Substituted Heterocyclic Compounds

Abstract

Formula I: Disclosed is a compound represented by the formula TIFF2025537201000059.tif43127, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein all substituents are as defined herein, and which is useful for modulating IL-12, IL-23, and / or IFNα by acting on Tyk2 to cause signal transduction inhibition. The compounds of the present invention are useful for treating neurodegenerative diseases or disorders.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 382,747, filed November 8, 2022, the disclosure of which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION The present invention relates to compounds useful for modulating IL-12, IL-23, and / or IFNα by acting on Tyk-2, causing inhibition of signal transduction. Provided herein are substituted heterocyclic compounds, compositions containing such compounds, and methods of their use. The present invention further relates to pharmaceutical compositions containing at least one compound according to the present invention, which are useful for treating conditions associated with the modulation of IL-12, IL-23, and / or IFNα in mammals. In particular, the present invention relates to compounds that demonstrate utility in neurodegenerative diseases. [Background technology]

[0003] Interleukin (IL)-12 and IL-23, heterodimeric cytokines that share a common p40 subunit, are produced by activating antigen-presenting cells and are crucial for the differentiation and proliferation of Th1 and Th17 cells, two effector T cell lineages that play important roles in autoimmunity. IL-23 is composed of a p40 subunit and a unique p19 subunit. IL-23 acts through a heterodimeric receptor composed of IL-23R and IL-23Rβ1 and is essential for the survival and proliferation of Th17 cells, which produce proinflammatory cytokines such as IL-17A, IL-17F, IL-6, and TNF-α (McGeachy, MJ et al., "The link between IL-23 and Th17 cell-mediated immune pathologies," Semin. Immunol., 19:372-376 (2007)). These cytokines are crucial in mediating the pathophysiology of many autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and lupus. IL-12 contains a p35 subunit in addition to the p40 subunit shared with IL-23, and acts through a heterodimeric receptor composed of IL-12Rβ1 and IL-12Rβ2. IL-12 is essential for the development of Th1 cells and the secretion of IFNγ, and this cytokine plays an important role in immune function by stimulating MHC expression, B cell class switching to IgG subclasses, and macrophage activation (Gracie, J.A. et al., "Interleukin-12 induces interferon-gamma-dependent switching of IgG alloantibody subclasses," Eur. J. Immunol., 26:121-1221 (1996); Schroder, K. et al., "Interferon-gamma: an overview of signals, mechanisms, and functions," J. Leukoc. Biol., 75(2):163-189 (2004)).

[0004] The importance of p40-containing cytokines in autoimmunity is evidenced by the finding that mice lacking either p40, p19, or IL-23R are protected from diseases in animal models, such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, lupus, and psoriasis (Kyttaris, V.C. et al., "Cutting edge: IL-23 receptor deficiency prevents the development of lupus nephritis in C57BL / 6-lpr / lpr mice," J. Immunol., 184: 4605-4609 (2010); Hong, K. et al., "IL-12, independently of IFN-gamma, plays a crucial role in the pathogenesis of a murine psoriasis-like skin disorder," J. Immunol., 162: 7480-7491 (1999); Hue, S. et al., "Interleukin-23 drives innate and T cell-mediated intestinal ``Inflammation'', J. Exp. Med., 203: 2473-2483(2006);Cua, DJ et al., ``Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain'', Nature, 421: 744-748(2003);Murphy, CA et al., ``Divergent pro- and anti-inflammatory roles for IL-23 and "IL-12 in joint autoimmune inflammation", J. Exp. Med., 198: 1951-1957 (2003)).

[0005] In human disease, elevated expression of p40 and p19 has been measured in psoriatic lesions, and Th17 cells have been identified in active lesions in the brain from MS patients and in the intestinal mucosa of patients with active Crohn's disease (Lee, E. et al., "Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris," J. Exp. Med., 199: 125-130 (2004); Tzartos, JS et al., "Interleukin-17 production in central nervous system infiltrating T cells and glial cells is associated with active disease in multiple sclerosis," Am. J. Pathol., 172: 146-155 (2008)). The mRNA levels of p19, p40, and p35 in patients with active SLE have also been shown to be significantly higher than those in patients with inactive SLE (Huang, X. et al., "Dysregulated expression of interleukin-23 and interleukin-12 subunits in systemic lupus erythematosus patients," Mod. Rheumatol., 17: 220-223 (2007)), and T cells derived from lupus patients have a predominant Th1 phenotype (Tucci, M. et al., "Overexpression of interleukin-12 and T helper 1 predominance in lupus nephritis," Clin. Exp. Immunol., 154: 247-254 (2008)).

[0006] Moreover, genome-wide association studies have identified numerous genetic loci associated with chronic inflammatory and autoimmune diseases that encode factors that function in the IL-23 and IL-12 pathways. These genes include IL23A, IL12A, IL12B, IL12RB1, IL12RB2, IL23R, JAK2, TYK2, STAT3, and STAT4 (Lees, CW et al., "New IBD genetics: common pathways with other diseases," Gut, 60: 1739-1753 (2011); Tao, JH et al., "Meta-analysis of TYK2 gene polymorphisms association with susceptibility to autoimmune and inflammatory diseases," Mol. Biol. Rep., 38: 4663-4672 (2011); Cho, JH et al., "Recent insights into the genetics of inflammatory bowel disease," Gastroenterology, 140: 1704-1712 (2011)).

[0007] Indeed, anti-p40 therapy, which inhibits both IL-12 and IL-23, and IL-23-specific anti-p19 therapy have been shown to be effective in treating autoimmunity in diseases including psoriasis, Crohn's disease, and psoriatic arthritis (Leonardi, CL et al., "PHOENIX 1 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12 / 23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 1)," Lancet, 371: 1665-1674 (2008); Sandborn, WJ et al., "Ustekinumab Crohn's Disease Study Group. A randomized trial of ustekinumab, a human interleukin-12 / 23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease," Gastroenterology, 135: 1130-1141 (2008); Gottlieb, A. et al., "Ustekinumab, a human interleukin 12 / 23 monoclonal antibody, for psoriatic arthritis: randomized, double-blind, placebo-controlled, crossover trial," Lancet, 373: 633-640 (2009)). Therefore, drugs that inhibit the action of IL-12 and IL-23 may be expected to have therapeutic benefit in human autoimmune disorders.

[0008] Type I interferons (IFNs), including IFNα members as well as IFNβ, IFNε, IFNκ, and IFNω, act through the heterodimeric IFNα / β receptor (IFNAR). Type I IFNs have multiple effects in both the innate and adaptive immune systems, including activating both cellular and humoral immune responses and enhancing the expression and release of self-antigens (Hall, JC et al., "Type I interferons: crucial participants in disease amplification in autoimmunity," Nat. Rev. Rheumatol., 6: 40-49 (2010)).

[0009] In patients with systemic lupus erythematosus (SLE), a potentially fatal autoimmune disease, elevated serum levels of interferon (IFN) α (type I interferon) or increased expression of type I IFN-regulated genes (the so-called IFNα signature) in peripheral blood mononuclear cells and infected organs have been demonstrated in the majority of patients (Bennett, L. et al., "Interferon and granulopoiesis signatures in systemic lupus erythematosus blood," J. Exp. Med., 197: 711-723 (2003); Peterson, K.S. et al., "Characterization of heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of laser-captured glomeruli," J. Clin. Invest., 113: 1722-1733 (2004)), and some studies have shown that serum levels of IFNα correlate with both disease activity and severity (Bengtsson, AA et al., "Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies," Lupus, 9: 664-671 (2000)). A direct role for IFNα in the pathobiology of lupus is evidenced by the observation that administration of IFNα to patients with malignant or viral diseases can induce a lupus-like syndrome.Furthermore, deletion of IFNAR in lupus-susceptible mice provides a high degree of protection from autoimmunity, disease severity, and high mortality (Santiago-Raber, ML et al., "Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice," J. Exp. Med., 197: 777-788 (2003)), and genome-wide association studies have identified lupus-associated genetic loci encoding factors that function in the type I interferon pathway, including IRF5, IKBKE, TYK2, and STAT4 (Deng, Y. et al., "Genetic susceptibility to systemic lupus erythematosus in the genomic era," Nat. Rev. Rheumatol., 6: 683-692 (2010); Sandling, JK et al., "A candidate gene study of the type I interferon pathway implicates IKBKE and IL8 as risk loci for SLE”, Eur. J. Hum. Genet., 19: 479-484 (2011)).In addition to lupus, there is evidence that aberrant activation of the type I interferon-mediated pathway is important in the pathobiology of other autoimmune diseases, such as Sjögren's syndrome and scleroderma (Bave, U. et al., "Activation of the type I interferon system in primary Sjögren's syndrome: a possible etiopathogenic mechanism," Arthritis Rheum., 52: 1185-1195 (2005); Kim, D. et al., "Induction of interferon-alpha by scleroderma sera containing autoantibodies to topoisomerase I: association of higher interferon-alpha activity with lung fibrosis," Arthritis Rheum., 58: 2163-2173 (2008)). Therefore, agents that inhibit the action of the type I interferon response may be expected to have therapeutic benefit in human autoimmune disorders.

[0010] Tyrosine kinase 2 (Tyk2) is a member of the Janus kinase (JAK) family of non-receptor tyrosine kinases and has been reported in mice (Ishizaki, M. et al., "Involvement of Tyrosine Kinase-2 in Both the IL-12 / Th1 and IL-23 / Th17 Axes In Vivo," J. Immunol., 187: 181-189 (2011); Prchal-Murphy, M. et al., "TYK2 kinase activity is required for functional type I interferon responses in vivo," PLoS One, 7: e39141 (2012)) and humans (Minegishi, Y. et al., "Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity," Immunity, 25: Both Tyk2 and Tyk3 have been shown to be crucial for regulating signaling cascades downstream of the receptors for IL-12, IL-23, and type I interferon. Tyk2 mediates receptor-induced phosphorylation of members of the STAT family of transcription factors, an essential signal that leads to the dimerization of STAT proteins and the transcription of STAT-dependent proinflammatory genes.Tyk2-deficient mice are resistant to experimental models of colitis, psoriasis, and multiple sclerosis, demonstrating the importance of Tyk2-mediated signaling in autoimmune and related disorders (Ishizaki, M. et al., "Involvement of Tyrosine Kinase-2 in Both the IL-12 / Th1 and IL-23 / Th17 Axes In Vivo," J. Immunol., 187: 181-189 (2011); Oyamada, A. et al., "Tyrosine kinase 2 plays critical roles in the pathogenic CD4 T cell responses for the development of experimental autoimmune encephalomyelitis," J. Immunol., 183: 7539-7546 (2009)).

