Substituted Heterocyclic Compounds

Abstract

Formula I: TIFF2024518556000071.tif48142 [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 / 328,835, filed April 8, 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] 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

[0013] 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.

[0014] 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.

[0015] 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. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] 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 is alkyl; R 2 is F or C 1-3 is alkyl; R 3is oxadiazole, oxazole, pyridine, pyrimidine, thiadiazole, pyrazine, thiazole, pyrazole or isothiazole, all of which have 0 to 3 R 3a is substituted with a group; R 3a H, F, Cl, CN, NO 2 , C 1-4 Alkyl, OC 1-4 Alkyl, C 3-6 Cycloalkyl, (CH 2 )nF, CHF 2 , Hydroxy C 1-3 Alkyl or cyano C 1-3 is alkyl; and n is 1 or 2] or a stereoisomer or pharma- ceutically acceptable salt thereof.

[0017] In a second aspect of the present invention, a compound of formula II: [ka] [In formula: R 1 is C 1-3 is alkyl; R 2 is F or C 1-3 is alkyl; R 3 is oxadiazole, oxazole, pyridine, pyrimidine, thiadiazole, pyrazine, thiazole, pyrazole or isothiazole, all of which have 0 to 3 R 3a is substituted with a group; R 3a H, F, Cl, CN, NO 2 , C 1-4 Alkyl, OC 1-4 Alkyl, C 3-6 Cycloalkyl, (CH 2 )nF, CHF 2 , Hydroxy C 1-3 Alkyl or cyano C 1-3 is alkyl; and n is 1 or 2] or a stereoisomer or pharma- ceutically acceptable salt thereof.

[0018] In a third aspect of the present invention, a compound of formula III: [ka] [In formula: R 1 is C 1-3 is alkyl; R 2 is F or C 1-3 is alkyl; R 3 is oxadiazole, oxazole, pyridine, pyrimidine, thiadiazole, pyrazine, thiazole, pyrazole or isothiazole, all of which have 0 to 3 R 3a is substituted with a group; R 3a H, F, Cl, CN, NO 2 , C 1-4 Alkyl, OC 1-4 Alkyl, C 3-6 Cycloalkyl, (CH 2 )nF, CHF 2 , Hydroxy C 1-3 Alkyl or cyano C 1-3 is alkyl; and n is 1 or 2] or a stereoisomer or pharma- ceutically acceptable salt thereof.

[0019] 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.

[0020] In another embodiment, there is provided a compound selected from any subgroup list of compounds within the scope of any of the above embodiments.

[0021] In another aspect, 6-Cyclopropanamido-4-({3-[5-(fluoromethyl)-1,2,4-oxadiazol-3-yl]-2-methoxyphenyl}amino)-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-[(2-methoxy-3-{5-[(propan-2-yloxy)methyl]-1,2,4-oxadiazol-3-yl}phenyl)amino]-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-({3-[5-(ethoxymethyl)-1,2,4-oxadiazol-3-yl]-2-methoxyphenyl}amino)-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-({2-methoxy-3-[5-(2-methoxyethyl)-1,2,4-oxadiazol-3-yl]phenyl}amino)-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-({3-[5-(2-fluoroethyl)-1,2,4-oxadiazol-3-yl]-2-methoxyphenyl}amino)-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[2-methoxy-3-(1,3-oxazol-4-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-({3-[5-(difluoromethyl)pyridin-2-yl]-2-methoxyphenyl}amino)-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[2-methoxy-3-(6-methylpyrimidin-4-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[2-methoxy-3-(1,2,4-thiadiazol-5-yl)phenyl]amino}-N-(2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-(5-fluoropyrazin-2-yl)-2-methoxyphenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-(5-cyclopropylpyrazin-2-yl)-2-methoxyphenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide;

[0022] 6-Cyclopropanamido-4-{[2-methoxy-3-(5-nitropyrazin-2-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[2-methoxy-3-(3-methyl-1,2,4-thiadiazol-5-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-({3-[5-(1-hydroxycyclobutyl)pyrazin-2-yl]-2-methoxy-5-methylphenyl}amino)-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-({5-fluoro-3-[5-(1-hydroxycyclobutyl)pyrazin-2-yl]-2-methoxyphenyl}amino)-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-(5-cyclopropylpyrazin-2-yl)-5-fluoro-2-methoxyphenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[2-methoxy-3-(2-methyl-1,3-oxazol-4-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-(2,5-dimethyl-1,3-oxazol-4-yl)-2-methoxyphenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-({3-[5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]-2-methoxyphenyl}amino)-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-({4-[5-(2-hydroxypropan-2-yl)pyrazin-2-yl]-3-methoxypyridin-2-yl}amino)-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[2-methoxy-3-(2-methyl-1,3-thiazol-4-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide;

[0023] 6-Cyclopropanamido-4-{[2-methoxy-3-(5-methoxypyrazin-2-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[2-methoxy-3-(5-methylpyrazin-2-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 4-({3-[5-(1-cyano-1-methylethyl)pyridin-2-yl]-2-methoxyphenyl}amino)-6-cyclopropanamide-N-( 2 H3) methylpyridazine-3-carboxamide; 4-{[2-Methoxy-3-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)phenyl]amino}-N-( 2 H3) Methyl-6-[(1R,2R)-2-methylcyclopropanamido]pyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[4-fluoro-2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[5-fluoro-2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methoxyphenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 4-{[3-(5-cyanopyrazin-2-yl)-2-methoxyphenyl]amino}-6-cyclopropanamide-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[4-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methoxypyridin-2-yl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[4-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methoxypyridin-2-yl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[4-(1,5-dimethyl-1H-pyrazol-4-yl)-3-methoxypyridin-2-yl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide;

[0024] 6-Cyclopropanamido-4-{[3-methoxy-4-(1,3-thiazol-2-yl)pyridin-2-yl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[2-methoxy-3-(1,2-thiazol-5-yl)phenyl]amino}-N-(2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[2-methoxy-3-(1,2-thiazol-3-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[2-methoxy-3-(1,2-thiazol-4-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[5-fluoro-2-methoxy-3-(1,3-oxazol-4-yl)phenyl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-methoxy-4-(1,2-thiazol-4-yl)pyridin-2-yl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-methoxy-4-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-2-yl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 4-{[3-methoxy-4-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-2-yl]amino}-N-( 2 H3) Methyl-6-[(1R,2R)-2-methylcyclopropanamido]pyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-methoxy-4-(1,2,4-thiadiazol-5-yl)pyridin-2-yl]amino}-N-( 2 H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-({4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-methoxypyridin-2-yl}amino)-N-( 2 H3) methylpyridazine-3-carboxamide; and 6-Cyclopropanamido-4-{[3-(5-ethyl-1,2,4-oxadiazol-3-yl)-2-methoxyphenyl]amino}-N-( 2 H3) Methylpyridazine-3-carboxamide Provided is a compound (IUPAC nomenclature rules), or a pharma- ceutically acceptable salt thereof, selected from:

[0025] 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.

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

[0027] The present invention also provides methods for treating proliferative, metabolic, allergic, autoimmune and inflammatory diseases (or the use of compounds of the 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.

[0028] 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.

[0029] 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.

[0030] 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).

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] A dash "-" that is not between two letters or symbols is used to indicate a point of attachment of a substituent, for example, -CONH. 2 is bonded via a carbon atom.

[0044] 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.

[0045] As used herein, the term "at least one chemical entity" is interchangeable with the term "compound."

[0046] 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 C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , and C 10 It also includes alkyl groups, for example, "C 1 -C 6 "Alkyl" refers to an alkyl group having 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.

[0047] "Alkenyl" or "alkenylene" is intended to include a hydrocarbon chain of either a straight or branched configuration, with one or more double carbon-carbon bonds that may occur at any stable point along the chain. For example, "C2-6 alkenyl" (or alkenylene) is intended to include C2, C3, C4, C5, and C6 alkenyl groups. Examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.

[0048] "Alkynyl" or "alkynylene" is intended to include a hydrocarbon chain of either a straight or branched configuration having one or more triple carbon-carbon bonds that may occur at any stable point along the chain. For example, "C2-6 alkynyl" (or alkynylene) is intended to include C2, C3, C4, C5, and C6 alkynyl groups such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.

[0049] Those skilled in the art will recognize that "CO 2 As used herein, the term " [ka] It will be understood that this refers to the

[0050] 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.

[0051] When reference is made to a substituted alkenyl, alkynyl, alkylene, alkenylene, or alkynylene group, these groups are substituted with from 1 to 3 substituents, as described above for substituted alkyl groups.

[0052] 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.

[0053] 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.

[0054] 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).

[0055] 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. Presently, the compounds referred to include N-halo, S(O) 2 It is preferred that it does not contain H or S(O)H groups.

[0056] The term "cycloalkyl" refers to a cyclized alkyl group including monocyclic, bicyclic or polycyclic ring systems. Ccycloalkyl refers to C 3 , C 4 , C 5 , C 6 , 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 mono- 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.

[0057] 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.

[0058] 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.

[0059] Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term "halo" or "halogen" refers to chloro, bromo, fluoro and iodo. The term "haloalkyl" refers to a substituted alkyl having one or more halo substituents. For example, "haloalkyl" includes mono-, bi-, and trifluoromethyl. The term "haloalkoxy" refers to an alkoxy group having one or more halo substituents. For example, "haloalkoxy" includes OCF3.

[0060] 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.

[0061] 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:

[0062] 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.

[0063] 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.

[0064] Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydroisoindolyl, tetrahydroquinolinyl, and the like.

[0065] Exemplary tricyclic heteroaryl groups include carbazolyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[0066] In compounds of formula I, preferred heteroaryl groups include: [ka] and the like, which may be optionally substituted at any available carbon or nitrogen atom.

[0067] 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.

[0068] 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.

[0069] The term "heteroatom" is intended to include oxygen, sulfur and nitrogen.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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).

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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).

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] "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.

[0096] 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.

[0097] An exemplary composition for topical administration includes PLASTIBASE® (mineral oil gelled with polyethylene).

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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).

[0105] 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.

[0106] Figure 1 [ka]

[0107] Scheme 1 shows how intermediates Ia and / or Id can be formed from Ib or Ie, respectively, where in some cases the amine of Ie may need to be protected via standard protecting groups prior to the boronation reaction. The boronation reaction can be carried out via metal halide exchange followed by quenching with a trialkylborate, particularly trimethylborate or triisopropylborate. A preferred base for the metal halide exchange can be isopropylmagnesium chloride-lithium chloride complex in THF at low temperature. Alternatively, PdCl 2 Conversion of the halides to the corresponding boronates can be achieved by cross-coupling using a palladium source such as (dppf)[DCM] and a boron source such as bis(pinacolato)diborane in the presence of potassium acetate or a related substance for a suitable time and temperature.

[0108] Scheme 1 [ka]

[0109] Scheme 2 shows how one skilled in the art can combine intermediates Ia or Ib with intermediates Ie or Id to obtain intermediates of general formula III. The transformation, commonly referred to as the Suzuki reaction, can be accomplished by one skilled in the art using a transition metal catalyzed coupling of an appropriate boronate with an appropriate halide. More specifically, this transformation can be accomplished using PdCl as a catalyst. 2 (dppf)[DCM] can be accomplished in a Suzuki-type coupling using aqueous potassium phosphate tribasic as the base at elevated temperatures in a solvent such as 1,4-dioxane.

[0110] Scheme 2 [ka]

[0111] Scheme 3 shows how a person skilled in the art of organic synthesis can couple an intermediate of general formula If (Moslin et al., J. Med. Chem 2019, 62, 8953-8972) with an intermediate of general formula III to obtain an intermediate of general formula IV. 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 particular III, and adding a suitable base, in particular lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide or sodium hydride.

[0112] Scheme 3 [ka]

[0113] Scheme 4 illustrates how one skilled in the art of organic synthesis can couple compound IV to an appropriate substrate in one or more steps to produce a compound of general formula I. The one-step method involves coupling a compound of general formula IV with a primary amide of general formula Ih under transition metal catalyzed conditions. In particular, preferred conditions for this reaction include coupling with Pd 2 (dba) 3 , xantphos as the ligand, and Cs as the base. 2 CO 3in 1,4-dioxane as solvent at elevated temperatures. This catalyst / ligand / base system can be modified in ways known to those skilled in the art. Alternatively, compounds of general formula IV can be treated with a primary amine at elevated temperatures in a suitable solvent, in particular 4-methoxybenzylamine, to give a product which can be deprotected to give the corresponding primary amine of general formula V. The product of this reaction can be deprotected with TFA at elevated temperatures to give V. Compounds of general formula I can then be prepared from V by coupling with an appropriate carboxylic acid under amide coupling conditions known to those skilled in the art.

[0114] Scheme 4 [ka]

[0115] Scheme 5 shows an alternative synthesis of compounds of general formula I. Compound If is reacted with an aliphatic sulfide nucleophile to give VI, thus allowing the regioselective coupling of amides of type Ih using the palladium catalyzed conditions described above. Oxidation of the sulfide in VI to the sulfoxide (VII) reactivates the position of nucleophilic substitution before coupling with palladium catalyst in this case. The skilled artisan can also devise a synthesis in which oxidation of the sulfide occurs after the coupling reaction with palladium catalyst, either of which ultimately leads to VIII. Reaction of VIII with an arylamine of type Ie in the presence of a strong base such as lithium hexamethyldisilazide in a polar aprotic solvent such as THF gives compounds of general formula IX. Compound IX can then be directly coupled with a boronate of type Ia using standard Suzuki conditions to give I. Alternatively, IX can be converted to a boronate X using conditions similar to the conversion of Ie to Id, which can then be coupled with an aryl halide of general formula Ib.

