Substituted Heterocyclic Compounds

Abstract

Formula I: TIFF2024518792000065.tif46137 [wherein: the substituents are as defined in the specification] or a pharma- ceutically acceptable salt thereof, which is useful for modulating IL-12, IL-23 and / or IFNα by acting on Tyk-2 to cause inhibition of signal transduction. The compounds of the present invention may be 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 / 188,498, filed May 14, 2021, and U.S. Provisional Patent Application No. 63 / 340,629, filed May 11, 2022, the disclosures of which are incorporated herein by reference in their entireties.

[0002] FIELD OF THEINVENTION The present invention relates to compounds useful for modulating IL-12, IL-23 and / or IFNα by acting on Tyk-2 to cause inhibition of signal transduction. Provided herein are substituted heterocyclic compounds, compositions comprising 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 show utility against neurodegenerative diseases. [Background technology]

[0003] Interleukin (IL)-12 and IL-23, heterodimeric cytokines that share a common p40 subunit, are produced upon activation of antigen-presenting cells and are crucial for the differentiation and proliferation of Th1 and Th17 cells, two effector T cell lineages that play key roles in autoimmunity. IL-23 is composed of a p40 subunit together with a unique p19 subunit. IL-23 acts through a heterodimeric receptor composed of IL-23R and IL-12Rβ1 and is essential for the survival and proliferation of Th17 cells, which produce inflammatory 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 pathology 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 consisting of IL-12Rβ1 and IL-12Rβ2. IL-12 is essential for developing Th1 cells and secreting IFNγ, a cytokine that plays a key role in immune function by stimulating MHC expression, class switching of B cells to IgG subclasses, and activation of macrophages (Gracie, JA et al., "Interleukin-12 induces interferon-gamma-dependent switching of IgG alloantibody subclass," Eur. J. Immunol., 26:1217-1221(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 demonstrated by the finding that mice lacking either p40, p19 or IL-23R are protected from disease in experimental multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, lupus and psoriasis, among others (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, high expression of p40 and p19 has been measured in psoriatic lesions, and Th17 cells have been identified in brains 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)). It has also been shown that p19, p40 and p40 mRNA levels are significantly higher in active SLE patients compared to inactive SLE patients (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 encoding factors that function in the IL-23 and IL-12 pathways that are associated with chronic inflammatory and autoimmune diseases. 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 blocks both IL-12 and IL-23, as well as IL-23-specific anti-p19 therapy, have been shown to be effective in treating autoimmune diseases including psoriasis, Crohn's disease, and psoriatic arthritis (Leonardi, CL et al., "PHOENIX1 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 (PHOENIX1)", Lancet, 371:1665-1674 (2008); Sandborn, WJ et al., "Ustekinumab Crohn's Disease Sudy Group. A randomized trial of Ustekinumab, 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)). Thus, agents that inhibit the action of IL-12 and IL-23 may be considered therapeutic in human autoimmune disorders.

[0008] The type I group of interferons (INFs), which include IFNα members as well as IFNβ, IFNε, IFNκ and IFNω, act through the heterodimeric IFNα / β receptor (IFNAR). Type I INFs have multiple effects in both the innate and adaptive immune systems, including activation of both cellular and humoral immune responses, and enhancement of 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 the potentially fatal autoimmune disease systemic lupus erythematosus (SLE), elevated serum levels of interferon (IFN) alpha (type I interferon) or increased expression of type I INF-regulated genes in peripheral blood mononuclear cells and infected organs (the so-called INF alpha signature) 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, KS et al., "Characterization of heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of laser-captured glomeruli," J. Clin. Invest., 197:711-723 (2003)). 113:1722-1733(2004)), and several studies have shown that serum IFNα levels 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 pathogenesis of lupus is demonstrated by the observation that administration of IFNα to patients with malignant or viral disease can induce a lupus-like syndrome.Moreover, deletion of IFNAR in lupus-prone mice confers high protection from autoimmune disease severity and mortality, and genome-wide association studies have identified lupus-associated genetic loci that encode factors that act 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 type I interferon-mediated pathways 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 Sogren'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)). Thus, agents that inhibit the action of type I interferon responses may have therapeutic value 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 shown to be important in regulating signaling cascades downstream of the receptors for IL-12, IL-23, and type I interferon in both mice and humans (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 in 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, 25:745-755 (2006). Tyk2 mediates receptor-induced phosphorylation of members of the STAT family of transcription factors, an essential signal that leads to dimerization of STAT proteins and transcription of STAT-dependent inflammatory genes.Tyk2-deficient mice are resistant to experimental models of colitis, psoriasis, and multiple sclerosis, highlighting 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 possibly 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 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] TYK2 inhibition may also be utilized in both solid tumors and hematological malignancies, both as monotherapy and in combination with existing standards of care, including immunotherapy.

[0013] Ex vivo studies in T-cell acute lymphoblastic leukemia (T-ALL) revealed that Tyk2 is required for T-ALL survival, suggesting that TYK2 inhibitors may be involved in a direct cancer killing mechanism 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 were detected and characterized in T-ALL cell lines. NPM1-TYK2 gene fusions have also been identified in a subgroup of cutaneous T-cell lymphomas (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 reduce this transforming potential.

[0014] Effective TYK2 inhibitors have been described; however, these compounds tend to be highly polar compounds that are subject to 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 established that one pathway of 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 carcinogenic indications.

[0016] In view of 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 of using these compounds, may provide substantial therapeutic benefit to a wide variety of patients in need thereof. Summary of the Invention

[0017] The present invention relates to compounds of formula I, inter alia, which are useful as modulators of IL-12, IL-23 and / or IFNα by inhibiting Tyk2-mediated signaling. The present invention also provides processes and intermediates for making the compounds of the present invention. The present invention also provides pharmaceutical compositions comprising a pharma- ceutically acceptable carrier and at least one compound of the present invention.

[0018] 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. The present invention also provides a method of treating a neurodegenerative disease, comprising administering a therapeutically effective amount of at least one compound of the present invention to a host in need of such treatment.

[0019] The present invention also provides a compound of the invention for use in therapy. These and other features of the invention will be described in expanded form as the present disclosure continues. In another embodiment, pharmaceutical compositions are provided comprising one or more compounds of formula I and a pharma- ceutically acceptable carrier or diluent.

[0020] The present invention also provides 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 pharma- ceutical acceptable salt thereof and a pharma- ceutical acceptable carrier or diluent.

[0021] 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.

[0022] The present invention also provides methods for treating proliferative, metabolic, allergic, autoimmune and inflammatory diseases (or the use of compounds of the present invention for the manufacture of medicaments for the treatment of these diseases), comprising administering to a host in need of such treatment a therapeutically effective amount of at least one compound of the present invention.

[0023] The invention also provides a method of treating an inflammatory or autoimmune disease (or the use of a compound of the invention for the manufacture of a medicament for the treatment of such a disease), which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I.

[0024] The invention also relates to a method of treating a disease (or use of a compound of the invention for the manufacture of a medicament for the treatment of said disease), comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I, 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 scleroderma, ulcerative colitis, Graves' syndrome, and the like. disease, discoid lupus erythematosus, adult-onset Still's disease, systemic-onset juvenile idiopathic arthritis, gout, gouty arthritis, type 1 diabetes mellitus, insulin-dependent diabetes mellitus, sepsis, septic shock, dysentery, pancreatitis (acute or chronic), glomerulonephritis, autoimmune gastritis, diabetes mellitus, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, myasthenia gravis, pancreatitis (acute or chronic), ankylosing spondylitis, pemphigus vulgaris, Goodpasture's disease disease), antiphospholipid syndrome, idiopathic thrombocytopenia, ANCA-associated vasculitis, pemphigus, Kawasaki disease, chronic inflammatory demyelinating polyneuropathy (CIDP), dermatomyositis, polymyositis, uveitis, Guillain-Barre syndrome, autoimmune pneumonia, autoimmune thyroiditis, autoimmune inflammatory eye disease, and chronic demyelinating polyneuropathy.

[0025] The invention also provides a method of treating a neurodegenerative disease (or use of a compound of the invention for the manufacture of a medicament for the treatment of said disease), comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I, wherein the disease is selected from Alzheimer's disease, Parkinson's disease, ALS, multiple sclerosis (including CIS, optic neuritis, neuromyelitis optica, RMS and / or progressive MS).

[0026] The invention also provides a method of treating rheumatoid arthritis (or use of a compound of the invention for the manufacture of a medicament for the treatment of rheumatoid arthritis), which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I.

[0027] Additionally, the present invention also relates to a method of treating a condition (or use of a compound of the present invention for the manufacture of a medicament for the treatment of such a condition), comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I, wherein the condition is selected from the group consisting of acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, solid tumors, ocular neohemangiomas and / or infantile hemangiomas, B cell lymphoma, systemic lupus erythematosus (SLE), rheumatoid arthritis, The method includes treating a disease selected from psoriatic arthritis, polyangiitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, multiple sclerosis (MS), transplant rejection, type I diabetes mellitus, membranous nephritis, inflammatory bowel disease, autoimmune hemolytic anemia, autoimmune thyroiditis, cold-warm agglutinin disease, Evans syndrome, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura (HUS / TTP), sarcoidosis, Sjogren's syndrome, peripheral neuropathy, pemphigus vulgaris, and asthma.

[0028] 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 for the manufacture of a medicament for the treatment of these diseases), comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I.

[0029] 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 for the manufacture of a medicament for the treatment of these diseases), 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 modulated by IL-12, IL-23, and / or IFNα.

[0030] The present invention also provides a method of 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 another therapeutic agent. The present invention also provides compounds of the invention for use in therapy.

[0031] In another embodiment, the compound of formula I is selected from an exemplified compound, or a combination of the exemplified compounds, or other embodiments described herein. In another embodiment, the IC 50 <1000 nM.

[0032] The present invention may be embodied in other specific forms without departing from the spirit or essential attributes of the present invention. The present invention includes all combinations of the preferred aspects and / or embodiments of the invention described herein. It is understood that any and all embodiments of the present invention may be applied in combination with any other embodiment to describe additional further preferred embodiments. It is also understood that each individual element of a preferred embodiment is itself an independent preferred embodiment. Furthermore, any element of an embodiment shall be combined with any and all other elements from any embodiment to describe further embodiments. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] In a first aspect of the present invention, a compound of formula I: [ka] [In formula: X is -N- or -CH-; R 1 is C 1-3 alkyl or -NHCD3; R 2 -N(CH3)2, -OR 2a or C 3-6 Cycloalkyl (0 to 2 R 2b substituted with; R 2a is C 1-3 is alkyl; R 2b is F or C 1-3 is alkyl; R 3 is C 1-3 Fluoroalkyl or C 3-6 cycloalkyl; and R 4 is hydrogen, halogen or C 1-3 is alkyl] or a steric or pharma- ceutically acceptable salt thereof.

[0034] In a second embodiment of the present invention, a compound of the formula: [ka] [In formula: X is -N- or -CH-; R 1 is C 1-3 alkyl or -NHCD3; R 2 -N(CH3)2, -OR 2a or C 3-6 Cycloalkyl (0 to 2 R 2b substituted with; R 2a is C 1-3 is alkyl; R 2b is F or C 1-3 is alkyl; R 3 is CHF2 or C 3-6 cycloalkyl; and R 4 is hydrogen, halogen or C 1-3 is alkyl] or a stereoisomer or a pharma- ceutically acceptable salt thereof.

[0035] In a third aspect of the present invention, a compound of formula II: [ka] [In formula: R 1 is C 1-3 alkyl or -NHCD3; R 2 -N(CH3)2, -OR 2a or C 3-6 Cycloalkyl (0 to 2 R 2b substituted with; R 2a is C 1-3 is alkyl; R 2b is F or C 1-3 is alkyl; R 3is CHF2 or C 3-6 cycloalkyl; and R 4 is hydrogen, halogen or C 1-3 is alkyl] or a stereoisomer or a pharma- ceutically acceptable salt thereof.