[0011] In humans, individuals expressing an inactive variant of Tyk2 are protected from multiple sclerosis and potentially other autoimmune disorders (Couturier, N. et al., "Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility," Brain, 134: 693-703 (2011)). Genome-wide association studies have shown that other variants in Tyk2 are associated with autoimmune disorders such as Crohn's disease, psoriasis, systemic lupus erythematosus, and rheumatoid arthritis, further demonstrating the importance of Tyk2 in autoimmunity (Ellinghaus, D. et al., "Combined Analysis of Genome-Wide Association Studies for Crohn's Disease and Psoriasis Identifies Seven Shared Susceptibility Loci," Am. J. Hum. Genet., 90: 636-647 (2012); Graham, D. et al., "Association of polymorphisms across the tyrosine kinase gene, TYK2 in UK SLE families," Rheumatology (Oxford), 46: 927-930 (2007); Eyre, S. et al., "High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis," Nat. Genet., 44: 1336-1340(2012)).

[0012] NPSLE and other neurodegenerative disorders are characterized by widespread involvement of inflammatory processes and CNS-specific cellular inflammation (e.g., CNS-resident microglia and the blood-brain barrier). Signs of these conditions include cognitive impairment, and this pathological process is known to be associated with upregulation of TYK2 and its downstream pathway mediators and effectors. Preclinical models of neurodegenerative disorders demonstrate that only CNS-penetrant TYK2i molecules can inhibit the centrally mediated inflammatory and activation processes associated with disease pathogenesis and progression in patients. Therefore, the development of potent, selective, and centrally penetrating inhibitors of TYK2 is necessary to optimize therapeutic benefit.

[0013] TYK inhibition may also be utilized in both solid tumors and hematopoietic malignancies, both as monotherapy and in combination with existing standard therapies, including immunotherapy. Ex vivo studies in T-cell acute lymphoblastic leukemia (T-ALL) have demonstrated that TYK2 is required for cell survival, suggesting a potential direct cancer-killing mechanism for TYK2 inhibitors in this indication (Sanda, T. et al., TYK2-STAT1-BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia. Cancer Discov. 3, 564-577 (2013)). Multiple TYK2-activating mutations have been detected and characterized in T-ALL cell lines. The NPM1-TYK2 gene fusion has also been identified in a subset of cutaneous T-cell lymphoma (CTCL), revealing TYK2 as an oncogenic driver of transformation (Kuravi, S. et al., Functional characterization of NPM1-TYK2 fusion oncogene. Npj Precis. Oncol. 6, 3 (2022)). Loss of TYK2 signaling can inhibit this transforming potential.

[0014] Although effective TYK2 inhibitors have been described, these compounds tend to be highly polar, resulting in high efflux ratios in standard efflux models (Wrobleski, ST et al., Highly selective inhibition of tyrosine kinase 2 (TYK2) for the treatment of autoimmune diseases: Discovery of the allosteric inhibitor BMS-986165, J. Med. Chem. 62, 8973-8995 (2019)). It is well known that one pathway to multidrug resistance is increased expression of efflux transporters (Gottesman, MM et al., Multidrug Resistance in Cancer: Role of ATP-Dependent Transporters. Nature Rev. Cancer 2, 48-58 (2002); Fletcher, JI et al., ABC transporters in cancer: more than just drug efflux pumps. Nature Rev. Cancer 10, 147-156 (2010)).

[0015] Therefore, compounds with low efflux ratios in in vitro experiments may potentially have a greater chance of effectively treating some oncogenic indications. In light of the conditions that may benefit from treatment involving modulation of cytokines and / or interferons, novel compounds capable of modulating cytokines and / or interferons, such as IL-12, IL-23 and / or IFNα, and methods using these compounds, may provide substantial therapeutic benefit to a wide variety of patients in need thereof. Summary of the Invention

[0016] The present invention is directed to compounds of Formula I that are useful as modulators of IL-12, IL-23 and / or IFNα, inter alia, by inhibiting Tyk2-mediated signaling. The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one compound of the present invention. The present invention also provides methods for modulating IL-12, IL-23 and / or IFNα by inhibiting Tyk2-mediated signaling, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one compound of the present invention.

[0017] The present invention also provides methods for treating neurodegenerative diseases, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one compound of the present invention. The present invention also provides compounds of the invention for use in therapy. These and other features of the present invention will be set forth in expanded form as the disclosure continues. DETAILED DESCRIPTION OF THE INVENTION

[0018] In a first aspect of the present invention, a compound of the formula: [ka] [In formula: X is -N- or -CH-; Y is -N- or -CH-; R is [ka] and; R 1 CF3, C 1-6 Alkyl or C 3-6 is cycloalkyl; R 2 is H or C 1-6 is alkyl; Z is CHR 1 , CH2, CR 1 2, O, NR 1 or C(O); n is 0, 1, 2, or 3. or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0019] In a second embodiment of the present invention, a compound of formula: [ka] [In formula: R is [ka] and; R 1 CF3, C 1-6 Alkyl or C 3-6 is cycloalkyl; R 2 is H or C 1-6 is alkyl; Z is CHR 1 , CH2, CR 1 2, O, NR 1 or C(O); n is 0, 1, 2, or 3. or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0020] In a third aspect of the present invention, a compound of formula: [ka] [In formula: R is [ka] and; R 1 CF3, C 1-6 Alkyl or C 3-6 is cycloalkyl; Z is CHR 1 , CH2, CR 1 2, O, NR 1 or C(O); n is 0, 1, 2, or 3. or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0021] In a fourth aspect of the present invention, a compound of formula: [ka] [In formula: R is [ka] and; R 1 CF3, C 1-6 Alkyl or C 3-6 is cycloalkyl; Z is CHR 1 , CH2, CR 1 2, O, NR 1 or C(O); n is 0, 1, 2, or 3. or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0022] In a fifth embodiment of the present invention, a compound of formula: [ka] [In formula: R is [ka] and; R 1 CF3, C 1-6 Alkyl or C 3-6 is cycloalkyl; Z is CHR 1 , CH2, CR 1 2, O, NR 1 or C(O); n is 0, 1, 2, or 3. or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0023] In another aspect, there is provided a compound selected from the illustrative examples falling within the scope of the first aspect. In another aspect, there is provided a compound selected from any series of subgroups of compounds within the above-described aspects.

[0024] In another aspect, 4-{[3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) methyl-6-[2-oxo-3-(propan-2-yl)imidazolidin-1-yl]pyridazine-3-carboxamide; 4-{[3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) methyl-6-[2-oxo-3-(propan-2-yl)imidazolidin-1-yl]pyridine-3-carboxamide; 4-{[2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( 2 H3) methyl-6-[2-oxo-3-(propan-2-yl)imidazolidin-1-yl]pyridine-3-carboxamide; 6-(3-cyclopropyl-2-oxoimidazolidin-1-yl)-4-{[3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-(3-cyclopropyl-2-oxoimidazolidin-1-yl)-4-{[2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-(3-isopropyl-2-oxoimidazolidin-1-yl)-4-((3-methoxy-6-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 6-(3-cyclopropyl-2-oxoimidazolidin-1-yl)-4-((3-methoxy-6-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 6-(3-cyclobutyl-2-oxoimidazolidin-1-yl)-4-{[3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; and 4-{[2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( 2 H3) Methyl-6-[2-oxo-3-(trifluoromethyl)imidazolidin-1-yl]pyridine-3-carboxamide A compound selected from (IUPAC nomenclature rules) or a pharmaceutically acceptable salt thereof is provided.

[0025] In another embodiment, a pharmaceutical composition is provided comprising one or more compounds of formula I and a pharmaceutically acceptable carrier or diluent. The present invention is also directed to a pharmaceutical composition useful for treating diseases associated with the regulation of IL-12, IL-23 and / or IFNα by acting on Tyk2 and causing inhibition of signal transduction, the pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

[0026] The present invention further relates to a method for treating a disease associated with the regulation of IL-12, IL-23 and / or IFNα, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I. The present invention also provides processes and intermediates for making the compounds of the present invention.

[0027] The present invention also provides methods for treating proliferative, metabolic, allergic, autoimmune and inflammatory diseases (or the use of compounds of the invention in the manufacture of medicaments for treating such diseases), comprising administering to a host in need of such treatment a therapeutically effective amount of at least one compound of the invention. The present invention also provides a method of treating an inflammatory or autoimmune disease (or the use of a compound of the invention in the manufacture of a medicament for treating such a disease), which method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I.

[0028] The invention also relates to methods of treating a disease (or use of a compound of the invention in the manufacture of a medicament for treating such a disease), comprising administering a therapeutically effective amount of a compound of formula I to a patient in need of such treatment, wherein the disease is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus, inflammatory bowel disease, psoriasis, Crohn's disease, psoriatic arthritis, Sjogren's syndrome, systemic sclerosis, ulcerative colitis, Graves' disease, discoid lupus erythematosus, adult-onset Still's disease, systemic-onset juvenile idiopathic arthritis, gout, gouty arthritis, type 1 diabetes, insulin-dependent diabetes mellitus, sepsis, septic shock, bacterial dysentery, pancreatitis (acute or chronic), glomerulonephritis, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, myasthenia gravis, pancreatitis (acute or chronic), ankylosing spondylitis, pemphigus vulgaris, Goodpasture's disease, antiphospholipid syndrome, idiopathic thrombocytopenia, ANCA-associated vasculitis, pemphigus, Kawasaki disease, chronic inflammatory demyelinating polyneuropathy (CIDP), dermatomyositis, polymyositis, uveitis, Guillain-Barré syndrome, autoimmune pneumonia, autoimmune thyroiditis, autoimmune inflammatory eye disease, and chronic demyelinating polyneuropathy.

[0029] The invention also provides a method of treating a neurodegenerative disease (or use of a compound of the invention in the manufacture of a medicament for treating said disease), comprising administering a therapeutically effective amount of a compound of formula I to a patient in need of such treatment, wherein the disease is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (including RMS and / or progressive MS, clinically isolated syndrome (CIS)), optic neuritis, or neuromyelitis optica. The present invention also provides a method of treating rheumatoid arthritis (or use of a compound of the invention in the manufacture of a medicament for treating rheumatoid arthritis), which method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I.

[0030] Additionally, the present invention also provides a method of treating a condition (or use of a compound of the invention in the manufacture of a medicament for treating such a condition) comprising administering a therapeutically effective amount of a compound of Formula I to a patient in need of such treatment, wherein the condition is acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, solid tumors, ocular neovascularization, and infantile hemangioma, B-cell lymphoma, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis. , polyangiitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, multiple sclerosis (MS), transplant rejection, type 1 diabetes, membranous nephritis, inflammatory bowel disease, autoimmune hemolytic anemia, autoimmune thyroiditis, cold and warm agglutinin disease, Evans syndrome, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura (HUS / TTP), sarcoidosis, Sjogren's syndrome, peripheral neuropathy, pemphigus vulgaris, and asthma.