[0116] Scheme 5 [ka]

[0117] There are many other methods of assembling the heteroaryl moiety without resorting to palladium-catalyzed reactions, including constructing the moiety from functional groups such as carboxylic acids, amides, and cyano groups that are already attached to the desired point of attachment. Specific examples are included herein, and for a general description of the methods, see Moslin et al., U.S. Patent No. 9,505,748.

[0118] Method A: 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: 1.0ml / min Column: Kinetex XB-C18 (75x3.0) mm, 2.6 μm Subjected to ultraviolet ("UV") visualization at 220 nanometers ("nm")

[0119] Method B: Run a linear gradient from 0% to 100% solvent B over 3 min, hold at 100% B for 0.75 min Subjected to ultraviolet ("UV") visualization at 220 nanometers ("nm") Column: Acquity UPLC® BEH (2.1x50mm) C18 1.7μM Flow rate: 1.11mL / min Solvent A: 10 mM ammonium acetate, 95% water, 5% acetonitrile Solvent B: 10 mM ammonium acetate, 5% water, 95% acetonitrile

[0120] Method C: Run a linear gradient from 0% to 100% solvent B over 2 min, hold at 100% B for 0.5 min Subjected to ultraviolet ("UV") visualization at 254 nanometers ("nm") Column: Acquity UPLC (registered trademark) BEH C18 1.7 μM Flow rate: 1mL / min Solvent A: 0.05% trifluoroacetic acid, 95% water, 5% acetonitrile Solvent B: 0.05% trifluoroacetic acid, 5% water, 95% acetonitrile

[0121] Method D: Run a linear gradient from 2% to 98% solvent B over 1 min, hold at 98% B for 0.5 min. Subjected to ultraviolet ("UV") visualization at 254 nanometers ("nm") Column: Acquity UPLC (registered trademark) BEH C18 1.7 μM Flow rate: 0.8 milliliters ("mL") per minute Solvent A: Water Solvent B: Acetonitrile

[0122] Method E: A linear gradient from 5% to 95% solvent B over 2.5 min, held at 95% B for 1.5 min, followed by a 0.5 min gradient to 5% B, held at 5% B for 1.5 min Solvent A:H 2 0.1% TFA in O Solvent B: 0.1% TFA in ACN Flow rate: 1.5ml / min Column: XBridge C8 (50x4.6) mm, 3.5 μm Subjected to ultraviolet ("UV") visualization at 220 nanometers ("nm")

[0123] Method F: 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: 1.0ml / min Column: Kinetics XB-C18 (75x3.0) mm, 2.6 μm Subjected to ultraviolet ("UV") visualization at 220 nanometers ("nm")

[0124] Method G: A linear gradient from 5% to 95% solvent B over 2.5 min, held at 95% B for 1.5 min, followed by a 0.5 min gradient to 5% B, held at 5% B for 1.5 min Solvent A:H 2 0.1% TFA in O Solvent B: 0.1% TFA in ACN Flow rate: 1.5ml / min Column: Xbridge C8 (50x4.6) mm, 3.5 μm Subjected to ultraviolet ("UV") visualization at 220 nanometers ("nm")

[0125] GCMS method H: Chromatography column: HP-5 (30m x 320μm x 0.25μm) Column length: 30 m, inner diameter: 0.32 mm, thickness: 0.25 μm Inlet temperature: 250°C; carrier gas: He; Detector temperature: 300°C; column flow: 2 mL / min; Airflow: 400mL / min;H 2 Flow: 40mL / min Heating schedule: 120°C hold for 3 minutes, then ramp to 300°C at 40°C / min and hold for 2 minutes; Source temperature: 230℃ Recorded: 7890BGC equipped with 5977B MSD from Agilent Technologies

[0126] Method I: Run a linear gradient from 0% to 100% solvent B over 3 min, hold at 100% B for 0.5 min Subjected to ultraviolet ("UV") visualization at 254 nanometers ("nm") Column: Acquity UPLC (registered trademark) BEH C18 1.7 μM Flow rate: 1mL / min Solvent A: 0.05% trifluoroacetic acid, 95% water, 5% acetonitrile Solvent B: 0.05% trifluoroacetic acid, 5% water, 95% acetonitrile

[0127] [Table 1] [Table 2]

[0128] Intermediate 1: [ka]

[0129] Step 1: To a solution of lithium 4,6-dichloropyridazine-3-carboxylate (10.0 g, 51.8 mmol) in DCM (200 mL) was added oxalyl chloride (9.07 mL, 104.0 mmol) and 1 mL of DMF at 0° C. The reaction mixture was allowed to warm to room temperature for 1 h. The solvent was removed under reduced pressure and DCM (200 mL) was added to the reaction mixture. The resulting solution was cooled to −30° C. and deuterated methylamine hydrochloride (4.02 g, 57.0 mmol) was added followed by DIPEA (18.1 mL, 104.0 mmol). The reaction mixture was stirred at −30° C. for 1 h and then allowed to warm to room temperature and stirring was continued for another 1 h. The reaction mixture was concentrated under reduced pressure and the crude residue was dissolved in ethyl acetate (200 mL) and washed with water (2×100 mL) and brine (100 mL). The organic layer was extracted with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml and then concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (10-15% ethyl acetate in petroleum ether) to give the desired product, 4,6-dichloro-N-(methyl-d3 ) Pyridazine-3-carboxamide (4.1 g, 19.42 mmol, 37.5% yield) was obtained as a pale yellow solid. MS (M+1) m / z: 208.6 (M+H) + LC retention time 1.18 min [G]

[0130] Step 2: LiHMDS (7.65 mL, 7.65 mmol, 1.0 M solution in THF) was dissolved in 3-amino-2-methoxybenzonitrile (0.35 g, 2.39 mmol) and 4,6-dichloro-N-(methyl-d 3 ) pyridazine-3-carboxamide (0.5 g, 2.39 mmol) in THF (10 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 1 h and then NH 4 The reaction mixture was quenched with saturated aqueous Cl (20 mL). The reaction mixture was partitioned between ethyl acetate (50 mL) and water (40 mL). The organic layer was collected and washed with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (30% ethyl acetate in petroleum ether) to give 6-chloro-4-((3-cyano-2-methoxyphenyl)amino)-N-(methyl-d 3 ) Pyridazine-3-carboxamide (505 mg, 65.8%) was obtained as a brown solid. MS (M+1) m / z: 321.0 (M+H) + ;LC retention time 2.09 min [F]; 1 H-NMR (400 MHz, DMSO-d 6 ):δ 11.12(s,1H), 9.42(s,1H), 7.88(dd,J=1.60, 8.20Hz,1H), 7.68(dd,J=1.60, 7.80Hz,1H), 7.36(t,J=7.60Hz,1H), 7.23(s,1H), 3.92(s,3H)

[0131] Step 3: 6-Chloro-4-((3-cyano-2-methoxyphenyl)amino)-N-(methyl-d 3) To a solution of pyridazine-3-carboxamide (0.5 g, 1.56 mmol), cyclopropanecarboxamide (0.66 g, 7.79 mmol) in dioxane (20 mL), Pd 2 (dba) 3 (0.14 g, 0.16 mmol), Xantphos (0.18 g, 0.31 mmol) and Cs 2 CO 3 (1.27 g, 3.90 mmol) was added. The reaction mixture was then rinsed with N 2 The mixture was degassed under reduced pressure for 5 min. The vessel was sealed and stirred at 120° C. for 16 h. The reaction mixture was filtered through a pad of Celite and washed with methanol (50 mL). The filtrate was collected, concentrated under reduced pressure, and purified by silica gel column chromatography (5% MeOH in DCM) to give the desired product, 4-((3-cyano-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d 3 ) Pyridazine-3-carboxamide (380 mg, 66.0%) was obtained as a brown solid. MS (M+1) m / z: 370.0 (M+H) + ;LC retention time 2.02 min [F]

[0132] Step 4: 4-((3-cyano-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d 3 ) To a solution of pyridazine-3-carboxamide (0.15 g, 0.42 mmol) in ethanol (5 mL) was added hydroxylamine hydrochloride (0.14 g, 2.07 mmol) and KOH (0.11 g, 1.99 mmol). The reaction mixture was heated to reflux at 85° C. for 1 h. An additional aliquot of hydroxylamine hydrochloride (0.14 g, 2.07 mmol) and KOH (0.11 g, 1.99 mmol) was added and the reaction was stirred at 85° C. for 8 h. The reaction mixture was cooled and concentrated under reduced pressure. The crude reaction mixture was partitioned between DCM (50 mL) and water (30 mL). The organic layer was collected and the aqueous layer was extracted with DCM (50 mL). The organic extracts were combined and washed with anhydrous Na 2 SO 4The crude residue was purified using silica gel column chromatography (10% MeOH in DCM) to give (Z)-6-(cyclopropanecarboxamido)-4-((3-(N'-hydroxycarbamimidoyl)-2-methoxyphenyl)amino)-N-(methyl-d 3 ) Pyridazine-3-carboxamide (90 mg, 55.1%) was obtained as a brown solid. MS (M+1) m / z: 403.0 (M+H) + ;LC retention time 0.63 min [F]

[0133] Intermediate 2 [ka]

[0134] Step 1: To a solution of 1-bromo-2-methoxy-3-nitrobenzene (2.0 g, 8.62 mmol) in ethanol (20 mL) and water (5 mL) was added iron (3.37 g, 60.3 mmol) and ammonium chloride (2.3 g, 43.3 mmol). The reaction was stirred at 60° C. for 3 h, diluted with ethanol (50 mL) and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give the crude product (2.5 g). The crude residue was diluted with EtOAc (100 mL) and washed with water (2×20 mL) and brine (2×20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3-bromo-2-methoxyaniline (1.8 g, 8.55 mmol, 99% yield) as a brown liquid. MS (M+1) m / z: 202.0 (M+H) + ;LC retention time 1.84[A]

[0135] Step 2: To a stirred solution of 3-bromo-2-methoxyaniline (1.80 g, 8.91 mmol) in 1,4-dioxane (15 mL) in a sealed test tube was added bis(pinacolato)diboron (3.39 g, 13.36 mmol) and potassium acetate (2.62 g, 26.7 mmol). The reaction was purged with nitrogen gas for 1 min and then diluted with PdCl. 2(dppf)·[DCM] (0.73 g, 0.89 mmol) was added. The reaction mixture was stirred at 90° C. for 5 h, then cooled to room temperature and diluted with EtOAc (100 mL). The reaction mixture was filtered through a pad of Celite and the filtrate was washed with water (2×50 mL) and brine (2×50 mL). The organic extracts were combined and washed with Na 2 SO 4 After drying over low pressure and concentration under reduced pressure, the crude product was purified by silica gel column chromatography (25% ethyl acetate in petroleum ether) to give 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.8 g, 6.88 mmol, 77% yield) as a light brown solid. MS (M+1) m / z: 250.4 (M+H). + ;LC retention time 2.11[A]

[0136] Intermediate 3 [ka]

[0137] 3-Bromo-5-fluoro-2-methoxyaniline (hydrochloride) (4.5 g, 17.5 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (5.79 g, 22.8 mmol), PdCl 2 A sealed vessel containing (dppf)·DCM (0.716 g, 0.877 mmol) and potassium acetate (6.03 g, 61.4 mmol) in dioxane (100 mL) was heated to 105° C. Heating was continued overnight at which point the reaction was cooled to room temperature, absorbed onto Celite®, and dried under reduced pressure. The crude material was then purified using automated chromatography (solid loading) eluting with 0-50% EtOAc / hexanes. Fractions containing the product were combined and concentrated under reduced pressure to give 5-fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.55 g, 54% yield) as a pale yellow solid. MS(M+1) m / z: 268.3 (MH +);LC retention time 1.50 min [C]

[0138] Intermediate 4: [ka]

[0139] Step 1: 4,6-Dichloro-N-(methyl-d 3 To a solution of pyridazine-3-carboxamide (2.0 g, 9.57 mmol) in THF (80 mL) was added sodium thiomethoxide (1.0 g, 14.27 mmol) in water (25 mL) in three portions spaced 5 min apart at 0° C., and the reaction was stirred at room temperature for 1 h after the addition was complete. The reaction mixture was diluted with water (80 mL) and extracted with DCM (3×50 mL). The organic extracts were combined and diluted with Na 2 SO 4 The mixture was dried over ice, concentrated in vacuum, and purified by silica gel column chromatography using 20% ​​EtOAc in hexane to give 6-chloro-N-(methyl-d 3 )-4-(methylthio)pyridazine-3-carboxamide (2.1 g, 8.74 mmol, 91% yield) was obtained as a pale yellow solid. MS (M+1) m / z: 222.3 (M+H). + ;LC retention time 0.71 min [F]