[0036] In a fourth aspect of the present invention, a compound of formula II: [ka] [In formula: R 1 is C 1-3 is alkyl; R 2 -N(CH3)2, -OR 2a or C 3-6 Cycloalkyl (0 to 2 R 2b substituted with; R 2a is C 1-3 is alkyl; R 2b is F or C 1-3 is alkyl; R 3 is CHF2 or C 3-6 cycloalkyl; and R 4 is hydrogen, halogen or C 1-3 is alkyl] or a stereoisomer or a pharma- ceutically acceptable salt thereof.

[0037] In a fifth embodiment of the present invention, a compound of formula III: [ka] [In formula: R 1 is C 1-3 alkyl or -NHCD3; R 2 -N(CH3)2, -OR 2a or C 3-6 Cycloalkyl (0 to 2 R2b substituted with; R 2a is C 1-3 is alkyl; R 2b is F or C 1-3 is alkyl; R 3 is CHF2 or C 3-6 cycloalkyl; and R 4 is hydrogen, halogen or C 1-3 is alkyl] or a stereoisomer or a pharma- ceutically acceptable salt thereof.

[0038] In a sixth embodiment of the present invention, a compound of formula III: [ka] [In formula: R 1 is -NHCD3; R 2 -N(CH3)2, -OR 2a or C 3-6 Cycloalkyl (0 to 2 R 2b substituted with; R 2a is C 1-3 is alkyl; R 2b is F or C 1-3 is alkyl; R 3 is CHF2 or C 3-6 cycloalkyl; and R 4 is hydrogen, halogen or C 1-3 is alkyl] or a stereoisomer or a pharma- ceutically acceptable salt thereof.

[0039] In another aspect, there is provided a compound selected from the specific examples within the scope of the first aspect, or a pharma- ceutically acceptable salt thereof.

[0040] In another embodiment, there is provided a compound selected from any subgroup list of compounds within the scope of any of the above embodiments.

[0041] In another aspect, 6-(cyclopropanecarboxamido)-4-((3-(cyclopropylsulfonyl)-pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; Methyl (5-((3-(cyclopropyl-sulfonyl)pyridin-2-yl)amino)-6-((methyl-d3)-carbamoyl)-pyridazin-3-yl)-carbamate; N-(4-((3-(cyclopropyl-sulfonyl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclo-propanecarboxamide; 6-(cyclopropanecarboxamido)-4-((3-((difluoromethyl)-sulfonyl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; Methyl (5-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-6-((methyl-d3)carbamoyl)pyridazin-3-yl)carbamate; 4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-6-(3,3-dimethylureido)-N-(methyl-d3)pyridazine-3-carboxamide; 4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-N-(methyl-d3)-6-(3-methyl-2-oxoimidazolidin-1-yl)pyridazine-3-carboxamide; 4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-N-(methyl-d3)-6-((1R,2R)-2-methylcyclopropane-1-carboxamido)pyridazine-3-carboxamide; (R)-4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-N-(methyl-d3)-6-(spiro[2.2]pentane-1-carboxamido)pyridazine-3-carboxamide; 4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-N-(methyl-d3)-6-((1S,2S)-2-methylcyclopropane-1-carboxamido)pyridazine-3-carboxamide; (R)-4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-6-(2,2-dimethylcyclopropane-1-carboxamide)-N-(methyl-d3)pyridazine-3-carboxamide; 4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-6-((1R,2S)-2-fluorocyclopropane-1-carboxamide)-N-(methyl-d3)pyridazine-3-carboxamide; 4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-N-(methyl-d3)-6-(2-methylcyclopropane-1-carboxamido)pyridazine-3-carboxamide; 4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide; N-(4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide; 3-(4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)-1,1-dimethylurea; ((R)-N-(4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)spiro[2.2]pentane-1-carboxamide; (1S,2S)—N-(4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)-2-methylcyclopropane-1-carboxamide; (R)—N-(4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)-2,2-dimethylcyclopropane-1-carboxamide; (1R,2S)—N-(4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)-2-methylcyclopropane-1-carboxamide; and 1-(4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-6-((6-fluoropyridin-2-yl)amino)pyridin-3-yl)propan-1-one Provided is a compound (IUPAC nomenclature rules), or a pharma- ceutically acceptable salt thereof, selected from:

[0042] In another embodiment, pharmaceutical compositions are provided comprising one or more compounds of formula I and a pharma- ceutically acceptable carrier or diluent. The present invention also provides 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 pharma- ceutical acceptable salt thereof and a pharma- ceutical acceptable carrier or diluent.

[0043] 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.

[0044] The present invention also provides methods for treating proliferative, metabolic, allergic, autoimmune and inflammatory diseases (or the use of compounds of the present invention for the manufacture of medicaments for the treatment of these diseases), comprising administering to a host in need of such treatment a therapeutically effective amount of at least one compound of the present invention.

[0045] The invention also provides a method of treating an inflammatory or autoimmune disease (or the use of a compound of the invention for the manufacture of a medicament for the treatment of such a disease), which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I.

[0046] The invention also relates to a method of treating a disease (or use of a compound of the invention for the manufacture of a medicament for the treatment of said disease), comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I, 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 scleroderma, ulcerative colitis, Graves' syndrome, and the like. disease, discoid lupus erythematosus, adult-onset Still's disease, systemic-onset juvenile idiopathic arthritis, gout, gouty arthritis, type 1 diabetes mellitus, insulin-dependent diabetes mellitus, sepsis, septic shock, dysentery, pancreatitis (acute or chronic), glomerulonephritis, autoimmune gastritis, diabetes mellitus, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, myasthenia gravis, pancreatitis (acute or chronic), ankylosing spondylitis, pemphigus vulgaris, Goodpasture's disease disease), antiphospholipid syndrome, idiopathic thrombocytopenia, ANCA-associated vasculitis, pemphigus, Kawasaki disease, chronic inflammatory demyelinating polyneuropathy (CIDP), dermatomyositis, polymyositis, uveitis, Guillain-Barre syndrome, autoimmune pneumonia, autoimmune thyroiditis, autoimmune inflammatory eye disease, and chronic demyelinating polyneuropathy.

[0047] The invention also provides a method of treating a neurodegenerative disease (or use of a compound of the invention for the manufacture of a medicament for the treatment of said disease), comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I, wherein the disease is selected from Alzheimer's disease, Parkinson's disease, ALS, multiple sclerosis (including CIS, optic neuritis, neuromyelitis optica, RMS and / or progressive MS).

[0048] The invention also provides a method of treating rheumatoid arthritis (or use of a compound of the invention for the manufacture of a medicament for the treatment of rheumatoid arthritis), which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I.

[0049] Additionally, the present invention also relates to a method of treating a condition (or use of a compound of the present invention for the manufacture of a medicament for the treatment of such a condition), comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I, wherein the condition is selected from the group consisting of acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, solid tumors, ocular neohemangiomas and / or infantile hemangiomas, B cell lymphoma, systemic lupus erythematosus (SLE), rheumatoid arthritis, The method includes treating a disease selected from psoriatic arthritis, polyangiitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, multiple sclerosis (MS), transplant rejection, type I diabetes mellitus, membranous nephritis, inflammatory bowel disease, autoimmune hemolytic anemia, autoimmune thyroiditis, cold-warm agglutinin disease, Evans syndrome, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura (HUS / TTP), sarcoidosis, Sjogren's syndrome, peripheral neuropathy, pemphigus vulgaris, and asthma.

[0050] 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 for the manufacture of a medicament for the treatment of these diseases), comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I.

[0051] 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 for the manufacture of a medicament for the treatment of these diseases), 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 modulated by IL-12, IL-23, and / or IFNα.

[0052] The present invention also provides a method of 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 another therapeutic agent. The present invention also provides compounds of the invention for use in therapy. In another embodiment, the compound of formula I is selected from an exemplified compound, or a combination of the exemplified compounds, or other embodiments described herein.

[0053] The present invention may be embodied in other specific forms without departing from the spirit or essential attributes of the present invention. The present invention includes all combinations of the preferred aspects and / or embodiments of the invention described herein. It is understood that any and all embodiments of the present invention may be applied in combination with any other embodiment to describe additional further preferred embodiments. It is also understood that each individual element of a preferred embodiment is itself an independent preferred embodiment. Furthermore, any element of an embodiment shall be combined with any and all other elements from any embodiment to describe further embodiments.

[0054] Detailed Description of the Invention The following are definitions of terms used in the specification and the appended claims. The definition first given 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 stated.

[0055] The compounds of the present invention may have 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 may also exist 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 isomers. The compounds of the present invention may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolving racemates or by synthesis from optically active starting materials. All chiral (enantiomers and diastereomers) and racemic forms of a structure and all geometric isomers are intended, unless the specific stereochemistry or isomer is specifically indicated.

[0056] In any structure or formula of a compound, any variable group (e.g., R 3 When R occurs multiple times, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, R 3 When a group is shown to be substituted with, then the group may be substituted with up to two R 3 R 3 is R 3 or combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0057] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom to which such substituent is bonded to the remainder of the compound represented by a given formula, then such substituent may be bonded through any atom on such substituent. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0058] Where there are nitrogen atoms (e.g., amines) on the compounds of the invention, 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 nitrogen atoms designated and claimed are intended to include both the designated nitrogen and its N-oxide (N→O) derivative.

[0059] According to the practice used in the art, [ka] is used herein in structural formulas to represent the bond that is the point of attachment of a moiety or substituent to a core or backbone structure.

[0060] A dash "-" that is not between two letters or symbols is used to indicate the point of attachment of a substituent, for example, -CONH2 is attached through a carbon atom.

[0061] The term "optionally substituted" with respect to certain moieties of compounds of formula I (e.g., optionally substituted heteroaryl groups) refers to moieties having zero, one, two or more substituents. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" below. With respect to any group that contains one or more substituents, one of skill in the art will understand that such groups are not intended to introduce any substituents or substitution patterns that are sterically impractical, synthetically impractical, and / or inherently unstable.

[0062] As used herein, the term "at least one chemical entity" is interchangeable with the term "compound."

[0063] As used herein, the terms "alkyl" and "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 any of the following alkyl groups: C1, C2, C3, C4, C5, C6, C7, C8, C9, and C 10 Alkyl groups are intended to be encompassed. Further, for example, "C1-C6 alkyl" refers to 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 are replaced with another chemical group. Exemplary 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.

[0064] Those skilled in the art will understand that when the term "CO" is used herein, it means [ka] It will be understood that this refers to the

[0065] When the term "alkyl" is used with another group, such as "arylalkyl," the linkage more specifically defines at least one substituent that the substituted alkyl may contain. For example, "arylalkyl" refers to a substituted alkyl group as defined above, where at least one of the substituents is an aryl, such as benzyl. Thus, aryl (C 0-4 The term "aryl(C0)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(C0)alkyl. The term "heteroarylalkyl" refers to substituted alkyl groups as defined above where at least one of the substituents is a heteroaryl.

[0066] The term "alkoxy" refers to an oxygen atom substituted with an alkyl or substituted alkyl, as defined herein. For example, the term "alkoxy" refers to -OC, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, etc. 1-6 It includes alkyl groups."Lower alkoxy" refers to alkoxy groups having 1 to 4 carbons.

[0067] It should be understood that all groups, including, for example, alkoxy, thioalkyl, and aminoalkyl, will be selected by one of ordinary skill in the art to provide stable compounds.

[0068] The term "substituted" as used herein means that any one or more hydrogens on the designated atom or group are replaced with a selection from the indicated group, provided that the normal valence of the designated atom is not exceeded. If the substituent is oxo or keto (i.e., =O), then two hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. Unless otherwise noted, the substituents are named on the core structure. For example, if (cycloalkyl)alkyl is listed as a possible substituent, it should be understood that the attachment point 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).

[0069] 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 is intended to encompass compounds that are sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and subsequent formulation into an effective therapeutic agent. It is presently preferred that the compounds referred to do not contain N-halo, S(O)2H, or S(O)H groups.