[0031] The invention also provides methods for treating IL-12, IL-23 and / or IFNα mediated diseases (or use of a compound of the invention in the manufacture of a medicament for treating these diseases), which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I.

[0032] The invention also provides a method of treating an IL-12-, IL-23- and / or IFNα-mediated disease (or use of a compound of the invention in the manufacture of a medicament for treating such a disease), comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I, wherein the IL-12-, IL-23- and / or IFNα-mediated disease is a disease mediated by IL-12, IL-23 and / or IFNα. The present invention also provides a method for treating a disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I in combination with other therapeutic agents.

[0033] The present invention also provides compounds of the invention for use in therapy. In another embodiment, the compound of Formula I is selected from the compounds described herein as examples or from the exemplary compounds or combinations of other embodiments. In another embodiment, IC 50 Compounds are provided in which the

[0034] The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The present invention includes any and all combinations of the preferred aspects and / or embodiments of the invention set forth herein. It is understood that any and all embodiments of the invention may be combined with any other embodiment to describe an even more preferred embodiment. It is also understood that each individual component of a preferred embodiment is itself an independently preferred embodiment. Furthermore, any component of an embodiment may be combined with any and all other components from any embodiment to describe an additional embodiment.

[0035] (Detailed Description of the Invention) The following definitions are provided for terms that may be used in this specification and the appended claims. The first definition provided for a group or term herein applies to that group or term throughout the specification and claims, individually or as part of another group, unless otherwise specified.

[0036] The compounds of the present invention may contain one or more asymmetric centers. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemic forms of the compounds of the present invention are included in the present invention. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. Cis- and trans-geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. The compounds can be isolated in optically active or racemic forms. How to prepare optically active forms, such as by resolution of racemic forms or synthesis from optically active starting materials, is well known in the art. Unless otherwise specified, a specific stereochemistry or isomeric form is intended to include all chiral, (enantiomers and diastereomers) and racemic forms of the structure and all geometric isomeric forms.

[0037] Any variable group (e.g., R 3 When any group R occurs more than once, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, R 3 When the group is indicated to be substituted with, then the group may have up to two R 3 R 3 is R 3 Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0038] When a bond to a substituent is shown to cross the bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When substituents are listed without indicating through which atom such substituent is bonded to the remainder of the compound represented by a given formula, then such substituent may be bonded through any atom of such substituent. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0039] Where compounds of the invention contain nitrogen atoms (e.g., amines), these can be converted to N-oxides by treatment with an oxidizing agent (e.g., MCPBA and / or hydrogen peroxide) to provide other compounds of the invention. Thus, all designated and claimed nitrogen atoms are equivalent to the designated nitrogen and its N-oxide. [ka] The term "amino acids" is intended to include both amino acids and derivatives thereof. According to convention used in the art, the symbol "" is used in the structural formulas herein to indicate the bond that is the point of attachment of a moiety or substituent to a core or background structure. [ka] is used. A dash "-" that is not between two letters or symbols is used to indicate a point of attachment for a substituent, for example, -CONH2 is attached through a carbon atom.

[0040] The term "optionally substituted" with reference to a particular moiety in a compound of Formula I (e.g., an optionally substituted heteroaryl group) refers to a moiety having zero, one, two, or more substituents. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl," as defined below. Those of skill in the art will understand that with respect to any group containing one or more substituents, such group is not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically impossible, and / or inherently unstable. As used herein, the term "at least one chemical entity" is interchangeable with the term "compound."

[0041] As used herein, the terms "alkyl" or "alkylene" are intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C 1-10 "Alkyl" (or alkylene) is a group consisting of C1, C2, C3, C4, C5, C6, C7, C8, C9, and C 10 Alkyl groups are intended to be encompassed. Additionally, for example, "C1-C6 alkyl" means an alkyl having from 1 to 6 carbon atoms. An alkyl group can be unsubstituted or substituted such that one or more of its hydrogens have been replaced with another chemical group. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.

[0042] Those skilled in the art will recognize that when the designation "CO" is used herein, it refers to the group: [ka] It will be understood that this refers to

[0043] When the term "alkyl" is used with another group, such as in "arylalkyl," the combination more specifically defines at least one substituent that the substituted alkyl may contain. For example, "arylalkyl" refers to a substituted alkyl group as described above, where at least one of the substituents is an aryl, such as benzyl. Thus, aryl (C 0-4 The term "(C)alkyl" includes substituted lower alkyl groups having at least one aryl substituent, and also includes aryl groups directly bonded to another group, i.e., aryl(C)alkyl. The term "heteroarylalkyl" refers to a substituted alkyl group as defined above where at least one of the substituents is a heteroaryl.

[0044] The term "alkoxy" refers to an oxygen atom substituted with an alkyl or substituted alkyl, as defined herein. For example, the term "alkoxy" can be substituted with groups such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, and the like. 1-6 "Lower alkoxy" refers to an alkoxy group having 1 to 4 carbon atoms. It is understood that selection of all groups, including, for example, alkoxy, thioalkyl, and aminoalkyl, will be made by one of ordinary skill in the art to obtain stable compounds.

[0045] As used herein, the term "substituted" means that any one or more hydrogens on the designated atom or group have been replaced with a group selected from the specified group, provided that the normal valence of the designated atom is not exceeded. When the substituent is oxo or keto (i.e., =0), two hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. Unless otherwise specified, substituents are specified in the core structure. For example, if (cycloalkyl)alkyl is listed as a possible substituent, it is understood that the point of attachment of this substituent to the core structure is on the alkyl portion. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0046] Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure implies a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and subsequent formulation into an effective therapeutic agent. Preferably, the compounds presented herein do not contain N-halo, S(O)H, or S(O)H groups.

[0047] The term "cycloalkyl" refers to cyclized alkyl groups, including monocyclic, bicyclic, or polycyclic ring systems. 3-7Cycloalkyl is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic ring, or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated, unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As noted above, bridged rings (e.g., [2.2.2]bicyclooctane) are also included in the definition of carbocycle. Preferred carbocycles, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. When the term "carbocycle" is used, it is intended to include "aryl." A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.

[0048] The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl and naphthyl, each of which may be substituted. Thus, in compounds of Formula I, the term "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclooctyl, and the like, as well as the following ring systems: [ka] etc., which may be optionally substituted on any available atom of the ring.

[0049] Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term "halo" or "halogen" refers to chloro, bromo, fluoro, and iodo. The term "haloalkyl" refers to a substituted alkyl having one or more halo substituents. For example, "haloalkyl" includes mono-, bi-, and trifluoromethyl. The term "haloalkoxy" refers to an alkoxy group having one or more halo substituents. For example, "haloalkoxy" includes OCF.

[0050] Unless otherwise specified, when a reference is made to a specifically named aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl), heterocyclo (e.g., pyrrolidinyl, piperidinyl, and morpholinyl), or heteroaryl (e.g., tetrazolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, and furyl), the reference is intended to include rings having 0 to 3, preferably 0 to 2, substituents selected from the groups described above for aryl, cycloalkyl, heterocyclo, and / or heteroaryl groups, as appropriate.

[0051] The term "carbocyclyl" or "carbocyclic" refers to a saturated or unsaturated monocyclic or bicyclic ring in which all atoms of all rings are carbon. Thus, the term encompasses cycloalkyl and aryl rings. Monocyclic carbocycles have 3 to 6 ring atoms, more typically 5 or 6 ring atoms. Bicyclic carbocycles have, for example, 7 to 12 ring atoms arranged as a bicyclo[4,5], [5,5], [5,6], or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo[5,6] or [6,6] system. Examples of monocyclic and bicyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, and naphthyl. The carbocyclic rings may be substituted, in which case the substituents are selected from the groups listed above for the cycloalkyl and aryl groups.

[0052] When the term "unsaturated" is used herein to refer to a ring or group, the ring or group may be fully unsaturated or partially unsaturated. Throughout the specification, unsaturated groups and substituents may be selected by one of skill in the art to provide stable moieties and compounds, and compounds that are useful as pharmaceutically acceptable compounds and / or intermediate compounds that are useful in making pharmaceutically acceptable compounds.

[0053] Compounds of Formula I may exist in a free form (non-ionized) or may form salts, which are also within the scope of the present invention. Unless otherwise specified, reference to a compound of the present invention is understood to include reference to the free form and to its salts. The term "salt" refers to acidic and / or basic salts formed with inorganic and / or organic acids and bases. In addition, the term "salt" can include zwitterions (internal salts), for example, when a compound of Formula I contains both a basic moiety, such as an amine, or a pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as acceptable metal and amine salts in which the cation does not contribute significantly to the toxicity or biological activity of the salt. However, other salts may be useful, for example, in isolation or purification steps that may be employed during preparation, and are thus considered within the scope of the present invention. Salts of compounds of formula I may be formed, for example, by reacting a compound of formula I with a certain amount, such as an equivalent amount, of acid or base in a medium such that the salt precipitates, or in an aqueous medium, followed by lyophilization.

[0054] Examples of acid addition salts include acetate (such as acetate formed with acetic acid or trihaloacetic acids, e.g., trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride (formed with hydrochloric acid), hydrobromide (formed with hydrogen bromide), iodide, and the like. Hydrogen salts, 2-hydroxyethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as salts formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.

[0055] Examples of base salts include ammonium salts; alkali metal salts such as sodium, lithium, and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; barium, zinc, and aluminum salts; salts with organic bases (e.g., organic amines) such as trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, N,N'-dibenzylethylene-diamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine, or similar pharmaceutically acceptable amines; and salts with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfate), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), etc. Preferred salts include monohydrochlorides, hydrogen sulfates, methanesulfonates, phosphates, or nitrates.

[0056] The term "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the skin of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0057] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amines; and alkali or organic acid salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include, for example, the conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; and those prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, oxalic acid, isethionic acid, and the like.

[0058] The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two; non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are generally preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, PA (1990), the disclosure of which is incorporated herein by reference.

[0059] All stereoisomers of the compounds of the present invention are contemplated, either in admixture or in pure or substantially pure form. Stereoisomers include compounds that are optical isomers through the possession of one or more chiral atoms, as well as compounds that are optical isomers through restricted rotation about one or more bonds (atropisomers). The definition of a compound of the present invention encompasses all possible stereoisomers and mixtures thereof. The present invention specifically encompasses racemates and isolated optical isomers of specific activity. Racemic forms can be resolved by physical methods, such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. Individual optical isomers can be obtained from the racemates by conventional methods, such as salt formation with an optically active acid followed by crystallization.