[0140] Step 2: 6-Chloro-N-(methyl-d 3 To a solution of m-4-(methylthio)pyridazine-3-carboxamide (2.2 g, 9.97 mmol) in DCM (80 mL) was added m-CPBA (8.60 g, 49.8 mmol) at 0° C. and the reaction mixture was cooled to 5° C. with N 2 The mixture was stirred at room temperature under atmospheric conditions for 2 hours. After completion of the reaction, it was quenched with saturated aqueous sodium bicarbonate (50 mL) and extracted with DCM (4x50 mL). The organic layers were combined and washed with anhydrous Na 2 SO 4 The crude residue was purified by silica gel column chromatography to give 6-chloro-N-(methyl-d 3)-4-(methylsulfonyl)pyridazine-3-carboxamide (1.5 g, 5.94 mmol, 59.5% yield) as a white solid. 1 H NMR (DMSO-d 6 ):9.08(s,1H), 8.32(s,1H), 3.58(s,3H)

[0141] Step 3: 6-Chloro-N-(methyl-d 3 To a stirred solution of 1.1 g (4.35 mmol)-4-(methylsulfonyl)pyridazine-3-carboxamide and 1.11 g (13.06 mmol) of cyclopropanecarboxamide in 1,4-dioxane (15 mL) was added Cs 2 CO 3 (3.55 g, 10.88 mmol) was added. The reaction mixture was then rinsed with N 2 The mixture was degassed for 10 minutes under reduced pressure. 2 (dba) 3 (0.8 g, 0.871 mmol) and Xantphos (0.50 g, 0.87 mmol) were added to the reaction mixture, which was then stirred in a sealed tube at 100° C. for 3 h. After completion, the reaction mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (50% EtOAc in hexanes) to give 6-(cyclopropanecarboxamido)-N-(methyl-d 3 )-4-(methylsulfonyl)pyridazine-3-carboxamide (0.38 g, 0.95 mmol, 21.84% yield) was obtained as a yellow solid. MS (M+1) m / z: 302.1 (M+H). + ;LC retention time 0.72 min [F]

[0142] Step 4: 6-(Cyclopropanecarboxamide)-N-(methyl-d 3To a solution of 4-((3-bromo-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d)-4-(methylsulfonyl)pyridazine-3-carboxamide (0.19 g, 0.627 mmol) and 3-bromo-2-methoxyaniline (0.13 g, 0.63 mmol) in THF (15 mL) was added LiHMDS (1.65 mL, 2.51 mmol, 1.5 M solution in THF) at 0° C. The reaction was allowed to warm to room temperature and stirred under nitrogen atmosphere for 2 hours. After completion of the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (2×30 mL). The crude product was purified using silica gel column chromatography (60% EtOAc in hexanes) to give 4-((3-bromo-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d)-4-(methylsulfonyl)pyridazine-3-carboxamide (0.19 g, 0.627 mmol) and 3-bromo-2-methoxyaniline (0.13 g, 0.63 mmol) in THF (15 mL). 3 ) Pyridazine-3-carboxamide (100 mg, 0.198 mmol, 31.6% yield) was obtained as a semi-solid. MS (M+1) m / z: 424.8 (M+H) + LC retention time 2.66 min [F]

[0143] Step 5: 4-((3-bromo-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d 3 To a stirred solution of pyridazine-3-carboxamide (0.2 g, 0.47 mmol) and bis(pinacolato)diboron (0.24 g, 0.95 mmol) in 1,4-dioxane (15 mL) was added potassium acetate (0.12 mg, 1.18 mmol). The reaction mixture was cooled to 5° C. for 2 h and cooled to 3° C. for 1 h. 2 The mixture was degassed for 10 minutes using PdCl 2 The (dppf)-DCM adduct (77 mg, 0.094 mmol) was added to the reaction mixture and the reaction was heated to 100° C. and stirred for 16 h. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (60% ethyl acetate in hexanes) to give 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-N-(methyl-d 3) Pyridazine-3-carboxamide (0.5 g, 0.276 mmol, 58.5% yield) was obtained as a brown syrup. MS (M+1) m / z: 471.1 (M+H) + LC retention time 2.71 min [F]

[0144] Intermediate 5: [ka]

[0145] Step 1: To a stirred solution of 1-(2-hydroxy-3-nitrophenyl)ethan-1-one (2.0 g, 11.04 mmol) in N,N-dimethylformamide (20 mL), 2 CO 3 (6.10 g, 44.2 mmol) was added and stirring was continued for 30 min, at which point iodomethane (2.071 mL, 33.1 mmol) was added. The reaction mixture was stirred at room temperature for an additional 16 h. After completion of the reaction, cold water (100 mL) was added and the product was extracted with EtOAc (2x100 mL). The organic layers were combined, washed with brine (50 mL) and diluted with anhydrous Na 2 SO 4 After drying over 500 ml of hexane and concentrating under reduced pressure, the crude product was purified by column chromatography on silica gel 230-400 mesh (3% EtOAc in petroleum ether) to give 1-(2-methoxy-3-nitrophenyl)ethan-1-one (2.0 g, 10.14 mmol, 92% yield) as a yellow solid. 1 H-NMR (400 MHz, DMSO-d 6 ):d 7.95(dd,J=1.60, 8.00Hz,1H), 7.84(dd,J=1.60, 7.80Hz,1H), 7.31(dd,J=3.60, 13.60Hz,1H), 3.97(s,3H), 2.69(s,3H)

[0146] Step 2: A solution of 1-(2-methoxy-3-nitrophenyl)ethan-1-one (1.5 g, 7.69 mmol) in chloroform (10 mL) and ethyl acetate (10 mL) was cooled to 0° C., followed by the addition of copper(II) bromide (2.06 g, 9.22 mmol). The reaction was allowed to warm to 70° C. and stirred for 6 hours. Upon completion, the reaction mixture was filtered through a pad of Celite and washed with water (50 mL) and ethyl acetate (50 mL). The organic layer was separated and washed with anhydrous Na 2 SO 4 After drying over 50° C. and concentrating under reduced pressure, 2-bromo-1-(2-methoxy-3-nitrophenyl)ethan-1-one (1.1 g, 2.81 mmol, 36.6% yield) was obtained as a yellow solid. GCMS m / z: 272.9 (M) + ;GC retention time 4.5 minutes [H]

[0147] Step 3: 2-Bromo-1-(2-methoxy-3-nitrophenyl)ethan-1-one (1.0 g, 3.65 mmol) in acetamide (4.31 g, 73.0 mmol) was stirred at 100° C. for 16 h. After completion, the reaction mixture was diluted with water (50 mL) and EtOAc (50 mL). The organic layer was separated and washed with anhydrous Na 2 SO 4 The mixture was dried over hexane, filtered and concentrated under reduced pressure to give a crude residue. The crude product was purified by silica gel (100-200 mesh) column chromatography using 30% EtOAc in petroleum ether to give 4-(2-methoxy-3-nitrophenyl)-2-methyloxazole (0.78 g, 2.60 mmol, 71.2% yield) as a brown liquid. MS (M+1) m / z: 235.0 (M+H). + ;LC retention time 2.06 min [F]

[0148] Step 4: To a stirred solution of 4-(2-methoxy-3-nitrophenyl)-2-methyloxazole (0.65 g, 2.78 mmol) in acetonitrile (1.5 mL) was added zinc (1.27 g, 19.43 mmol) and acetic acid (1.5 mL). The reaction mixture was stirred at 25° C. for 3 h. After completion, the reaction mixture was filtered through a pad of Celite, washed with EtOAc (20 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried over hexane and concentrated under reduced pressure to give 2-methoxy-3-(2-methyloxazol-4-yl)aniline (0.4 g, 1.665 mmol, 60.0% yield) as a brown liquid. MS (M+1) m / z: 205.2 (M+H). + LC retention time 1.27 min [F]

[0149] Intermediate 6: [ka]

[0150] Step 1: To a stirred solution of 1-(2-hydroxyphenyl)propan-1-one (1.0 g, 6.66 mmol) in acetic acid (1.91 ml, 33.3 mmol) was added nitric acid (0.387 ml, 8.66 mmol) in acetic acid (5 mL) dropwise. The reaction mixture was stirred at 25° C. for 6 h. After completion, the reaction mixture was quenched with cold water (200 mL) and the product was extracted with ethyl acetate (2×100 mL). The organic extracts were combined, washed with brine (100 mL) and diluted with anhydrous Na 2 SO 4 After drying over 100° C. and concentrating under reduced pressure, the crude product was purified by silica gel column chromatography to give 1-(2-hydroxy-3-nitrophenyl)propan-1-one (0.7 g, 3.37 mmol, 50.6% yield) as a pale yellow solid. 1 H-NMR (400 MHz, CDCl 3 ) 13.25(s,1H), 8.14(dd,J=1.60, 8.00Hz,2H), 7.05(dd,J=8.00Hz,2H), 3.13(q,J=7.20Hz,2H), 1.28(t,J=7.20Hz,3H)

[0151] Step 2: To a stirred solution of 1-(2-hydroxy-3-nitrophenyl)propan-1-one (2.0 g, 10.25 mmol) in N,N-dimethylformamide (20 mL), 2 CO 3 (5.66 g, 41.0 mmol) and iodomethane (1.922 mL, 30.7 mmol) were added at 25° C. The reaction mixture was stirred at 25° C. for 16 h. After completion, the reaction mixture was diluted with cold water (100 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined, washed with brine (50 mL) and extracted with anhydrous Na 2 SO 4 After drying over 100° C. and concentration under reduced pressure, a residue was obtained which was purified by column chromatography on silica gel 230-400 mesh (3% EtOAc in petroleum ether) to give 1-(2-methoxy-3-nitrophenyl)propan-1-one (2.0 g, 9.18 mmol, 90% yield) as a yellow liquid. MS (M+1) m / z: 210.1 (M+H). + LC retention time 1.86 min [G]

[0152] Step 3: To a stirred solution of 1-(2-methoxy-3-nitrophenyl)propan-1-one (1.8 g, 8.60 mmol) in acetonitrile (3 mL) was added NBS (1.991 g, 11.19 mmol) and p-TsOH (0.164 g, 0.860 mmol). The reaction mixture was stirred at 60° C. for 6 h. After completion, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×50 mL). The organic layers were combined and washed with anhydrous Na 2 SO 4 The mixture was dried over 100 ml of water and concentrated under reduced pressure to give 2-bromo-1-(2-methoxy-3-nitrophenyl)propan-1-one (1.4 g, 4.13 mmol, 48.0% yield) as a yellow solid. MS (M-1) m / z: 285.9 (MH). + LC retention time 2.74 min [F]

[0153] Step 4: 2-Bromo-1-(2-methoxy-3-nitrophenyl)propan-1-one (1.35 g, 4.69 mmol) in acetamide (5.54 g, 94 mmol) was stirred at 100° C. for 16 h. After completion, the reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (2×50 mL). The organic layer was collected and washed with anhydrous Na 2 SO 4 The mixture was dried over hexane, filtered and concentrated under reduced pressure to give a crude residue which was purified by column chromatography on silica gel 100-200 mesh (25% EtOAc in petroleum ether) to give 4-(2-methoxy-3-nitrophenyl)-2,5-dimethyloxazole (1.1 g, 4.21 mmol, 90% yield) as a brown liquid. MS (M+1) m / z: 249.1 (M+H). + LC retention time 2.17 min [G]

[0154] Step 5: To a stirred solution of 4-(2-methoxy-3-nitrophenyl)-2,5-dimethyloxazole (1.0 g, 4.03 mmol) in acetonitrile (5 mL) was added zinc (1.844 g, 28.2 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. Upon completion, the reaction mixture was diluted with cold water (50 mL) and extracted into EtOAc (2×100 mL). The organic layers were combined, washed with brine (100 mL) and concentrated with anhydrous Na 2 SO 4 The mixture was dried over hexane, filtered, and concentrated under reduced pressure to give 3-(2,5-dimethyloxazol-4-yl)-2-methoxyaniline (0.65 g, 2.73 mmol, 67.6% yield) as a brown liquid. MS (M+1) m / z: 219.0 (M+H). + ;LC retention time 1.20 min [F]

[0155] Example 1 [ka]

[0156] Step 1: (Z)-6-(cyclopropanecarboxamido)-4-((3-(N'-hydroxycarbamimidoyl)-2-methoxyphenyl)amino)-N-(methyl-d 3 ) To a solution of pyridazine-3-carboxamide (0.18 g, 0.44 mmol) in DMF (1 mL) was added 2-hydroxyacetic acid (49.6 mg, 0.65 mmol) and DIC (0.14 mL, 0.87 mmol). The reaction mixture was stirred at room temperature for 1 h. To this reaction mixture was added TBAF (1.74 mL, 1.74 mmol, 1 M solution in THF) and the reaction was stirred at room temperature for 1 h. The reaction mixture was diluted with NH 4 The mixture was quenched with saturated aqueous Cl (10 mL) and extracted with ethyl acetate (50 mL). 2 SO 4 The crude product was purified by silica gel column chromatography (10% MeOH in DCM) to give 6-(cyclopropanecarboxamido)-4-((3-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d 3 ) Pyridazine-3-carboxamide (105 mg, 54.6%) was obtained as an off-white solid. MS (M+1) m / z: 443.2 (M+H) + LC retention time 1.67 min [F]