[0070] The term "cycloalkyl" refers to cyclized alkyl groups including monocyclic, bicyclic or polycyclic ring systems. C3-7 cycloalkyl 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 moiety" is intended to mean any stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic, 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 above, bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane). 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. Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a bicyclic ring. When rings are bridged, the substituents present on the ring may also be present on the bridge.

[0071] 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 groups, each of which may be substituted.

[0072] 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 at any available atom of the ring.

[0073] Preferred cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and [ka] Examples include: 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 OCF3.

[0074] The terms "heterocycle", "heterocycloalkyl", "heterocyclo", "heterocyclic" or "heterocyclyl" may be used interchangeably and refer to substituted and unsubstituted 3- to 7-membered monocyclic, 7- to 11-membered bicyclic, and 10- to 15-membered tricyclic groups, at least one of which has at least one heteroatom (O, S, or N), and the heteroatom-containing ring preferably has 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of such a heteroatom-containing group may contain 1 or 2 oxygen or sulfur atoms, and / or 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less, and further that the ring contains at least 1 carbon atom. The nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized. The fused rings completing the bicyclic or tricyclic group may contain only carbon atoms and may be saturated, partially saturated, or fully unsaturated. The heterocyclo group may be attached at any available nitrogen or carbon atom. As used herein, the terms "heterocycle," "heterocycloalkyl," "heterocyclo," "heterocyclic," and "heterocyclyl" include "heteroaryl," as defined below.

[0075] In addition to the heteroaryl groups described below, exemplary monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 1-pyridonyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-1,1-dioxothienyl, and the like. Exemplary bicyclic heterocyclo groups include quinuclidinyl. Further monocyclic heterocyclyl groups include: [ka] Includes:

[0076] The term "heteroaryl" refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic, 9- or 10-membered bicyclic, and 11- to 14-membered tricyclic groups having at least one heteroatom (O, S, or N) in at least one of the rings, preferably with 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of a heteroatom-containing heteroaryl group can contain 1 or 2 oxygen or sulfur atoms, and / or 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less, and each ring has at least 1 carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen atoms may be optionally quaternized. Heteroaryl groups that are bicyclic or tricyclic must contain at least one fully aromatic ring, and other fused rings may or may not be aromatic. Heteroaryl groups may be attached at any available nitrogen or carbon atom of any ring. If the additional ring is a cycloalkyl or heterocyclo, it may be further optionally substituted with =O (oxo), as far as valence allows.

[0077] Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.

[0078] Unless otherwise specified, when a specific name is referred to 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 those given above for aryl, cycloalkyl, heterocyclo and / or heteroaryl groups, as appropriate.

[0079] 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 or 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 ring may be substituted, in which case the substituents are selected from those listed above for the cycloalkyl and aryl groups.

[0080] The term "heteroatom" is intended to include oxygen, sulfur and nitrogen.

[0081] When the term "unsaturated" is used herein to refer to a ring or group, the ring or group can be fully unsaturated or partially unsaturated.

[0082] Throughout the specification, groups and substituents thereof may be selected by one skilled in the art to give stable moieties and compounds, and compounds useful as pharma- ceutically acceptable compounds, and / or intermediate compounds useful in making pharma-ceutically acceptable compounds.

[0083] The compounds of formula I may exist in free form (non-ionized state) or may form salts, which are also within the scope of the present invention. Unless otherwise specified, a reference to a compound of the present invention is understood to include a reference to its free form and to a salt. The term "salt" refers to acidic and / or basic salts formed with inorganic and / or organic acids and bases. In addition, the term "salt" may include zwitterions (inner 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, for example, 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 utilized during preparation, and thus are considered to be within the scope of the present invention. Salts of compounds of formula I can be formed, for example, by reacting a compound of formula I with an equivalent or similar amount of acid or base in a medium such that the salt precipitates, or in an aqueous medium, followed by lyophilization.

[0084] Exemplary acid addition salts include acetates (salts formed with acetic acid or trihaloacetic acids, e.g., trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecyl sulfate, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfinates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), iodides, and the like. These include the hydrochloride, 2-hydroxyethanesulfonate, lactate, maleate (formed with maleic acid), methanesulfonate (formed with methanesulfonic acid), 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (such as those formed with sulfuric acid), sulfonate (such as those mentioned herein), tartrate, thiocyanate, toluenesulfonate such as tosylate, undecanoate, and the like.

[0085] Exemplary 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'-dibenzylethylenediamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine, or similar pharma- ceutically 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 sulfates), 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.

[0086] The term "pharmacologically 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 tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, and are commensurate with a reasonable benefit / risk ratio.

[0087] As used herein, "pharmaceutical acceptable salt" refers to a derivative of the disclosed compound, in which the parent compound is modified by making its acid or base salt. Examples of pharmaceutical acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic 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; as well as 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, palmoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothioic acid, and the like.

[0088] The pharma- ceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, PA (1990), the contents of which are incorporated herein by reference.

[0089] All stereoisomers of the compounds of the invention are intended to be either in the form of a mixture or in pure or substantially pure form. Stereoisomers may include compounds that are optical isomers by having one or more chiral atoms, as well as compounds that are optical isomers by restricting rotation about one or more bonds (atropisomers). The definition of the compounds of the invention includes all possible stereoisomers and mixtures thereof. In particular, racemates and isolated optical isomers with specific activity are included. Racemates can be resolved by physical methods, such as, for example, 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, for example, salt formation with an optically active acid followed by crystallization.

[0090] The present invention is intended to encompass all isotopes of atoms present 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 include 13 C and 14 C. Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those of skill in the art, or by methods analogous to those described herein, substituting appropriately isotopically labeled reagents for the unlabeled reagents otherwise utilized.

[0091] Prodrugs and solvates of the compounds of the invention are also contemplated. The term "prodrug" refers to a compound that, when administered to a subject, undergoes chemical conversion by metabolic or chemical processes to produce the compound of formula I, and / or its salts and / or solvates. Any compound that will be converted in vivo to provide a bioactive agent (i.e., the compound of formula I) is a prodrug within the scope and spirit of the invention. For example, compounds containing a carboxy group can form physiologically hydrolyzable esters that serve as prodrugs by hydrolysis in the body to produce the compound of formula I itself. In many cases, such prodrugs are preferably administered orally, since hydrolysis occurs primarily under the influence of digestive enzymes. Parenteral administration may also be used when the ester itself is active, or when hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of the compound 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 methoxycarbonyl-oxymethyl 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 may be prepared by conventional techniques known in the art.

[0092] 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).

[0093] The compounds of formula I and their salts may exist in the form of their tautomers, 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 forms of tautomers are included in the present invention, insofar as they exist.In addition, the compounds of the present invention may have trans and cis isomers.

[0094] It should 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.

[0095] usefulness The compounds of the 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 invention include, but are not limited to, responses to IL-12 stimulation.

[0096] Thus, the compounds of formula I have utility in treating conditions associated with modulating IL-23 and / or IFNα function, in particular selectively inhibiting IL-23, IL-12 and / or IFNα function, by acting on Tyk2 and mediating signal transduction, including IL-23-, IL-12- or IFNα-associated diseases whose pathogenic mechanisms are mediated by these cytokines with subsequent activation of the TyK2 pathway and subsequent inflammatory responses in peripheral and / or central compartments.

[0097] As used herein, the term "treat" or "treatment" encompasses the treatment of a condition in a mammal, particularly a human, and includes (a) preventing or delaying the onset of the condition in a mammal where such mammal is predisposed to, but has not yet been diagnosed with, the condition; (b) inhibiting the condition, i.e., arresting or delaying its onset; 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.

[0098] 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, but not limited to, Crohn's disease, ulcerative colitis, asthma, graft-versus-host disease, allograft rejection, chronic obstructive pulmonary disease; autoimmune diseases, such as Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, cutaneous lupus, discoid lupus erythematosus, psoriasis; autoinflammatory diseases, including CAPS, TRAPS, FMF, adult-onset Still's, systemic-onset juvenile idiopathic arthritis, gout, gouty arthritis; metabolic diseases, such as type 2 diabetes, atherosclerosis, myocardial infarction; bone resorption diseases, osteoarthritis, osteoporosis, multiple myeloma-related bone disease, osteoporosis ... and IL-23-, IL-12- and / or IFNα-related diseases, including destructive bone disorders such as osteoporosis; proliferative disorders such as acute myeloid leukemia, chronic myeloid leukemia; angiogenic disorders such as angiogenic disorders including solid tumors, ocular neovascularization, and infantile hemangiomas; sepsis, septic shock; and infectious diseases such as dysentery; neurodegenerative diseases, e.g., Alzheimer's disease, Parkinson's disease, ALS, multiple sclerosis (RMS and / or progressive MS, including CIS, optic neuritis, neuromyelitis optica), neurodegenerative diseases due to cerebral ischemia or traumatic injury, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, neoplastic and viral diseases such as HIV infection and CMV retinitis, AIDS.

[0099] More particularly, 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 neutropenia, 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 responses, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic beta-cell diseases; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis, and other arthritic conditions; cerebral malaria, chronic pulmonary inflammatory diseases, silicosis, pulmonary sarcoidosis, bone resorption diseases, allograft rejection, fever and myalgia due to infection, secondary infections due to infection secondary cachexia, keloid formation, scar tissue formation, ulcerative colitis, pyresis, influenza, osteoporosis, osteoarthritis, acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, and dysentery; Alzheimer's disease, Parkinson's disease, multiple sclerosis (including CIS, optic neuritis, neuromyelitis optica, RMS and / or progressive MS), neurodegenerative diseases caused by cerebral ischemia or traumatic injury; solid tumors, ocular neovascularization, and infantile hemangiomas. viral diseases, including acute hepatitis infections (including hepatitis A, B and C), HIV infection and CMV retinitis, AIDS, ARC or malignancies, and herpes; stroke, myocardial ischemia, ischemia in heart attacks, organ hypoxia, vascular hyperplasia, 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 (including CIS, optic neuritis, neuromyelitis optica, RMS and / or progressive MS).

[0100] When the terms "IL-23-, IL-12- and / or IFNα-related condition" or "IL-23-, IL-12- and / or IFNα-related disease or disorder" are used herein, each is intended to encompass, as if repeated at length, all of the conditions listed above, as well as any other condition affected by IL-23, IL-12 and / or IFNα.

[0101] Thus, the present invention provides a method 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 include an amount of a compound of the present invention that, when administered alone or in combination, is effective to inhibit the function of IL-23, IL-12 and / or IFNα and / or treat the disease.

[0102] Methods of treating IL-23-, IL-12- and / or IFNα-related conditions may include administering a compound of formula I alone or in combination with each other and / or other suitable therapeutic agents useful in treating such conditions. Thus, a "therapeutically effective amount" is also intended to encompass an amount of a combination of the claimed compounds that is effective to inhibit the function of IL-23, IL-12 and / or IFNα and / or treat a disease associated with IL-23, IL-12 and / or IFNα.

[0103] Examples of such other therapeutic agents include corticosteroids, rolipram, 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, e.g., tanidap, anti-TNF antibodies or soluble TNF receptors, and rapamycin (sirolimus or RAPAMUNE®) or derivatives thereof.

[0104] The other therapeutic agents described above, when utilized in combination with the compounds of the present invention, may be used, for example, in amounts as set forth in the Physicians' Desk Reference (PDR) or as may otherwise be determined by one of skill in the art. In the methods of the present invention, such other therapeutic agents may be administered prior to, simultaneously with, or after 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 IL-23-, IL-12-, and / or IFNα-mediated diseases, by inhibiting Tyk2-mediated signal transduction, as described above.

[0105] 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 mode of administration, according to techniques such as those well known in the art of pharmaceutical formulation. Accordingly, the present invention further includes preparations comprising one or more compounds of formula I and a pharma- ceutically acceptable carrier.

[0106] "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering biologically active agents to animals, particularly mammals. Pharmaceutically acceptable carriers are formulated according to many factors well within the purview 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 agent is to be administered; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include many different ingredients and additives in addition to the active agent, and such additional ingredients are included in the formulation for a variety of reasons well known to those skilled in the art, such as stabilization of the active agent, binders, etc. Descriptions of suitable pharmacopoeia acceptable carriers and the factors involved in selecting them are described in a variety of readily available sources, such as, for example, Remington's Pharmaceutical Sciences, 17th Edition (1985), which is incorporated herein by reference in its entirety.