[0060] The present invention is intended to include all isotopes of atoms occurring in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon are 13 C and 14 C. Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described herein, utilizing an appropriate isotopically labeled reagent in place of an unlabeled reagent.

[0061] Prodrugs and solvates of the compounds of the present invention are also contemplated. The term "prodrug" refers to a compound that, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to produce a compound of Formula I, and / or a salt and / or solvate thereof. Any compound that is converted in vivo to provide a biologically active agent (i.e., a compound of Formula I) is a prodrug within the scope and spirit of the present invention. For example, a compound containing a carboxy group can be hydrolyzed in the body to produce the compound of Formula I itself, thereby forming a physiologically hydrolyzable ester that functions as a prodrug. Oral administration of such prodrugs is often preferred, as hydrolysis occurs primarily under the influence of digestive enzymes. Parenteral administration may also be used when the ester itself is active, or in those cases where hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of compounds of Formula I include C 1-6 Alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C 1-6 Alkanoyloxy C 1-6 Alkyl, for example, acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl, C 1-6 Alkoxycarbonyloxy C 1-6 Included are alkyl, such as methoxycarbonyloxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl, and other well-known physiologically hydrolyzable esters used, for example, in the penicillin and cephalosporin fields. Such esters can be prepared by conventional techniques known in the art.

[0062] Various forms of prodrugs are well known in the art and are described in Rautio, J. et al., Nature Review Drug Discovery, 17, 559-587 (2018). The compounds of formula I and their salts may exist in their tautomeric forms, in which hydrogen atoms are transferred to other parts of the molecule, resulting in rearrangement of the chemical bonds between the atoms of the molecule. It should be understood that all tautomeric forms, if any, are included in the present invention. In addition, the compounds of the present invention may have trans and cis isomers. It will further be understood that solvates (eg, hydrates) of the compounds of Formula I are also within the scope of the present invention. Methods of solvation are generally known in the art.

[0063] usefulness The compounds of the present invention modulate IL-23-stimulated and IFNα-stimulated cellular functions, including gene transcription. Other types of cellular functions that may be modulated by the compounds of the present invention include, but are not limited to, responses to IL-12 stimulation. Thus, the compounds of Formula I, by acting on Tyk2 to mediate signal transduction, have utility in treating conditions associated with modulation of IL-23 and / or IFNα function, particularly selective inhibition of IL-23, IL-12 and / or IFNα function, including cytokine-associated diseases in which the pathogenic mechanism is mediated by IL-23, IL-12 or IFNα, with subsequent activation of the Tyk2 pathway and subsequent inflammatory responses in peripheral and / or central compartments.

[0064] As used herein, the terms "treating" or "treatment" include the treatment of a condition in a mammal, particularly a human, and include (a) preventing or delaying the onset of the condition in a mammal, particularly where the mammal has not yet been diagnosed with the condition but is predisposed to the condition; (b) inhibiting the condition, i.e., halting or slowing its progression; and / or (c) achieving complete or partial alleviation of the symptoms or condition, and / or palliating, ameliorating, alleviating, or curing the disease or disorder and / or its symptoms.

[0065] In view of their activity as modulators of IL-23, IL-12 and / or IFNα stimulated cellular responses, the compounds of Formula I are useful in treating inflammatory diseases such as Crohn's disease, ulcerative colitis, asthma, graft-versus-host disease, allograft rejection, and chronic obstructive pulmonary disease; autoimmune diseases such as Graves' disease, rheumatoid arthritis, systemic lupus erythematosus (SLE), cutaneous lupus, lupus nephritis, discoid lupus erythematosus, neuropsychiatric SLE, and psoriasis; autoinflammatory diseases including CAPS, TRAPS, FMF, adult-onset stills, systemic-onset juvenile idiopathic arthritis, gout, and gouty arthritis; metabolic diseases including type 1 diabetes, type 2 diabetes, atherosclerosis, and myocardial infarction; bone resorption diseases, osteoarthritis, osteoporosis, and multiple myeloma-related bone disease. proliferative disorders such as acute myeloid leukemia and chronic myeloid leukemia; angiogenic disorders including solid tumors, ocular neovascularization, and infantile hemangiomas; infectious diseases such as sepsis, septic shock, and Shigellosis; Alzheimer's disease, Parkinson's disease, ALS, multiple sclerosis (including clinically isolated syndrome (CIS), RMS, and / or progressive MS), optic neuritis, neuromyelitis optica, cerebral ischemia or neurodegenerative diseases caused by trauma; metastatic melanoma, Kaposi's sarcoma, multiple myeloma, and oncogenic and viral diseases such as HIV infection and CMV retinitis, AIDS.

[0066] More specifically, specific conditions or diseases that may be treated with the compounds of the present invention include, but are not limited to, pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, cutaneous lupus, lupus nephritis, discoid lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutrophilemia, and the like. Thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft-versus-host disease, endotoxin-induced inflammatory response, tuberculosis, atherosclerosis, muscle degeneration, cachexia, ulcerative arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella-related arthritis, acute synovitis, pancreatic beta-cell disease; diseases characterized by massive neutrophil infiltration; and rheumatoid spondylitis. Gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, allograft rejection, fever and myalgia due to infection, cachexia secondary to infection, keloid formation, scar tissue formation, ulcerative colitis, fever, influenza, osteoporosis, osteoarthritis, acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, and shigellosis; Alzheimer's disease, Parkinson's disease, multiple sclerosis (including clinically isolated syndrome (CIS), RMS and / or progressive MS), optic neuritis, neuromyelitis optica, and trauma cerebral ischemia or neurodegenerative diseases caused by: solid tumors, ocular neovascularization, and infantile hemangiomas; angiogenic disorders including acute hepatitis infections (including hepatitis A, B, and C), HIV infection, and CMV retinitis, AIDS, ARC or malignant tumors, and viral diseases including herpes; stroke, myocardial ischemia, ischemia in apoptotic heart attacks, organ hypoxia, vascular hypertrophy, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, conditions associated with prostaglandin endoperoxidase synthase-2, and pemphigus vulgaris.Preferred methods of treatment are those in which the condition is selected from Alzheimer's disease, Parkinson's disease, ALS, multiple sclerosis (RMS and / or progressive MS, including clinically isolated syndrome (CIS)), optic neuritis or neuromyelitis optica.

[0067] When the terms "IL-23-, IL-12- and / or IFNα-associated condition" or "IL-23-, IL-12- and / or IFNα-associated disease or disorder" are used herein, each is intended to encompass, as if repeated at length, all of the conditions identified above, as well as any other condition affected by IL-23, IL-12 and / or IFNα. The present invention thus provides methods of treating such conditions, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of Formula I, or a salt thereof. A "therapeutically effective amount" is intended to encompass an amount of a compound of the invention that, when administered alone or in combination, is effective to inhibit IL-23, IL-12 and / or IFNα function and / or treat the disease.

[0068] Methods of treating IL-23, IL-12 and / or IFNα-associated disorders may involve administering compounds of Formula I alone or in combination with each other and / or other appropriate therapeutic agents useful in treating such conditions. Accordingly, a "therapeutically effective amount" is also intended to encompass the amount of the claimed compound combination that is effective to inhibit IL-23, IL-12 and / or IFNα function and / or treat disorders associated with IL-23, IL-12 and / or IFNα.

[0069] Examples of such other therapeutic agents include corticosteroids, rotipram, calphostin, cytokine suppressive anti-inflammatory drugs (CSAIDs), interleukin-10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear translocation inhibitors such as deoxyspergualin (DSG); nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, celecoxib, and rofecoxib; steroids such as prednisone or dexamethasone; antiviral agents such as abacavir; antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, PROGRAF®); antimalarials such as hydroxychloroquine; cytotoxic agents such as azathiprine and cyclophosphamide; TNF-α inhibitors such as tenizap, anti-TNF antibodies, or soluble TNF receptors, and rapamycin (sirolimus or RAPAMUNE®) or its derivatives.

[0070] When other therapeutic agents as described above are utilized in combination with the compounds of the present invention, the therapeutic agents may be used in amounts as set forth, for example, in the U.S. Pharmaceutical Register (PDR) or as otherwise determined by one of ordinary skill in the art. In the methods of the present invention, such other therapeutic agents may be administered prior to, simultaneously with, or after the administration of the compounds of the present invention. The present invention also provides pharmaceutical compositions capable of treating IL-23-, IL-12-, or IFNα-associated conditions, including the IL-23-, IL-12-, and / or IFNα-mediated disorders described above, by inhibiting Tyk2-mediated signaling.

[0071] The compositions of the present invention may contain other therapeutic agents as described above and may be formulated, for example, by utilizing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives (e.g., excipients, binders, preservatives, stabilizers, flavorings, etc.) of a type appropriate for the desired method of administration, according to techniques such as those well known in the art of pharmaceutical formulation. Accordingly, the present invention further includes compositions comprising one or more compounds of Formula I and a pharmaceutically acceptable carrier.

[0072] A "pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering a biologically active agent to an animal, particularly a mammal. Pharmaceutically acceptable carriers are formulated according to numerous factors well within the understanding of those skilled in the art. These factors include, but are not limited to, the type and nature of the active agent being formulated; the subject to whom the composition containing the active agent is to be administered; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutically acceptable carriers encompass both aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms. Such carriers can contain many different components and additives in addition to the active agent; such additional components are included in the formulation for various reasons, such as stabilization of the active agent, binders, etc., as is well known in the art. A description of suitable pharmaceutically acceptable carriers and the factors involved in their selection can be found in a variety of readily available sources, such as Remington's Pharmaceutical Sciences, 17th Edition (1985), the contents of which are incorporated herein by reference in their entirety.

[0073] The compound of formula I can be administered by any means suitable for the condition to be treated, depending on the need for site-specific treatment or the amount of drug to be delivered.For skin-related diseases, topical administration is generally preferred, and for cancerous or precancerous conditions, systemic treatment is preferred, but other delivery modes are also considered.For example, the compound can be orally administered in the form of tablets, capsules, granules, powders, or liquid preparations including syrups; topically administered in the form of solutions, suspensions, gels, or ointments; sublingually administered; buccally administered; parenterally administered by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (for example, as sterile injectable aqueous or non-aqueous solutions or suspensions); intranasally administered by inhalation sprays; topically administered in the form of creams or ointments; rectally administered in the form of suppositories; or by using liposomes.A dosage unit formulation containing a non-toxic and pharmaceutically acceptable vehicle or diluent can be administered.The compound can be administered in a form suitable for immediate release or sustained release. Immediate or sustained release may be achieved with suitable pharmaceutical compositions, or, particularly in the case of sustained release, may be achieved using devices such as subcutaneous implants or osmotic pumps.