[0157] Step 2: 6-(Cyclopropanecarboxamido)-4-((3-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d 3To a solution of pyridazine-3-carboxamide (0.1 g, 0.23 mmol) in THF (2.5 mL) was added perfluorobutanesulfonyl fluoride (0.081 mL, 0.452 mmol), DIPEA (0.237 mL, 1.356 mmol) and triethylamine trihydrofluoride (0.184 mL, 0.339 mmol, 30% solution) at room temperature. The reaction mixture was stirred at room temperature for 24 h. Another aliquot of perfluorobutanesulfonyl fluoride (0.081 mL, 0.452 mmol), DIPEA (0.237 mL, 1.356 mmol) and triethylamine trihydrofluoride (0.184 mL, 0.339 mmol, 30% solution) was added and the reaction was stirred at room temperature for another 24 h. One more aliquot of reagents was added and stirring was continued at room temperature for 72 h. The reaction mixture was diluted with NH 4 The mixture was quenched with saturated aqueous Cl (10 mL) and extracted with ethyl acetate (2x25 mL). The organic extracts were combined and collected, and washed with anhydrous Na 2 SO 4 The crude product was purified by preparative HPLC to give the desired product, 6-(cyclopropanecarboxamido)-4-((3-(5-(fluoromethyl)-1,2,4-oxadiazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d 3 ) Pyridazine-3-carboxamide formate (20 mg, 18% yield) was obtained as an off-white solid. MS (M+1) m / z: 445.2 (M+H). + LC retention time 1.76 min [F] 1 H-NMR (400 MHz, DMSO-d 6 ):11.37(s,1H), 11.05(s,1H), 9.18(s,1H), 8.16(s,1H), 7.75-7.70(m,2H), 7.40(dd,J=5.2 0, 13.20Hz,1H), 5.98(s,1H), 5.83(s,1H), 3.75(s,3H), 2.09-2.08(m,1H), 0.84-0.81(m,4H)

[0158] Example 2 [ka]

[0159] (Z)-6-(cyclopropanecarboxamido)-4-((3-(N'-hydroxycarbamimidoyl)-2-methoxyphenyl)amino)-N-(methyl-d 3 ) To a solution of pyridazine-3-carboxamide (0.2 g, 0.224 mmol) and 2-isopropoxyacetic acid (26.4 mg, 0.224 mmol) in DMF (0.3 mL) was added DIC (0.070 mL, 0.447 mmol). The reaction mixture was stirred at room temperature for 1 h. TBAF (0.67 mL, 0.67 mmol, 1 M solution in THF) was added and stirring was continued at room temperature for another 1 h. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (2x10 mL). The organic layers were combined and washed with Na 2 SO 4 The crude compound was purified by preparative HPLC to give the desired 6-(cyclopropanecarboxamido)-4-((3-(5-(isopropoxymethyl)-1,2,4-oxadiazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d 3 ) Pyridazine-3-carboxamide·TFA (37 mg, 0.061 mmol, 27.4% yield) was obtained as an off-white solid. MS (M+1) m / z: 485.2 (M+H) + ;LC retention time 2.41 min [F] 1 H-NMR (400 MHz, DMSO-d 6 ):δ 11.37(s,1H), 11.05(s,1H), 9.18(s,1H), 8.15(s,1H), 7.73-7.68(m,2H), 7.42-7.38(m,1H), 4.8 8(s,2H), 3.85-3.79(m,1H), 3.75(s,3H), 2.10-2.07(m,1H), 1.19-1.18(m,6H), 0.84-0.82(m,4H)

[0160] The following examples (3-4) were prepared in a manner similar to that of Example 2. [ka]

[0161] [Table 3]

[0162] Example 5: [ka]

[0163] Step 1: (Z)-6-(cyclopropanecarboxamido)-4-((3-(N'-hydroxycarbamimidoyl)-2-methoxyphenyl)amino)-N-(methyl-d 3 ) To a solution of pyridazine-3-carboxamide (950 mg, 1.369 mmol) and 3-ethoxy-3-oxopropanoic acid (0.178 mL, 1.506 mmol) in DMF (5 mL) was added DIC (0.213 mL, 1.369 mmol). The reaction mixture was stirred at room temperature for 1 h. TBAF (1.369 mL, 1.369 mmol) was added and stirring was continued at room temperature for another 1 h. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (2x50 mL). The organic layers were combined and washed with Na 2 SO 4 The mixture was dried over hexanes, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using ethyl acetate:hexane (4:1). The column fractions were collected and the solvent was removed under reduced pressure. The pure product was isolated as an off-white solid. MS (M+1) m / z: 499.2 (M+H). + ;LC retention time 2.1 min [F]

[0164] Step 2: Ethyl 2-(3-(3-((6-(cyclopropanecarboxamido)-3-((methyl-d3 To a solution of (280 mg, 0.562 mmol) carbamoylpyridazin-4-ylamino-2-methoxyphenyl-1,2,4-oxadiazol-5-yl acetate in ethanol (5 mL), LiBH 4 (0.562 mL, 1.123 mmol) was added as a solution in THF at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction was purified by NH 4 The mixture was quenched through the addition of saturated aqueous Cl (10 mL). The ethanol was removed under reduced pressure. The crude product was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was collected and washed with anhydrous Na 2 SO 4 The crude product was purified by silica gel column chromatography using 10% MeOH:DCM to give the desired product as an off-white solid. MS(M+1) m / z: 457.2(M+H). + ;LC retention time 1.43 min [F]

[0165] Step 3: 6-(Cyclopropanecarboxamido)-4-((3-(5-(2-hydroxyethyl)-1,2,4-oxadiazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d 3 ) To a stirred solution of pyridazine-3-carboxamide (70 mg, 0.153 mmol) in DCM (1 mL), add DAST (0.041 mL, 0.307 mmol) in DCM (4 mL) at -78 °C with N 2 The reaction was stirred at this temperature for 1 h, then allowed to reach room temperature and then stirred at room temperature for 1 h. The reaction mixture was diluted with NH 4 It was quenched with saturated aqueous Cl (10 mL) and extracted with DCM (2x20 mL). The organic layers were combined, dried, concentrated under reduced pressure and purified by preparative HPLC to give 6-(cyclopropanecarboxamido)-4-((3-(5-(2-fluoroethyl)-1,2,4-oxadiazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d 3) Pyridazine-3-carboxamide formate (3 mg, 5.35 μmol, 3.49% yield) was obtained as an off-white solid. MS(M+1) m / z:459.2(M+H) + ;LC retention time 2.30 min [F]; 1 H-NMR (400MHz, MeOH-d4):δ 8.25(s,1H), 7.83(dd,J=1.60, 8.00Hz,1H), 7.73(dd,J=1.60, 8.00Hz,1H), 7.39(t,J=8.00Hz,1H), 4.99(t,J=6.40Hz,1H), 4.91(t,J=17.60Hz,1H), 3.85(s,3H), 3.51(t,J=1.60Hz,1H), 3.48(t,J=13.20Hz,1H), 1.97-1.93(m,1H), 0.95-0.91(m,4H)

[0166] Example 6: [ka]

[0167] Step 1: To a stirred solution of 4-bromooxazole·HCl (300 mg, 1.627 mmol) and 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (446 mg, 1.790 mmol) in 1,4-dioxane (10 mL) was added aqueous 2N K 3 PO 4 (2.440 mL, 4.88 mmol) was added at ambient temperature and the reaction was cooled to room temperature with N 2 The gas was purged for 10 min. 2(dppf)·DCM (133 mg, 0.163 mmol) was then added to the reaction mixture and the reaction was allowed to warm to 90° C. and stirred in a sealed tube for 6 h. Upon completion, the reaction mixture was diluted with ethyl acetate (30 mL), filtered through a pad of Celite and washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel (100-200 mesh) column chromatography using 40-45% EtOAc in petroleum ether as eluent to give the desired product 2-methoxy-3-(oxazol-4-yl)aniline (220 mg, 1.073 mmol, 66.0% yield) as a brown solid. MS(M+1) m / z: 191.0(M+H) + ;LC retention time 1.05 min [F]

[0168] Step 2: 4,6-Dichloro-N-(methyl-d 3 To a stirred solution of 2-methoxy-3-(oxazol-4-yl)aniline (130 mg, 0.684 mmol) and pyridazine-3-carboxamide (130 mg, 0.622 mmol) in THF (10 mL) was added a 1 M solution of LiHMDS in THF (2.488 mL, 2.488 mmol) dropwise at 0° C. The reaction mixture was allowed to warm slowly to ambient temperature and stirred for 2 h, at which point it was diluted with NH 4 The mixture was quenched with saturated aqueous Cl and extracted with EtOAc (2x100 mL). The organic layers were combined, washed with water (50 mL) and brine (50 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 30-35% EtOAc in petroleum ether as eluent to give 6-chloro-4-((2-methoxy-3-(oxazol-4-yl)phenyl)amino)-N-(methyl-d 3 ) Pyridazine-3-carboxamide (140 mg, 0.367 mmol, 59.0% yield) was obtained as an off-white solid. MS (M+1) m / z: 363.0 (M+H) + ;LC retention time 2.33 min [F]

[0169] Step 3: 6-Chloro-4-((2-methoxy-3-(oxazol-4-yl)phenyl)amino)-N-(methyl-d 3 ) To a stirred solution of pyridazine-3-carboxamide (120 mg, 0.331 mmol) and cyclopropanecarboxamide (84 mg, 0.992 mmol) in 1,4-dioxane (3 mL), Cs 2 CO 3 (269 mg, 0.827 mmol) was added and the vessel was filled with N 2 The mixture was purged for 10 min with 1,1'-bis(dicyclohexylphosphino)ferrocene (38.3 mg, 0.066 mmol) and Pd 2 dba 3 (30.3 mg, 0.033 mmol) was added to the reaction mixture and the vessel was sealed. The reaction was stirred at 100° C. for 12 h. The reaction mixture was diluted with ethyl acetate (20 mL), filtered through a pad of Celite and washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (100-200 mesh) using 85-90% EtOAc in petroleum ether as eluent to give the product 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(oxazol-4-yl)phenyl)amino)-N-(methyl-d 3 ) Pyridazine-3-carboxamide (43.74 mg, 0.106 mmol, 32.0% yield) was obtained as a white solid. MS (M+1) m / z: 412.0 (M+H) + ;LC retention time 1.92 min [F]; 1 H-NMR (400 MHz, DMSO-d 6 ):11.33(s,1H), 10.97(s,1H), 9.16(s,1H), 8.55-8.52(m,1H), 8.12(s,1H), 7.84-7.82(m,1 H), 7.44-7.42(m,1H), 7.33-7.29(m,1H), 3.70(s,3H), 2.39-2.33(m,1H), 2.11-2.07(m,4H)

[0170] Example 7: [ka]

[0171] 6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-N-(methyl-d 3 ) Pyridazine-3-carboxamide (100 mg, 0.21 mmol) and 2-bromo-5-(difluoromethyl)pyridine (0.044 g, 0.213 mmol) in 1,4-dioxane (2 mL) and H 2 To a stirred solution of Na 2 CO 3 (45.0 mg, 0.425 mmol) was added. The reaction mixture was diluted with N 2 The reaction mixture was degassed under atmospheric pressure for 10 minutes. Tris(triphenylphosphine)palladium (25.0 mg, 0.021 mmol) was added to the reaction mixture, which was then heated to 90° C. under microwave irradiation for 2 hours. Upon completion, the reaction was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give methyl 6-(cyclopropanecarboxamido)-4-((3-(5-(difluoromethyl)pyridin-2-yl)-2-methoxyphenyl)amino)-N-(methyl-d 3 ) Pyridazine-3-carboxamide formate (15 mg, 13.5% yield) was obtained as an off-white solid. MS (M+1) m / z: 472.2 (M+H). + ;LC retention time 2.54 min [F]; 1 H NMR (400 MHz, DMSO-d 6 ):δ 11.36(s,1H), 11.01(s,1H), 9.17(s,1H), 8.92(s,1H), 8.13(s,1H), 8.11-8.11(m,1H), 8.01-8.03(m,1H ), 7.56-7.59(m,2H), 7.33-7.37(m,1H), 7.16(s,1H), 3.50(s,3H), 2.07-2.13(m,1H), 0.83-0.88(m,4H)

[0172] The following Examples 8-13 were prepared in a manner similar to that of Example 7. [ka]

[0173] [Table 4]

[0174] Example 14: [ka]

[0175] Step 1:

[0176] 2-Bromo-5-chloropyrazine (1.0 g, 5.17 mmol) 2 To a stirred solution in toluene (15 mL) under atmosphere was added n-butyllithium (2.58 mL, 5.17 mmol, 2 M solution in hexanes) at -78°C. The reaction solution turned dark red and was allowed to stir at -78°C for an additional 20 minutes. To this solution was added cyclobutanone (0.4 g, 5.69 mmol) in toluene (2 mL) dropwise and the reaction was stirred at -78°C for 30 minutes. The reaction was allowed to reach room temperature and stirred for approximately 1 hour. The reaction mixture was diluted with NH 4 The mixture was quenched with saturated aqueous Cl (20 mL) and extracted with ethyl acetate (2x30 mL). The organic layers were combined and washed with anhydrous Na 2 SO 4 The crude residue was purified by silica gel column chromatography (10% EtOAc in hexanes) to give 1-(5-chloropyrazin-2-yl)cyclobutan-1-ol (800 mg, 4.33 mmol, 84% yield) as an orange oil. GCMS (M) m / z: 184.1 (M) + ;GC retention time 7.43 minutes [H]