[0107] The compound of formula I may be administered by any means suitable for the condition to be treated, which may depend 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, although other delivery methods are also contemplated. For example, the compound may be delivered orally, such as in the form of a liquid preparation, including tablets, capsules, granules, powders, or syrups; topically, such as in the form of a solution, suspension, gel, or ointment; sublingually; buccally; parenterally (e.g., as a sterile injectable aqueous or non-aqueous solution or suspension), such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques; nasally, such as by inhalation spray; topically, such as in the form of a cream or ointment; rectally, such as in the form of a suppository; or liposomally. A dosage unit formulation containing a non-toxic, pharma- ceutically acceptable vehicle or diluent may be administered. The compound may be administered in a form suitable for immediate release or sustained release. Immediate release or sustained release may be achieved by the use of appropriate pharmaceutical compositions or, particularly in the case of sustained release, by the use of devices such as subcutaneous implants or osmotic pumps.

[0108] An exemplary composition for topical administration includes PLASTIBASE® (mineral oil gelled with polyethylene).

[0109] Exemplary compositions for oral administration include suspensions that may contain, for example, microcrystalline cellulose for bulking, alginic acid or sodium alginate as a suspending agent, methylcellulose as a thickening agent, and sweeteners or flavoring agents known in the art; and immediate release tablets that may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, and / or lactose, and / or other excipients, binders, fillers, disintegrants, diluents, and lubricants known in the art. Compounds of the present invention may also be delivered orally by sublingual and / or buccal administration, for example, in molded, compressed, or lyophilized tablets. Exemplary compositions may contain 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 to aid in mucoadhesion such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (SCMC) and / or maleic anhydride copolymers (e.g., GANTREZ®); and agents to control release 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.

[0110] Exemplary compositions for nasal aerosol or inhalation administration include solutions which may contain, for example, benzyl alcohol or other suitable preservatives, absorption enhancers to enhance absorption and / or bioavailability, and / or other solubilizing or dispersing agents, such as those known in the art.

[0111] 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 di-glycerides, and fatty acids, for example, oleic acid.

[0112] Exemplary compositions for rectal administration include suppositories which may contain suitable nonirritating 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.

[0113] Therapeutically effective amounts of the compounds of the present invention may be determined by one of skill in the art and include exemplary dosage amounts in mammals of about 0.05-1000 mg / kg body weight; 1-1000 mg / kg body weight; 1-50 mg / kg body weight; 5-250 mg / kg body weight; 250-1000 mg / kg body weight per day of the active compound, which may be administered in a single dose or in the form of individual divided doses, such as 1-4 times per day. It will be understood that the specific dose level and frequency of administration for any particular subject may vary and will depend on a variety of factors, including the activity of the particular compound utilized, the metabolic stability and duration of action of that compound, the species, age, weight, general health, sex, and diet of the subject, the method 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, domestic animals such as dogs, cats, horses, and the like. Thus, when the term "subject" is used herein, this term is intended to include all subjects, most preferably mammalian species, that are affected by modulating IL-23, IL-12 and / or IFNα-mediated function.

[0114] Manufacturing method The compounds of the present invention can be prepared by a number of methods well known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized by the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or with modifications thereto as would be understood by those skilled in the art. Preferred methods include, but are not limited to, the methods described below. All references cited herein are incorporated herein in their entirety by reference.

[0115] The compounds of the present invention may be prepared using the reactions and techniques described in this section. The reactions are carried out in solvents appropriate for the reagents and materials utilized and are appropriate for the transformations being carried out. It should also be understood that in the following description of the synthetic methods, all reaction conditions proposed, including the choice of solvent, reaction environment, reaction temperature, experimental time, and work-up procedures, are selected to be standard conditions for the reactions, which would be readily understood by one skilled in the art. Those skilled in the art of organic synthesis will understand that the functionality present on the various portions of the molecule must be compatible with the reagents and reactions proposed. Such limitations on the substituents compatible with the reaction conditions will be obvious to those skilled in the art, and alternative methods must be used in the presence of limitations. This will sometimes require judgment to modify the order of synthetic steps or to select one particular process scheme over another to obtain the desired compounds of the present invention. It should also be understood that another major consideration in planning any synthetic route in this field is the correct selection of protecting groups used to protect reactive functional groups present in the compounds described in the present invention. An authoritative text explaining the many options to one of skill in the art is Greene and Wuts (Protective Groups In Organic Synthesis, Third Edition, Wiley and Sons, 1999).

[0116] The key intermediates depicted in FIG. 1 can be assembled to give compound 1 in a variety of ways known to those skilled in the art of synthetic organic chemistry.

[0117] Figure 1 [ka]

[0118] Scheme 1 shows how a person skilled in the art of organic synthesis can couple an intermediate of general formula Ib (see Moslin et al., J. Med. Chem 2019, 62, 8953-8972 or US Pat. No. 9,505,748) with an intermediate of general formula Ia to obtain an intermediate of general formula II. The reaction involves mixing the two reagents in a suitable aprotic solvent, in particular THF or 2-methyl-THF, at between 0° C. and 50° C. depending on the specific Ia, and adding a suitable base, in particular lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide or sodium hydride.

[0119] Scheme 1 [ka]

[0120] Scheme 2 shows how one skilled in the art of organic synthesis can couple compound II to an appropriate substrate Ic to produce a compound of general formula I. The process involves coupling a compound of general formula II with a primary amide of general formula Ic under transition metal catalyzed conditions. In particular, preferred conditions for this reaction include utilizing a Buchwald-type coupling using Pd2(dba)3 as catalyst, 1,1'-bis(dicyclohexylphosphino)ferrocene as ligand, and Cs2CO3 as base in 1,4-dioxane as solvent at elevated temperature. This catalyst / ligand / base system can be modified in ways known to those skilled in the art.

[0121] Scheme 2 [ka]

[0122] Conversion of the penultimate sulfide (I;Y=S) can be achieved using a variety of oxidation conditions, such as oxone or sodium tungstate and hydrogen peroxide. In the event that a single oxidation occurs at the pyridine / pridazine nitrogen, the desired product can be formed via subsequent borane-mediated reduction to give the desired I (Y=SO2).

[0123] Scheme 3 [ka]

[0124] manufacturing Unless otherwise stated, all commercially available reagents were used without further purification. All reactions involving air- or moisture-sensitive reagents were carried out under an inert atmosphere. Proton and carbon magnetic resonance ( 1 H and 13 C NMR spectra were recorded on either a Bruker Avance 400 or a JEOL Eclipse 500 spectrometer and are reported in ppm relative to the reference solvent for the sample on which they were run. HPLC and LCMS analyses were performed using a Shimadzu LC-10AS liquid chromatograph and SPD UV-vis detector at 220 or 254 nm, and MS detection was performed on a Micromass Platform LC spectrometer. GCMS analyses were performed using an Agilent Technologies GC (7890B)-MS (5977B).

[0125] Analysis method LCMS-Method A: A linear gradient from 2% to 40% solvent B over 4 min, held at 100% B for 0.6 min, followed by a 0.1 min gradient to 20% B, held at 20% B for 0.3 min 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 Subjected to ultraviolet ("UV") visualization at 220 nanometers ("nm")

[0126] LCMS-Method B: A linear gradient from 20% to 100% solvent B over 4 min, held at 100% B for 0.6 min, followed by a 0.1 min gradient to 20% B, held at 20% B for 0.3 min Solvent A: 5 mM ammonium formate pH 3.3:ACN (98:02) Solvent B:ACN:Buffer (98:02) Flow rate: 1.0 ml / min; Column: Kinetics XB-C18 (75x3.0) mm, 2.6 μm Subjected to ultraviolet ("UV") visualization at 220 nanometers ("nm")

[0127] LCMS-Method C: A linear gradient from 20% to 98% solvent B over 1.5 min, held at 98% B for 0.6 min, followed by a 0.1 min gradient to 20% B, held at 20% B for 0.4 min Solvent A: 0.1% TFA in HO Solvent B: 0.1% TFA in ACN Flow rate: 0.7 ml / min; Column: Aquity Uplc BEH C18 (50x2.1) mm, 1.7 μm Subjected to ultraviolet ("UV") visualization at 220 nanometers ("nm")

[0128] LCMS-Method D: A linear gradient from 20% to 98% solvent B over 1.5 min, held at 98% B for 0.5 min, followed by a 0.1 min gradient to 20% B, held at 20% B for 0.4 min Solvent A: 5 mM ammonium formate pH 3.3:ACN (98:02) Solvent B:ACN:Buffer (98:02) Flow rate: 0.7 ml / min; Column: Acquity Uplc BEH C18 (50x3.0) mm, 1.7 μm Subjected to ultraviolet ("UV") visualization at 220 nanometers ("nm")

[0129] The following abbreviations may be relevant for purposes of this application: Abbreviation [Table 1] [Table 2]

[0130] Intermediate A Preparation of 3-(cyclopropylthio)pyridin-2-amine [ka]

[0131] To a well-stirred solution of 3-bromopyridin-2-amine (0.25 g, 1.445 mmol) in THF (5 mL) in a 100 mL two-neck round bottom flask, nBuLi (3.61 ml, 5.78 mmol) was added dropwise at -78°C and stirred for 15 min, followed by the addition of 1,2-dicyclopropyldisulfane (0.423 g, 2.89 mmol) in THF (5 mL). The reaction mixture was allowed to warm slowly to room temperature and stirred for 30 min. After 30 min, the reaction mixture was quenched with saturated aqueous ammonium chloride (5 mL). The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The crude material was used directly in the next step. MS(M+1) m / z: 167(M+H) + LC retention time 0.572 minutes [Method A]

[0132] Example 1 6-(Cyclopropanecarboxamido)-4-((3-(cyclopropylsulfonyl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka]

[0133] Preparation of 6-chloro-4-((3-(cyclopropylthio)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka]

[0134] To a cooled (0° C.) solution of 3-(cyclopropylthio)pyridin-2-amine (0.05 g, 0.301 mmol) in THF (5 mL) in a 50 mL 3-neck round bottom flask, 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (0.063 g, 0.301 mmol) was added, the mixture was stirred for 5 min, and LiHMDS (0.602 mL, 0.602 mmol) was added dropwise over 5 min. The reaction mixture was stirred at room temperature for 30 min and monitored by TLC. After complete consumption of the starting material, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (15 mL). The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a brown solid (100 mg). The crude solid compound was triturated with n-pentane:diethyl ether (1:1) to give 6-chloro-4-((3-(cyclopropylthio)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (60 mg, 0.094 mmol, 31.2% yield) as a light brown solid. MS(M+1) m / z: 339(M+H) + LC retention time 2.775 min [Method A]

[0135] Preparation of 6-(cyclopropanecarboxamido)-4-((3-(cyclopropylthio)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka]

[0136] To a well-stirred solution of 6-chloro-4-((3-(cyclopropylthio)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (60 mg, 0.177 mmol) in 1,4-dioxane (4 mL) in a 20 mL sealed vial, cyclopropanecarboxamide (15.07 mg, 0.177 mmol) and Pd2(dba)3 (162 mg, 0.177 mmol), DCPF (102 mg, 0.177 mmol) were added followed by Cs2CO3 (57.7 mg, 0.177 mmol). The reaction mixture was degassed with N2 for 5 min. The resulting reaction mixture was heated at 110 °C for 3 h and monitored by TLC. After completion of the reaction, the mixture was diluted with ethyl acetate (100 mL) and filtered through a celite pad, washing the pad thoroughly with ethyl acetate (100 mL). The filtrate was washed with water (2x50 mL) followed by brine (50 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude residue obtained was subjected to reverse phase column (C18) purification using 45-50% water in acetonitrile (0.1% ammonium acetate) to give 6-(cyclopropanecarboxamido)-4-((3-(cyclopropylthio)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (10 mg, 0.023 mmol, 12.83% yield) as an off-white solid. MS(M+1) m / z:388(M+H) + LC retention time 2.550 min [Method A]

[0137] Preparation of 6-(cyclopropanecarboxamido)-4-((3-(cyclopropylsulfonyl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka]

[0138] To a well-stirred solution of 6-(cyclopropanecarboxamido)-4-((3-(cyclopropylthio)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (10 mg, 0.026 mmol) in methanol (5 mL):water (0.5 mL) in a 10 mL 2-neck round bottom flask was added oxone (79 mg, 0.129 mmol). The resulting mixture was stirred at room temperature for 24 h. After completion of the reaction, the mixture was diluted with DCM (50 mL) and filtered through a celite pad, which was washed extensively with DCM (50 mL). The filtrate was washed with water (2x50 mL), followed by brine (50 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude residue was subjected to reverse phase column (C18) purification using 45-50% water in acetonitrile (0.1% ammonium formate) to give 6-(cyclopropanecarboxamido)-4-((3-(cyclopropylsulfonyl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (4 mg, 9.48 μmol, 36.7% yield) as an off-white solid.