[0074] Exemplary compositions for topical administration include a topical carrier such as PLASTIBASE® (mineral oil gelled with polyethylene). Exemplary compositions for oral administration include suspensions, which may contain, for example, microcrystalline cellulose to provide bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a thickener, and sweeteners or flavorings, such as substances known in the art; and immediate-release tablets, which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, and / or lactose, and / or other excipients, binders, expanders, disintegrants, diluents, and lubricants, such as substances known in the art.The compounds of the present invention can also be orally delivered by sublingual and / or buccal administration, for example, in molded, compressed, or freeze-dried tablets.Exemplary compositions may include fast-dissolving diluents, such as mannitol, lactose, sucrose, and / or cyclodextrin. Such formulations may also include high molecular weight excipients such as cellulose (AVICEL®) or polyethylene glycol (PEG); excipients that promote mucoadhesion such as hydroxycellulose (HPC), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (SCMC), and / or maleic anhydride copolymers (e.g., GANTREZ®); and release-controlling agents such as polyacrylic acid copolymers (e.g., CARBOPOL 934®). Lubricants, glidants, flavors, colorants, and stabilizers may also be added for ease of manufacture and use.

[0075] Exemplary compositions for nasal aerosol or inhalation administration include solutions which may contain, for example, benzyl alcohol or other suitable preservatives, absorption enhancers to facilitate absorption and / or bioavailability, and / or other solubilizing or dispersing agents, such as those known in the art. Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain a suitable non-toxic parenterally acceptable diluent or solvent such as, for example, mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or other suitable dispersing or wetting agents and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

[0076] Exemplary compositions for rectal administration include suppositories, which may contain suitable non-irritating excipients such as, for example, cocoa butter, synthetic glyceride esters or polyethylene glycols, and which are solid at ordinary temperatures but liquefy and / or melt in the rectal cavity to release the drug.

[0077] Therapeutically effective amounts of the compounds of the present invention may be determined by one skilled in the art, with exemplary dosages for mammals ranging from about 0.05 to 1000 mg / kg of body weight per day, 1-1000 mg / kg of body weight per day, 1-50 mg / kg of body weight per day, or 250-1000 mg / kg of body weight per day, which may be administered as a single dose or in the form of individual divided doses, such as 1-4 times per day. The specific dose level and frequency of administration for a particular subject may vary and will depend on a variety of factors, including the activity of the particular compound utilized, the metabolic stability and length of action of that compound, the subject's species, age, body weight, general health, sex, and diet, the mode and time of administration, excretion rate, drug combination, and the severity of the particular condition. Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats, horses, etc. Thus, when the term "patient" is used herein, it is intended to encompass all subjects, most preferably mammalian species, affected by modulating IL-23, IL-12 and / or IFNα-mediated functions.

[0078] Manufacturing method The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon that would be recognized by those skilled in the art. Preferred methods include, but are not limited to, the following: All references cited herein are incorporated herein in their entirety by reference.

[0079] The compounds of the present invention can be prepared using the reactions and techniques described in this section. Reactions are carried out in solvents appropriate to the reagents and materials employed, which are suitable for the transformations affected. Furthermore, in the following description of synthetic methods, all proposed reaction conditions, including solvent selection, reaction environment, reaction temperature, experimental duration, and workup procedures, are selected to be standard conditions for the reactions and would be readily recognized by those skilled in the art. Those skilled in the art of organic synthesis will understand that functional groups present on various portions of the molecule must be compatible with the proposed reagents and reactions. Such limitations on substituents compatible with the reaction conditions will be apparent to those skilled in the art, and in such cases, alternative methods must be used. This may sometimes necessitate judgment to modify the order of synthetic steps or select one particular process scheme over another to obtain the desired compounds of the present invention. It will also be appreciated that another major consideration in designing any synthetic route in this field is the careful selection of protecting groups used to protect reactive functional groups present in the compounds described herein. An authoritative account describing many alternative methods for the skilled artisan is Greene and Wuts (Protective Groups In Organic Synthesis, Third Edition, Wiley and Sons, 1999).

[0080] Key intermediates shown in Figure 1 can be assembled to provide compound I using building blocks such as those shown in Figure 1 in a variety of ways known to those skilled in the art of synthetic organic chemistry. Figure 1 [ka]

[0081] Scheme 1 Scheme 1 illustrates how one skilled in the art can treat compound Ib with a strong base, particularly n-BuLi / TMEDA, followed by quenching with a trialkyl borate, particularly triisopropyl borate, to obtain compound Ic. The resulting compound Ic can be treated with compound Ia under palladium catalysis, particularly Suzuki conditions, to obtain compound Id. Id can be reacted with various reagents known to those skilled in the art, particularly 2,4-dimethoxybenzylamine, to obtain protected amines such as compound Ie. These protected amines can be deprotected using appropriate methods known to those skilled in the art, particularly trifluoroacetic acid in the case of Ie, to obtain key intermediate IIa.

[0082] [ka]

[0083] Scheme 2 The commercially available compound If can be reduced to the corresponding amine Ig using various conditions known to those skilled in the art, particularly iron and ammonium chloride at elevated temperatures in ethanol and water. Compound Ig can be treated with bis(pinacolato)diboron under palladium-catalyzed conditions to give pinacol boronate 1g. Other reagents known to those skilled in the art, such as tin reagents and other boron-based reagents, can be used in place of the reaction system shown to give compounds similar in utility to compound 1g. 1g can be coupled with Ia under various palladium-catalyzed conditions known to those skilled in the art to give key compound IIa.

[0084] [ka]

[0085] Scheme 3 Scheme 3 shows how a person skilled in the art of organic synthesis can couple compound III (see Moslin et al., J. Med. Chem 2019, 62, 8953-8972 or U.S. Pat. No. 9,505,748) with a compound of general formula II to obtain an intermediate of general formula IIIa. The reaction involves mixing the two reagents in a suitable aprotic solvent, particularly THF or 2-methyl-THF, at 0° C. to 50° C., and adding a suitable base, particularly lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, or sodium hydride, depending on the individual case.

[0086] [ka]

[0087] Scheme 4 Compounds of general formula IV are either commercially available or can be prepared by those skilled in the art of organic synthesis by the method illustrated in Scheme 4 (or other known methods). Chloroethyl isocyanate can be reacted with a primary amine, followed by treatment with various bases in a variety of aprotic solvents, particularly sodium hydride in tetrahydrofuran, to give compounds of general formula IV. Additionally, when the primary amine is unavailable or unreactive, such as when R=CF3, the cyclic urea IVa can be monoprotected with a labile group, particularly 4-methoxybenzyl, to give compound IVb. Treatment of IVb with trimethylsilyltrifluoromethane in the presence of silver triflate, cesium fluoride, 2-fluoropyridine, and Selectfluor® gives compound IVc. IVc can then be deprotected using trifluoroacetic acid under various conditions known to those skilled in the art, particularly at elevated temperatures, to give compound IVd.

[0088] [ka]

[0089] Scheme 5 Scheme 5 illustrates a method by which one skilled in the art of organic synthesis can couple a compound of general formula III to a suitable substrate IV in one step to produce a compound of general formula I. The one-step method involves coupling a compound of general formula III with a urea of ​​general formula IV under transition metal catalyzed conditions. In particular, preferred conditions for this reaction utilize a Buchwald-type coupling using Pd(dba) as the catalyst, 1,1'-bis(dicyclohexylphosphino)ferrocene as the ligand, and CsCO as the base at elevated temperatures, particularly 110°C. This catalyst / ligand / base system can be modified in ways known to those skilled in the art of organic synthesis.

[0090] [ka]

[0091] First, identify the method (e.g., LCMS), e.g.: LCMS-Method A: A linear gradient of 2% to 40% solvent B over 4 minutes, held at 100% B for 0.6 minutes, followed by a gradient to 20% B over 0.1 minutes and a hold at 20% B for 0.3 minutes. Solvent A: 5 mM ammonium formate (pH 3.3):ACN (98:02) Solvent B:ACN:Buffer (98:02) Flow rate: 1.0ml / min Column: Kinetex XB-C18 (75x3.0) mm, 2.6 μm Ultraviolet ("UV") visualization at 220 nanometers ("nm")

[0092] LCMS-Method B: A linear gradient from 20% to 100% solvent B over 4 minutes, held at 100% B for 0.6 minutes, followed by a gradient to 20% B over 0.1 minutes and a hold at 20% B for 0.3 minutes. Solvent A: 5 mM ammonium formate (pH 3.3):ACN (98:02) Solvent B:ACN:Buffer (98:02) Flow rate: 1.0ml / min Column: Kinetex XB-C18 (75x3.0) mm, 2.6 μm Ultraviolet ("UV") visualization at 220 nanometers ("nm")

[0093] LCMS-Method C: A linear gradient of 5% to 95% solvent B over 2.5 minutes, held at 95% B for 1.5 minutes, followed by a gradient to 5% B over 0.5 minutes and a hold at 5% B for 1 minute. Solvent A: 0.1% TFA in HO Solvent B: 0.1% TFA in ACN Flow rate: 1.5ml / min Column: XBridge C18 (50 x 4.6) mm, 3.5 μm Ultraviolet ("UV") visualization at 220 nanometers ("nm")

[0094] GCMS-Method D: Chromatography column: HP-5 (30m x 320μm x 0.25μm) Column length: 30 m, inner diameter: 0.32 mm, thickness: 0.25 μm Injection port temperature: 250°C; Carrier gas: He Detector temperature: 300°C; column flow rate: 2 mL / min Air flow: 400 mL / min; H2 flow: 40 mL / min Heating schedule: 120°C, hold for 3 minutes; then ramp to 300°C at 40°C / min and hold for 2 minutes Source temperature: 230℃ Recording: Agilent Technologies 5977B MSD7890B GC using 5977B MSD is.