[0177] Step 2: To a stirred solution of 1-(5-chloropyrazin-2-yl)cyclobutan-1-ol (500 mg, 2.71 mmol) in 1,4-dioxane (30 mL) was added 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (750 mg, 2.85 mmol) and 2M K 3 PO 4 (5 mL, 10.00 mmol) was added. The reaction mixture was then rinsed with N 2 Purge under vacuum for 5 min and add PdCl 2 (dppf)·DCM (200 mg, 0.245 mmol) was added. The reaction mixture was sealed and stirred at 90° C. for 16 h, then cooled to room temperature and diluted with ethyl acetate (100 mL). The reaction mixture was filtered through a pad of Celite and the filtrate was washed with water (2×50 mL) and brine (2×50 mL). The organic extracts were combined and diluted with Na 2 SO 4 After drying over low pressure and concentration under reduced pressure, the crude product was obtained, which was purified by silica gel column chromatography (30% EtOAc in petroleum ether) to give 1-(5-(3-amino-2-methoxy-5-methylphenyl)pyrazin-2-yl)cyclobutan-1-ol (440 mg, 1.542 mmol, 56.9% yield) as a light brown semi-solid. MS (M+1) m / z: 286.2 (M+H). + ;LC retention time 1.42 min [F]

[0178] Step 3: 4,6-Dichloro-N-(methyl-d 3 To a stirred solution of 1-(5-(3-amino-2-methoxy-5-methylphenyl)pyrazin-2-yl)cyclobutan-1-ol (300 mg, 1.051 mmol) and 1-(5-(3-amino-2-methoxy-5-methylphenyl)pyrazin-2-yl)cyclobutan-1-ol (300 mg, 1.051 mmol) in THF (10 mL) was added LiHMDS (3.6 mL, 3.60 mmol, 1 M solution in THF) at 0° C. The reaction mixture was stirred at 0° C. for 4 h and then allowed to reach room temperature. The reaction mixture was diluted with NH 4The mixture was quenched with saturated Cl solution (20 mL) and the product was extracted with ethyl acetate (2x50 mL). The organic layers were combined, washed with brine (25 mL) and anhydrous Na 2 SO 4 The mixture was dried over ice, filtered and concentrated. The crude product was purified by silica gel column chromatography using 70% EtOAc in petroleum ether to give 6-chloro-4-((3-(5-(1-hydroxycyclobutyl)pyrazin-2-yl)-2-methoxy-5-methylphenyl)amino)-N-(methyl-d 3 ) Pyridazine-3-carboxamide (200 mg, 0.336 mmol, 28.1% yield) was obtained as a pale yellow solid. MS (M+1) m / z: 458.2 (M+H) + LC retention time 2.26 min [F]

[0179] Step 4: 6-Chloro-4-((3-(5-(1-hydroxycyclobutyl)pyrazin-2-yl)-2-methoxy-5-methylphenyl)amino)-N-(methyl-d 3 ) To a stirred solution of pyridazine-3-carboxamide (200 mg, 0.437 mmol) in 1,4-dioxane (10 mL) was added cyclopropanecarboxamide (37.2 mg, 0.437 mmol) and Cs 2 CO 3 (427 mg, 1.310 mmol) was added. The reaction mixture was diluted with N 2 The mixture was degassed under 50° C. for 10 min, and then 1,1'-bis(dicyclohexylphosphino)ferrocene (50.5 mg, 0.087 mmol) and Pd 2 (dba) 3 (40.0 mg, 0.044 mmol) was added and the vessel was cooled for an additional 10 min (N 2The reaction vessel was degassed via FT-IR (via FT-IR). The reaction vessel was sealed and stirred under microwave irradiation at 100° C. for 2 h. The reaction mixture was filtered through a pad of Celite and washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure and the crude compound was purified by silica gel (230-400 mesh) column chromatography using 50-60% EtOAc in hexane as eluent to give the desired product 6-(cyclopropanecarboxamido)-4-((3-(5-(1-hydroxycyclobutyl)pyrazin-2-yl)-2-methoxy-5-methylphenyl)amino)-N-(methyl-d 3 ) Pyridazine-3-carboxamide (26 mg, 0.050 mmol, 11.52% yield) was obtained as a pale yellow solid. MS (M+1) m / z: 507.2 (M+H) + ;LC retention time 2.14 min [F]; 1 H-NMR (400 MHz, DMSO-d 6 ):δ 11.33(s,1H), 10.91(s,1H), 9.16(s,1H), 9.02(s,1H), 8.91(s,1H), 8.14(s,1H), 7.41(d,J=8.80Hz,1H), 6.06(s,2H), 3.50(s ,3H), 2.68-2.61(m,3H), 2.53-2.50(m,2H), 2.35(d,J=1.60Hz,2H), 2.34-2.33(m,1H), 2.08(m,1H), 1.86(m,1H), 0.84(s,4H)

[0180] The following Example 15 was prepared in a manner similar to the preparation of Example 14. [ka] [Table 5]

[0181] Example 16: [ka]

[0182] Step 1: To a stirred solution of 2-bromo-5-chloropyrazine (2.5 g, 12.92 mmol) in 1,4-dioxane (40 mL) and water (10 mL) was added cyclopropylboronic acid (1.11 g, 12.92 mmol) and K 3 PO 4 (8.23 g, 38.8 mmol) followed by PdCl 2 (dppf)·DCM (0.528 g, 0.646 mmol) was added. The reaction mixture was then rinsed with N 2 The resulting reaction mixture was degassed under 50° C. for 10 min. The resulting reaction mixture was heated at 90° C. for 16 h. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (100 mL), filtered through a celite pad and washed with ethyl acetate (100 mL). The filtrate was washed with water (100 mL) followed by brine (100 mL). The organic layer was extracted with Na 2 SO 4 The mixture was dried over 100 ml and filtered. The solvent was evaporated under reduced pressure and the crude residue was purified by column chromatography on silica gel (230-400 mesh) using 5-10% EtOAc in petroleum ether to give 2-chloro-5-cyclopropylpyrazine (800 mg, 5.17 mmol, 40.0% yield) as a pale yellow solid. 1 H-NMR (400 MHz, DMSO-d 6 ):δ 8.28(d,J=1.20Hz,1H), 8.41(dd,J=1.60, 5.80Hz,1H), 2.10-2.04(m,1H), 1.13-1.07(m,4H)

[0183] Step 2: To a stirred solution of 5-fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.5 g, 1.872 mmol) in 1,4-dioxane (20 mL) and water (5 mL) in a 100 mL sealed test tube was added 2-chloro-5-cyclopropylpyrazine (0.405 g, 2.62 mmol) and K 3 PO 4 (1.192 g, 5.62 mmol) followed by PdCl 2(dppf)·DCM (0.076 g, 0.094 mmol) was added. The reaction mixture was then rinsed with N 2 The mixture was degassed under vacuum for 10 min. The resulting reaction mixture was heated at 90° C. for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL), filtered through a pad of Celite, and washed with ethyl acetate (100 mL). The filtrate was washed with water (100 mL), followed by brine (100 mL), and added with Na 2 SO 4 The crude residue was purified by column chromatography on silica gel (230-400 mesh) using 5-10% EtOAc in petroleum ether to give 3-(5-cyclopropylpyrazin-2-yl)-5-fluoro-2-methoxyaniline (0.12 g, 0.435 mmol, 23.24% yield) as a pale yellow liquid. MS(M+1) m / z: 260.2(M+H) + LC retention time 2.43 min [F]

[0184] Step 3: To a solution of 3-(5-cyclopropylpyrazin-2-yl)-5-fluoro-2-methoxyaniline (0.12 g, 0.463 mmol) in THF (5 mL) was added 4,6-dichloro-N-(methyl-d 3 ) Pyridazine-3-carboxamide (0.116 g, 0.555 mmol) was added dropwise over 5 min at 0 °C, followed by LiHMDS (1.157 mL, 1.157 mmol, 1 M solution in THF). The reaction was stirred at room temperature for 30 min and then NH 4 The reaction mixture was quenched with saturated aqueous Cl (15 mL). The reaction mixture was partitioned between EtOAc (100 mL) and water (50 mL). The organic layer was washed with brine solution (50 mL) and anhydrous Na 2 SO 4 The resulting crude product was triturated with n-pentane:diethyl ether (1:1) and 6-chloro-4-((3-(5-cyclopropylpyrazin-2-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d 3) Pyridazine-3-carboxamide (0.13 g, 0.217 mmol, 46.8% yield) was obtained as an off-white solid. MS (M+1) m / z: 432.2 (M+H) + ;LC retention time 2.81 min [F]

[0185] Step 4: 6-Chloro-4-((3-(5-cyclopropylpyrazin-2-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d 3 ) To a stirred solution of pyridazine-3-carboxamide (0.15 g, 0.347 mmol) in 1,4-dioxane (10 mL) was added cyclopropanecarboxamide (0.03 g, 0.347 mmol), Pd 2 (dba) 3 (0.016 g, 0.017 mmol), Xantphos (10.05 mg, 0.017 mmol) and Cs 2 CO 3 (0.113 g, 0.347 mmol) was added. The reaction mixture was then rinsed with N 2 The mixture was degassed at 40° C. for 5 min. The resulting reaction mixture was heated under microwave irradiation at 130° C. for 3 h. The reaction mixture was diluted with ethyl acetate (100 mL), filtered through a pad of Celite, and washed with ethyl acetate (100 mL). The filtrate was washed with water (100 mL) and brine (100 mL), and added with Na 2 SO 4 The solvent was evaporated under reduced pressure and the resulting crude residue was purified by reverse phase column chromatography (C18 column) using 70% acetonitrile in 0.1% aqueous ammonium acetate to give 6-(cyclopropanecarboxamido)-4-((3-(5-cyclopropylpyrazin-2-yl)-5-fluoro-2-methoxyphenyl)amino)-N-(methyl-d 3 ) Pyridazine-3-carboxamide (50 mg, 0.100 mmol, 28.8% yield) was obtained as an off-white solid. MS (M+1) m / z: 481.1 (M+H) + ;LC retention time 2.14 min [G]; 1 H-NMR (400 MHz, DMSO-d6 ):δ 11.42(s,1H), 11.17(s,1H), 9.21(s,1H), 8.95(d,J=0.80Hz,1H), 8.77(d,J=0.80Hz,1H), 8.27(s,1H), 7.49-7.45(m,1H), 7.37 -7.34(m,1H), 3.52(s,3H), 2.31-2.27(m,1H), 2.12-2.09(m,1H), 1.14-1.09(m,2H), 1.06-1.03(m,2H), 0.86(d,J=6.00Hz,4H)

[0186] Example 17 [ka]

[0187] Process 1 4,6-Dichloro-N-(methyl-d 3 To a stirred solution of 2-methoxy-3-(2-methyloxazol-4-yl)aniline (0.586 g, 2.87 mmol) and pyridazine-3-carboxamide (1.0 g, 4.78 mmol) in THF (20 mL) was added LiHMDS (9.57 mL, 14.35 mmol, 1 M solution in THF) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate (2x50 mL). The organic layers were combined and washed with anhydrous Na 2 SO 4 The crude residue was purified by column chromatography on silica gel 100-200 mesh (30% EtOAc in petroleum ether) to give 6-chloro-4-((2-methoxy-3-(2-methyloxazol-4-yl)phenyl)amino)-N-(methyl-d 3 ) Pyridazine-3-carboxamide (0.66 g, 1.156 mmol, 24.17% yield) was obtained as a brown solid. MS (M+1) m / z: 377.0 (M+H) + ;LC retention time 2.12 min [F]

[0188] Process 2 6-Chloro-4-((2-methoxy-3-(2-methyloxazol-4-yl)phenyl)amino)-N-(methyl-d 3 ) To a solution of pyridazine-3-carboxamide (0.2 g, 0.531 mmol) in 1,4-dioxane (10 mL), cyclopropanecarboxamide (0.090 g, 1.062 mmol), Cs 2 CO 3 (0.346 g, 1.062 mmol) and 1,1'-bis(dicyclohexylphosphino)ferrocene (0.061 g, 0.106 mmol). The vessel was then filled with N 2 Purge for 10 min under Pd 2 (dba) 3 (0.097 g, 0.106 mmol) was added. The vessel was heated to 105° C. and stirred for 16 h. The reaction mixture was filtered through a pad of Celite and washed with ethyl acetate (50 mL). The filtrate was collected, concentrated under reduced pressure, and purified by reverse phase preparative HPLC to give 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(2-methyloxazol-4-yl)phenyl)amino)-N-(methyl-d 3 ) Pyridazine-3-carboxamide (0.020 g, 0.043 mmol, 8.09% yield) was obtained as an off-white solid. MS (M+1) m / z: 426.0 (M+H) + ;LC retention time 1.94 min [F]; 1 H-NMR (400 MHz, DMSO-d 6 ):d 11.33(s,1H), 10.96(s,1H), 9.17(s,1H), 8.38(s,1H), 8.12(s,1H), 7.78(d,J=1.60Hz,1H), 7.40(d ,J=1.20Hz,1H), 7.26-7.30(m,1H), 3.68(s,3H), 2.51(s,3H), 2.09-2.07(m,1H), 0.83-0.81(m,4H)

[0189] The following Example 18 was prepared from Intermediate 4 in a manner similar to the preparation of Example 17. [ka] [Table 6]

[0190] Example 19: [ka]