[0139] Analytical data: HPLC-purity: 99.455%; Method info: Column: Kinetex Biphenyl (100x4.6) mm, 2.6 μm Mobile phase A: 0.05% TFA:ACN (95:5) in water Mobile phase B: ACN: 0.05% TFA in water (95:5) Flow rate: 1.0mL / min RT-6.786 minutes

[0140] LC-MS-purity: 98.960%; m / z(E+):420.2[M+H] + Method Info: Column: Kinetics XB-C18 (75x3) mm, 2.6 μm Mobile phase A: 5 mM ammonium formate pH 3.3:ACN (98:02) Mobile phase B: ACN: Buffer (98:02) Flow rate: 1.0ml / min RT-1.763 minutes. 1 H-NMR (400MHz, DMSO-d6):δ 12.10(s,1H), 11.45(s,1H), 9.42(s,1H), 9.20(s,1H), 8.61(d,J=2.80Hz,1H), 8.24(t,J=6.00Hz,1H), 7.34-7.31(m,1H), 3.10(t,J=4.40Hz,1H), 2.12(t,J=5.60Hz,1H), 1.18-1.06(m,4H), 0.87-0.86(m,4H)

[0141] Example 2 Methyl (5-((3-(cyclopropylsulfonyl)pyridin-2-yl)amino)-6-((methyl-d3)carbamoyl)pyridazin-3-yl)carbamate [ka]

[0142] Preparation of methyl (5-((3-(cyclopropylthio)pyridin-2-yl)amino)-6-((methyl-d3)carbamoyl)pyridazin-3-yl)carbamate [ka]

[0143] To a well-stirred solution of 6-chloro-4-((3-(cyclopropylthio)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (200 mg, 0.590 mmol) in 1,4-dioxane (8.0 mL) in a 20 mL sealed vial, methyl carbamate (133 mg, 1.771 mmol) and Pd2dba3 (27.0 mg, 0.030 mmol), DCPF (17.08 mg, 0.030 mmol) were added followed by Cs2CO3 (288 mg, 0.885 mmol). The reaction mixture was degassed with N2 for 5 min. The resulting reaction mixture was heated at 110 °C for 3 h and monitored by TLC. After completion of the reaction, the mixture was diluted with ethyl acetate (100 mL) and filtered through a celite pad, washing the pad thoroughly with ethyl acetate (100 mL). The filtrate was washed with water (2x50 mL) followed by brine (50 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude residue obtained was subjected to reverse phase column (C18) purification using 45-50% water in acetonitrile (0.1% ammonium acetate) to give methyl (5-((3-(cyclopropylthio)pyridin-2-yl)amino)-6-((methyl-d3)carbamoyl)pyridazin-3-yl)carbamate (50 mg, 0.123 mmol, 20.87% yield) as an off-white solid. MS(M+1) m / z:378(M+H) + LC retention time 2.397 min [Method A]

[0144] Preparation of methyl (5-((3-(cyclopropylsulfonyl)pyridin-2-yl)amino)-6-((methyl-d3)carbamoyl)pyridazin-3-yl)carbamate [ka]

[0145] To a well-stirred solution of methyl (5-((3-(cyclopropylthio)pyridin-2-yl)amino)-6-((methyl-d3)carbamoyl)pyridazin-3-yl)carbamate (50 mg, 0.132 mmol) in methanol (10 mL):water (1.0 mL) in a 25 mL 2-neck round bottom flask was added oxone (244 mg, 0.397 mmol). The resulting reaction mixture was stirred at room temperature for 24 h. After completion of the reaction, the mixture was diluted with DCM (50 mL) and filtered through a celite pad, which was washed extensively with DCM (50 mL). The filtrate was washed with water (2x50 mL), followed by brine (50 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude residue was purified by reverse phase column (C18) chromatography using 40-45% water in acetonitrile (0.1% ammonium formate) to give methyl (5-((3-(cyclopropylsulfonyl)pyridin-2-yl)amino)-6-((methyl-d3)carbamoyl)pyridazin-3-yl)carbamate (15 mg, 0.034 mmol, 25.7% yield) as an off-white solid.

[0146] Analytical data: HPLC-Purity: 92.883%. Method Info: Column: Kinetics Biphenyl (100x4.6) mm, 2.6 μm Mobile phase A: 0.05% TFA:ACN (95:5) in water Mobile phase B: ACN: 0.05% TFA in water (95:5) Flow rate: 1.0mL / min, RT=5.969min)

[0147] LC-MS-purity:94.12%;m / z(E+):410.2[M+H] + Method Info: Column: Kinetics XB-C18 (75x3) mm, 2.6 μm Mobile phase A: 5 mM ammonium formate pH 3.3:ACN (98:02) Mobile phase B: ACN: Buffer (98:02) Flow rate: 1.0ml / min RT:1.296 minutes 1 H-NMR (400MHz, DMSO-d6):δ 12.12(s,1H), 10.96(s,1H), 9.27(s,1H), 9.17(s,1H), 8.64(dd,J=1.60, 4.80Hz,1H), 8.25(dd,J=2.00 , 7.80Hz,1H), 7.35-7.32(m,1H), 3.72(s,3H), 3.15-3.08(m,1H), 1.21-1.17(m,2H), 1.09-1.05(m,2H)

[0148] Preparation of 3-(cyclopropylsulfonyl)pyridin-2-amine (intermediate B) [ka]

[0149] To a solution of 3-bromopyridin-2-amine (0.5 g, 2.89 mmol) in DMSO (10 mL) was added sodium cyclopropanesulfinate (0.481 g, 3.76 mmol), L-proline (0.067 g, 0.578 mmol), copper(I) iodide (0.110 g, 0.578 mmol) and sodium hydroxide (0.023 g, 0.578 mmol). The resulting mixture was degassed with N2 for 5 min, heated at 120 °C for 12 h and monitored by TLC. After completion of the reaction, the mixture was quenched with H2O (100 mL) and extracted with EtOAc (100 mL x 3). The organic layers were combined and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (PE / EtOAc=2 / 1) to give 3-(cyclopropylsulfonyl)pyridin-2-amine (0.15 g, 0.681 mmol, 23.56% yield) as an off-white solid. MS(M+1) m / z: 199(M+H) + LC retention time 0.827 min [Method A]

[0150] Example 3 Preparation of N-(4-((3-(cyclopropylsulfonyl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)-cyclopropanecarboxamide [ka]

[0151] To a well-stirred solution of 3-(cyclopropylsulfonyl)pyridin-2-amine (140 mg, 0.706 mmol) in 1,4-dioxane (8 mL) in a 20 mL sealed test tube, N-(4-chloro-5-propionylpyridin-2-yl)-cyclopropanecarboxamide (178 mg, 0.706 mmol) and BINAP (21.99 mg, 0.035 mmol), Pd2(dba)3 (32.3 mg, 0.035 mmol) were added followed by Cs2CO3 (460 mg, 1.412 mmol). The reaction mixture was degassed under N2 for 5 min. The resulting mixture was heated at 110 °C for 3 h and monitored by TLC. After completion of the reaction, the mixture was diluted with ethyl acetate (100 mL) and filtered through a celite pad, which was washed extensively with ethyl acetate (100 mL). The filtrate was washed with water (2x50 mL), followed by brine (50 mL) and dried over Na2SO4. The solvent was concentrated by evaporation under reduced pressure. The crude residue obtained was purified by preparative HPLC purification to give N-(4-((3-(cyclopropylsulfonyl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide (75 mg, 0.179 mmol, 25.3% yield) as an off-white solid.

[0152] Analytical data: HPLC-purity: 98.894%; Method Info: Column: Kinetics Biphenyl (100x4.6) mm, 2.6 μm Mobile phase A: 0.05% TFA:ACN (95:5) in water. Mobile phase B: ACN: 0.05% TFA in water (95:5) Flow rate: 1.0mL / min RT:7.320 minutes

[0153] LC-MS-purity:93.35%;m / z(E+):415.2[M+H]+ Method Info: Column: Kinetics XB-C18 (75x3.0)mm, 2.6μm Mobile phase A: 5 mM ammonium formate pH 3.3:ACN (98:02) Mobile phase B: ACN: Buffer (98:02) Flow rate: 1.0ml / min RT:2.179 minutes 1 H-NMR (400MHz, DMSO-d6):δ 11.89(s,1H), 10.98(s,1H), 8.98(d,J=14.80Hz,2H), 8.60(dd,J=2.00, 4.80Hz,1H), 8.24(dd,J=1.60, 7.80Hz,1H), 7.34-7.31(m, 1H), 3.14(q,J=7.20Hz,2H), 3.00-2.96(m,1H), 2.08-2.02(m,1H), 1.15-0.11(m,4H), 1.08-1.04(m,4H), 0.96(t,J=402.80Hz,3H)

[0154] Preparation of methyl (4-((3-(cyclopropylsulfonyl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)-carbamate

[0155] Preparation of 3-((difluoromethyl)thio)pyridin-2-amine (Intermediate C) [ka]

[0156] Step 1: To a stirred solution of 3-bromopyridin-2-amine (10.0 g, 57.8 mmol) in DCM (100 mL) was added DIPEA (16.11 mL, 116 mmol) followed by pivaloyl chloride (8.53 mL, 69.4 mmol) at 0° C. The reaction mixture was then stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and then extracted with DCM (2×300 mL). The organic layers were combined, washed with 10% aqueous NaHCO3 (100 mL), saturated aqueous brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude residue was purified by column chromatography (Biotage, SiO2) eluting with 40-70% ethyl acetate in petroleum ether to give the desired product N-(3-bromopyridin-2-yl)pivalamide (15 g, 56.6 mmol, 98% yield) isolated as a brown solid. MS(M+1) m / z:259(M+H) + LC retention time 1.277 min [Method D] 1 H-NMR (400MHz, DMSO-d6): δ 9.72(s,1H), 8.44(dd,J=1.60, 4.80Hz,1H), 8.13(dd,J=1.60, 8.00Hz,1H), 7.26(dd,J=4.80, 8.00Hz,1H), 1.23(s,9H)

[0157] Step 2: 3-Mercaptopropionic acid 2-ethylhexyl ester (7.64 g, 35.0 mmol) and DIPEA (15.28 mL, 88 mmol) were added to a mixture of N-(3-bromopyridin-2-yl)pivalamide (7.5 g, 29.2 mmol), Pd2(dba)3 (1.336 g, 1.458 mmol) and Xantphos (1.688 g, 2.92 mmol) in 1,4-dioxane (100 mL) under N2 atmosphere. The reaction was heated at 100° C. in a sealed test tube for 16 h. The reaction mixture was filtered through a Celite pad and the pad was washed with EtOAc (200 mL). The filtrate was collected and then washed with H2O (50 mL) and aqueous brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the crude residue was purified by column chromatography (Biotage, SiO2) eluting with 40-70% ethyl acetate in petroleum ether to give 2-ethylhexyl 3-((2-pivalamidopyridin-3-yl)thio)propanoate (8.0 g, 20.07 mmol, 68.8% yield). MS(M+1) m / z:395.2(M+H) + LC retention time = 1.80 min [Method D]