[0095] [Table 1]

[0096] Intermediate 1 [ka]

[0097] Step 1: To a stirred solution of 2-fluoro-3-methoxypyridine (10 g, 79 mmol) and TMEDA (23.74 mL, 157 mmol) in THF (120 mL) was added n-butyllithium (37.8 mL, 94 mmol) at −78° C. Then, it was stirred at the same temperature for 2 hours. Triisopropyl borate (27.4 mL, 118 mmol) was added to the reaction mixture at −78° C. and stirred for 2 hours. The reaction mixture was quenched with water (50 ml) at −78° C. and then extracted with diethyl ether (2×100 mL). The aqueous layer was acidified (pH 4) with acetic acid and extracted with ethyl acetate (2×100 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The desired product, (2-fluoro-3-methoxypyridin-4-yl)boronic acid (11 g, 63.7 mmol, 81% yield), was isolated as an off-white solid. MS(M+1) m / z:172.2[M+1] + ;LC retention time: 0.63 min [Method A]

[0098] Step 2: To a stirred solution of (2-fluoro-3-methoxypyridin-4-yl)boronic acid (5 g, 29.3 mmol) in water (6 mL) and 1,4-dioxane (60 mL), KPO (12.74 g, 73.1 mmol) was added at ambient temperature, which was then degassed under a N atmosphere for 10 minutes. 4-Bromo-2-methyl-2H-1,2,3-triazole (4.74 g, 29.3 mmol) and PdCl(dppf) [DCM adduct] (2.389 g, 2.93 mmol) were added to the reaction mixture, which was then degassed for 5 minutes. The reaction mixture was stirred in a sealed tube at 80 °C for 6 hours. The reaction mixture was filtered through a Celite pad and washed with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by silica gel (230-400 mesh) column chromatography eluting with 10-15% ethyl acetate in petroleum ether to give 2-fluoro-3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridine (5.2 g, 22.98 mmol, 79% yield) as an off-white solid. MS(M+1) m / z:209.0[M+1] + ;LC retention time: 1.49 minutes [Method B] 1 H-NMR (400MHz, DMSO-d6): δ 8.29(s,1H), 7.98(dd,J=1.20, 5.00Hz,1H), 7.78(dd,J=0.40, 5.00Hz, 1H), 4.27(s,3H), 3.98(d,J=2.40Hz,3H)

[0099] Step 3: 2-Fluoro-3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridine (5 g, 24.02 mmol) and (2,4-dimethoxyphenyl)methanamine (25 g, 150 mmol) were stirred in a sealed tube at 100° C. for 16 hours. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×150 mL). The organic layers were combined, washed with brine solution (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by silica gel (230-400 mesh) column chromatography eluting with 20-25% ethyl acetate in petroleum ether to give N-(2,4-dimethoxybenzyl)-3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine (6.2 g, 14.31 mmol, 59.6% yield) as an off-white solid. MS(M+1)m / z: 356.2[M+1] + ;LC retention time: 1.45 minutes [Method B]

[0100] Step 4: To a stirred solution of N-(2,4-dimethoxybenzyl)-3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine (6 g, 16.88 mmol) in CHCl (60 mL) was added TFA (13.01 mL, 169 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was quenched with 10% NaHCO solution (100 mL), and then it was extracted with ethyl acetate (2×200 mL). The organic layers were combined, washed with brine solution (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was washed with 5% EtOAc in petroleum ether to give the desired 3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine (3.80 g, 14.81 mmol, 88% yield) as an off-white solid. MS(M+1)m / z:206.2[M+1] + ;LC retention time: 0.89 min [Method A] 1H-NMR (400MHz, DMSO-d6): δ 8.17(s,1H), 7.74(d,J=5.60Hz,1H), 6.98(d,J=5.60Hz,1H), 6.17(s,2H), 4.24(s,3H), 3.65(s,3H)

[0101] Intermediate 2 [ka]

[0102] Step 1: To a solution of 1-bromo-2-methoxy-3-nitrobenzene (2.0 g, 8.62 mmol) in ethanol (20 mL) and water (5 mL) was added iron (3.37 g, 60.3 mmol) and ammonium chloride (2.3 g, 43.3 mmol). The reaction mixture was stirred at 60 °C for 3 h, diluted with ethanol (50 mL), and filtered through a Celite pad. The filtrate was concentrated under reduced pressure to give the crude product. The crude residue was diluted with EtOAc (100 mL) and washed with water (2 × 20 mL) and brine (2 × 20 mL). The organic layer was collected, dried over anhydrous NaSO, and concentrated under reduced pressure to give 3-bromo-2-methoxyaniline (1.8 g, 8.55 mmol, 99% yield) as a brown liquid. MS(M+1)m / z:202.0(M+H) + ;LC retention time: 1.84[A]

[0103] Step 2: To a stirred solution of 3-bromo-2-methoxyaniline (1.80 g, 8.91 mmol) in 1,4-dioxane (15 mL) in a sealed test tube was added bis(pinacolato)diboron (3.39 g, 13.36 mmol) and potassium acetate (2.62 g, 26.7 mmol). The reaction mixture was purged with nitrogen gas for 5 minutes, and then PdCl(dppf)[DCM adduct] (0.73 g, 0.89 mmol) was added. The reaction mixture was stirred at 90° C. for 5 hours, then cooled to room temperature and diluted with EtOAc (100 mL). The reaction mixture was filtered through a Celite® pad, and the filtrate was washed with water (50 mL) and brine (50 mL). The organic extracts were combined, dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (25% ethyl acetate in petroleum ether) to give 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.8 g, 6.88 mmol, 77% yield) as a light brown solid. MS(M+1)m / z:250.4(M+H) + ;LC retention time: 2.11[A]

[0104] Step 3: To a stirred solution of 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.31 g, 9.26 mmol) and 4-bromo-2-methyl-2H-1,2,3-triazole (1.50 g, 9.26 mmol) in DME (15 mL) and water (5 mL) was added sodium carbonate (2.45 mg, 23.15 mmol). The reaction mixture was purged with nitrogen gas for 5 minutes, and Pd(PhP) (1.07 g, 0.93 mmol) was added. The reaction mixture was stirred at 90 °C for 6 hours. The reaction mixture was filtered through a Celite pad and washed with methanol (50 mL). The filtrate was concentrated under reduced pressure, and the crude residue was partitioned between ethyl acetate (150 mL) and water (150 mL). The organic layer was collected, dried over anhydrous NaSO, filtered, and concentrated. The crude residue was purified by silica gel chromatography (50% ethyl acetate in petroleum ether) to give the desired 2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (1.70 g, 7.67 mmol, 83% yield) as a brown crystalline solid. MS(M+1)m / z:205.2(M+H) + ;LC retention time: 1.20[A]

[0105] Intermediate 3 [ka]

[0106] Step 1: To a solution of lithium 4,6-dichloropyridazine-3-carboxylate (10.0 g, 51.8 mmol) in DCM (200 mL) was added oxalyl chloride (9.07 mL, 104.0 mmol) and 1 mL of DMF at 0° C. The reaction mixture was allowed to warm to room temperature over 1 hour. The solvent was removed under reduced pressure, and DCM (200 mL) was added to the reaction mixture. The resulting solution was cooled to −30° C., and deuterated methylamine hydrochloride (4.02 g, 57.0 mmol) was added, followed by DIPEA (18.1 mL, 104.0 mmol). The reaction mixture was stirred at −30° C. for 1 hour, then allowed to warm to room temperature, which continued for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude residue was dissolved in ethyl acetate (200 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was collected, dried over anhydrous NaSO, and then concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (10-15% ethyl acetate in petroleum ether) to give the desired product, 4,6-dichloro-N-(methyl-d)pyridazine-3-carboxamide (4.1 g, 19.42 mmol, 37.5% yield) as a pale yellow solid. MS(M+1)m / z:208.6(M+H) + LC retention time: 1.18 min [B]

[0107] Step 2: To a stirred solution of 3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine (2.5 g, 12.18 mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (3.06 g, 14.62 mmol) in THF (50 mL) was added LiHMDS (48.7 mL, 48.7 mmol, 1 M solution in THF) at ambient temperature. The reaction mixture was stirred at this temperature for 2 hours and quenched with aqueous NH4Cl (50 mL), which was then extracted with ethyl acetate (2 x 100 mL). The organic layers were combined, washed with saturated brine solution (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel (230-400 mesh) column chromatography eluting with 90% ethyl acetate in petroleum ether to give the desired 6-chloro-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (3.2 g, 7.45 mmol, 61.2% yield) as an off-white solid. MS(M+1)m / z:378.2(M+H) + LC retention time: 1.39 min [Method B]

[0108] The following intermediates (3a-3c) were prepared in a similar manner to the preparation of intermediate 3:

[0109] [ka] [Table 2]

[0110] Intermediate 4 [ka]

[0111] To a stirred solution of cyclopropanamine (0.541 g, 9.48 mmol) in THF (20 mL) was added 1-chloro-2-isocyanatoethane (1.0 g, 9.48 mmol) dropwise at ambient temperature. The reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the crude product was dissolved in THF (10 mL), followed by the portionwise addition of NaH (0.455 g, 18.95 mmol) at 0 °C. The reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was quenched with cold water (50 mL). The crude product was extracted with ethyl acetate (2 × 50 mL), washed with brine solution, dried over sodium sulfate, and concentrated. The crude product was washed with n-pentane (20 mL) to afford the desired 1-cyclopropylimidazolidin-2-one (870 mg, 6.83 mmol, 72.0% yield) as an off-white solid. GCMS(M)m / z:127.2(M) + ;Retention time: 0.34 minutes [D]

[0112] Intermediate 5 [ka]

[0113] Step 1: To a stirred solution of imidazolidin-2-one (2 g, 23.23 mmol) in DMF (5 mL) was added cesium carbonate (11.35 g, 34.8 mmol), p-methoxybenzyl chloride (3.64 g, 23.23 mmol), and potassium iodide (0.771 g, 4.65 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ice-cold water (50 mL) and extracted with ethyl acetate (2 × 100 mL). The organic fractions were combined, dried over anhydrous NaSO, and concentrated in vacuo to give the crude product. The crude product was purified by reverse-phase column chromatography using 0.1% aqueous ammonium formate in ACN as the eluent to give the desired product, 1-(4-methoxybenzyl)imidazolidin-2-one (1.5 g, 6.55 mmol, 28.2% yield), as a white crystalline solid. MS(M+1)m / z:207.2(M+H)+ ;LC retention time: 0.75[C]

[0114] Step 2: To a stirred solution of 1-(4-methoxybenzyl)imidazolidin-2-one (500 mg, 2.424 mmol) in THF (20 mL) and chlorobenzene (2 mL), silver trifluoromethanesulfonate (685 mg, 2.67 mmol), Selectfluor® (3435 mg, 9.70 mmol), 2-fluoropyridine (0.229 mL, 2.67 mmol), and trifluoromethyltrimethylsilane (1724 mg, 12.12 mmol) were added at 0°C, followed by CsF (1841 mg, 12.12 mmol). It was then stirred at ambient temperature for 16 hours. The reaction mixture was filtered under reduced pressure and washed with EtOAc (100 mL). The filtrate was concentrated in vacuo. The crude product was purified by reverse phase column chromatography using 0.1% ammonium formate in ACN to give the desired 1-(4-methoxybenzyl)-3-(trifluoromethyl)imidazolidin-2-one (300 mg, 0.941 mmol, 38.8% yield) as a brown gummy solid. MS(M+1)m / z:275.2(M+H) + ;LC retention time: 1.22[C]

