’R” or SR’ where R’ and R” are independently H, Ci-C6alkyl or C3-C8cycloalkyl; or,R2and R2’ are taken together to form a C3-C8cycloalkyl ring optionally substituted with one or more of halo, Ci-C6alkoxy, or cyano;R3is selected from the group consisting of H, deuterium, Ci-C8alkyl, C3-C8cycloalkyl, phenyl, naphthyl, a 5- or 6-membered heteroaryl or heterocycloalkyl containing one, two, three or four heteroatoms selected from the group consisting of N, S and O atoms, and a 8-, 9- or 10-membered bicyclic aryl, heteroaryl or heterocycloalkyl containing one, two or three heteroatoms selected from the group consisting of N, S and O atoms;wherein each of said alkyl, cycloalkyl, phenyl, naphthyl, heteroaryl or heterocycloalkyl may be unsubstituted or substituted by one or more of phenyl, halo, cyano, deuterium, oxo, hydroxy, amino, C1-C6alkyl optionally substituted with cyano, C1-C6haloalkyl, C1-C6alkoxy, C1-C6alkoxyalkyl, C1-C8haloalkoxy, C1-C8hydroxyalkyl, C3-C8cycloalkyl optionally substituted with one or more of cyano or fluoro, 3- to 8-membered heterocycloalkyl, -(CH2)„-(3- to 8-membered heterocycloalkyl), -SO2-R’, NHR’, NR’R”, -CONR’R”, NR’COR”, -NR’CONR’R”, -NR’CO2R”, -(CH2)„-SO2-R’, -(CH2)n-CN, -NHSO2-R’, -NR”SO2-R’, -SO2NR’R”, -(CH2)„-NR’R”, -(CH2)„-NHR’, -P(O)R’R”, or SR’ where R’ and R” are independently H, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkoxy, C1-C6alkoxyalkyl, C1-C6hydroxyalkyl, C3-C8cycloalkyl, phenyl, or 5- or 6-membered heteroaryl or heterocycloalkyl containing one, two, three or four heteroatoms selected from the group consisting of N, S and O atoms; or two substituents on each of said alkyl, cycloalkyl, phenyl, naphthyl, heteroaryl or heterocycloalkyl are taken together to form a cyclic group selected from C4-C8cycloalkyl or heterocycloalkyl wherein the cyclic group may be optionally substituted with one or more of deuterium, cyano, oxo, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3alkoxy, Ci-C3haloalkoxy, or halo;R4and R5are independently selected from the group consisting of H, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, C3-C8cycloalkyl, and NR’R” where R’ and R” are independently H, Ci-C6alkyl or C3-C8cycloalkyl, wherein each of said alkyl and cycloalkyl may be unsubstituted or substituted by halo, cyano, deuterium, hydroxy, Ci-C8alkyl and Ci-C8alkoxy; orR4and R5are taken together to form a C4-C8cycloalkyl or heterocycloalkyl ring optionally substituted with one or more of deuterium, cyano, oxo, Ci-C3alkyl, Ci-C3haloalkyl, or halogen;m is 0, 1, 2 or 3; andn is 0, 1, 2, or 3.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein each of Ai, A2, and A3is N; A4is N or CH; X is O; and R2and R2’ are independently selected from the group consisting of H, fluoro and methyl; or R2and R2’ are taken together to form a C3-C4cycloalkyl ring optionally substituted with one or more of fluoro.3 The compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein each of Ai, A2, A3,and A4is N; X is O; and R2and R2’ are independently selected from the group consisting of H and methyl.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein each of A1, A2, A3, and A4is N; X is O; and R4and R5are independently selected from the group consisting of methyl and trifluoromethyl.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein R3is phenyl, 5- or 6-membered heteroaryl containing one, two, three or four heteroatoms selected from the group consisting of N, S and O atoms, or 8-, 9- or 10-membered bicyclic aryl or heteroaryl containing one, two or three heteroatoms selected from the group consisting of N, S and O atoms; wherein each of said phenyl, aryl or heteroaryl may be unsubstituted or substituted by one or more of phenyl, halo, cyano, deuterium, oxo, hydroxy, amino, Ci-C8alkyl optionally substituted with cyano, Ci-C8haloalkyl, Ci-C8alkoxy, Ci-C8alkoxyalkyl, Ci-C6haloalkoxy, Ci-C6hydroxyalkyl, C3-C8cycloalkyl optionally substituted with one or more of cyano or fluoro, 3- to 8-membered heterocycloalkyl, -(CH2)„-(3- to 8-membered heterocycloalkyl), -SO2-R’, NHR’, NR’R”, -CONR’R”, NR’COR”, -NR’CONR’R”, -NR’CO2R”, -(CH2)„-SO2-R’, -(CH2)n-CN, -NHSO2-R’, -NR”SO2-R’, -SO2NR’R”, -(CH2)n-NR’R”, -(CH2)„-NHR’, -P(O)R’R”, or SR’ where R’ and R” are independently H, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6alkoxyalkyl, Ci-C6hydroxyalkyl, C3-C8cycloalkyl, phenyl, or 5- or 6-membered heteroaryl