[0158] Step 3: A 21% w / w solution of NaOEt in ethanol (11.9 mL, 34.87 mmol) was added to a solution of 2-ethylhexyl 3-((2-pivalamidopyridin-3-yl)thio)propanoate (12.5 g, 31.7 mmol) in THF (30 mL) at 0° C. The reaction mixture was stirred at room temperature under nitrogen for 30 min. DCM (100 mL) was added, which was stirred for 5 min, then water (50 mL) was added. The aqueous phase was collected, brought to pH approx. 5 with acetic acid, and extracted with ethyl acetate (2×100 mL). The organic phases were pooled, washed with saturated aqueous brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give crude N-(3-mercaptopyridin-2-yl)pivalamide (5.5 g, 25.4 mmol, 80% yield). The crude product was used as is without further purification. MS(M+1) m / z:211.0(M+H)+ LC retention time = 0.739 min [Method D]

[0159] Step 4: KOH (53.4 g, 951 mmol) was added in portions to water (100 mL) and the solution was cooled to 0° C. Acetonitrile (100 mL) and N-(3-mercaptopyridin-2-yl)pivalamide (10.0 g, 47.6 mmol) were added to the above reaction mixture. Diethyl (bromodifluoromethyl)phosphonate (16.90 mL, 95 mmol) was added and the reaction mixture was allowed to reach room temperature and stirred at this temperature for 16 h. The reaction mixture was diluted with Et2O (500 mL) and then washed with H2O (50 mL) followed by saturated aqueous brine solution (50 mL). The organic layer was collected, dried over Na2SO4, filtered and the solvent was removed under reduced pressure to give the crude product. The crude residue was purified by column chromatography (Biotage, SiO2) eluting with 20-50% ethyl acetate in petroleum ether to give N-(3-((difluoromethyl)thio)pyridin-2-yl)pivalamide (6.6 g, 25.4 mmol, 53.3% yield). MS(M+1) m / z:261.2(M+H) + LC retention time 1.171 min [Method D] 1 H-NMR (400MHz, DMSO-d6): δ 10.08(s,1H), 8.49(dd,J=2.00, 4.80Hz,1H), 8.06(dd,J=1.60, 7.80Hz,1H), 7.53-7.26(m,2H), 1.23(s,9H)

[0160] Step 5: To a stirred solution of N-(3-((difluoromethyl)thio)pyridin-2-yl)pivalamide (1.8 g, 6.92 mmol) in chloroform (25 mL), acetonitrile (25 mL) and water (37.5 mL) was added ruthenium(III) chloride trihydrate (0.362 g, 1.383 mmol) and sodium metaperiodate (11.83 g, 55.3 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution. It was then extracted with DCM (100 mL). The organic layer was collected, dried over Na2SO4, filtered and the solvent was removed under reduced pressure to give the crude product. The crude product was used as is without further purification. MS(M+1) m / z:293.0(M+H) + LC retention time 1.12 min [Method D]

[0161] Step 6: Intermediate C N-(3-((difluoromethyl)sulfonyl)pyridin-2-yl)pivalamide (8.1 g, 27.7 mmol) was dissolved in 4N aqueous HCl (41.6 ml, 166 mmol) and the reaction mixture was stirred at 80° C. for 3 h. After completion, the reaction mixture was cooled in an ice bath, neutralized with solid NaHCO3, the aqueous phase was extracted with DCM (2×100 mL) followed by CHCl3 (100 mL), the organic phases were combined and dried over anhydrous Na2SO4. After filtration, the solvent was removed under reduced pressure. The crude product was triturated with petroleum ether and then with a small amount of EtOAc. The product was further purified by RP column purification to give 3-((difluoromethyl)sulfonyl)pyridin-2-amine (3.8 g, 15.15 mmol, 54.7% yield) as a white solid. MS(M+1) m / z:209.0(M+H) + ;LC retention time 0.88 min [Method D]; 1 H-NMR (DMSO-d6): δ 8.39(dd,J=4.8&1.8Hz,1H), 7.90(dd,J=8&1.6Hz,1H), 7.23(t,J=52Hz,1H), 7.05(bs,2H), 6.81(dd,J=8 7 4.8Hz,1H)

[0162] Step 6: Intermediate D To a solution of N-(3-((difluoromethyl)thio)pyridin-2-yl)pivalamide (4.5 g, 17.29 mmol) in a 100 mL three-neck round bottom flask, 2N HCl (51.9 mL, 104 mmol) was added and the resulting reaction mixture was stirred at 100° C. for 16 h. After completion, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (200 mL), and the aqueous layer was neutralized with saturated aqueous sodium bicarbonate (200 mL) and extracted with DCM (2×200 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 3-((difluoromethyl)thio)pyridin-2-amine (2.5 g, 13.85 mmol, 80% yield) as a brown solid. MS(M+1) m / z:177.0(M+H) + LC retention time = 0.528 min [Method D]

[0163] Example 4 6-(Cyclopropanecarboxamido)-4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka]

[0164] Preparation of 6-chloro-4-((3-((difluoromethyl)thio)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka]

[0165] To a stirred solution of 3-((difluoromethyl)thio)pyridin-2-amine (2.5 g, 14.19 mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (7.42 g, 35.5 mmol) in THF (25 mL) was added LiHMDS (35.5 mL, 35.5 mmol, 1 M solution in THF) dropwise over 10 min. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with water (250 mL) and stirred for 10 min. The reaction mixture was filtered and the solid compound was washed with n-pentane:diethyl ether (250 mL, 5:1) and then dried to give the desired 6-chloro-4-((3-((difluoromethyl)thio)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (3 g, 8.53 mmol, 60% yield) as an off-white solid. MS(M+1) m / z:349.0(M+H) + ; LC retention time = 2.69 min [Method A]

[0166] Preparation of 6-(cyclopropanecarboxamido)-4-((3-((difluoromethyl)thio)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka]

[0167] To a solution of 6-chloro-4-((3-((difluoromethyl)thio)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (25 mg, 0.072 mmol) in dioxane (2 mL) was added cyclopropanecarboxamide (6.71 mg, 0.079 mmol), Pd2(dba)3 (3.28 mg, 3.58 μmol), 1,1'-bis(dicyclohexylphosphino)ferrocene (4.15 mg, 7.17 μmol) and cesium carbonate (70.1 mg, 0.215 mmol). The reaction mixture was degassed under N2 for 5 min. The reaction mixture was sealed in a pressure release vial and stirred at 120° C. for 1.5 h. The reaction solution was filtered through a celite pad, washed with 10% methanol in DCM (20 mL) and the filtrate was concentrated under reduced pressure. The crude product was triturated with diethyl ether to give the crude product, which was further purified by crystallization in MeOH and hexanes. The desired product, 6-(cyclopropanecarboxamido)-4-((3-((difluoromethyl)thio)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (25 mg, 0.027 mmol, 37.0% yield), was isolated as a brown solid.

[0168] LC-MS analysis: Column: Acquity Uplc BEH C18 (50x3.0) mm, 1.7 μm Mobile phase A: 0.1% TFA in water Mobile phase B: 0.1% TFA in ACN Flow rate: 1.0ml / min Mass of desired product m / z: 398.0 (M+H) + ; LC retention time 1.57 minutes

[0169] Preparation of 6-(cyclopropanecarboxamido)-4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide [ka]

[0170] A solution of 6-(cyclopropanecarboxamide)-4-((3-((difluoromethyl)thio)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (0.25 g, 0.629 mmol) in acetic acid (5 mL) was heated to 55° C. and stirred for 5 min, then sodium tungstate dihydrate (0.415 g, 1.258 mmol) and H2O2 (0.386 mL, 12.58 mmol) were added at 55° C. The reaction mixture was stirred at 55° C. for 2 h. After completion of the reaction, it was diluted with ice water, neutralized to pH 7-8 with saturated NH4CO3, and then extracted with 10% MeOH in DCM (150 mL). The organic layers were combined, washed with brine (10 mL), dried over Na2SO4, filtered, and evaporated to give 40 mg of crude product. The crude material was dissolved in 5 mL of dioxane, 100 mg of bispinacolatodiboron was added, and the mixture was stirred at 100 °C for 2 h. After completion of the reaction, the mixture was concentrated and n-hexane (3 mL) was added. The solid formed was filtered and purified by reverse phase preparative HPLC to give the desired product 6-(cyclopropanecarboxamido)-4-((3-((difluoromethyl)sulfonyl)-pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide·TFA salt (30 mg, 0.050 mmol, 7.96% yield).

[0171] HPLC-01: Method Information Column: Kinetics Biphenyl (100x4.6) mm, 2.6 μm Mobile phase A: 0.05% TFA:ACN (95:5) in water Mobile phase B: ACN: 0.05% TFA in water (95:5) Flow rate: 1.0mL / min RT=7.413, Purity=91%

[0172] HPLC-02: Method Information Column: Kinetex EVO C18 (100x4.6) mm, 2.6 μm Mobile phase A: 0.05% TFA:ACN (95:5) in water Mobile phase B: ACN: 0.05% TFA in water (95:5) Flow rate: 1.0mL / min RT=6.558 min, purity=94%

[0173] LCMS: Method Information: Column: Kinetics XB-C18 (75x3.0) mm, 2.6 μm Mobile phase A: 5 mM ammonium formate pH 3.3:ACN (98:02) Mobile phase B: ACN: Buffer (98:02) Flow rate: 1.0ml / min Mass of desired product m / z=430.0(M+1); Retention time=1.646 minutes 1 H-NMR (400MHz, DMSO-d6):δ 12.29(s,1H), 11.48(s,1H), 9.43(s,1H), 9.19(s,1H), 8.73-8.75(m,1H), 8 .73-8.75(m,1H), 7.27-7.41(m,2H), 7.27-7.41(m,1H), 0.86-0.88(m,4H),

[0174] Example 5 Methyl (5-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-6-((methyl-d3)carbamoyl)-pyridazin-3-yl)carbamate [ka]

[0175] Preparation of methyl (5-((3-((difluoromethyl)thio)pyridin-2-yl)amino)-6-((methyl-d3)carbamoyl)-pyridazin-3-yl)carbamate [ka]

[0176] To a solution of 6-chloro-4-((3-((difluoromethyl)thio)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (300 mg, 0.860 mmol) in dioxane (10 mL) was added methyl carbamate (646 mg, 8.60 mmol), Pd2(dba)3 (39.4 mg, 0.043 mmol), 1,1'-bis(dicyclohexylphosphino)ferrocene (49.8 mg, 0.086 mmol) and cesium carbonate (841 mg, 2.58 mmol). The reaction mixture was degassed under N2 for 5 min. The sealed reaction mixture was stirred at 120 °C for 2 h. The reaction solution was filtered through a celite pad, washed with 10% methanol in DCM (100 mL) and concentrated under reduced pressure. The crude product was washed with diethyl ether (50 mL) to remove the ligand by-product. The desired product, methyl (5-((3-((difluoromethyl)thio)pyridin-2-yl)amino)-6-((methyl-d3)carbamoyl)pyridazin-3-yl)carbamate (200 mg, 0.516 mmol, 60.0% yield), was isolated as a brown solid. Mass of desired product m / z: 388.0 (M+1) + ;holding time=1.81 minutes

[0177] LC-MS Analysis: Method Information: Column: Kinetics XB-C18 (75x3.0) mm, 2.6 μm Mobile phase A: 5 mM ammonium formate pH 3.3:ACN (98:02) Mobile phase B: ACN: Buffer (98:02) Flow rate: 1.0ml / min

[0178] Preparation of methyl (5-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-6-((methyl-d3)carbamoyl)-pyridazin-3-yl)carbamate [ka]

[0179] A stirred solution of methyl (5-((3-((difluoromethyl)thio)pyridin-2-yl)amino)-6-((methyl-d3)carbamoyl)pyridazin-3-yl)carbamate (0.2 g, 0.516 mmol) in acetic acid (5 mL) was heated to 55° C. and stirred for 5 min, then sodium tungstate dihydrate (0.341 g, 1.033 mmol) and H2O2 (1.055 mL, 10.33 mmol) were added. The reaction mixture was stirred at 55° C. for 2 h. After completion of the reaction, the mixture was diluted with ice water, basified to pH 7-8 with saturated NH4CO3, and extracted with 10% MeOH in DCM (150 mL). The organic layers were combined, washed with brine (10 mL), dried over Na2SO4, filtered, and evaporated to give 40 mg of crude product. The crude product was dissolved in 5 mL of dioxane, 100 mg of bis-pinacolatodiboron was added, and the mixture was stirred at 100° C. for 2 h. Upon completion, the reaction was concentrated, n-hexane (3 mL) was added, and the solid was filtered and purified by reverse phase preparative HPLC to give the desired product, methyl (5-((3-((difluoromethyl)-sulfonyl)pyridin-2-yl)amino)-6-((methyl-d3)carbamoyl)-pyridazin-3-yl)carbamate·TFA salt (7.3 mg, 0.013 mmol, 2.509% yield).