[0115] Step 3: Trifluoroacetic acid (8 mL, 38.3 mmol) was added to 1-(4-methoxybenzyl)-3-(trifluoromethyl)imidazolidin-2-one (350 mg, 1.276 mmol) at 0° C. The reaction mixture was stirred at 50° C. for 4 hours. After completion, the reaction mixture was concentrated under reduced pressure and washed with n-pentane (20 mL) to give the desired 1-(trifluoromethyl)imidazolidin-2-one (150 mg, 0.146 mmol, 11.44% yield) as a brown gummy solid. The crude product was used directly without further purification. MS(M+1)m / z:155.2(M+H) + ;LC retention time: 0.56[C]

[0116] Example 1 [ka]

[0117] To a stirred solution of 6-chloro-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)nicotinamide (0.2 g, 0.531 mmol) in 1,4-dioxane (10 mL) in a 40 mL pressure-release vial, 1-isopropylimidazolidin-2-one (0.068 g, 0.531 mmol), Pd2dba3 (0.024 g, 0.027 mmol), 1,1'-bis(dicyclohexylphosphino)ferrocene (0.015 g, 0.027 mmol), followed by Cs2CO3 (0.432 g, 1.327 mmol) were added. The reaction mixture was degassed with N2 for 5 minutes. The resulting reaction mixture was heated to 110 °C for 3 hours. After completion, the reaction mixture was diluted with ethyl acetate (100 mL), filtered through a Celite® pad, and thoroughly washed with ethyl acetate (100 mL). The filtrate was washed with water (50 mL) followed by brine (50 mL) and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and the resulting crude residue was purified by reverse-phase column chromatography (C18 column) using a 50% acetonitrile in 1% ammonium formate in water eluent to afford the desired product, 6-(3-isopropyl-2-oxoimidazolidin-1-yl)-4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)nicotinamide (80 mg, 0.167 mmol, 31.4% yield) as an off-white solid. MS(M+1)m / z:469.2(M+H) + ;LC retention time: 1.76[A]

[0118] 1H-NMR (400MHz, DMSO-d6):δ 12.33(s,1H), 9.96(s,1H), 9.29(s,1H), 8.31(s,1H), 8.16(d,J=5.20Hz,1H), 7.46(d,J=5.20Hz, 1H), 4.28(s,3H), 4.18-4.11(m,3H), 3.82(s,3H), 3.50(t,J=7.60Hz,2H), 1.17(d,J=6.40Hz,6H)

[0119] The following Examples (2-6) were prepared in the same manner as in Example 1. [ka] [Table 3] [Table 4]

[0120] Example 8 [ka] [ka]

[0121] Step 1: 4-Bromo-6-methyl-2-nitropyridin-3-ol Concentrated sulfuric acid (1 mL) was added dropwise to solid 4-bromo-6-methylpyridin-3-ol (0.267 g, 1.420 mmol) in a flask at -10 °C (in a salt and ice bath). Fuming nitric acid (0.063 mL, 1.420 mmol) was then added dropwise. The reaction mixture was stirred overnight while the reaction was allowed to slowly warm to room temperature. The reaction mixture was poured onto approximately 50 g of ice. After the ice had melted, the mixture was transferred to a separatory funnel and extracted with DCM (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give 4-bromo-6-methyl-2-nitropyridin-3-ol (165 mg, 0.708 mmol, 49.9% yield) as a yellow solid.1 H NMR (400 MHz, chloroform-d) δ 10.63 (s, 1H), 7.75 (s, 1H), 2.57 (s, 3H)

[0122] [ka]

[0123] Step 2: 4-Bromo-3-methoxy-6-methyl-2-nitropyridine A mixture of 4-bromo-6-methyl-2-nitropyridin-3-ol (160 mg, 0.687 mmol), potassium carbonate (474 ​​mg, 3.43 mmol), and MeI (0.215 mL, 3.43 mmol) in DMF was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc (30 mL) and water (30 mL). The organic layer was washed with 10% LiCl (2×30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give 4-bromo-3-methoxy-6-methyl-2-nitropyridine (133 mg, 0.538 mmol, 78% yield) as a brown solid. MS (M+1) m / z: 247.0 (249.0) (M+H). + ;LC retention time: 1.02[E]

[0124] [ka]

[0125] Step 3: 4-Bromo-3-methoxy-6-methylpyridin-2-amine To a solution of 4-bromo-3-methoxy-6-methyl-2-nitropyridine (133 mg, 0.538 mmol) in ethanol (0.6 mL), acetic acid (0.3 mL), and water (0.6 mL) was added iron powder (210 mg, 3.77 mmol) while stirring at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for a total of 2 hours. The reaction mixture was filtered through Celite®, and the filter cake was rinsed with EtOAc and water. The filtrate was transferred to a separatory funnel, and 50 ml of 1.5 M dipotassium hydrogen phosphate was added. After shaking, the layers were separated, and the organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate, and concentrated to give 4-bromo-3-methoxy-6-methylpyridin-2-amine (101 mg, 0.465 mmol, 86% yield) as a cream-colored solid. MS (M+1) m / z: 217.0 (219.0) (M+H). + ;LC retention time: 0.64[E]

[0126] [ka]

[0127] Step 4: 3-Methoxy-6-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine A stirred mixture of (2-methyl-2H-1,2,3-triazol-4-yl)boronic acid (Intermediate 19) (89 mg, 0.698 mmol), 4-bromo-3-methoxy-6-methylpyridin-2-amine (101 mg, 0.465 mmol), and PdCl(dppf)-CHCl adduct (19.00 mg, 0.023 mmol) in dioxane (3.5 mL) was degassed by bubbling nitrogen through the mixture for 5 minutes. 2M KPO (aqueous) (0.698 mL, 1.396 mmol) was added quickly, and the reaction mixture was heated at 100 °C for 0.75 hours. After cooling to room temperature, the reaction mixture was partitioned between EtOAc (30 mL) and brine (20 mL). After drying over anhydrous sodium sulfate solution, the organic layer was concentrated and the residue was chromatographed on a 12 g ISCO silica gel cartridge eluting with a 0-100% EtOAc / Hex gradient. The purified fractions were concentrated to give 3-methoxy-6-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine (75 mg, 0.342 mmol, 73.5% yield) as a light yellow solid. MS (M+1) m / z: 220.2 (M+H). + ;LC retention time: 0.68[E]

[0128] [ka]

[0129] Step 5: 6-chloro-4-((3-methoxy-6-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide To a solution of 3-methoxy-6-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amine (75 mg, 0.342 mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (143 mg, 0.684 mmol) in THF (3 mL) was added dropwise KHMDS (1 M in THF, 1.539 mL, 1.539 mmol) over 10 minutes at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. After quenching with 2 mL of saturated ammonium chloride solution, the organics were removed on a rotovap and the residue was diluted with water. Filtration, rinsing the filter cake with ethyl ether, and drying gave 6-chloro-4-((3-methoxy-6-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (40 mg, 0.102 mmol, 29.8% yield) as a tan solid. MS (M+1) m / z: 392.2 (M+H). + ;LC retention time: 1.13[E]

[0130] Example 8: 6-(3-isopropyl-2-oxoimidazolidin-1-yl)-4-((3-methoxy-6-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide A mixture of 6-chloro-4-((2-methoxy-5-(methoxymethyl)-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (25 mg, 0.059 mmol), 1-isopropylimidazolidin-2-one (40.9 mg, 0.319 mmol), Pd2(dba)3·chloroform adduct (6.59 mg, 6.38 μmol), Xantphos (7.38 mg, 0.013 mmol), and Cs2CO3 (83 mg, 0.255 mmol) in dioxane (0.5 mL) was degassed by bubbling N2 through the mixture for 5 min. The reaction vessel was sealed and heated to 130 °C for 30 min. The reaction mixture was diluted with DMSO and filtered. The filtrate was purified via preparative LC / MS under the following conditions: Column: Xbridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water + 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water + 10 mM ammonium acetate; Gradient: 28% B hold for 0 minutes, 28-70% B over 20 minutes, then 100% B hold for 4 minutes; Flow rate: 20 mL / min; Column temperature: 25°C. Fraction collection was triggered by the MS signal. Fractions containing the desired product were combined and dried via centrifugal evaporation to give 6-(3-isopropyl-2-oxoimidazolidin-1-yl)-4-((3-methoxy-6-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (10.8 mg; 35% yield). MS (M+1) m / z: 484.7 (M+H). + ;LC retention time:2.04[F]; 1 H NMR (500 MHz, DMSO-d6) δ 12.20 (s, 1H), 10.18 (s, 1H), 9.22 (s, 1H), 8.25 (s, 1H), 7.30 (s, 1H), 4.25 (s, 3H), 4.16-4.08 (m, 3H), 3.76 (s, 3H), 1.15 (d, J = 6.8 Hz, 6H); two protons buried under the water peak and the methyl group buried under the DMSO peak.

[0131] Example 9 [ka]

[0132] Example 9: 6-(3-cyclopropyl-2-oxoimidazolidin-1-yl)-4-((3-methoxy-6-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide The compound was prepared using the same procedure as in Example 8. MS(M+1)m / z:482.1(M+H) + ;LC retention time: 1.65[G]; 1 H NMR (500MHz, DMSO-d6)δ 12.23(s,1H), 10.17(s,1H), 9.26(s,1H), 8.27(s,1H), 7.32(s,1H), 4.27(s,3H), 4.07(t,J= 7.9Hz,2H), 3.78(s,3H), 3.49(t,J=8.0Hz,2H), 2.70-2.64(m,1H), 2.53(s,3H), 0.72(s,4H)

[0133] Biological assays The following assays are used to demonstrate the activity of the compounds of the present invention. In vivo assay of brain permeability Pharmacokinetic studies were conducted using C57BL6 wild-type mice (n=3 per experiment) to measure the brain and plasma exposure of the compounds of the present invention. The compounds were orally administered at 5 mL / kg in a solution of 5% ethanol; 90% PEG300; 5% TPGS to a final concentration of 10 mg / kg. The mice were sacrificed 1 hour after administration, and plasma and brain were collected and frozen for analysis. Brain tissue was homogenized in a 1:1 volume ratio with blank C57BL6 mouse plasma. The compound concentrations in plasma and brain homogenates were measured by LC-MS analysis.

[0134] Bidirectional permeability assay in Caco-2 cells overview The compounds were tested in a Caco-2 bidirectional permeability assay to assess their permeability and substrate efflux capacity. Compounds (3 μM in triplicate) were incubated with Caco-2 cells in assay buffer (pH 7.4) containing 0.5% bovine serum albumin (BSA) at 37°C for 2 hours and then extracted for LC-MS analysis. The concentrations in the reaction mixtures were measured, and the permeability coefficients, efflux ratios, and recovery rates were calculated.