[0191] Step 1: To a stirred solution of 2-methoxy-3-nitrobenzonitrile (3 g, 16.84 mmol) in ethanol (50 mL) was added hydroxylamine (50% in water) (2.223 g, 33.7 mmol). The reaction mixture was allowed to stir at 80° C. for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure and quenched with ice-cold water (50 mL). The crude product was extracted with ethyl acetate (2×100 mL), the organic layers were combined, washed with water (100 mL) and brine (100 mL), and concentrated with NaCl. 2 SO 4 The organic solvent was evaporated under reduced pressure and the resulting crude product was triturated with diethyl ether to give the desired (Z)-N'-hydroxy-2-methoxy-3-nitrobenzimidamide (3.00 g, 11.36 mmol, 67.5% yield) as a brown solid. MS (M+1) m / z: 212.1 (M+H). + LC retention time 1.04 min [G]

[0192] Step 2: To a stirred solution of (E)-N'-hydroxy-2-methoxy-3-nitrobenzimidamide (2.50 g, 11.8 mmol) in DMF (50 mL) was added N,N-diisopropylcarbodiimide (2.99 g, 23.68 mmol) and difluoroacetic anhydride (1.089 g, 11.84 mmol) at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h, then TBAF (11.84 mL, 11.84 mmol) was added and stirring was continued for 1 h. The reaction mixture was concentrated and partitioned between water (50 mL) and ethyl acetate (100 mL). The organic layer was separated and washed with brine (100 mL) and then with NaCl. 2 SO4 The organic solvent was evaporated under reduced pressure and the resulting crude product was purified by silica gel column chromatography using 100-200 mesh to give the desired 5-(difluoromethyl)-3-(2-methoxy-3-nitrophenyl)-1,2,4-oxadiazole (3.0 g, 10.51 mmol, 89% yield) as a brown solid. MS(M+1) m / z:273.0(M+H) + LC retention time 2.27 min [F]

[0193] Step 3: To a stirred solution of 5-(difluoromethyl)-3-(2-methoxy-3-nitrophenyl)-1,2,4-oxadiazole (1.5 g, 5.53 mmol) in ethanol (25 mL) was added tin(II) chloride dihydrate (2.496 g, 11.06 mmol). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was filtered through a Celite pad and washed with methanol (100 mL). The filtrate was concentrated and partitioned between ethyl acetate (100 mL) and water (50 mL). The organic layer was washed with water (100 mL) and brine (100 mL) and concentrated with NaCl. 2 SO 4 Dry on a rack. 2 SO 4 The was removed via filtration and the filtrate was concentrated under reduced pressure to give the crude product 3-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)-2-methoxyaniline (1.0 g, 3.48 mmol, 63.0% yield), which was used in the subsequent step without further purification. MS (M+1) m / z: 242.2 (M+H). + ;LC retention time 2.01 min [F]

[0194] Step 4: 4,6-Dichloro-N-(methyl-d 3To a stirred solution of pyridazine-3-carboxamide (500 mg, 2.392 mmol) in THF (15 mL) was added 3-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)-2-methoxyaniline (692 mg, 2.87 mmol). The mixture was cooled to -78°C, and then LiHMDS (7.18 mL, 7.18 mmol, 1 M solution in THF) was added. The reaction mixture was stirred for 2 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water (100 mL) and the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water (100 mL) and brine (100 mL) and diluted with anhydrous Na 2 SO 4 Dry on a rack. 2 SO 4 The filtrate was filtered off and concentrated under reduced pressure to give the crude product, which was triturated with diethyl ether and petroleum ether (1:1, 50 mL) to give the desired 6-chloro-4-((3-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d 3 ) Pyridazine-3-carboxamide (500 mg, 0.834 mmol, 34.9% yield) was obtained as a brown solid. MS (M+1) m / z: 414.0 (M+H) + ;LC retention time 2.72 min [F]; 1 H-NMR (400 MHz, DMSO-d 6 ):δ 11.20(s,1H), 9.41(s,1H), 7.85-7.81(m,2H), 7.59(t,J=51.20Hz,1H), 7.43(d,J=8.00Hz,1H), 7.26(s,1H), 3.76(s,3H)

[0195] Step 5: 6-Chloro-4-((3-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d 3 ) To a stirred solution of pyridazine-3-carboxamide (200 mg, 0.483 mmol) in 1,4-dioxane (5 mL), Cs 2 CO 3(472 mg, 1.450 mmol) and cyclopropanecarboxamide (82 mg, 0.967 mmol) were added. The reaction mixture was cooled to 5° C. 2 for 10 min, then 1,1-bis(dicyclohexylphosphino)ferrocene (28.0 mg, 0.048 mmol) and Pd 2 (dba) 3 (44.3 mg, 0.048 mmol) was added. The resulting reaction mixture was heated at 120° C. and stirred in a sealed tube for 4 h. The reaction mixture was filtered through a pad of Celite and washed with ethyl acetate (100 mL). The organic solvent was evaporated under reduced pressure and the resulting crude product was purified via reverse phase preparative HPLC to give the desired 6-(cyclopropanecarboxamido)-4-((3-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d 3 ) Pyridazine-3-carboxamide (25 mg, 0.051 mmol, 10.48% yield) was obtained as an off-white solid. MS (M+1) m / z: 463.2 (M+H) + ;LC retention time 2.58 min [F]; 1 H-NMR (400MHz, DMSO-D6):δ 11.38(s,1H), 11.08(s,1H), 9.19(s,1H), 8.17(s,1H), 7.84(s,1H), 7.78-7.76( m,2H), 7.74-7.42(m,2H), 3.77(s,3H), 2.13-2.06(m,1H), 0.84(t,J=2.00Hz,3H)

[0196] Example 20 [ka]

[0197] Step 1: To a solution of 4-bromo-3-methoxypyridin-2-amine (370 mg, 1.822 mmol) and bis(pinacolato)diborane (972 mg, 3.83 mmol) in 1,4-dioxane (10 mL) was added potassium acetate (537 mg, 5.47 mmol) and the mixture was cooled to 5° C.2 The gas was purged for 10 min. 2 (dppf)·DCM (298 mg, 0.364 mmol) was added to the reaction and the mixture was heated to 130° C. and stirred for 5 h. The reaction mixture was filtered through a pad of Celite and washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure to give the crude product. The crude residue was dissolved in 1,4-dioxane (10 mL) and potassium acetate (537 mg, 5.47 mmol) was added at ambient temperature. The mixture was irradiated with N 2 Purge under gas for 10 min. 2 (dppf)·DCM (298 mg, 0.364 mmol) and 2-(5-chloropyrazin-2-yl)propan-2-ol (315 mg, 1.822 mmol) were added and the mixture was heated at 130° C. and stirred for 5 h. The reaction mixture was diluted with ethyl acetate (50 mL), filtered through a pad of Celite and washed with ethyl acetate (40 mL). The filtrate was concentrated under reduced pressure to give the crude product. The crude residue was purified by column chromatography using silica gel (100-200 mesh) and 100% EtOAc as eluent to give 2-(5-(2-amino-3-methoxypyridin-4-yl)pyrazin-2-yl)propan-2-ol (195 mg, 0.622 mmol, 34.1% yield) as a brown semi-solid. MS(M+1) m / z: 260.7(M+H) + ;LC retention time 1.15 min [F]

[0198] Step 2: 2-(5-(2-amino-3-methoxypyridin-4-yl)pyrazin-2-yl)propan-2-ol (195 mg, 0.749 mmol) and 4,6-dichloro-N-(methyl-d 3 To a stirred solution of pyridazine-3-carboxamide (157 mg, 0.749 mmol) in THF (10 mL) was added LiHMDS (2.24 mL, 2.24 mmol, 1 M solution in THF) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The reaction was purified with NH 4The mixture was quenched through the addition of saturated aqueous Cl (20 mL). The product was extracted with ethyl acetate (50 mL). The organic layer was washed with water (20 mL) and brine (20 mL). The organic extracts were combined and washed with anhydrous Na 2 SO 4 The crude product was triturated with diethyl ether (50 mL) and dried to give the desired 6-chloro-4-((4-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-3-methoxypyridin-2-yl)amino)-N-(methyl-d 3 ) Pyridazine-3-carboxamide (100 mg, 22%) was obtained as a white solid. MS (M+1) m / z: 433.2 (M+H) + ;LC retention time 2.42 min [F]

[0199] Step 3: 6-Chloro-4-((4-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-3-methoxypyridin-2-yl)amino)-N-(methyl-d 3 ) A solution of pyridazine-3-carboxamide (40 mg, 0.092 mmol) in 1,4-dioxane (2 mL) and NMP (0.2 mL) was added with cyclopropanecarboxamide (15.73 mg, 0.185 mmol), Xantphos (10.69 mg, 0.018 mmol), Cs 2 CO 3 (75 mg, 0.231 mmol) and Pd 2 dba 3 (16.92 mg, 0.018 mmol) was added. The reaction mixture was stirred at 145° C. under microwave irradiation for 1 h. The reaction mixture was diluted with ethyl acetate (50 mL), filtered through a pad of Celite and washed with ethyl acetate (40 mL). The filtrate was concentrated under reduced pressure to give a crude residue. The crude product was purified by reverse phase preparative HPLC to give the desired 6-(cyclopropanecarboxamido)-4-((4-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-3-methoxypyridin-2-yl)amino)-N-(methyl-d 3) Pyridazine-3-carboxamide (5.6 mg, 0.011 mmol, 12.37% yield) was obtained as an off-white solid. MS (M+1) m / z: 482.2 (M+H) + ;LC retention time 1.89 min [F]; 1 H-NMR (400 MHz, DMSO-d 6 ):δ 12.47(s,1H), 11.38(s,1H), 9.89(s,1H), 9.28(s,1H), 9.11(dd,J=1.60, 17.20Hz,2H), 8.23(d,J=5.20Hz ,1H), 7.43(d,J=5.20Hz,1H), 5.60(s,1H), 3.69(s,3H), 2.25-2.10(m,1H), 1.54(s,6H), 0.91-0.88(m,4H)

[0200] The following examples were prepared from the intermediates noted, along with commercially available reagents, using the conditions noted in the table (below), allowing for some minor modifications in solvents, reaction times, etc.

[0201] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] (*) - Using the procedure described in US Patent RE47929

[0202] Headpiece arrangement α [ka]

[0203] 4-Bromooxazole·HCl (78 mg, 0.424 mmol), 5-fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (103 mg, 0.386 mmol), and PdCl 2 A solution of (dppf)·DCM (15.75 mg, 0.019 mmol) in toluene (3 ml) was degassed by bubbling nitrogen through the reaction solution for 5 min, then sodium carbonate (10% in water) (1.23 ml, 1.16 mmol) was added and the mixture was stirred at 100° C. for 2 h. The two layers were partitioned and the organic layer was collected and purified by automated chromatography eluting with 0-100% EtOAc in hexanes. 5-Fluoro-2-methoxy-3-(oxazol-4-yl)aniline (17 mg, 0.082 mmol, 21.18% yield) was obtained as a yellow oil that appears to be quite volatile under vacuum. m / z (M+H)=209.1; RT=1.06 min [C]

[0204] Headpiece arrangement β [ka]

[0205] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isothiazole (135 mg, 0.640 mmol), 4-bromo-3-methoxypyridin-2-amine (100 mg, 0.493 mmol), and PdCl 2A mixture of (dppf)·DCM (20.11 mg, 0.025 mmol) in toluene (3 mL) and ethanol (1 mL) was degassed by bubbling nitrogen through the reaction solution for 5 min. Sodium carbonate (10% in water) (1.8 mL, 1.7 mmol) was added, the vessel was sealed, and the reaction was stirred at 85 °C for 4 h. The two layers of the biphasic reaction mixture were separated, and the organic layer was concentrated to an oil and purified by automated chromatography eluting with 0-100% EtOAc in hexanes. 4-(isothiazol-4-yl)-3-methoxypyridin-2-amine (58 mg, 0.280 mmol, 56.8% yield) was obtained as an off-white waxy solid. m / z (M+H) = 208.1; RT = 0.62 min [C]

[0206] Headpiece arrangement γ [ka]

[0207] Process 1

[0208] DMAP (0.277 g, 2.266 mmol) and BOC anhydride (3.29 mL, 14.16 mmol) in DCM (24 mL) were added to a solution of 4-bromo-3-methoxypyridin-2-amine (1.15 g, 5.66 mmol) in acetonitrile (24 mL) at 0° C. The resulting mixture was allowed to warm to room temperature and after 1 h, an additional 200 mg of BOC anhydride was added in 2 mL of DCM and the reaction was stirred overnight. The crude reaction was concentrated under reduced pressure and purified by automated chromatography eluting with 0-50% EtOAc in hexanes. Pure fractions were combined and concentrated to give tert-butyl (4-bromo-3-methoxypyridin-2-yl)(tert-butoxycarbonyl)carbamate (2.29 g, 5.39 mmol, 95% yield) as an off-white crystalline solid. m / z(M+H)=404.9; RT=1.66 min [C]

[0209] Process 2 In a pressure vial, tert-butyl (4-bromo-3-methoxypyridin-2-yl)(tert-butoxycarbonyl)carbamate (800 mg, 1.984 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (655 mg, 2.58 mmol), PdCl 2 A solution of (dppf)·DCM (81 mg, 0.099 mmol) and potassium acetate (681 mg, 6.94 mmol) in dioxane (8 mL) was heated to reflux. Upon completion of the reaction, as determined via LCMS, the reaction was absorbed directly onto Celite and the Celite was dried under reduced pressure. The reaction was then purified by automated chromatography (dry loading) eluting with 0-100% EtOAc in hexanes. tert-Butyl (tert-butoxycarbonyl)(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate (575 mg, 1.28 mmol, 64.4% yield) was obtained as a colorless oil. m / z (M+H)=369.0 (observed by MS for the formation of boronic acid). RT=1.26 min [C]; 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.15(s,1H), 8.49(d,J=5.1Hz,1H), 8.21(d,J=5.0Hz,1H), 4.01(s,3H), 1.39(s,18H)