or heterocycloalkyl containing one, two, three or four heteroatoms selected from the group consisting of N, S and O atoms; or two substituents on each of said phenyl, aryl or heteroaryl are taken together to form a cyclic group selected from C4-C8cycloalkyl or heterocycloalkyl wherein the cyclic group may be optionally substituted with one or more of deuterium, cyano, oxo, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3alkoxy, C1-C3haloalkoxy, or halo;6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein Ri is selected from the group consisting of C3-C8cycloalkyl, phenyl, and a 6-membered heteroaryl; wherein each of said cycloalkyl, phenyl, or heteroaryl may be unsubstituted or substituted by one or more of halo, cyano, deuterium, Ci-C8alkyl, Ci-C8haloalkyl, Ci-C8alkoxy, or Ci-C6haloalkoxy.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein each of Ai, A2, A3,and A4is N; X is O; and Ri is selected from the group consisting of C3-C8cycloalkyl, phenyl, and a 6-membered heteroaryl; wherein each of said cycloalkyl, phenyl, or heteroaryl may be unsubstituted or substituted by halo, cyano, deuterium, Ci-C8alkyl, Ci-C8haloalkyl, Ci-C8alkoxy, or Ci-C8haloalkoxy.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein each of Ai, A2, A3,and A4is N; X is O; and Ri is selected from the group consisting of phenyl, and a 6-membered heteroaryl; wherein each of said phenyl or heteroaryl may be unsubstituted or substituted by halo, cyano, deuterium, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy, or Ci-C6haloalkoxy.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein each of Ai, A2, A3,and A4is N; X is O; and Ri is C3-C8cycloalkyl unsubstituted or substituted by halo, cyano, deuterium, Ci-C8alkyl, Ci-C8haloalkyl, Ci-C8alkoxy, or Ci-C8haloalkoxy.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein the compound is selected from the group consisting of1-(4-chloro-2-fluorophenyl)-3-(cis-2-(1-cyclopropyl-1 H-pyrazol-4-yl)-6-methylmorpholino)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1H)-one (single cis stereoisomer, absolute stereochemical configuration not determined);1-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1H)-one;1-(4-chloro-2-fluorophenyl)-3-(2-(4-fluorophenyl)-6-methylmorpholino)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1H)-one;1-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-((S)-2-(4-((R)-S-methylsulfonimidoyl)phenyl)morpholino)pyrazino[2,3-b]pyrazin-2(1 H)-one (single stereoisomer, absolute stereochemical configuration not determined);3-(2-(4-(1H-1,2,4-triazol-1-yl)phenyl)morpholino)-1-(4-chloro-2-fluorophenyl)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1H)-one;1-(4-chloro-2-fluorophenyl)-3-(2-(1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)morpholino)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1H)-one;1-(4,4-difluorocyclohexyl)-6,7-dimethyl-3-(2-(2-(trifluoromethyl)pyridin-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1H)-one;1-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(2-(1-oxo-1,2-dihydroisoquinolin-6-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1H)-one;1-(4-chloro-2-fluorophenyl)-3-(2-(isoquinolin-6-yl)morpholino)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1H)-one;4-(4-(4-(4,4-difluorocyclohexyl)-6,7-dimethyl-3-oxo-3,4-dihydropyrazino[2,3-b]pyrazin-2-yl)morpholin-2-yl)-2-methoxybenzonitrile;1-(4,4-difluorocyclohexyl)-3-(2-(4-(N, S-dimethylsulfonimidoyl)phenyl)morpholino)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1H)-one;4-(4-(4-(4,4-difluorocyclohexyl)-6,7-dimethyl-3-oxo-3,4-dihydropyrazino[2,3-b]pyrazin-2-yl)morpholin-2-yl)-2-(trifluoromethyl)benzonitrile;3-(2-(4-(cyclopropylsulfonyl)phenyl)morpholino)-1-(4,4-difluorocyclohexyl)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1H)-one;1-(4,4-difluorocyclohexyl)-3-(2-(2-(1,1-difluoroethyl)pyridin-4-yl)morpholino)-6,7-dimethylpyrazino[2,3-b]pyrazin-2(1H)-one;1-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)pyrazino[2,3-b]pyrazin-2(1 H)-one (racemic, cis);(S)-1-(4,4-difluorocyclohexyl)-6,7-dimethyl-3-(2-(2-methylpyridin-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1H)-one (absolute stereochemical configuration not determined); and,rel-(R or S)-1-(4-chloro-2-fluorophenyl)-6,7-dimethyl-3-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrazino[2,3-b]pyrazin-2(1H)-one; or, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt.

11. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, and a pharmaceutically acceptable excipient.

12. A method of treating a disease or condition selected from inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, systemiclupus erythematous, lupus nephritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoidosis, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, brain edema, brain trauma, neurodegeneration, liver disease, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration, glaucoma, diabetes (type 1 and type 2), diabetic neuropathy, viral and bacterial infection, myalgia, endotoxic shock, toxic shock syndrome, osteoporosis, multiple sclerosis, endometriosis, menstrual cramps, vaginitis, candidiasis, cancer, fibrosis, obesity, muscular dystrophy, polymyositis, dermatomyositis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, vitiligo, Alzheimer’s disease, skin flushing, eczema, psoriasis, atopic dermatitis, sunburn, keloid, hypertrophic scar, rheumatic diseases, urticaria, discoid lupus, cutaneous lupus, central nervous system lupus, psoriatic arthritis, asthma, allergic asthma, type I interferonopathies including Aicardi–Goutières syndrome and other mendelian diseases of overexpression of type I interferon, primary progressive multiple sclerosis, relapsing remitting multiple sclerosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, scleroderma, alopecia areata, scarring alopecia, prurigo, prurigo nodularis, CPUO, lichen diseases, lichen planus, Steven’s Johnson’s syndrome, spondylopathy, myositis, vasculitis, pemphigus, lupus, major depression disorder, allergy, dry eye syndrome, transplant rejection, cancer, septic shock, cardiopulmonary dysfunction, acute respiratory disease, ankylosing spondylitis, cachexia, chronic graft-versus-host disease, acute graft-versus-host disease, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, thrombotic thrombocytopenic purpura, myasthenia gravis, Sjogren's syndrome, epidermal hyperplasia, cartilage inflammation, bone degradation, juvenile arthritis, juvenile rheumatoid arthritis, pauciarticular juvenile rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenile enteropathic arthritis, juvenile Reter's Syndrome, SEA Syndrome, juvenile dermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma, juvenile systemic lupus erythematosus, juvenile vasculitis, pauciarticular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemic onset rheumatoid arthritis, enteropathic arthritis, reactive arthritis, Reter's Syndrome, myolitis, polymyolitis, dermatomyolitis, polyarteritis nodosa, Wegener's granulomatosis, arteritis, polymyalgia rheumatica, sarcoidosis, sclerosis, primary biliary sclerosis, sclerosing cholangitis, dermatitis, Still's disease, chronic obstructive pulmonary disease, Guillain-Barre disease, Graves' disease, Addison's disease, Raynaud's phenomenon, psoriatic epidermal hyperplasia, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, an immune disorder associated with or arising from activity of pathogenic lymphocytes, noninfectious uveitis, Behcet’s disease and Vogt–Koyanagi–Harada syndrome, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 to 15, or apharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

13. The method of claim 12 wherein the compound or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, is administered orally or topically.

14. The method of claim 12, wherein the compound or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, is administered as a tablet, capsule or lozenge, if administered orally; or, as a cream, ointment, lotion, gel, solution, suspension, foam, aerosol, spray, shampoo, patch or tape, if administered topically.

15. A method of treating Alzheimer's Disease, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 to 10 or a pharmaceutically acceptable salt thereof, ora pharmaceutically acceptable solvate of said compound or salt.

16. The method of claim 15, wherein the compound ora pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, is administered orally.

17. The method of claim 15, wherein the compound ora pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, is administered as a tablet, capsule or lozenge.

18. A method of treating a neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Frontotemporal lobar degeneration (FTLD), frontotemporal dementia (FTD), Parkinson's disease, Nasu-Hakola disease, FTLD-like syndrome, Huntington disease, Amyotrophic lateral sclerosis, multiple sclerosis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathies, Charcot-Marie-Tooth disease, prion disease, stroke, a tauopathy, a TDP-43 proteinopathy, a synucleinopathy, dementia, amyloidosis, a demyelinating disorder of the CNS, a demyelinating disorder of the PNS, a Leukoencephalopathy, a leukodystrophy, a transmissible spongiform encephalopathy (TSE) and a lysosomal storage disorder (LSD), comprising administering to the subject a therapeutically effective amount of a compound of claim 1 to 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

19. The method of claim 18 wherein the compound or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, is administered orally.

20. The method of claim 18, wherein the compound ora pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, is administered as a tablet, capsule or lozenge.

21. Use of a compound according to any of claims 1 to 10 for the manufacture of a medicament for the treatment of a condition associated with a loss of function of TREM2.

22. Use of a compound according to any of claims 1 to 10 for the manufacture of a medicament for the treatment a neurodegenerative disease.

23. A compound according to any of claims 1 to 10 for use in the treatment of a disorder for which a modulator of the TREM2 pathway is indicated.

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