[0180] HPLC-01: Method Information Column: Kinetics Biphenyl (100x4.6) mm, 2.6 μm Mobile phase A: 0.05% TFA:ACN (95:5) in water Mobile phase B: ACN: 0.05% TFA in water (95:5) Flow rate: 1.0mL / min RT=6.896 minutes, purity=96.65%

[0181] HPLC-02: Method Information Column: Kinetics EVO C18 (100x4.6) mm, 2.6 μm Mobile phase A: 0.05% TFA:ACN (95:5) in water Mobile phase B: ACN: 0.05% TFA in water (95:5) Flow rate: 1.0mL / min RT=6.035, Purity=94.6%

[0182] LCMS: Method Information: Column: Kinetics XB-C18 (75x3.0) mm, 2.6 μm Mobile phase A: 5 mM ammonium formate pH 3.3:ACN (98:02) Mobile phase B: ACN: Buffer (98:02) Flow rate: 1.0ml / min Mass of desired product m / z = 420.0 (M+1); retention time = 1.459 min 1 H-NMR (400MHz, DMSO-d6):δ 12.31(s,1H), 10.99(s,1H), 9.27(s,1H), 9.17(s,1H), 8.76-8.78(m,1H), 8.36-8.38(m,1H), 7.28-7.54(m,2H), 3.72(s,3H)

[0183] Example 6

[0184] 4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-6-(3,3-dimethylureido)-N-(methyl-d3)pyridazine-3-carboxamide [ka]

[0185] Preparation of 4-((3-((difluoromethyl)thio)pyridin-2-yl)amino)-6-(3,3-dimethylureido)-N-(methyl-d3)pyridazine-3-carboxamide [ka]

[0186] To a stirred solution of 1,1-dimethylurea (168 mg, 1.911 mmol) and 6-chloro-4-((3-((difluoromethyl)thio)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (400 mg, 1.147 mmol) in 1,4-dioxane (10 mL) was added Cs2CO3 (934 mg, 2.87 mmol), Pd2dba3 (88 mg, 0.096 mmol), 1,1'-bis(dicyclohexylphosphino)ferrocene (60.3 mg, 0.096 mmol) and the mixture was purged with N2 for 5 min. The reaction mixture was sealed and stirred at 120 °C for 2 h. The reaction mixture was filtered through a celite pad, washed with ethyl acetate (100 mL) and concentrated under reduced pressure. The crude residue was purified by reverse phase column chromatography to give the desired product 4-((3-((difluoromethyl)-thio)pyridin-2-yl)amino)-6-(3,3-dimethylureido)-N-(methyl-d3)pyridazine-3-carboxamide (160 mg, 0.276 mmol, 28.8% yield) as a brown solid. MS(M+1) m / z: 401.0(M+H) + LC retention time = 0.845 min [Method D]

[0187] The following intermediates were prepared similarly: [Table 3]

[0188] Preparation of 4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-6-(3,3-dimethylureido)-N-(methyl-d3)pyridazine-3-carboxamide [ka]

[0189] A stirred solution of 4-((3-((difluoromethyl)thio)pyridin-2-yl)amino)-6-(3,3-dimethylureido)-N-(methyl-d3)pyridazine-3-carboxamide (160 mg, 0.400 mmol) and sodium tungstate dihydrate (264 mg, 0.799 mmol) in acetic acid (5 mL) was heated to 55 °C and stirred for 5 min, then H2O2 (0.816 mL, 7.99 mmol) was added at 55 °C. The reaction mixture was stirred at 55 °C for 2 h. Upon completion, the reaction mixture was diluted with ice water, basified to pH 7-8 with saturated aqueous NaHCO3, and extracted with 10% MeOH in DCM (150 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude residue was dissolved in 1,4-dioxane (5 mL), 100 mg of bispin was added, and the mixture was stirred at 100° C. for 2 h. Upon completion, the solvent was evaporated and the crude product was purified by reverse-phase preparative HPLC (0.1% TFA in ACN) to give the desired product 4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-6-(3,3-dimethylureido)-N-(methyl-d3)pyridazine-3-carboxamide·TFA salt (9.1 mg, 0.015 mmol, 3.81% yield) as a pale yellow solid. MS(M+1) m / z:433.0(M+H) + LC retention time = 1.26 min [Method A] 1 H-NMR (400MHz, DMSO-d6): δ 12.21(s,1H), 9.63(s,1H), 9.08(s,2H), 8.75-8.73(m,1H), 8.36-8.33(m,1H), 7.52-7.36(m,2H), 2.97(s,6H)

[0190] The following example (7) was prepared in a manner similar to that of Example 6. [Table 4]

[0191] Example 8 [ka]

[0192] To a stirred solution of 4-((3-((difluoromethyl)thio)pyridin-2-yl)amino)-N-(methyl-d3)-6-((1R,2R)-2-methylcyclopropane-1-carboxamido)pyridazine-3-carboxamide (0.120 g, 0.292 mmol) in THF (10 mL):methanol (10 mL):water (2 mL) was added oxone (0.896 g, 1.458 mmol). The resulting reaction mixture was stirred at room temperature for 36 h. After completion, the reaction mixture was diluted with DCM (100 mL), filtered through a pad of celite and washed with DCM (100 mL). The filtrate was washed with water (2x100 mL), followed by saturated aqueous brine solution (100 mL) and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure. To the resulting crude residue (140 mg) in 1,4-dioxane (10 mL) was added bispin (0.148 g, 0.583 mmol) and stirred for 2 h at 100° C. The reaction mixture was then concentrated under reduced pressure and the resulting crude compound was purified by reverse phase preparative HPLC (0.1% ammonium formate in ACN) to give 4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-N-(methyl-d3)-6-((1R,2R)-2-methylcyclopropane-1-carboxamido)pyridazine-3-carboxamide (12 mg, 0.027 mmol, 9.13% yield) as a yellow solid. MS(M+1) m / z:441.1(M+H) + LC retention time = 2.33 min [Method B] 1 H-NMR (400MHz, DMSO-d6):δ 12.28(s,1H), 11.40(s,1H), 9.40(s,1H), 9.19(s,1H), 8.74-8.73(m,1H), 8.37-8.34(m,1H), 7.52-7.27(m,2H), 1.90-1.86(m,1H), 1.32-1.27(m,1H), 1.11-1.04(m,4H), 0.75-0.71(m,1H)

[0193] [Table 5] *Isomers separated using chiral SFC

[0194] [Table 6]

[0195] Example 15 N-(4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)-cyclopropanecarboxamide [ka]

[0196] Preparation of N-(4-chloro-5-propionylpyridin-2-yl)cyclopropanecarboxamide [ka]

[0197] To a stirred solution of 1-(4,6-dichloropyridin-3-yl)propan-1-one (300 mg, 1.470 mmol) in 1,4-dioxane (5 mL) in a microwave vial, Cs2CO3 (1437 mg, 4.41 mmol) and cyclopropanecarboxamide (125 mg, 1.470 mmol) were added. The reaction mixture was degassed for 10 min, followed by the addition of 1,1-bis(dicyclohexylphosphino)ferrocene (1021 mg, 1.764 mmol), Pd2(dba)3 (269 mg, 0.294 mmol) and degassing continued for another 2 min. The reaction mixture was then sealed and stirred at 80° C. for 2 h. The reaction mixture was filtered through a syringe pad, then transferred into water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The crude compound was subjected to flash column chromatography eluting with 10-12% ethyl acetate in hexane to give N-(4-chloro-5-propionylpyridin-2-yl)cyclopropane-carboxamide (150 mg, 0.522 mmol, 35.5% yield) as a pale yellow solid. LCMS:MS: m / z:[M+1]:253

[0198] Column: Kinetics XB-C18 (75x3.0) mm, 2.6 μm Mobile phase A: 5 mM ammonium formate pH 3.3:ACN (98:02) Mobile phase B: ACN: Buffer (98:02) Flow rate: 1.0ml / min, RT: 2.236.

[0199] Preparation of N-(4-((3-((difluoromethyl)thio)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)-cyclopropanecarboxamide [ka]

[0200] To a stirred solution of N-(4-chloro-5-propionylpyridin-2-yl)cyclopropanecarboxamide (430 mg, 1.703 mmol), 3-((difluoromethyl)thio)pyridin-2-amine (300 mg, 1.703 mmol) in 1,4-dioxane (5 mL) in a 20 mL reaction vial, Cs2CO3 (1110 mg, 3.41 mmol), Pd2(dba)3 (78 mg, 0.085 mmol), 1,1'-bis(dicyclohexyl-phosphino)ferrocene (99 mg, 0.170 mmol) were added with constant N2 purging. The reaction mixture was stirred at 120 °C for 2 h and monitored by TLC. After the starting material was consumed, the crude product was filtered through a celite pad, washed with ethyl acetate (25 mL), and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage, SiO2, eluted with 5-25% ethyl acetate in petroleum ether) to give 200 mg of a brown solid, which gave the desired product methyl (4-((3-((difluoromethyl)thio)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)carbamate (200 mg, 0.272 mmol, 33.0% yield).

[0201] Mass of desired product m / z=393.1 (M+1); retention time=2.251 min Method information: Column: Kinetics XBC18 2.6μm, (75x3)mm Mobile phase: 5 mM ammonium formate in water (pH 3.3 with formic acid) Mobile phase A: Buffer:Acetonitrile (98:02) Mobile phase B: Acetonitrile:Buffer (98:02) Flow rate: 1.0mL / min

[0202] Preparation of N-(4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)-cyclopropanecarboxamide [ka]

[0203] A stirred solution of N-(5-((3-((difluoromethyl)thio)pyridin-2-yl)amino)-6-propionylpyridin-3-yl)cyclopropanecarboxamide (0.2 g, 0.510 mmol) in acetic acid (5 mL) was heated to 55° C. and stirred for 5 min, then sodium tungstate dihydrate (0.336 g, 1.019 mmol) and H2O2 (1.041 mL, 10.19 mmol) were added. The reaction mixture was stirred at 55° C. for 2 h. After completion of the reaction, the mixture was diluted with ice water, the pH was adjusted to 7-8 with saturated NH4CO3, and then extracted with 10% MeOH in DCM (150 mL). The organic layers were combined, washed with brine (10 mL), dried over Na2SO4, filtered, and evaporated to give 41 mg of crude product. The crude was dissolved in 5 mL of dioxane, 100 mg of bis-pinacolatodiboron was added, and the mixture was stirred at 100 °C for 2 h. After completion of the reaction, the mixture was concentrated and n-hexane (3 mL) was added. The formed solid was filtered and subjected to purification by reverse phase preparative HPLC to give the desired product N-(4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide·TFA salt (3.0 mg, 5.13 μmol, 1.006% yield).