[0210] Process 3 A stirred mixture of 5-bromo-1,2,4-thiadiazole (274 mg, 1.660 mmol), tert-butyl (tert-butoxycarbonyl)(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate (575 mg, 1.28 mmol) and sodium carbonate (10% aqueous solution) (4.06 mL, 3.83 mmol) in toluene (4 mL) and ethanol (2 mL) was degassed by bubbling nitrogen through the mixture for 5 min. PdCl 2(dppf)·DCM (52.1 mg, 0.064 mmol) was added quickly and the reaction mixture was heated at 90° C. for 40 min. The reaction mixture was cooled to room temperature and then diluted with EtOAc (75 mL). The solution was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by automated chromatography eluting with 0-100% EtOAc in hexanes. tert-Butyl (tert-butoxycarbonyl)(3-methoxy-4-(1,2,4-thiadiazol-5-yl)pyridin-2-yl)carbamate (279 mg, 0.683 mmol, 53.5% yield) was obtained as an off-white solid. m / z (M+H)=409.2; RT=1.62 min [C]; 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.15(s,1H), 8.49(d,J=5.1Hz,1H), 8.21(d,J=5.0Hz,1H), 4.01(s,3H), 1.39(s,18H)

[0211] Process 4 A solution of tert-butyl (tert-butoxycarbonyl)(3-methoxy-4-(1,2,4-thiadiazol-5-yl)pyridin-2-yl)carbamate (278 mg, 0.681 mmol) in DCM (2 mL) and TFA (1 mL) was stirred at room temperature for 30 min. The crude reaction was concentrated under reduced pressure to give a white solid. To this was added EtOAc and 1.5 M (aqueous) potassium phosphate solution. The layers were separated and the aqueous layer was extracted twice with EtOAc. The organic layers were combined and washed once with brine. The organic layers were then dried over sodium sulfate, filtered and concentrated under reduced pressure to give 3-methoxy-4-(1,2,4-thiadiazol-5-yl)pyridin-2-amine (130 mg, 0.624 mmol, 92% yield) as the free base as a light yellow solid. m / z (M+H)=209.0; RT=0.65 min [C]

[0212] SnAr condition A: [ka]

[0213] 3-Methoxy-4-(1,2,4-thiadiazol-5-yl)pyridin-2-amine (110 mg, 0.528 mmol) and 4,6-dichloro-N-(methyl-d 3 To a solution of pyridazine-3-carboxamide (221 mg, 1.056 mmol) in THF (4 mL) at room temperature, LiHMDS (1 M in THF, 2.38 mL, 2.38 mmol) was added dropwise over 5 min. The reaction mixture was allowed to stir at room temperature for 30 min. After quenching with saturated ammonium chloride solution, THF was removed under reduced pressure and the reaction mixture was diluted with water. After filtration, the filter cake was washed with water and ether and dried to give a brown solid suspended in ether. After concentration, the suspension was filtered and dried to give 6-chloro-4-((3-methoxy-4-(1,2,4-thiadiazol-5-yl)pyridin-2-yl)amino)-N-(methyl-d 3 ) Pyridazine-3-carboxamide (171 mg, 0.404 mmol, 77% yield) was obtained as a tan solid. m / z (M+H) = 381.0; RT = 1.49 min [C]

[0214] SnAr condition B: [ka]

[0215] 4,6-Dichloro-N-(methyl-d 3To a solution of 4-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methoxypyridin-2-amine (44 mg, 0.202 mmol) in tetrahydrofuran (2 mL) was added potassium bis(trimethylsilyl)amide (0.907 mL, 0.907 mmol) in a dropwise fashion and the reaction was stirred until complete (approximately 15 min). A solution of saturated ammonium chloride (aqueous) was added to quench the remaining base. The reaction was then partitioned between EtOAc and water. The aqueous layer was extracted once with EtOAc, then the organic layers were combined and washed once with saturated aqueous ammonium chloride and once with brine. The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified using automated chromatography eluting with 0-100% EtOAc in hexanes. 6-Chloro-4-((4-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methoxypyridin-2-yl)amino)-N-(methyl-d 3 ) Pyridazine-3-carboxamide (27 mg, 0.069 mmol, 34.3% yield) was obtained as a pale yellow solid. m / z (M+H) = 391.1; RT = 1.30 min [C]

[0216] SnAr condition C: [ka]

[0217] 4,6-Dichloro-N-(methyl-d 3) Pyridazine-3-carboxamide (55 mg, 0.263 mmol) and 3-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methoxyaniline (60.3 mg, 0.263 mmol) in tetrahydrofuran (2 mL) was added 1M lithium bis(trimethylsilyl)amide (0.658 mL, 0.658 mmol) in a dropwise fashion (<5 min) via syringe and the reaction was stirred until complete (~15 min). Saturated aqueous ammonium chloride solution was added to quench remaining base. The reaction was partitioned between EtOAc and water. The aqueous layer was washed once with EtOAc and the organic layers were combined and washed once with saturated aqueous ammonium chloride and once with brine solution. The organic layers were combined, then dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 6-chloro-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methoxyphenyl)amino)-N-(methyl-d 3 ) to give pyridazine-3-carboxamide (69 mg, 0.172 mmol, 65.3% yield). m / z (M+H) = 402.1, RT = 1.39 min [C]

[0218] Example 43 [ka]

[0219] Step 1: To a stirred solution of 2-methoxy-3-nitrobenzonitrile (4.0 g, 22.23 mmol) in THF:MeOH (1:1, 80 mL) was added zinc powder (14.7 g, 230.2 mmol) followed by ammonium chloride (6.0 g, 112.1 mmol) at room temperature. After stirring at room temperature for 4 h, the reaction mixture was filtered through a pad of Celite and washed with ethyl acetate (2x50 mL). The filtrate was concentrated under reduced pressure. The crude product was triturated in diethyl ether (50 mL) to give 3-amino-2-methoxybenzonitrile (3.3 g, 7.69 mmol, 97% yield) as an off-white solid. 1 H NMR (DMSO-d 6):6.97-6.96(s,2H), 6.85-6.82(m,1H), 5.45(s,2H), 3.80(s,3H)

[0220] Step 2: To a stirred solution of 4,6-dichloro-N-trideutero-methylpyriazine-3-carboxamide (325 mg, 1.56 mmol) and 3-amino-2-methoxybenzonitrile (255 mg, 1.72 mmol) in THF (14 mL) was added LiHMDS (1 M in THF, 3.9 mL, 3.9 mmol) in a dropwise fashion. The resulting solution was stirred at room temperature for 1 h and then quenched through the addition of saturated (aqueous) ammonium chloride (2 mL). The mixture was partitioned between EtOAc (40 ml) and saturated ammonium chloride solution (40 ml). The organic layer was washed with brine (40 ml) and dried (Na 2 SO 4 ) and concentrated to give a solid residue which was purified by automated chromatography eluting with a 0-100% EtOAc / Hexanes gradient. Pure fractions were concentrated to give the partially purified product which was triturated with ether and dried to give 6-chloro-4-((3-cyano-2-methoxyphenyl)amino)-N-trideutero-methylpyridazine-3-carboxamide (385 mg, 1.200 mmol, 77% yield) as a tan solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.10(s,1H), 9.39(brs,1H), 7.87(d,J=7.9Hz,1H), 7.67(d,J=7.7Hz,1H), 7.35(t,J=7.9Hz,1H), 7.22(s,1H), 3.91(s,3H);LC retention time=0.82 min[D];m / z 321.2(MH + )

[0221] Step 3: 6-Chloro-4-((3-cyano-2-methoxyphenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide (240 mg, 0.748 mmol), cyclopropanecarboxamide (127 mg, 1.496 mmol), Pd 2(dba) 3 Chloroform adduct (77 mg, 0.075 mmol), xantphos (87 mg, 0.150 mmol) and Cs 2 CO 3 (975 mg, 2.99 mmol) in dioxane (5 mL) and the mixture was added with N 2 The mixture was degassed by bubbling air through it for 5 min. The reaction vessel was sealed and heated at 130° C. for 1.5 h. The reaction mixture was filtered hot (approximately 90° C.) through Celite and the filter cake was washed with EtOAc (100 mL). The filtrate was concentrated and the residue was triturated with MeOH. Filtration and drying afforded 4-((3-cyano-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-trideutero-methylpyridazine-3-carboxamide (215 mg, 0.582 mmol, 78% yield) as a tan solid. LC retention time = 0.74 min [D]; m / z 370.4 (MH + )

[0222] Step 4: A mixture of 4-((3-cyano-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamide)-N-trideuteromethylpyridazine-3-carboxamide (215 mg, 0.582 mmol), hydroxylamine hydrochloride (121 mg, 1.746 mmol) and triethylamine (0.406 mL, 2.91 mmol) in DMA (5 mL) was heated at 80° C. for 2 weeks (incomplete conversion). Further hydroxylamine hydrochloride (121 mg, 1.746 mmol) and triethylamine (0.406 mL, 2.91 mmol) were added and the reaction mixture was heated at 100° C. for 16 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc (50 mL) and 10% (aqueous) LiCl solution (50 mL). The organic layer was washed with 10% (aqueous) LiCl solution (2×50 mL) and brine (50 mL). Drying (Na 2 SO 4), filtered, and the organic layer was concentrated to give a yellow oil which was purified using automated chromatography to give (Z)-6-(cyclopropanecarboxamido)-4-((3-(N'-hydroxycarbamimidoyl)-2-methoxyphenyl)amino)-N-trideutero-methylpyridazine-3-carboxamide (78 mg, 0.194 mmol, 33.3% yield) as a tan solid. LC retention time = 0.51 min [D]; m / z 403.3 (MH + )

[0223] Step 5: A mixture of (Z)-6-(cyclopropanecarboxamido)-4-((3-(N'-hydroxycarbamimidoyl)-2-methoxyphenyl)amino)-N-trideutero-methylpyridazine-3-carboxamide (25 mg, 0.062 mmol), propionic acid (9.30 μL, 0.124 mmol), HOBT (10.46 mg, 0.068 mmol), EDC (13.10 mg, 0.068 mmol) and triethylamine (0.035 mL, 0.248 mmol) was stirred at room temperature for 5 h. The reaction mixture was diluted with EtOAc (20 mL) and saturated (aqueous) NaHCO 3 (20 mL). The organic layer was washed with 10% (aqueous) LiCl solution (2x20 mL) and brine (20 mL). Dry (Na 2 SO 4 ), filtered, and the organic layer was concentrated to give (Z)-6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(N'-(propionyloxy)carbamimidoyl)phenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide (27 mg, 0.059 mmol, 95% yield) as an off-white solid. LC retention time = 0.76 min [D]; m / z 459.5 (MH + )

[0224] Step 6: A mixture of (Z)-6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(N'-(propionyloxy)carbamimidoyl)phenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide (27 mg, 0.059 mmol) and 1 M TBAF in THF (0.088 mL, 0.088 mmol) in acetonitrile (1 mL) was allowed to stir at room temperature for 3 h. The solvent was removed in vacuo and the residue was dissolved in DMSO and purified by preparative HPLC to give the desired product (13.8 mg, 50% yield). LC retention time = 1.38 min [B]; m / z = 441.3 (MH + ); 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.34(s,1H), 11.01(s,1H), 9.15(s,1H), 8.13(s,1H), 7.68(dd,J=18.0, 7.9Hz,2H), 7.37(t,J=7.9 Hz,1H), 3.72(s,3H), 3.02(q,J=7.4Hz,2H), 2.06(brs,1H), 1.35(t,J=7.6Hz,3H), 0.87-0.72(m,4H)

[0225] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17] [Table 18]

[0226] Biological assays The following assays are used to demonstrate activity for the compounds of the invention.

[0227] IFNα-induced STAT phosphorylation in human whole blood After 1 hour of 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.

[0228] Bidirectional permeability assay in Caco-2 cells overview The compounds described were tested in a Caco-2 bidirectional permeability assay to assess their permeability and efflux substrate potential. Compounds (at 3 μM in triplicate) were incubated with Caco-2 cells in pH 7.4 assay buffer (containing 0.5% bovine serum albumin [BSA]) for 2 h at 37° C. and then extracted for LC-MS analysis, their concentrations in the reaction mixture were measured, and the permeability coefficients, efflux fractions, and recovery rates were calculated.

[0229] material and method Caco-2 (Caucasian colon adenocarcinoma) cells were obtained from the American Type Culture Collection (Manassas, VA). Dulbecco's modified Eagle's medium (DMEM), N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) buffer, non-essential amino acids, L-glutamine, penicillin-G-streptomycin, and heat-inactivated fetal bovine serum (FBS) were purchased from GIBCO / Invitrogen (Carlsbad, CA). 96-well plates (surface area: 0.11 cm) were used. 2 Polycarbonate membrane transwell plates with 0.4 μm pore size and low-binding transwell cluster plates were purchased from Sigma Aldrich (St. Louis, MO). Low-binding 96-well plates were purchased from Corning (Corning, NY). Modified Hanks Balanced Salt Solution (MHBSS) was prepared by adjusting Hanks Balanced Salt Solution (HBSS) to pH 7.4 with HEPES. HBSS, digoxin, and bovine serum albumin (BSA) were purchased from Sigma (St. Louis, MO). Filtration blocks (2 mL, 96 wells) were purchased from Whatman (Freiburg, Germany). All solvents were analytical grade.