[0135] material and method Caco-2 (Caucasian colon adenocarcinoma) cells were obtained from the American Type Culture Collection (Manassas, VA). Dulbecco's modified Eagle's medium (DMEM), N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) buffer, non-essential amino acids, L-glutamine, penicillin-G-streptomycin, and heat-inactivated fetal bovine serum (FBS) were purchased from GIBCO / Invitrogen (Carlsbad, CA). A 96-well plate (surface area: 0.11 cm) with a 0.4 μm pore size polycarbonate membrane was used. 2 ) Transwell plates and low-binding Transwell cluster plates were purchased from Sigma-Aldrich (St. Louis, MO). Low-binding 96-well plates were purchased from Corning (Corning, NY). Modified Hank's Balanced Salt Solution (MHBSS) was prepared by adjusting Hank's Balanced Salt Solution (HBSS) to pH 7.4 with HEPES. HBSS, digoxin, and bovine serum albumin (BSA) were purchased from Sigma (St. Louis, MO). Filtration blocks (2 mL, 96 wells) were purchased from Whatman (Freiburg, Germany). All solvents were analytical grade.

[0136] Cell preparation 14–28 days before the assay, Caco-2 cells were plated at 1.8 × 10 cells on polycarbonate filter membranes in 96-well transwell plates. 5 cells / cm 2 at a density of approximately 2.0x10 per well 4Cells were seeded and cultured in a medium consisting of DMEM supplemented with 10% fetal bovine serum, 10 mM HEPES, 1% non-essential amino acids, 2 mM L-glutamine, 100 U / mL penicillin-G, and 100 μg / mL streptomycin. The medium was changed every 3 days, and cells were maintained at 37°C in a 95% relative humidity and 5% CO2 atmosphere. Immediately prior to the assay, cells were assessed for tight junction formation (see the Quality Control section below).

[0137] Compound production Compounds were solubilized to 10 mM in 100% DMSO. After visual confirmation of complete solubilization, 10 mM compound stocks were plated in 96-well plates and serially diluted with 100% DMSO to create a 100x stock concentration of 0.3 mM. Four control compounds were tested in parallel with the listed compounds and plated in quadruplicate at 100x the concentration of 0.3 mM.

[0138] Permeability evaluation The compounds listed were tested in triplicate in a single experiment at a final concentration of 3 μM. The cell passages used in the assay met QC standards (see Quality Control section below). Studies were performed using monolayers of Caco-2 cells at passages 20-80, cultured for 14-28 days.

[0139] The assay (transport) buffer consisted of MHBSS adjusted to pH 7.4 and 0.5% BSA. Eight microliters of a 100% DMSO stock solution of compound from the 100x compound plate was added to 800 μL of assay buffer, mixed well, and filtered to remove any precipitate as a final preparation step before assay incubation. The targeted final test concentration of the reference and control compounds was 3 μM. The filtrate represents the initial stock compound solution used as the donor solution for the (bidirectional) assay. The reservoir solution was assay buffer alone.

[0140] Immediately prior to performing the assay, each cell monolayer was washed three times with assay buffer to remove any traces of medium. Permeability studies were initiated by adding 100 μL of assay buffer + / - compound to the apical transwell compartments of 96-well transwell low-binding cluster plates and 200 μL of assay buffer + / - compound to the basolateral compartments.

number

number

[0141] Assay sample analysis The concentrations of the compounds and control compounds in the assay samples were determined by LC-MS / MS. The AB Sciex 4500 / 5500 / 6500 multiplex system consisted of a Shimadzu 20ADvp dual pump with two sets of SCL-20Avp controllers for gradient elution, an LS1 autosampler, and an AB Sciex 4500 / 5500 / 6500 triple quadrupole mass spectrometer operating in electrospray ionization (ESI) mode. To obtain optimal SRM conditions for analyzing the samples, MS / MS optimization for each compound was performed using a Discovery Quant® (AB Sciex) instrument featuring saturation control with a 5 μM standard solution in a 1:1 mixture of methanol and water (v / v) prepared from the compound's stock solution. Optimization was performed using flow injection analysis with an injection volume of 40 μL under isocratic elution with 75% mobile phase B (0.2% formic acid in acetonitrile) and 25% mobile phase A (0.2% formic acid in water).

[0142] A 5 μL aliquot of the sample was injected onto a Kinetex XB-C18, 2.6 μm, 2.1×30 mm column and then separated under gradient elution with a mobile phase consisting of A (0.2% formic acid in water) and B (0.2% formic acid in acetonitrile).

[0143] [Table 5]

[0144] The optimal ionization polarity (positive or negative), precursor and product ions, declustering potential, and collision energy for the compounds listed and reference compounds were automatically determined using DiscoveryQuant®. Optimized SRM MS / MS conditions were used for sample analysis. The peak area ratio of the listed or reference compounds relative to the internal volume was used for quantification. The peak area ratio of the compound in the compound dose solution was used to determine the compound concentration in the sample.

[0145] Data analysis For the compounds listed, the following results were reported: permeability coefficient (Pc [nanometers / second]), efflux ratio, and percent recovery.

[0146] The Pc value is calculated using the following formula:

number

[0147] The discharge ratio is as follows:

number

[0148] Percent recovery was calculated by expressing the total amount of test compound (nmoles) present (combined) in the donor and receiver assay compartments at the end of the incubation period as a fraction (percentage) of the total amount of test compound (nmoles) added to the donor compartment prior to assay incubation, using the following formula:

number

[0149] quality control On the day of the assay, Caco-2 cells in one of the transwell plates were assessed for tight junction formation via transepithelial electrical resistance (TEER) measurements. TEER assessment was performed using an EVOM resistivity meter (World Precision Instruments, Sarasota, FL). Each well of the transwell plate had a resistance of >600 Ω cm. 2 The cells of this plating batch were passaged and all plates were accepted for the assay. Four control compounds with Pc values ​​spanning the permeability range were tested in parallel with the compounds listed in each experiment. The assay acceptance criteria required that the control compound results at 3 μM be within the historically acceptable range. The historically observed Pc values ​​and acceptable ranges for efflux ratios for these four control compounds are shown in Table B.

[0150] In these studies, the results for all control compounds were within their respective historical ranges, and thus the assay data were employed for data analysis and evaluation of compounds that describe bidirectional permeability in Caco-2 cells. [Table 6]

[0151] IFNα-induced STAT phosphorylation in human whole blood After incubation with compounds for 1 hour, human whole blood (collected using ACD-A as an anticoagulant) was stimulated with 1000 U / mL recombinant human IFNα A / D (R&D Systems, 11200-2) for 15 minutes. Stimulation was terminated by the addition of fixation / lysis buffer (BD558049). Cells were stained with CD3 FITC antibody (BD555916), washed, and permeabilized with PermIII buffer (BD558050) on ice. Cells were then stained with Alexa-Fluor 647 pSTAT5 (pY694) antibody (BD612599) for 60 minutes and then analyzed using an iQue Plus system. pSTAT5 expression was quantified as median fluorescence intensity after gating on the CD3-positive population.

[0152] [Table 7]

Claims

1. Formula I: 【Chemistry 1】 [In the formula: X is —N— or —CH—; Y is —N— or —CH—; R is 【Chemistry 2】 and R １ is CF ３ , C １－６ Alkyl or C ３－６ is cycloalkyl; R ２ is H or C １－６ is alkyl; Z is CHR １ , C.H. ２ , C.R. １ ２ , O., N.R. １ or C(O); n is 0, 1, 2 or 3. or a stereoisomer or a pharmaceutically acceptable salt thereof.

2. formula: 【Transformation 3】 [In the formula: R is 【Chemistry 4】 and R １ is CF ３ , C １－６ Alkyl or C ３－６ is cycloalkyl; R ２ is H or C １－６ is alkyl; Z is CHR １ , C.H. ２ , C.R. １ ２ , O., N.R. １ or C(O); n is 0, 1, 2 or 3.

2. The compound of claim 1, wherein:

3. formula: 【Transformation 5】 [In the formula: R is 【Transformation 6】 and R １ is CF ３ , C １－６ Alkyl or C ３－６ is cycloalkyl; Z is CHR １ , C.H. ２ , C.R. １ ２ , O., N.R. １ or C(O); n is 0, 1, 2 or 3.

2. The compound of claim 1, wherein:

4. formula: 【Transformation 7】 [In the formula: R is 【Transformation 8】 and R １ is CF ３ , C １－６ Alkyl or C ３－６ is cycloalkyl; Z is CHR １ , C.H. ２ , C.R. １ ２ , O., N.R. １ or C(O); n is 0, 1, 2 or 3.

2. The compound of claim 1, wherein:

5. formula: 【Chemistry 9】 [In the formula: R is 【Chemistry 10】 and R １ is CF ３ , C １－６ Alkyl or C ３－６ is cycloalkyl; Z is CHR １ , C.H. ２ , C.R. １ ２ , O., N.R. １ or C(O); n is 0, 1, 2 or 3.

2. The compound of claim 1, wherein:

6. 4-{[3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( ２ H3) methyl-6-[2-oxo-3-(propan-2-yl)imidazolidin-1-yl]pyridazine-3-carboxamide; 4-{[3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( ２ H3) methyl-6-[2-oxo-3-(propan-2-yl)imidazolidin-1-yl]pyridine-3-carboxamide; 4-{[2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( ２ H3) methyl-6-[2-oxo-3-(propan-2-yl)imidazolidin-1-yl]pyridine-3-carboxamide; 6-(3-cyclopropyl-2-oxoimidazolidin-1-yl)-4-{[3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 6-(3-cyclopropyl-2-oxoimidazolidin-1-yl)-4-{[2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 6-(3-isopropyl-2-oxoimidazolidin-1-yl)-4-((3-methoxy-6-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d ３ ) pyridazine-3-carboxamide; 6-(3-cyclopropyl-2-oxoimidazolidin-1-yl)-4-((3-methoxy-6-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; 6-(3-cyclobutyl-2-oxoimidazolidin-1-yl)-4-{[3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; and 4-{[2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl]amino}-N-( ２ H3) Methyl-6-[2-oxo-3-(trifluoromethyl)imidazolidin-1-yl]pyridine-3-carboxamide or a pharmaceutically acceptable salt thereof.

7. 10. A pharmaceutical composition comprising one or more compounds of claim 1 and a pharmaceutically acceptable carrier or diluent.

8. 10. A pharmaceutical composition comprising one or more compounds of claim 6 and a pharmaceutically acceptable carrier or diluent.

9. A method for treating a disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1, wherein the disease is a neurodegenerative disease.

10. 10. The method of claim 9, wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, optic neuritis, or neuromyelitis optica.

11. 11. The method of claim 10, wherein MS includes relapsing MS and / or progressive MS, including clinically isolated syndrome (CIS).

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