[0204] HPLC-01: Method Information Column: Kinetics Biphenyl (100x4.6) mm, 2.6 μm Mobile phase A: 0.05% TFA:ACN (95:5) in water Mobile phase B: ACN: 0.05% TFA in water (95:5) Flow rate: 1.0mL / min RT=7.484, Purity=92.5%

[0205] HPLC-02: Method Information Column: Kinetics EVO C18 (100x4.6) mm, 2.6 μm Mobile phase A: 0.05% TFA:ACN (95:5) in water Mobile phase B: ACN: 0.05% TFA in water (95:5) Flow rate: 1.0mL / min RT=6.136, Purity=92%

[0206] LCMS: Method Information: Column: Kinetics XB-C18 (75x3.0) mm, 2.6 μm Mobile phase A: 5 mM ammonium formate pH 3.3:ACN (98:02) Mobile phase B: ACN: Buffer (98:02) Flow rate: 1.0ml / min. Mass of desired product m / z = 425.0 (M+1); retention time = 2.028 min 1 H-NMR (400MHz, MeOD):δ 9.03(s,1H), 8.91(s,1H), 8.81(d,J=3.20Hz,1H), 8.45(d,J=7.20Hz,1H), 7.45(t,J=8.00Hz,1H), 6.9 6(t,J=52.40Hz,2H), 3.16(t,J=1.60Hz,3H), 1.91-1.93(m,1H), 1.24-1.34(m,3H), 1.03-1.22(m,4H)

[0207] Example 16 3-(4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)-1,1-dimethylurea [ka]

[0208] Preparation of 3-(4-chloro-5-propionylpyridin-2-yl)-1,1-dimethylurea [ka]

[0209] To a stirred solution of 1-(4,6-dichloropyridin-3-yl)propan-1-one (375 mg, 1.838 mmol) and 1,1-dimethylurea (243 mg, 2.76 mmol) in 1,4-dioxane (15 mL) was added Cs2CO3 (1796 mg, 5.51 mmol) at ambient temperature, and the reaction mixture was then degassed under N2 for 5 min. BINAP (114 mg, 0.184 mmol) and Pd2(dba)3 (84 mg, 0.092 mmol) were then added to the reaction mixture, which was then degassed for another 5 min. The resulting mixture was heated at 130° C. in a sealed tube for 0.5 h. Upon completion, the reaction mixture was diluted with ethyl acetate (100 mL) and filtered through a celite pad, and the celite was washed with ethyl acetate (100 mL). The combined filtrate was washed with water (100 mL) followed by brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (230:400 mesh) eluted with 0-50% ethyl acetate in petroleum ether to give the desired product as a yellow solid. MS(M+1) m / z:256.0(M+H) + LC retention time 1.01 min [Method D]

[0210] The following intermediates (3-8) were prepared in a similar manner to the preparation of intermediate 2. [ka]

[0211] [Table 7]

[0212] Preparation of 3-(4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)-1,1-dimethylurea [ka]

[0213] To a stirred solution of 3-(4-chloro-5-propionylpyridin-2-yl)-1,1-dimethylurea (300 mg, 1.173 mmol) and 3-((difluoromethyl)sulfonyl)pyridin-2-amine (318 mg, 1.525 mmol) in 1,4-dioxane (15 mL) was added potassium phosphate (747 mg, 3.52 mmol) at ambient temperature and the reaction mixture was then degassed under N2 for 5 min. Next, Ruphos Pd G4 (200 mg, 0.235 mmol) was added to the reaction mixture and degassed for another 5 min. The resulting reaction mixture was heated at 130° C. in a sealed tube for 1.5 h. Upon completion, the reaction mixture was diluted with ethyl acetate (50 mL) and filtered through a celite pad, which was washed with ethyl acetate (100 mL). The filtrates were combined and washed with water (20 mL) followed by brine (20 mL), then dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by RP column chromatography and the fractions collected and lyophilized to give the desired 3-(4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)-1,1-dimethylurea (41 mg, 0.087 mmol, 7.44% yield) as an off-white solid. MS(M+1) m / z:428.2(M+H) + LC retention time 1.68 min [Method A] 1 H-NMR (400MHz, DMSO-d6):δ 11.98(s,1H), 9.15(s,1H), 8.88(s,1H), 8.74-8.72(m,2H), 8.33(dd,J=1.60, 8.00Hz ,1H), 7.51-7.25(m,2H), 3.10(q,J=7.20Hz,2H), 2.93(s,6H), 1.09(t,J=7.20Hz,3H)

[0214] The following example was prepared in a manner similar to the preparation of Example 16. [ka]

[0215] [Table 8] "a" NaHCO3 was used instead of K3PO4 in the Buchwald reaction "*" Cis isomer was separated by chiral SFC

[0216] [Table 9] [Table 10]

[0217] Biological assays The following assays are used to demonstrate activity for the compounds of the invention.

[0218] IFNα-induced STAT phosphorylation in human whole blood After 1 hour incubation with compounds, human whole blood (drawn with ACD-A as anticoagulant) was stimulated with 1000U / mL recombinant human IFNα A / D (R&D Systems, 11200-2) for 15 minutes. Stimulation was stopped by adding Fix / Lyse buffer (BD 558049). Cells were stained with CD3 FITC antibody (BD 555916), washed, and permeabilized with Perm III buffer (BD 558050) on ice. Cells were then stained with Alexa-Fluor 647 pSTAT5 (pY694) antibody (BD 612599) for 60 minutes and analyzed on an iQue Plus. pSTAT5 expression was quantified as median fluorescence intensity after gating on the CD3 positive population.

[0219] Table 1: The potency of example compounds in the human whole blood assay is shown in Table 1. [Table 11]

Claims

1. Formula I: 【Chemistry 1】 [In the formula: X is -N- or -CH-; R １ is C １－３ Alkyl or -NHCD ３ and R ２ HA -N(CH ３ ) ２ , -OR ２ａ , or C ３－６ Cycloalkyl (0 to 2 R ２ｂ substituted with; R ２ａ is C １－３ is alkyl; R ２ｂ is F or C １－３ is alkyl; R ３ is C １－３ Fluoroalkyl or C ３－６ Cycloalkyl; R ４ is hydrogen, halogen or C １－３ is alkyl] or a stereoisomer or a pharma- ceutically acceptable salt thereof.

2. formula: 【Chemistry 2】 [In the formula: X is -N- or -CH-; R １ is C １－３ Alkyl or -NHCD ３ and R ２ HA -N(CH ３ ) ２ , -OR ２ａ Or C ３－６ Cycloalkyl (0 to 2 R ２ｂ substituted with; R ２ａ is C １－３ is alkyl; R ２ｂ is F or C １－３ is alkyl; R ３ is CHF ２ Or C ３－６ Cycloalkyl; R ４ is hydrogen, halogen or C １－３ is alkyl] 2. The compound of claim 1, wherein:

3. Formula II: 【Chemistry 3】 [In the formula: R １ is C １－３ Alkyl or -NHCD ３ and R ２ HA -N(CH ３ ) ２ , -OR ２ａ Or C ３－６ Cycloalkyl (0 to 2 R ２ｂ substituted with; R ２ａ is C １－３ is alkyl; R ２ｂ is F or C １－３ is alkyl; R ３ is CHF ２ Or C ３－６ Cycloalkyl; R ４ is hydrogen, halogen or C １－３ is alkyl] 2. The compound of claim 1, wherein:

4. formula: 【Chemistry 4】 [In the formula: R １ is C １－３ is alkyl; R ２ HA -N(CH ３ ) ２ , -OR ２ａ Or C ３－６ Cycloalkyl (0 to 2 R ２ｂ substituted with; R ２ａ is C １－３ is alkyl; R ２ｂ is F or C １－３ is alkyl; R ３ is CHF ２ Or C ３－６ Cycloalkyl; R ４ is hydrogen, halogen or C １－３ is alkyl] 4. The compound of claim 3, wherein:

5. Formula III: 【Chemistry 5】 [In the formula: R １ is C １－３ Alkyl or -NHCD ３ and R ２ HA -N(CH ３ ) ２ , -OR ２ａ Or C ３－６ Cycloalkyl (0 to 2 R ２ｂ substituted with; R ２ａ is C １－３ is alkyl; R ２ｂ is F or C １－３ is alkyl; R ３ is CHF ２ Or C ３－６ Cycloalkyl; R ４ is hydrogen, halogen or C １－３ is alkyl] 2. The compound of claim 1, wherein:

6. formula: 【Chemistry 6】 [In the formula: R １ Ha-NHCD ３ and R ２ HA -N(CH ３ ) ２ , -OR ２ａ Or C ３－６ Cycloalkyl (0 to 2 R ２ｂ substituted with; R ２ａ is C １－３ is alkyl; R ２ｂ is F or C １－３ is alkyl; R ３ is CHF ２ Or C ３－６ Cycloalkyl; R ４ is hydrogen, halogen or C １－３ is alkyl] 6. The compound of claim 5, wherein:

7. 6-(cyclopropanecarboxamido)-4-((3-(cyclopropylsulfonyl)-pyridin-2-yl)amino)-N-(methyl-d ３ ) pyridazine-3-carboxamide; Methyl(5-((3-(cyclopropyl-sulfonyl)pyridin-2-yl)amino)-6-((methyl-d ３ )-carbamoyl)-pyridazin-3-yl)-carbamate; N-(4-((3-(cyclopropyl-sulfonyl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide; 6-(cyclopropanecarboxamido)-4-((3-((difluoromethyl)-sulfonyl)pyridin-2-yl)amino)-N-(methyl-d ３ ) pyridazine-3-carboxamide; Methyl(5-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-6-((methyl-d ３ ) carbamoyl) pyridazin-3-yl) carbamate; 4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-6-(3,3-dimethylureido)-N-(methyl-d ３ ) pyridazine-3-carboxamide; 4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-N-(methyl-d ３ )-6-(3-methyl-2-oxoimidazolidin-1-yl)pyridazine-3-carboxamide; 4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-N-(methyl-d ３ )-6-((1R,2R)-2-methylcyclopropane-1-carboxamido)pyridazine-3-carboxamide; (R)-4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-N-(methyl-d ３ )-6-(spiro[2.2]pentane-1-carboxamido)pyridazine-3-carboxamide; 4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-N-(methyl-d ３ )-6-((1S,2S)-2-methylcyclopropane-1-carboxamido)pyridazine-3-carboxamide; (R)-4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-6-(2,2-dimethylcyclopropane-1-carboxamide)-N-(methyl-d ３ ) pyridazine-3-carboxamide; 4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-6-((1R,2S)-2-fluorocyclopropane-1-carboxamide)-N-(methyl-d ３ ) pyridazine-3-carboxamide; 4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-N-(methyl-d ３ )-6-(2-methylcyclopropane-1-carboxamido)pyridazine-3-carboxamide; 4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-6-((6-fluoropyridin-2-yl)amino)-N-(methyl-d ３ ) pyridazine-3-carboxamide; N-(4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide; 3-(4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)-1,1-dimethylurea; ((R)—N-(4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)spiro[2.2]pentane-1-carboxamide; (1S,2S)—N-(4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)-2-methylcyclopropane-1-carboxamide; (R)—N-(4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)-2,2-dimethylcyclopropane-1-carboxamide; (1R,2S)—N-(4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)-2-methylcyclopropane-1-carboxamide, and 1-(4-((3-((difluoromethyl)sulfonyl)pyridin-2-yl)amino)-6-((6-fluoropyridin-2-yl)amino)pyridin-3-yl)propan-1-one or a pharma- ceutically acceptable salt thereof.

8. 10. A pharmaceutical composition comprising one or more compounds according to claim 1, or stereoisomers or pharma- ceutically acceptable salts thereof, and a pharma- ceutically acceptable carrier or diluent.

9. 10. A pharmaceutical composition comprising one or more compounds according to claim 7, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or diluent.

10. 10. A medicament for treating a neurodegenerative disease, comprising a compound of claim 1, or a stereoisomer or a pharma- ceutically acceptable salt thereof.

11. The method of claim 10, wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, ALS, or multiple sclerosis.

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