[0230] 1. Preparation of Cells 14–28 days prior to the assay, Caco-2 cells were plated onto polycarbonate filter membranes in 96-well transwell plates at 1.8 × 10 5 cells / cm 2 At a density of approximately 2.0x10 per well 4 Cells were grown in medium consisting of DMEM supplemented with 10% fetal bovine serum, 10 mM HEPES, 1% non-essential amino acids, 2 mM L-glutamine, 100 U / mL penicillin-G, and 100 μg / mL streptomycin. Medium was changed every 3 days and cells were maintained at 95% relative humidity and 5% CO. 2The cells were maintained in an atmosphere at 37° C. Cells were assessed for tight junction formation immediately prior to the assay (see Quality Control section below).

[0231] Compound Production Compounds were dissolved in 100% DMSO to 10 mM. After visual inspection to ensure complete solubilization, 10 mM compound stocks were placed in 96-well plates and further serially diluted in 100% DMSO to create a 100x stock concentration of 0.3 mM. Four control compounds were tested in parallel with the listed compounds and were plated in quadruplicate at 100x the concentration of 0.3 mM.

[0232] Permeability evaluation Listed compounds were tested in triplicate in one experiment at a final concentration of 3 μM. Cell passages used in the assay passed QC criteria (see Quality Control section below). Studies were performed with monolayers of Caco-2 cells cultured for 14-28 days with passage numbers between 20 and 80. Assay (transport) buffer consisted of MHBSS adjusted to pH 7.4 and 0.5 BSA. From the 100x compound plate, 8 μL of 100% DMSO stock solution of compound was added to 800 μL of assay buffer, mixed well, and filtered to remove any precipitate as a final preparation step before assay incubation. The target final test concentration of listed and control compounds was 3 μM. The filtrate represented the original compound stock solution that was used as the donor solution (in both directions) in the assay. The receiver solution was assay buffer alone.

[0233] Before performing the assay, each cell monolayer was washed three times with assay buffer to remove all traces of medium. Permeability studies were initiated by adding 100 μL of assay buffer + / - compound to the top compartment and 200 μL of assay buffer + / - compound to the basolateral compartment of a 96-well transwell low-binding cluster plate. For top-to-basolateral (A→B) permeability (absorption direction), buffer containing compound or a control compound (1x donor solution) was placed in the top compartment (donor well), while buffer alone was placed in the corresponding basolateral compartment (receiver well). For basolateral-to-top (B→A) permeability (secretion direction), buffer containing compound or a control compound (1x donor solution) was placed in the basolateral compartment (donor well), while buffer alone was placed in the corresponding top compartment (receiver well). The transwells were then incubated at 95% relative humidity and 5% CO. 2 The plates were incubated at 37° C. for 2 hours in a 37° C. atmosphere. After incubation, 75 μL was removed from each of the apical and basolateral compartments and transferred to a 96-well low-binding plate pre-filled with 75 μL / well of acetonitrile containing 250 nM propranolol, 250 nM diclofenac, and 500 nM tolbutamide as internal standards. Samples were then analyzed by LC-MS / MS to determine the concentrations of the indicated and control compounds.

[0234] Analysis of assay samples Concentrations of the indicated and control compounds in the assay samples were measured using LC-MS / MS. The AB Sciex 4500 / 5500 / 6500 multiplex system consisted of a binary Shimadzu 20ADvp pump with two SCL-20Avp controllers for gradient elution, an LS1 autosampler, and an AB Sciex 4500 / 5500 / 6500 triple quadrupole mass spectrometer operating under electrospray ionization (ESI) mode. To obtain optimal SRM for the analysis of the samples, MS / MS optimization of each compound was performed using Discovery Quant® (AB Sciex) featuring saturation control using 5 μM standard solutions in a mixture of methanol and water (1:1, v / v) prepared from the stock solutions of the compounds. Optimization was performed using flow injection analysis with an injection volume of 40 μL under isocratic elution of 75% mobile phase B (0.2% formic acid in acetonitrile) and 25% mobile phase A (0.2% formic acid in water).

[0235] A 5 μL aliquot of sample was injected and then separated on a Kinetex XB-C18, 2.6 μm, 2.1×30 mm column under gradient elution with a mobile phase consisting of A (0.2% formic acid in water) and B (0.2% formic acid in acetonitrile).

[0236] [Table 19] A = 0.2% formic acid in water; B = 0.2% formic acid in acetonitrile

[0237] Discovery Quant® automatically determined the optimal ionization polarity (anodic or cathodic), precursor and product ions, declustering potential, and collision energy for the listed and reference compounds. Optimized SRM MS / MS conditions were used to analyze the samples. Peak area ratios of the listed or reference compounds relative to an internal standard were used for quantification. The peak area ratios of the compounds in the dose solutions were used to determine the concentration of the compounds in the samples.

[0238] Data analysis The following results: permeability coefficient (Pc [nanometers per second]), efflux ratio, and recovery were reported for the compounds listed;

[0239] The Pc value is calculated using the following formula:

number

[0240] The emission ratio was calculated as follows:

number

[0241] Percent recovery was calculated by expressing the total amount of test compound (in nanomoles) present in the donor and receiver assay compartments (combined) at the end of the incubation period as a fraction (in nanomoles) of the total amount of test compound (in nanomoles) added to the donor compartment prior to assay incubation, according to the following formula:

number

[0242] quality control On the day of the assay, Caco-2 cells in one of the transwell plates were evaluated for tight junction formation by trans-epithelial electrical resistance (TEER) measurements. TEER was assessed using an EVOM resistance meter (World Precision Instruments, Salasola, FL). Each well of the transwell plate had a TEER value >600 Ω cm. 2 , indicating that cells were passaged and all plates of this plating batch were accepted for the assay.

[0243] Four control compounds with Pc values ​​spanning the permeability range were tested in parallel with the compounds described in each experiment. The acceptance criteria for this assay required that the control compound results at 3 μM be within the historical acceptance range. The historically observed Pc values ​​and efflux ratio acceptance ranges for these four controls are shown in Table B.

[0244] In these studies, the results of all control compounds were within the range of their respective previous results, and thus the assay data were acceptable for data analysis and evaluation of compounds that exhibit bidirectional permeability in Caco-2 cells.

[0245] [Table 20] Values ​​are means ± standard deviation. Pc = Permeability coefficient A → B = from top to bottom B → A = from bottom to top

[0246] Table 2: Potency and permeability data for example compounds in human whole blood assay and CACO2 permeability assay

Table 21

Table 22

Claims

1. Formula I: 【Chemistry 1】 [In the formula: X is -N- or -CH-; R １ is C １－３ is alkyl; R ２ is F or C １－３ is alkyl; R ３ is oxadiazole, oxazole, pyridine, pyrimidine, thiadiazole, pyrazine, thiazole, pyrazole or isothiazole, all of which have 0 to 3 R ３ａ is substituted with a group; R ３ａ H, F, Cl, CN, NO ２ , C １－４ Alkyl, O-C １－４ Alkyl, C ３－６ Cycloalkyl, (CH ２ ) nF, CHF ２ , Hydroxy C １－３ Alkyl or cyano C １－３ is alkyl; and n is 1 or 2. or a stereoisomer or a pharma- ceutically acceptable salt thereof.

2. Formula II: 【Chemistry 2】 [In the formula: R １ is C １－３ is alkyl; R ２ is F or C １－３ is alkyl; R ３ is oxadiazole, oxazole, pyridine, pyrimidine, thiadiazole, pyrazine, thiazole, pyrazole or isothiazole, all of which have 0 to 3 R ３ａ is substituted with a group; R ３ａ H, F, Cl, CN, NO ２ , C １－４ Alkyl, O-C １－４ Alkyl, C ３－６ Cycloalkyl, (CH ２ ) nF, CHF ２ , Hydroxy C １－３ Alkyl or cyano C １－３ is alkyl; and n is 1 or 2.

2. The compound of claim 1, wherein:

3. Formula III: 【Chemistry 3】 [In the formula: R １ is C １－３ is alkyl; R ２ is F or C １－３ is alkyl; R ３ is oxadiazole, oxazole, pyridine, pyrimidine, thiadiazole, pyrazine, thiazole, pyrazole or isothiazole, all of which have 0 to 3 R ３ａ is substituted with a group; R ３ａ are H, F, Cl, CN, and NO ２ , C １－４ Alkyl, O-C １－４ Alkyl, C ３－６ Cycloalkyl, (CH ２ ) nF, CHF ２ , Hydroxy C １－３ Alkyl or cyano C １－３ is alkyl; and n is 1 or 2.

2. The compound of claim 1, wherein:

4. 6-Cyclopropanamido-4-({3-[5-(fluoromethyl)-1,2,4-oxadiazol-3-yl]-2-methoxyphenyl}amino)-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-[(2-methoxy-3-{5-[(propan-2-yloxy)methyl]-1,2,4-oxadiazol-3-yl}phenyl)amino]-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-({3-[5-(ethoxymethyl)-1,2,4-oxadiazol-3-yl]-2-methoxyphenyl}amino)-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-({2-methoxy-3-[5-(2-methoxyethyl)-1,2,4-oxadiazol-3-yl]phenyl}amino)-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-({3-[5-(2-fluoroethyl)-1,2,4-oxadiazol-3-yl]-2-methoxyphenyl}amino)-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[2-methoxy-3-(1,3-oxazol-4-yl)phenyl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-({3-[5-(difluoromethyl)pyridin-2-yl]-2-methoxyphenyl}amino)-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[2-methoxy-3-(6-methylpyrimidin-4-yl)phenyl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[2-methoxy-3-(1,2,4-thiadiazol-5-yl)phenyl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-(5-fluoropyrazin-2-yl)-2-methoxyphenyl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-(5-cyclopropylpyrazin-2-yl)-2-methoxyphenyl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[2-methoxy-3-(5-nitropyrazin-2-yl)phenyl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[2-methoxy-3-(3-methyl-1,2,4-thiadiazol-5-yl)phenyl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-({3-[5-(1-hydroxycyclobutyl)pyrazin-2-yl]-2-methoxy-5-methylphenyl}amino)-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-({5-fluoro-3-[5-(1-hydroxycyclobutyl)pyrazin-2-yl]-2-methoxyphenyl}amino)-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-(5-cyclopropylpyrazin-2-yl)-5-fluoro-2-methoxyphenyl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[2-methoxy-3-(2-methyl-1,3-oxazol-4-yl)phenyl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-(2,5-dimethyl-1,3-oxazol-4-yl)-2-methoxyphenyl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-({3-[5-(difluoromethyl)-1,2,4-oxadiazol-3-yl]-2-methoxyphenyl}amino)-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-({4-[5-(2-hydroxypropan-2-yl)pyrazin-2-yl]-3-methoxypyridin-2-yl}amino)-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[2-methoxy-3-(2-methyl-1,3-thiazol-4-yl)phenyl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[2-methoxy-3-(5-methoxypyrazin-2-yl)phenyl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[2-methoxy-3-(5-methylpyrazin-2-yl)phenyl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 4-({3-[5-(1-cyano-1-methylethyl)pyridin-2-yl]-2-methoxyphenyl}amino)-6-cyclopropanamide-N-( ２ H3) methylpyridazine-3-carboxamide; 4-{[2-methoxy-3-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)phenyl]amino}-N-( ２ H3) methyl-6-[(1R,2R)-2-methylcyclopropanamido]pyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[4-fluoro-2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[5-fluoro-2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methoxyphenyl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 4-{[3-(5-cyanopyrazin-2-yl)-2-methoxyphenyl]amino}-6-cyclopropanamide-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[4-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methoxypyridin-2-yl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[4-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methoxypyridin-2-yl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[4-(1,5-dimethyl-1H-pyrazol-4-yl)-3-methoxypyridin-2-yl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-methoxy-4-(1,3-thiazol-2-yl)pyridin-2-yl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[2-methoxy-3-(1,2-thiazol-5-yl)phenyl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[2-methoxy-3-(1,2-thiazol-3-yl)phenyl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[2-methoxy-3-(1,2-thiazol-4-yl)phenyl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[5-fluoro-2-methoxy-3-(1,3-oxazol-4-yl)phenyl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-methoxy-4-(1,2-thiazol-4-yl)pyridin-2-yl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-methoxy-4-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-2-yl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 4-{[3-methoxy-4-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-2-yl]amino}-N-( ２ H3) methyl-6-[(1R,2R)-2-methylcyclopropanamido]pyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-methoxy-4-(1,2,4-thiadiazol-5-yl)pyridin-2-yl]amino}-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamide-4-({4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-methoxypyridin-2-yl}amino)-N-( ２ H3) methylpyridazine-3-carboxamide; 6-Cyclopropanamido-4-{[3-(5-ethyl-1,2,4-oxadiazol-3-yl)-2-methoxyphenyl]amino}-N-( ２ H3) Methylpyridazine-3-carboxamide or a pharma- ceutically acceptable salt thereof.

5. 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.

6. 10. A pharmaceutical composition comprising one or more compounds according to claim 4, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or diluent.

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

8. 8. The method of claim 7, wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, ALS, or multiple sclerosis (CIS, optic neuritis, neuromyelitis optica, RMS and / or progressive MS).

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